Synthesis of Structurally Diverse 3-, 4-, 5-, and 6-Membered Heterocycles from Diisopropyl Iminomalonates and Soft C-Nucleophiles

Abstract

Herein, we present a general synthetic strategy for the preparation of 3-, 4-, 5- and 6-membered heterocyclic unnatural amino acid derivatives by exploiting facile Mannich-type reactions between readily available N-alkyl- and N-aryl-substituted diisopropyl iminomalonates and a wide range of soft anionic C-nucleophiles without using any catalyst or additive. Fully substituted aziridines were obtained in a single step when enolates of α-bromo esters were employed as nucleophiles. Enantiomerically enriched azetidines, γ-lactones and tetrahydroquinolines were obtained via a two-step catalytic asymmetric reduction and cyclization sequence from ketone enolate-derived adducts. Finally, highly substituted γ-lactams were prepared in one pot from adducts obtained using acetonitrile-derived carbanions. Overall, this work clearly demonstrates the utility of iminomalonates as highly versatile building blocks for the practical and scalable synthesis of structurally diverse heterocycles.

Graphical Abstract

INTRODUCTION

We recently reported the convenient preparation of novel N-electrophilic diisopropyl iminomalonates (2) derived from readily available primary amines and their application for the synthesis of a large number of secondary amines (3) using organometallic C-nucleophiles such as Grignard reagents and alkyl- and aryllithiums (1).¹ These hard C-nucleophiles preferentially attacked the nitrogen atom of the imine moiety in the absence of catalysts or additives (Figure 1A). The experimental findings were also supported by DFT computational studies. In the same report we also disclosed the result of adding the lithium enolate of acetophenone 4 to the N-PMP-substituted diisopropyl iminomalonate 5 (Figure 1B). Based on routine NMR spectra (¹H and ¹³C) of the major product, we assigned putative structure 6 in which the α position of acetophenone was aminated. Subsequent ketone reduction and cyclization afforded presumed compound 7; this 6-membered lactone structure was also in good agreement with routine NMR spectra. Since the focus of this past work was the unique N-selective addition of hard C-nucleophiles to iminomalonates, no in-depth spectroscopic studies were performed on compound 7 at that time.

Figure 1.

Exploring the reactivity of hard and soft nucleophiles with iminomalonates.

During the follow-up studies, when we focused our attention on exploring the reactivity of iminomalonates with softer C-nucleophiles such as enolates derived from ketones and esters along with carbanions obtained from acetonitrile derivatives, we performed 1D and 2D NMR studies on presumed compound 7. These studies strongly pointed to the presence of a 5-membered lactone scaffold (9) instead of the originally presumed 6-membered lactone scaffold (7). The only way a 5-membered lactone product (9) could have formed was to have a preferential attack occur at the iminomalonate carbon atom during the enolate addition step to afford compound 8.

This surprising switch in chemoselectivity was in stark contrast with the predominant N-attack of hard C-nucleophiles on a wide variety of N-substituted iminomalonates.¹ Even though we originally anticipated predominant N-attack by most C-nucleophiles, based on the demonstrated reactivity pattern by Grignard reagents and alkyl/aryl lithium compounds, in-depth computational studies (vide infra) on the reactivity of iminomalonates toward soft C-nucleophiles confirmed our new experimental findings (Figure 1B).

We identified three unique structural features of the 5-membered lactone product 9, namely: (a) two stereogenic centers with one being fully substituted, (b) an aminoaryl substituent in the α-position of the lactone carbonyl group, and (c) the generation of a highly substituted, unnatural cyclic amino acid derivative (Figure 1B). In fact, nonproteinogenic amino acids have become important tools for modern pharmaceutical research.² While some occur naturally (e.g., ornithine, from urea cycle), the vast majority of these are chemically synthesized. Owing to their remarkable structural and functional diversity, they are often used as building blocks for drug discovery.²

We also realized that there are only a few reported examples of these highly substituted 5-membered lactone scaffolds, and even fewer methods exist for their synthesis.³ A survey of reported Mannich reactions between activated imines (10–14) and aldehydes/ketones is shown in Figure 2. The Mannich reaction is one of the classic methods for the synthesis of β-amino carbonyl compounds.^4–9 The versatility of this important carbon–carbon (C–C) bond-forming reaction lies in its potential to create both functional and structural diversity that generated a lot ofinterest in the synthetic community. However, the overwhelming majority of reported reactions produces compounds that have limited structural diversity with regard to both the imine and the carbonyl coupling partners.⁶ Even fewer reports attempted to make use of the initial Mannich adducts and convert these to more elaborated building blocks (i.e., γ-butyrolactones, Figure 2C).¹⁰ Of particular concern is the dearth of structural diversity with respect to the substituents on the nitrogen atom as well as in the γ-position of the lactone scaffold.

Figure 2.

Comparison of achievable structural diversity in known Mannich reactions and this study.

In contrast to known reports, we fully recognized the opportunity to convert our initial iminomalonate/ketone Mannich adducts into γ-butyrolactones (24) in which the nature of the substituents at each position (i.e., α, β, and γ), including the substituent on the nitrogen atom, can be widely varied (Figure 2D). This wide variation in the structure of substituents is possible because nearly all primary arylamines can be easily converted to the corresponding N-aryl iminomalonates¹ (25) and virtually any enolizable ketone (26) can be coupled to these in the absence of catalysts or additives. We argued that the absolute stereochemistry could be readily controlled in the next step by the well-known and predictable CBS reduction of the carbonyl group (27 → 28, Figure 3).¹¹

Figure 3.

Proposed synthesis of chiral nonracemic azetidines, tetrahydroquinolines, and lactones from iminomalonates via enantio- merically enriched secondary alcohols (28).

Moreover, the resulting enantiomerically enriched secondary alcohols (28) could open up a number of exciting possibilities for the synthesis of densely functionalized N- and O-heterocycles. For instance, activation of the benzylic alcohol moiety by inversion would allow for a subsequent intramolecular nucleophilic (S_Ni) substitution reaction by the N atom to furnish the corresponding azetidines (30) in which the benzylic stereocenter would retain its original configuration (i.e., double inversion). Alternatively, the aromatic ring attached to the nitrogen could also act as a nucleophile and perform the benzylic substitution with inversion in order to afford tetrahydroquinolines (31). A third option is to use the benzylic alcohol OH group as a nucleophile as we have already observed in our recent study (Figure 1B). Thus, an intramolecular nucleophilic acyl substitution reaction (S_NAc; i.e., lactonization) is expected to take place with one of the isopropyl ester groups to yield α-aminoaryl γ-lactones (24) under either acid-catalyzed or base-mediated conditions (Figure 3).

Additional synthetic possibilities for iminomalonates include a one-pot aza-Darzens-type reaction¹² with haloester enolates to form aziridines 33 (Figure 4) and also a two-step sequence that involves the addition of nitrile enolates. Reduction of the nitrile to a primary amine followed by intramolecular N-acylation is expected to furnish α-aminoaryl γ-lactams 36 (Figure 4).

Figure 4.

Proposed synthesis of aziridines and lactams from iminomalonates (25).

These exciting synthetic possibilities prompted us to investigate the scope of enolates that would also exclusively attack the imine carbon of the iminomalonate substrates 25. Accordingly, we selected readily available esters, ketones, and nitriles and carried out the reaction ofiminomalonates with their corresponding enolates (32) or alkylnitrile-derived carbanions (34) under a variety of conditions. While simple ester enolates did not react with either N-aryl or N-alkyl iminomalonates, the Li enolate of the nonsterically hindered methyl bromoacetate quickly furnished the corresponding N-aryl- as well as N-alkylaziridines (33). The mechanism of this process is necessarily similar to an aza-Darzens reaction.¹²

A thorough literature search revealed that there were very few examples involving the addition of alkylnitrile-derived carbanions (e.g., 34) to activated imines such as α-iminoesters.¹³ From a synthetic perspective, alkylnitriles are versatile building blocks as they can be readily converted to primary amines, aldehydes, amides, and carboxylic acids.

Gratifyingly, N-aryl iminomalonates (25) displayed remarkable reactivity toward arylacetonitrile-derived carbanions (34), yielding β-nitriloamines (35). As anticipated, reduction of the nitrile moiety followed by in situ cyclization allowed us to transform these compounds into highly sought-after γ-lactams (36), which are popular targets among medicinal chemists.¹⁴ As in the case of γ-lactones, a fully substituted α-stereocenter could be generated bearing an aminoaryl and an alkoxycarbonyl group. The resulting γ-lactams all feature α-amino acid backbones and these compounds can be utilized as amino acid surrogates.

Based on these encouraging initial findings we decided to explore the full synthetic potential of adding soft C-nucleophiles to iminomalonates. Herein we provide the detailed report for the successful synthesis of structurally diverse 3-, 4-, 5-, and 6-membered heterocycles via sequential Mannich reaction and cyclization. Since these heterocyclic scaffolds are prevalent in a wide variety of natural products and drug molecules (Figure 5), a unified synthetic strategy that exploits readily available and inexpensive iminomalonates¹ and enolates as starting materials would be a valuable addition to the toolbox of synthetic as well as medicinal chemists.

Figure 5.

Natural products and active pharmaceutical ingredients that contain 3-, 4-, 5-, and 6-membered heterocycles.

RESULTS AND DISCUSSION

The catalytic asymmetric synthesis of tetrasubstituted carbon stereocenters remains a significant challenge in organic synthesis.¹⁵ The stereoselective Mannich reaction between prochiral ketimines and enolates affords highly substituted chiral amines that are potentially valuable building blocks for further elaboration provided that the activating group, often present on the nitrogen, can be removed.^10e Our investigation began with the systematic study of the Mannich-type reaction between nonprochiral (i.e., symmetrical) N-aryl iminomalonates and ketone-derived enolates (Figure 3) as this approach would allow the control of absolute stereochemistry in a variety of ways.

First, we combined 2 equiv of preformed acetophenone-derived lithium enolate with 1 equiv of p-methoxyphenyl iminomalonate (25a; Ar = PMP) at −78 °C in THF. The reaction proceeded well and exclusively furnished the C-addition product 27a in 66% yield (see the SI, pp S5 and S6). The nature of the lithium base used for the preformation of the ketone enolate in THF was important: LiHMDS afforded the highest isolated yield of 27a (66%), while n-BuLi as well as LDA resulted in a reduced yield of the Mannich adduct (54% and 22%, respectively). Next, the impact of the reaction temperature was evaluated in THF as the solvent. Increasing the temperature from −78 °C to first −40 °C and then to −20 °C led to decreasing yields of 27a (36% and 0%, respectively), and at −20 °C the reaction mixture became too complex.

Switching the solvent from THF to 2-Me-THF significantly lowered the isolated yield (66% → 27%). Other ethereal solvents such as diethyl ether, MTBE, dioxane, and DME were inferior compared to THF when LiHMDS was used as the base for the preparation of the preformed enolate (see the SI, pp S5 and S6).

However, when KHMDS was employed as a base first in MTBE and then in DME at −78 °C, the yield of 27a dramatically improved to 61% and 70%, respectively. Subsequently, we examined the effect of the amount of enolate coupling partner on the isolated yield of 27a. Reducing the amount of the enolate from 2 to 1.1 equiv decreased the yield slightly (70%→ 63%); however, we found that employing 1.5 equiv of enolate coupling partner 26 was optimal, as it afforded 27a in 94% isolated yield. Changes in the concentration (0.1–0.3 M) did not have a significant effect on the isolated yield. Thus, the optimal Mannich coupling conditions called for the combination of reactants (i.e., 1:1.5 ratio of iminomalonate/potassium enolate) as a 0.2 M solution in DME at −78 °C (Figure 6).

Figure 6.

Scope of substrates using iminomalonates as electrophiles. All iminomalonates were prepared from the corresponding amines by simple condensation with ketomalonate hydrate. The enolate addition reactions were conducted on a 1–5 mmol scale with 0.2 M concentration of the iminomalonate at the indicated temperature and were considered complete upon the full consumption of the individual iminomalonates as determined by TLC analysis.

We were pleased to find that under the optimized coupling conditions a variety of N-aryl-substituted iminomalonates (25) smoothly reacted with different aromatic, heteroaromatic, and aliphatic ketone enolates (26), and the corresponding bench-stable Mannich adducts (27) were isolated in good to excellent yields. Ultimately, we explored the reactivity of 13 different ketone enolates with a diverse set of aromatic and heteroaromatic iminomalonates (10 structurally different examples, Figure 6).

Simple aromatic and aliphatic ketone-derived enolates afforded the corresponding Mannich adducts (27a–t, Figure 6) in excellent yields. However, in the case of nitrogen-containing heteroaromatic ketone enolates (e.g., pyridines and pyrroles; 27m, 27q–t), the yields were lower compared to oxygen- and sulfur-containing heteroaromatics (e.g., furans and thiophenes; 27i–k). Surprisingly, N-aliphatic iminomalonates were found to be unreactive with both aromatic and aliphatic ketone-derived enolates. This prompted us to use density functional theory (DFT) calculations to examine the reactivity and selectivity for enolate additions to these iminomalonates.

In Gaussian 09,²⁶ we used the M06–2X²⁷ functional with the def2-TZVP²⁸ basis set for final SCF energies and 6–31G(d,p) and [LANL2DZ for Br] for geometries and thermochemical analysis. Tetrahydrofuran was used as a substitute for DME with the continuum SMD²⁹ model. We used the N-Bu and N-Ph iminomalonates with methyl ester groups as model systems. For the enolates, we used the acetophenone-derived enolate (Figure 8a) as well as the potassium–oxygen stabilized version (Figure 8b).

Figure 8.

M06–2X/def2-TZVP//M06–2X/6–31G(d,p) transition-state structures and energies (Gibbs energy, enthalpy at 298 K) for (a) acetophenone-derived enolate and phenyl isopropyl ketone-derived enolate addition to N-Bu and N-Ph iminomalonates and (b) potassium-coordinated enolate addition to N-Bu and N-Ph iminomalonates. Energies are relative to separated reactants and in kcal/mol.

As expected from the outcome of the reactions presented in Figure 6, enolate addition to the N-Bu and N-Ph iminomalonate carbon is lower in Gibbs free energy (and enthalpy) than addition to the nitrogen. For the unstabilized enolate model, the C-attack transition states are 3–4 kcal/mol lower in energy. Interestingly, using the potassium-stabilized enolate model, the selectivity is much higher: the C-attack transition states are ~7–12 kcal/mol lower in energy than N-attack transition states, which is consistent with the experimental observation of C-attack products. The transition states also confirm that the N-Bu iminomalonate is significantly less reactive than the N-Ph derivative. For example, the unstabilized enolate C-attack transition state for N-Bu iminomalonate requires ΔG^‡ = 18.6 kcal/mol, while for the N-Ph derivative ΔG^‡ = 13.9 kcal/mol. The potassium-enolate model transition states for C-attack show a >7 kcal/mol lower barrier for the N-Ph iminomalonate.

Next we proceeded to reduce the carbonyl group of the Mannich adducts utilizing the well-established CBS reduction (Figure 7).¹¹ In order to identify the optimal conditions for the desired highly enantioselective carbonyl reduction (27 → 28), we carefully evaluated several combinations of chiral oxazaborolidine catalysts and borane reducing agents to obtain the corresponding secondary benzylic alcohols (see the SI, pp S35 and S36). A quick temperature study (between 25 and −20 °C) revealed that at −15 °C with 15 mol % catalyst loading the highest enanatioselectivity (94% ee) could be achieved. Any further increase in the catalyst loading as well as further lowering of the reaction temperature resulted in inferior isolated yields and significantly longer reaction times (e.g., at −20 °C the reaction took >96 h to go to completion). Ultimately, we found that the combination of 15 mol % of (S)-2-methyl oxazaborolidine catalyst, 2 equiv of BH₃·DMS in THF at −15 °C were optimal for the efficient reduction of ketones (i.e., up to 94% isolated yield). With these optimized conditions in hand, we proceeded with the asymmetric carbonyl reduction of over one dozen Mannich adducts and obtained the corresponding amino alcohols (28a–m, Figure 7) in good-to-excellent isolated yields and with very high enantioselectivities (up to 98% ee as in the case of 28f).

Figure 7.

Scope of substrates for the reduction of ketone adducts. All chiral and racemic alcohols were prepared from the corresponding ketone adducts by simple reduction using BH₃·DMS in the presence of CBS catalyst. The reductions were conducted on a 0.5–3 mmol scale with 0.2 M concentration of the ketone adduct at the indicated temperature and considered complete upon full consumption of the individual ketone adducts as determined by TLC analysis.

Both the isolated yields and enantioselectivities were slightly lowered in the case of pyridine-containing substrates (28l and 28m, Figure 7). The absolute configuration of these chiral 1,3-amino alcohols was unambiguously determined to be (R) by Mosher ester analysis¹⁶ (see Experimental section). The three Mannich adducts that were prepared by the addition of α-branched ketone enolates to N-aryl iminomalonates (27n–p, Figure 6) were subjected to simple borane reduction (BH₃·DMS, no CBS catalyst was employed), and the corresponding racemic 1,3-amino alcohols (28n–p, Figure 7) were obtained as single diastereomers. With the over one dozen enantiomerically enriched 1,3-amino alcohols in hand (28a–m), we were in the position to evaluate two possible intramolecular cyclization pathways to either furnish azetidines or tetrahydroquinolines (28 → 29 → 30 and 31, Figure 3 and Figure 9).

Figure 9.

Cyclization of chiral alcohols to corresponding azetidines and tetrahydroquinolines. The chiral alcohols obtained by reduction of ketone adducts were subjected to the above-mentioned conditions with 0.05 M concentration of starting material for cyclization to corresponding azetidines and tetrahydroquinolines considered complete upon full consumption of the individual chiral alcohols by TLC analysis.

Azetidines are one of the privileged classes of heterocycles in medicinal chemistry.¹⁷ This four-membered and rigid azaheterocycle displays higher metabolic stability, ligand efficiency, and physicochemical profiles compared to its higher homologues. Owing to the challenges associated with the formation of this strained four-membered ring, relatively few methods are available for their synthesis.¹⁷ Likewise, the tetrahydroquinoline ring system is a common structural motif prevalent in numerous natural products and therapeutic agents.¹⁸ Although several methods have been developed for the enantioselective synthesis of 2-substituted tetrahydroquinolines, synthetic routes leading to 3- and 4-substituted derivatives have garnered significantly less attention despite their industrial importance.¹⁹ Recently Han et al. and Ghosh et al. independently reported the synthesis of malonate-derived azetidines and tetrahydroquinolines by the ring-opening of donor–acceptor cyclopropanes.²⁰ Thus, we surmised that our versatile iminomalonates are the best precursors for the construction of these important structural moieties via sequential Mannich-type reaction, asymmetric carbonyl reduction, and cyclization. Initially, 1,3-amino alcohol 28h was treated with mesyl chloride (1.5 equiv) in the presence of triethylamine (1.5 equiv) at room temperature with the expectation of activating the benzylic alcohol moiety toward the subsequent intramolecular nucleophilic attack by conversion to the corresponding mesylate. While some of the desired cyclized products (30h and 31h) were formed, most of the starting material remained unreacted even after several hours of stirring (see Table S4, p S8). When the amounts of mesyl chloride and base were both increased (1.5 → 3.0 equiv) and the temperature was elevated (25 → 50 °C), complete consumption of the 1,3-amino alcohol substrate (28h) was observed and the corresponding O-mesylate was obtained as the major product. In this case, the anticipated cyclization was incomplete as only 25% of the O-mesylate intermediate was converted to the products 30h and 31h (obtained as a mixture of 2:1, respectively). In order to improve the efficiency of the intramolecular cyclization step, we decided to alter the nature of the leaving group by converting the benzylic alcohol moiety to the corresponding 2° alkyl bromide (29) via inversion of configuration. Two different bromination conditions were explored (PPh₃ with either CBr₄ or 2,4,5-tribromoimidazole; see Table S4, p S8), and the combination of triphenylphosphine with 2,4,5-tribromoimidazole was found to be optimal.

With the optimized cyclization conditions in hand, we examined the further reaction of four representative examples (Figure 9). We found that the aromatic substituent on the nitrogen had a significant impact on both the product distribution (i.e., azetidine or tetrahydroquinoline) and the stereoselectivity of the cyclization step. For example, the N-(3-trifluoromethylphenyl)-substituted amino alcohol (28e) did not furnish the anticipated tetrahydroquinoline (31e); only the azetidine product (30e) was observed. This suggests that the distribution of the electron density between the nitrogen substituent and the π system of the aryl ring dictates which one of these moieties will perform the nucleophilic displacement of bromine to afford either the azetidine or tetrahydroquinoline as the major product. If π-stacking interaction is possible during the cyclization (e.g., 28f → 31f), this secondary interaction can completely switch the product distribution compared to substrates in which such an interaction cannot occur (cf. 28h → 30h and 28c → 30c, Figure 9).

The γ-lactone moiety has attracted great interest in the synthetic organic chemistry community for two main reasons: (a) the molecules that contain this moiety exhibit a diverse range of biological activities and (b) its synthesis presents challenges. In fact, the γ-lactone substructure is present in more than 15000 natural products, and it is also a valuable building block for the preparation of structurally complex molecules as well as active pharmaceutical ingredients.²¹ While there are a number of efficient synthetic methods available for the preparation of structurally simple γ-lactones, access to highly substituted members of this family is limited. For example, to the best of our knowledge, there have been only a few reports for the synthesis of α-amino-substituted γ-lactones (see Figure 2C).¹⁰ Since our group found that N-aryliminomalonates reacted efficiently with ketone-derived enolates (Figure 6) and the resulting Mannich adducts afforded the corresponding 1,3-amino alcohols in high enantiomeric excess (Figure 7), the main question was how we could efficiently convert these amino alcohols (28a–p, Figures 10 and 11) to the corresponding γ-lactones (24)?

Figure 10.

Cyclization of chiral alcohols to corresponding lactones. The chiral alcohols, obtained by the reduction of ketone adducts, were subjected to the conditions A or B for cyclization with 0.2 M concentration of alcohol to the corresponding lactones and considered complete upon the full consumption of the individual alcohols by TLC analysis.

Figure 11.

Cyclization of chiral alcohols to the corresponding lactones. The enantiomerically enriched and racemic 2° alcohols, obtained by reductions of ketone adducts, were subjected to the conditions A or B for cyclization with 0.2 M concentration of alcohol to corresponding to lactones and considered complete upon the full consumption of the individual chiral and achiral alcohols by TLC analysis.

Importantly, when the solution of 1,3-amino alcohol 28a in toluene was treated with 20 mol % of TsOH·H₂O at 50 °C, the lactonization (i.e., between the benzylic alcohol and isopropyl ester moieties) took place in 24 h and the easy-to-separate diastereomeric lactones (24c and 24d) were obtained in a 2:1 ratio. Increasing the reaction temperature (e.g., 70 and 110 °C) resulted in significantly faster lactonization–at 70 °C, the lactonization was fast (1 h) and had minimal impurities. In order to increase the diastereoselectivity during lactonization, we turned to using chiral Brønsted acid (i.e., phosphoric acid) catalysts.²² It was anticipated that the use of a chiral phosphoric acid catalyst would lead to an efficient cyclization process in a highly stereoselective manner owing to the ability of the chiral phosphate counterion to influence the stereochemistry-determining step. Ultimately, we screened a total of seven chiral Brønsted acid catalysts (e.g., chiral phosphoric acids and camphor sulfonic acids) and identified (R)-3,3′-bis[3,5-bis-(trifluoromethyl)phenyl]-1,1′-binaphthyl-2,2′-diylhydrogen phosphate to be the most efficient, as it afforded the cyclized γ-lactone products 24c and 24d in a 3.3:1 diastereomeric ratio at 100 °C in just 2 h (see the SI, Table S5, pp S9 and S10).

All of the other combinations of solvent, temperature, and Brønsted acid furnished the γ-lactones in about a ~2:1 diastereomeric ratio. These results clearly indicated that the presence of a chiral counterion did not significantly improve the diastereoselectivity of the lactonization step (e.g., 2:1 dr → 3.3:1 dr, which represents only a 1.65× increase). Such a modest increase in the diasteromeric ratio could not justify the use of an expensive chiral phosphoric acid catalyst. Thus, we shifted our focus toward using cheaper achiral Bransted acids–p-toluenesulfonic acid monohydrate (TsOH·H₂O) was found to be the optimal catalyst in toluene at 70 °C as the reaction proceeded to completion in just 1 h.

With these optimized acid-catalyzed lactonization conditions in hand, we proceeded to cyclize 14 amino alcohols (Figures 10 and 11). Without exception, each of the isolated γ-lactones was obtained in excellent enantiomeric excess (up to 98:2 er). Surprisingly, the acid-catalyzed cyclization conditions were unsuitable for heterocycle-containing substrates and invariably led to complex reaction mixtures. For these heteroaromatic substrates, base-mediated conditions (e.g., DBU) were found to be optimal, and the desired lactone products were obtained in high isolated yields while the diastereoselectivities varied from 1.2:1 → 1.5:1 (24q,r, 24s,t, and 24u,v, Figures 10 and 11). The modest diastereoselectivity in the lactonization step can be attributed to the lack of substituents at the β-position of the γ-lactone moiety. However, amino alcohols 28n, 28o, and 28p underwent lactonization with complete diastereoselectivity; in all three cases, the product γ-lactones were substituted at their β-position (Figure 11).

Diversely substituted aziridines are not only valuable synthetic intermediates but they also occur as substructures in natural products and druglike molecules.^12a,23 Among these diverse families of aziridines, aziridine-2,2-diesters are special (i.e., donor–acceptor aziridines) as they serve as precursors of azomethine ylide intermediates that undergo a variety of cycloaddition reactions.^24,25 The synthesis of fully substituted aziridines remains a significant synthetic challenge.^23b Since synthetic access to structurally diverse donor–acceptor aziridines is fairly limited,²⁵ we saw an opportunity to access these valuable building blocks using an aza-Darzens reaction between haloester enolates and N-alkyl as well as N-aryl diisopropyl iminomalonates (Figure 12). We briefly reported about this transformation in our previous publication to show the additional synthetic possibilities from iminomalonates.¹ As we briefly mentioned (vide infra), simple ester enolates did not react with iminomalonates, but α-halogenated ester enolates 4 reacted quickly and efficiently affording the aziridine-2,2,3-triesters as single diastereomers. In fact, DFT calculations 4 showed that the trans-1-phenyl-3-methoxycarbonyl aziridine diastereomer (33a, Figure 12) is favored over the cis-diastereomer by ~4 kcal/mol (see the SI, pp S19–S35).

Figure 12.

Scope of substrates using aryl/alkyl iminomalonates as electrophiles. All of the aromatic as well as aliphatic iminomalonates have been prepared from the corresponding amines by simple condensation with ketomalonate hydrate. The aziridination reactions were conducted on a 1 mmol scale with 0.1 M concentration of iminomalonate at the indicated temperature and considered complete upon full consumption of the individual iminomalonates by TLC analysis.

We also carried out DFT calculations on the reaction pathway for aziridine formation. Similar to what we showed in Figure 8, the enolate derived from ester 46 has a lower energy transition state for C-attack compared to N-attack. The calculated structures along the aziridine reaction pathway are shown in Figure 15. After the C-attack, with a barrier of 17 kcal/mol, the resulting intermediate can then induce intramolecular nucleophilic substitution and bromide ejection with a barrier of 12 kcal/mol. This lower barrier for intramolecular substitution is consistent with the lack of observation of the addition intermediate (47).

Figure 15.

//M06–2X/6–31G(d,p)[LANL2DZ for Br] calculated reaction pathway structures and energies (Gibbs free energy, enthalpy at 298 K) for 46-derived enolate addition to N-Ph iminomalonate.

For the optimization study (see the SI Table S6, p S10), we have chosen methyl bromoacetate and N-phenyl iminomalonate as coupling partners. Various ethereal solvents and strong bases were screened: when either n-BuLi or NaHMDS was used as base, a complex reaction mixture was obtained and no desired aziridine product (33a) was isolated. When KHMDS was used, only 3% of product was isolated at −78 °C. Ultimately, LiHMDS was identified as the most suitable base and THF as the best solvent at −41 °C (i.e., acetonitrile–dry ice bath); using these conditions, 33a was isolated in 79% yield. With these optimized conditions in hand, we proceeded to explore the scope and limitations of this transformation (Figure 12). Both aliphatic and aromatic iminomalonates worked well as reaction partners, and the aziridines were isolated in moderate to excellent yields.

We then studied the reactivity of nitrile-derived carbanions with iminomalonates (Figure 13). For the optimization study, 4-fluorophenylacetonitrile (48i) was chosen as the coupling partner. Various solvents and bases were thoroughly screened at −78 °C. A very strong base, such as n-BuLi, only led to decomposition. Weaker bases, such as HMDS-derived bases, were then applied with varying results. LiHMDS and NaHMDS were totally ineffective: the 4-fluorophenylacetonitrile substrate was completely recovered in both THF and DME.

Figure 13.

Scope of substrates using iminomalonates as electrophiles. All iminomalonates were prepared from the corresponding amines by simple condensation with ketomalonate hydrate. The carbanion addition reactions were conducted on a 1–4 mmol scale with 0.13 M concentration of the iminomalonate at the indicated temperature and considered complete upon full consumption of the individual iminomalonate as determined by TLC analysis.

With the combination of KHMDS and either THF, Et₂O, or 1,4-dioxane, the product could only be obtained in low yields (8–11%). However, when the reaction was carried out with KHMDS in DME as the solvent, the yield improved significantly (58%). We also determined that decreasing the amount of carbanion from 1.5 to 1.35 equiv made the reaction much cleaner, hence simplifying the purification process. It was observed that use of over 1.5 equiv of the carbanion generally resulted in more complex reaction mixtures. With the optimized reaction conditions in hand (1.35 equiv of KHMDS and 1.35 equiv of nitrile at −78 °C in DME), we embarked upon exploring the generality of this method with a variety of nitrile coupling partners (Figure 13). The isolated yields of adduct 35 ranged from good to excellent on a 1–4 mmol scale. There was no dramatic substituent effect on the nitrogen atom of the imine partner on the yields. Imines with both electron-withdrawing groups and electron-donating groups on the nitrogen atom were tolerated (Figure 13). The structure of the acetonitrile coupling partner was also widely varied. While arylacetonitriles worked well, aliphatic acetonitriles either performed poorly or did not react. The use of very strong bases (e.g., n-BuLi) with these aliphatic acetonitriles only led to their complete decomposition even at −78 °C. From these results, it is clear that both the stability and reactivity of the acetonitrile-derived anions are important; it can be opined that the nature of the anion from the acetonitrile is of paramount importance as the metal counterion can significantly alter the reactivity pattern. The successful acetonitriles were those that had anion-stabilizing substituents; thus, an aromatic ring or a heavier atom such as sulfur in the α-position was found to be critical.

We then sought to find a method which would enable us to perform the reduction of the nitrile functionality (35 → 49, Figure 14) and the subsequent cyclization (49 → 36) to the corresponding γ-lactam in one step. After carefully exploring a number of methods, we found that the nickel-mediated hydrogenation of the nitrile addition products afforded the desired lactams in good isolated yields. It is important to note that some of the nitrile addition products, those with a chlorine substituent on their aromatic rings, failed to cyclize to the desired lactams. Presumably, the presence of nickel may have led to the decomposition of these substrates. To address these shortcomings, an alternative reduction method was performed on these substrates. Accordingly, treatment with excess borane was followed by an aqueous quench and subsequent reflux to facilitate a clean lactam formation (Figure 14). Both of these methods (A and B) delivered the γ-lactam products as single diastereomers. This is in contrast to the formation of γ-lactones (Figure 10 and 11) that were formed as a mixture of fully separable diastereomers. We believe that this difference in diastereoselectivity can be attributed to the presence or absence of substituents in the β-position (i.e., relative to the carbonyl group) of the 5-membered lactam ring.

Figure 14.

Scope of substrates for cyclization using nitrile adducts. All of the nitrile adducts were prepared by carbanion addition to the iminomalonate. These nitrile adducts were reduced and subsequently cyclized to the corresponding lactams using the above-mentioned conditions and considered complete upon the full consumption of the individual nitrile adducts by TLC analysis.

CONCLUSION

In summary, we have developed a practical and operationally simple protocol for the synthesis of five different classes of heterocycles (i.e., with ring sizes 3–6) using N-substituted iminomalonates as the common coupling partners. Each heterocycle features an unnatural amino acid backbone. The Mannich adducts, obtained via reaction with soft C-nucleophiles such as enolates of ketones, nitriles, and haloesters, were further functionalized (e.g., CBS reduction and cyclization) to afford structurally diverse heterocyclic moieties which are valuable building blocks for the preparation of biologically relevant molecules such as active pharmaceutical ingredients and structural analogs of natural products. The complete switch of chemoselectivity (i.e., predominant N-attack versus exclusive C-attack of the iminomalonate C=N bond) depending on the nature of the C-nucleophile (i.e., hard or soft) is unprecedented in the literature, and our experimental findings have been corroborated by detailed DFT calculations. Studies are currently underway in our laboratories to explore the reactivity of iminomalonates with additional soft C-nucleophiles and our findings will be reported in due course.

EXPERIMENTAL SECTION

General Information.

Reagents were purchased at the highest quality from commercially available sources and used without further purification. 1,2-Dimethoxyethane (DME), tetrahydrofuran (THF), and toluene for the reactions were obtained from pure process technology solvent system by passing the previously degassed solvents through an activated alumina column under argon. All reactions were carried out in flame-dried glassware under an atmosphere of argon with magnetic stirring. All reactions were monitored by either ¹H NMR or thin-layer chromatography (TLC) carried out on 0.25 mm precoated E. Merck silica plates (60F-254) using shortwave UV light as a visualizing agent and KMnO₄ or phosphomolybdic acid (PMA) and heat as developing agents. Flash column chromatography was performed using a Biotage Isolera One automated chromatograph with prepacked KP-Sil cartridges. 1D ¹H, ¹³C and DEPT-135 ¹³C NMR spectra were recorded on Bruker Avance III HD 600 and Bruker Avance III 500 spectrometers operating at 600 and 500 MHz for ¹H and 151 and 126 MHz for ¹³C. The spectra were calibrated using either TMS or the solvent as an internal reference (residual CHCl₃: 7.26 ppm ¹H NMR; CDCl₃: 77.00 ppm ¹³C NMR). 2D COSY, NOE, HSQC, and HMBC experiments were done on the 500 MHz spectrometer. ¹⁹F NMR spectra at 471 MHz were recorded on the 500 MHz spectrometer, and the chemical shifts were relative to CF³⁵Cl₃ defined as 0 ppm. For reporting NMR peak multiplicities, the following abbreviations were used: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, hept = heptet, m = multiplet. High-resolution mass spectra (HRMS) were recorded on an Agilent UHPLC TOF mass spectrometer using electrospray ionization time-of-flight (ESI-TOF) or chemical ionization time-of-flight (CI-TOF) reflectron experiments. Melting points and ranges were recorded on Mettler Toledo MP50 melting point system.

General Procedure for the Synthesis of Mannich Adducts Using Ketone Enolates, Figure 6.

In a thick-walled flame-dried reaction vial, ketone (1.5 equiv) was dissolved in anhydrous DME (0.4 M) under argon and cooled to −78 °C using dry ice/acetone bath. To this cooled reaction mixture was added commercially available KHMDS (1 M solution in THF) (1.6 equiv) dropwise and the resulting mixture stirred for 45 min. Then iminomalonate (1.0 equiv) dissolved in anhydrous DME (0.4M) was added slowly dropwise over 5 min to the enolate solution and stirring continued for 2 h or until the complete consumption of starting material at −78 °C. Then the reaction was quenched using saturated NH₄Cl solution (5 mL).

Workup and Purification.

After quenching, the reaction mixture was diluted with brine (20 mL), and the organic layer was separated. The aqueous layer was then extracted with EtOAc twice (2 × 30 mL), and the combined organic layers were washed with brine (30 mL) once, dried over anhydrous Na₂SO₄, and concentrated. The crude product was purified by automated flash column chromatography.

Diisopropyl 2-((4-Methoxyphenyl)amino)-2-(2-oxo-2-phenylethyl)malonate (27a).

The general procedure was followed using acetophenone (0.72 mL, 1.5 mmol), KHMDS (1 M solution in THF) (6.6 mL, 1.6 mmol), and p-methoxyphenyl iminomalonate (1.27 g, 4.1 mmol) as starting materials to afford the ketone adduct as a brown waxy solid (1.65 g, 94%). The compound was purified by flash column chromatography (R_f = 0.41 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.85 (d, J = 8.4 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.8 Hz, 2H), 6.66 (d, J = 8.9 Hz, 2H), 6.60 (d, J = 9.0 Hz, 2H), 5.11 (h, J = 6.3 Hz, 3H), 4.02 (s, 2H), 3.67 (s, 3H), 1.20 (d, J = 6.3 Hz, 6H), 1.15 (d, J = 6.3 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 196.3, 168.8, 153.3, 138.0, 36.5, 133.1, 128.4, 127.8, 117.7, 114.4, 70.1, 67.0, 55.4, 40.9, 21.3. HRMS (eSI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₃₀NO₆ 428.2068, found 428.2069. Note: The evidence for C-attack by the enolate was the generation of a quaternary aliphatic carbon, as shown by the presence of a signal at δ 67.0 in the standard ¹³C spectrum (p. S38) and the absence of this signal in the DEPT-135 ¹³C spectrum (p. S39).

Diisopropyl 2-((3,5-Dimethylphenyl)amino)-2-(2-oxo-2-phenylethyl)malonate (27b).

The general procedure was followed using acetophenone (0.40 mL, 3.4 mmol), KHMDS (1 M solution in THF) (3.66 mL, 3.6 mmol), and 3,5-dimethylphenyl iminomalonate (0.7 g, 2.2 mmol) as starting materials to afford the ketone adduct as a pale yellow viscous oily liquid (0.85 g, 87%). The compound was purified by flash column chromatography (R_f = 0.57 (20% EtOAc/hexanes). ¹H NMR (600MHz, CDCl₃): δ 7.89 (d, J = 7.4Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 6.36 (s, 1H), 6.26 (s, 2H), 5.35 (s, 1H), 5.13 (hept, J = 6.2 Hz, 2H), 4.13 (s, 2H), 2.18 (s, 6h), 1.22 (d, J = 6.3 Hz, 6H), 1.15 (d, J =6.3 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 196.2, 168.6, 144.1,138.4, 136.5, 133.1, 128.3, 127.8, 120.4, 112.5, 70.1, 66.1, 40.8, 21.27, 21.25, 21.1. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₅H₃₂NO₅ 426.2275, found 426.2275.

Diisopropyl 2-(2-(4-Bromophenyl)-2-oxoethyl)-2-((3,5-dimethylphenyl)amino)malonate (27c).

The general procedure was followed using 4-bromoacetophenone (0.68 g, 3.4 mmol), KHMDS (1 M solution in THF) (3.66 mL, 3.6 mmol), and 3,5-dimethylphenyl iminomalonate (0.7 g, 2.2 mmol) as starting materials to afford the ketone adduct as a pale yellow waxy solid (0.92 g, 80%). The compound was purified by flash column chromatography (R_f = 0.57 (20% EtOAc/hexanes). ¹H NMR (600MHz, CDCl₃): δ 7.73 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 6.36 (s, 1H), 6.22 (s, 2H), 5.29 (s, 1H), 5.11 (hept, J = 6.1 Hz, 2H), 4.05 (s, 2H), 2.17 (s, 6H), 1.21 (d, J = 6.3 Hz, 6H), 1.14 (d, J = 6.3 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 195.5, 168.6, 144.1, 138.6, 135.3, 131.7, 129.5, 128.4, 120.6, 112.6, 70.4, 66.2, 40.8, 21.38, 21.36, 21.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₅H₃₁BrNO₅ 504.1380, found 504.1378.

Diisopropyl 2-(Benzo[d][1,3]dioxol-5-ylamino)-2-(2-oxo-2-phenylethyl)malonate (27d).

The general procedure was followed using acetophenone (0.49 mL, 4.2 mmol), KHMDS (1 M solution in THF) (4.56 mL, 4.5 mmol), and 3,4-methylenedioxyphenyl iminomalonate (0.91 g, 2.8 mmol) as starting materials to afford the ketone adduct as a yellow waxy solid (1.05 g, 84%). The compound was purified by flash column chromatography (R_f = 0.49 (20% EtOAc/hexanes). ¹H NMR (600MHz, CDCl₃): δ 7.86 (d, J = 7.3 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.8 Hz, 2H), 6.53 (d, J = 8.3 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 6.06 (dd, J = 8.3, 2.3 Hz, 1H), 5.78 (s, 2h), 5.17 (s, 1H), 5.11 (hept, J = 6.2 Hz, 2H), 4.02 (s, 2H), 1.20 (d, J = 6.3 Hz, 6H), 1.16 (d, J = 6.3 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 196.2, 168.7, 148.0, 140.8, 139.3, 136.4, 133.2, 128.4, 127.8, 108.1, 107.9, 100.5, 99.1, 70.2, 66.8, 40.7, 21.3, 21.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₂₈NO₇ 442.1860, found 442.1868.

Diisopropyl 2-(2-Oxo-2-phenylethyl)-2-((3-(trifluoromethyl)phenyl)amino)malonate (27e).

The general procedure was followed using acetophenone (0.58 mL, 4.9 mmol), KHMDS (1 M solution in THF) (5.32 mL, 5.3 mmol), and 3-trifluoromethylphenyl iminomalonate (1.1 g, 3.3 mmol) as starting materials to afford theketone adduct as a white solid (0.82 g, 53%) (mp 132–134 °C). The compound was purified by flash column chromatography (R_f = 0.53 (20% EtOAc/hexanes). ¹H NMR (600MHz, CDCl₃): δ 7.89 (d, J =8.4Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.19 (t, J = 7.9 Hz, 1h), 6.93 (d, J = 7.6 Hz, 1H), 6.83 (s, 1H), 6.77 (d, J = 8.2 Hz, 1H), 5.70 (s, 1H), 5.13 (hept, J = 6.3 Hz, 2H), 4.12 (s, 2H), 1.21 (d, J = 6.3 Hz, 6H), 1.13 (d, J = 6.3 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 196.0, 168.2, 144.6, 136.3, 133.4, 131.4 (q, ²J_CF = 31.9 Hz), 129.6, 128.6, 128.0, 124.0 (q, ¹J_cf = 272.4 Hz), 117.3, 114.9 (q, ³J_cf = 3.9 Hz), 110.5 (q, ³J_cf = 3.9 Hz), 70.8, 66.0, 40.6, 21.28, 21.22. ¹⁹F NMR (471 MHz, CDCl₃): δ −62.0 (S). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₂₇F₃NO₅ 466.1836, found 466.1827.

Diisopropyl 2-((3,5-Dimethylphenyl)amino)-2-(2-(naphthalen-2-yl)-2-oxoethyl)malonate (27f).

The general procedure was followed using 2-acetonaphthone (0.48 g, 2.8 mmol), KHMDS (1 M solution in THF) (3.01 mL, 3.0 mmol), and 3,5-dimethylphenyl iminomalonate (0.57 g, 1.8 mmol) as starting materials to afford the ketone adduct as a yellowish brown viscous gummy oily liquid (0.75 g, 85%). The compound was purified by flash column chromatography (R_f = 0.5 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 8.37 (s, 1H), 7.95 (dd, J = 8.6, 1.5 Hz, 1H), 7.85 (d, J =8.1 Hz, 1H), 7.81 (d, J = 8.7 Hz, 2H), 7.55 (ddd, J = 8.2, 6.8, 1.4 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 6.38 (s, 1H), 6.32 (s, 2H), 5.41 (s, 1H), 5.19 (hept, J = 6.3 Hz, 2h), 4.28 (s, 2H), 2.19 (s, 6H), 1.26 (d, J = 6.3 Hz, 6H), 1.20 (d, J = 6.3 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 196.3, 168.7, 144.1, 138.5, 135.4, 133.8, 132.1, 129.8, 129.3, 128.3, 128.1, 127.5, 126.5, 123.3, 120.5, 112.6, 70.2, 66.3, 40.8, 21.27, 21.21. HRMS (ESI-TOF) m/z:[M + H]⁺ calcd for C₂₉H₃₄NO₅ 476.2431, found 476.2433.

Diisopropyl 2-(2-(Naphthalen-1-yl)-2-oxoethyl)-2-(p-tolylamino)malonate (27g).

The general procedure was followed using 1-acetonaphthone (0.47 g, 3.0 mmol), KHMDS (1 M solution in THF) (3.29 mL, 3.3 mmol), and 4-methylphenyl iminomalonate (0.6 g, 2.0 mmol) as starting materials to afford the ketone adduct as a yellow viscous oily liquid (0.61 g, 66%). The compound was purified by flash column chromatography (R_f = 0.53 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 8.45 (d, J = 7.8 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 7.1 Hz, 1H), 7.49 (p, J = 6.1, 5.5 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 6.93 (d, J = 8.1 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 5.40 (s, 1H), 5.18 (hept, J = 6.2 Hz, 2H), 4.21 (s, 2H), 2.20 (s, 3H), 1.28 (d, J = 6.3 Hz, 6H), 1.19 (d, J = 6.3 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 200.4, 168.8, 141.9, 135.3, 133.6, 132.6, 129.8, 129.5, 128.2, 128.1, 127.7, 127.5, 126.3, 125.5, 124.1, 115.5, 70.2, 66.7, 44.2, 21.37, 21.30, 20.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₈H₃₂NO₅ 462.2275, found 462.2277.

Diisopropyl 2-(2-Oxo-2-phenylethyl)-2-(phenylamino)malonate(27h).

The general procedure was followed using acetophenone (0.62 mL, 5.3 mmol), KHMDS (1 M solution in THF) (5.68 mL, 5.6 mmol), and phenyl iminomalonate (0.98 g, 3.5 mmol) as starting materials to afford the ketone adduct as a beige solid (mp 65–68 °C) (1.25 g, 89%). The compound was purified by flash column chromatography (R_f = 0.53 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.87 (d, J = 8.2 Hz, 2H), 7.50 (t, J = 6.8 Hz, 1H), 7.38 (t, J = 7.2 Hz, 2H), 7.10 (t, J = 7.9 Hz, 2h), 6.70 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 8.1 Hz, 2H), 5.46 (s, 1H), 5.12 (hept, J = 6.2 Hz, 2H), 4.14 (s, 2h), 1.21 (d, J = 6.3 Hz, 6H), 1.12 (d, J = 6.3 Hz, 6H). ¹³C{¹H}NMR (151 MHz, CDCl₃): δ 196.2, 168.6, 144.3, 136.5, 133.2, 129.0, 128.4, 127.9, 118.5, 114.5, 70.3, 66.1, 40.8, 21.29, 21.24. HRMS (ESI-TOf) m/z: [M + H]⁺ calcd for C₂₃H₂₈NO₅ 398.1962, found 398.1958.

Diisopropyl 2-(Benzo[d][1,3]dioxol-5-ylamino)-2-(2-(furan-2-yl)-2-oxoethyl)malonate (27i).

The general procedure was followed using 2-acetylfuran (0.33 g, 3.0 mmol), KHMDS (1 M solution in THF) (3.23 mL, 3.2 mmol), and 3,4-methylenedioxyphenyl iminomalonate (0.65 g, 2.0 mmol) as starting materials to afford the ketone adduct as a dark brown viscous oily liquid (0.66 g, 77%). The compound was purified by flash column chromatography (R_f = 0.27 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.49 (s, 1H), 7.06 (d, J = 3.5 Hz, 1H), 6.53 (d, J = 8.3 Hz, 1H), 6.43 (dd, J = 3.5,1.7 Hz, 1h), 6.24 (d, J = 2.3 Hz, 1H), 6.05 (dd, J = 8.3, 2.3 Hz, 1H), 5.79 (s, 2h), 5.08 (hept, J = 6.3 Hz, 3H), 3.85 (s, 2H), 1.20 (d, J = 6.3 Hz, 6H), 1.13 (d, J = 6.3 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 185.0, 168.4, 152.2, 147.9, 146.5, 140.8, 139.3, 117.5, 112.2, 108.1, 107.8, 100.5, 99.0, 70.3, 66.7, 40.5, 21.29, 21.27. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₆NO₈ 432.1653, found 432.1657.

Diisopropyl 2-((4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)phenyl)-amino)-2-(2-(furan-2-yl)-2-oxoethyl)malonate (27j).

The general procedure was followed using 2-acetylfuran (0.27 g, 2.4 mmol), KHMDS (1 M solution in THF) (2.64 mL, 2.6 mmol) and ((tert-butyldimethylsilyl)oxy)ethyl)phenyl iminomalonate (0.72 g, 1.6 mmol) as starting materials to afford the ketone adduct as a brown viscous oily liquid (0.67 g, 75%). The compound was purified by flash column chromatography (R_f = 0.44 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.45 (s, 1H), 7.02 (d, J = 3.5 Hz, 1H), 6.91 (d, J = 8.3 Hz, 2H), 6.52 (d, J = 8.4 Hz, 2H), 6.38 (dd, J = 3.6, 1.7 Hz, 1H), 5.25 (s, 1H), 5.08 (h, J = 6.3 Hz, 2H), 3.91 (s, 2H), 3.66 (t, J = 7.1 Hz, 2H), 2.63 (t, J = 7.0 Hz, 2H), 1.20 (d, J = 6.3 Hz, 6H), 1.09 (d, J = 6.3 Hz, 6H), 0.82 (s, 9H), −0.08 (s, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 184.9, 168.4, 152.1, 146.4, 142.4, 170.2, 66.1, 64.5, 40.4, 38.5, 25.7, 21.2, 21.1, 18.1, −5.5. HRMS (ESI-TOf) m/z: [M + H]⁺ calcd for C₂₉H₄₄NO₇Si 546.2882, found 546.2883.

Diisopropyl 2-(Benzo[d][1,3]dioxol-5-ylamino)-2-(2-oxo-2-(thio-phene-2-yl)ethyl)malonate (27k).

The general procedure was followed using 2-acetylthiophene (0.40 mL, 3.7 mmol), KHMDS (1 M solution in THF) (3.98 mL, 3.9 mmol), and 3,4-methylenedioxyphenyl iminomalonate (0.8 g, 2.4 mmol) as starting materials to afford the ketone adduct as a dark brownish yellow viscous gummy substance (0.84 g, 76%). The compound was purified by flash column chromatography (R_f = 0.38 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.60 (ddd, J = 14.6, 4.3, 0.8 Hz, 2H), 7.04 (dd, J = 4.8, 3.9 Hz, 1H), 6.55 (d, J =8.3 Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 6.07 (dd, J = 8.3, 2.3 Hz, 1H), 5.80 (s, 2H), 5.15–5.07 (m, 3H), 3.94 (s, 2H), 1.22 (d, J = 6.3 Hz, 6h), 1.17 (s, 6h). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 189.1, 168.5, 148.0, 143.8, 140.9, 139.3, 134.1, 132.2, 128.0, 108.2, 107.8, 100.6, 99.1, 70.3, 66.9, 41.2, 21.3. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₆NO₇S 448.1424, found 448.1425.

Diisopropyl 2-(2-(4-Bromophenyl)-2-oxoethyl)-2-(pyridin-3-ylamino)malonate (27l).

The general procedure was followed using 4-bromoacetophenone (0.85 g, 4.3 mmol), KHMDS (1 M solution in THF) (4.59 mL, 4.5 mmol), and 3-pyridyl iminomalonate (0.8 g, 2.8 mmol) as starting materials to afford the ketone adduct as a reddish brown viscous gummy substance (0.97 g, 71%). The compound was purified by flash column chromatography (R_f = 0.16 (30% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.98 (s, 1H), 7.92–7.87 (m, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2h), 6.96–6.91 (m, 1H), 6.84 (d, J = 7.0 Hz, 1H), 5.47 (s, 1H), 5.04 (hept, J = 6.2 Hz, 2H), 3.99 (s, 2H), 1.12 (d, J = 6.1 Hz, 6H), 1.04 (d, J = 6.1 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 194.7, 167.7, 140.2, 139.9, 137.1, 134.8, 131.7, 129.2, 128.5, 123.2, 120.2, 70.6, 65.6, 40.2, 21.0. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₆BrN₂O₅ 477.1020, found 477.1021.

Diisopropyl 2-((4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)phenyl)-amino)-2-(2-oxo-2-(pyridin-4-yl)ethyl)malonate (27m).

The general procedure was followed using 4-acetylpyridine (0.20 mL, 1.8 mmol), KHMDS (1 M solution in THF) (1.94 mL, 1.9 mmol), and ((tert-butyldimethylsilyl)oxy)ethyl)phenyl iminomalonate (0.53 g, 1.2 mmol) as starting materials to afford the ketone adduct as a brown viscous oily liquid (0.22 g, 34%). The compound was purified by flash column chromatography (R_f = 0.37 (30% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 8.70 (d, J = 5.9 Hz, 2H), 7.58 (d, J = 5.9 Hz, 2H), 6.92 (d, J = 8.3 Hz, 2H), 6.52 (d, J = 8.3 Hz, 2H), 5.27 (s, 1H), 5.10 (hept, J = 6.1, 5.2 Hz, 2H), 4.05 (s, 2H), 3.66 (t, J = 7.0 Hz, 2H), 2.63 (t, J = 7.0 Hz, 2H), 1.20 (d, J = 6.3 Hz, 6H), 1.12 (d, J = 6.3 Hz, 6H), 0.82 (s, 9H), −0.09 (s, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃):δ 196.1, [168.4, 150.7, 142.3, 142.1, 129.8, 129.7, 120.7, 114.9, 70.5, 66.2, 64.6, 40.8, 38.5, 25.8, 21.35, 21.30, 21.2, 18.2, −5.5. HRMS (ESI-TOf) m/z:[M + H]⁺ calcd for C₃₀H₄₅N₂O₆Si 557.3041, found 557.3041.

Diisopropyl 2-((4-Methoxyphenyl)amino)-2-(1-oxo-1-phenylpro-pan-2-yl)malonate (27n).

The general procedure was followed using propiophenone (0.42 mL, 3.1 mmol), KHMDS (1 M solution in THF) (3.38 mL, 3.3 mmol), and p-methoxyphenyl iminomalonate (0.65 g, 2.1 mmol) as starting materials to afford the ketone adduct as a yellow viscous oily liquid (0.65 g, 70%). The compound was purified by flash column chromatography (R_f = 0.36 (15% EtOAc/hexanes). ¹H NMR L (500 MHz, CDO₃):δ 7.84–7.88 (m, 2H, H-2/H-6); 7.49–7.53 (m, 1H, H-4); 7.38–7.42 (m, 2H, H-3/H-5); 6.68 (apparent s, all 4-methoxyphenyl ring protons); 5.19 (s, broad, NH); 4.67 (q, J = 7.2 Hz, 1H, CH next to quaternary aliphatic carbon); 3.69 (s, 3H, methoxy); 1.41 (d, J = 7.2 Hz, 3H, methyl bonded to methine next to quaternary aliphatic carbon); isopropoxy group 1:5.23 (hept, J = 6.3 Hz, 1H, methine), 1.31 (d, J = 6.3 Hz, 3H, methyl), 1.23 (d, J = 6.3 Hz, 3H, methyl); isopropoxy group 2:4.99 (hept, J = 6.3 Hz, 1H, methine), 1.14 (d, J = 6.3 Hz, 3H, methyl), 1.01 (d, J = 6.3 Hz, 3H, methyl). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 201.7 (ketone carbonyl); isopropoxy- carbonyl group 1:169.3 (carbonyl), 70.2 (CH), 21.6 (methyl correlating with methyl ¹H signal at δ1.31 in HSQC spectrum), 21.5 (methyl correlating with methyl ¹H signal at δ1.23 in HSQC spectrum); isopropoxycarbonyl group 2:168.7 (carbonyl), 70.0 (CH), 21.31 (methyl), 21.29 (methyl); 153.6 (C-4′); 138.3 (C-1′); 136.5 (C-1); 133.0 (C-4); 128.5 (C-3/C-5); 128.3 (C-2/C-6); 118.7 (C-2′/C-6′); 114.3 (C-3′/C-5′); 71.1 (quaternary aliphatic carbon); 55.5 (methoxy); 43.9 (CH next to quaternary aliphatic carbon); 14.7 (methyl bonded to CH next to quaternary aliphatic carbon). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₅H₃₂NO₆ 442.2224, found 442.2219.

Note: The evidence for C-attack by the enolate was the generation of a quaternary aliphatic carbon, as shown by the presence of a signal at δ 71.1 in the standard ¹³C spectrum (SI p S78) and the absence of this signal in the DEPT-135 ¹³C spectrum (SI p S79). Detailed chemical shift assignments could be made through a combination of ¹H (SI p. S77), ¹³C, DEPT-135 ¹³C, and DEPT-90 ¹³C (both optimized for ¹J_ch = 145 Hz), COSY (SI p S81), NOE with a 0.3 s mixing time SI p 80), HSQC optimized for ¹J_ch = 145 Hz (SI p S83), and HMBC optimized for ¹J_CH = 145 Hz and ⁿJ_CH = 6.25 Hz (SI p S82) experiments.

Diisopropyl 2-((4-Methoxyphenyl)amino)-2-(2-oxocyclohexyl)-malonate (27o).

The general procedure was followed using cyclohexanone (0.25 mL, 2.4 mmol), KHMDS (1 M solution in THF) (2.56 mL, 2.5 mmol), and p-methoxyphenyl iminomalonate (0.49 g, 1.6 mmol) as starting materials to afford the ketone adduct as a brown viscous oily liquid (0.46 g, 71%). The compound was purified by flash column chromatography (R_f = 0.37 (20% EtOAc/hexanes). ¹H NMR (500 MHz, CDO₃): δ 6.66–6.71 (m, AA′BB′ pattern, 4H, aromatic) ringprotons); isopropoxy group 1:5.05 (hept, J = 6.3 Hz, 1H, methine), 1.20 (d, J = 6.3 Hz, 3H, methyl), 1.19 (d, J = 6.3 Hz, 3H, methyl); isopropoxy group 2:4.97 (hept, J = 6.3 Hz, 1H, methine), 1.16 (d, J = 6.3 Hz, 3H, methyl), 0.99 (d, J = 6.3 Hz, 3H, methyl); 4.92 (s, broad, NH); 3.72 (s, 3H, methoxy); 3.51 (ddd, J = 12.6, 5.2, 1.0 Hz, 1H, methine next to ketone carbonyl); 2.55 and 1.86 [m, 2H, ring 3-CH₂ (next to ring methine)]; 1.94 and 1.72 (m, 2H, ring 4-CH₂); 2.06 and 1.63 (m, 2H, ring 5-CH₂); 2.37 and 2.26 [ring 6-CH₂ (next to ketone carbonyl)]. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 210.1 (ketone carbonyl); isopropoxycarbonyl group 1:169.2 (carbonyl), 70.0 (CH), 21.44 (methyl), 21.44 (methyl); isopropoxycarbonyl group 2:168.1 (carbonyl), 69.7 (CH), 21.44 (methyl), 21.19 (methyl); 153.6 (C-4); 139.3 (C-1); 119.1 (C-2/C-6); 114.1 (C-3/C-5); 69.9 (quaternary aliphatic carbon); 56.6 (ring methine carbon); 55.6 (methoxy); 42.5 (ring 6-CH₂); 30.4 (ring 3-CH₂); 27.5 (ring 5-CH₂); 25.4 (ring 4-CH₂). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₃₂NO₆ 406.2224, found 406.2227. The evidence for C-attack by the enolate was the generation of a quaternary aliphatic carbon, as shown by the presence of a signal at δ 69.9 in the standard ¹³C spectrum (SI p S85) and the absence of this signal in the DEPT-135 ¹³C spectrum (SI p S86) and the DEPT-90 ¹³C spectrum. Detailed chemical shift assignments could be made through a combination of ¹H (SI p S84), ¹³C, DEPT-135 ¹³C, DEPT-90 ¹³C, COSY (SI p S87), HSQC (SI p S89), and HMBC (SI p S88) experiments (with key parameters the same as for 27n).

Diisopropyl 2-(Benzo[d][1,3]dioxol-5-ylamino)-2-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)malonate (27p).

The general procedure was followed using α-tetralone (0.30 mL, 2.2 mmol), KHMDS (1 M solution in THF) (2.43 mL, 2.4 mmol), and 3,4-methylenedioxyphenyl iminomalonate (0.49 g, 1.5 mmol) as starting materials to afford the ketone adduct as a brown gummy substance (0.61 g, 86%). The compound was purified by flash column chromatography (R_f = 0.37 (20% EtOAc/hexanes). ¹H NMR (600MHz, CDCl₃): δ 7.98–7.96 (m, 1H), 7.43 (td, J = 7.5, 1.3 Hz, 1H), 7.28–7.24 (m, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 2.3 Hz, 1H), 6.21 (dd, J = 8.4, 2.3 Hz, 1H), 5.81 (s, 2H), 5.14 (dq, J = 12.5, 6.6 Hz, 2H), 4.98 (hept, J = 6.2 Hz, 1H), 3.71 (dd, J = 13.5, 4.0 Hz, 1H), 3.11 (td, J = 15.0, 13.1,4.0 Hz, 1H), 2.99 (dt, J = 16.6, 3.3 Hz, 1H), 2.70 (dq, J = 11.2, 3.9 Hz, 1H), 2.16 (qd, J = 13.0, 4.1 Hz, 1H), 1.24 (d, J = 6.3 Hz, 3H), 1.15 (dd, J = 16.3, 6.3 Hz, 6H), 0.99 (d, J = 6.3 Hz, 3h). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 196.6, 169.1, 167.7,147.6, 143.5, 140.9, 140.7, 133.4, 132.4, 128.3, 127.3, 126.5, 109.4, 107.8, 100.5, 100.0, 70.7, 70.3, 69.6, 54.3, 29.4, 26.5, 21.37, 21.32, 21.2, 21.1. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₆H₃₀NO₇ 468.2017, found 468.2016.

Diisopropyl 2-(2-(1-Methyl-1H-pyrrol-3-yl)-2-oxoethyl)-2-((3-(trifluoromethyl)phenyl)amino)malonate (27q).

The general procedure was followed using 3-acetyl-1-methyl pyrrole (0.41 mL, 3.4 mmol), KHMDS (1 M solution in THF) (3.7 mL, 3.7 mmol), and 3-trifluoromethylphenyl iminomalonate (0.8 g, 2.3 mmol) as starting materials to afford the ketone adduct as a white solid (mp 160–162 °C) (0.57 g, 53%). The compound was purified by flash column chromatography (R_f = 0.31 (30% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.18 (t, J = 7.9 Hz, 1H),7.07 (t, J = 1.7 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.80 (s, 1H), 6.78–6.73 (m, 1H), 6.53–6.44 (m, 2h), 5.66 (s, 1H), 5.12 (hept, J = 6.3 Hz, 2H), 3.82 (s, 2H), 3.58 (s, 3h), 1.23 (d, J = 6.3 Hz, 6H), 1.13 (d, J = 6.3 Hz, 6H). ¹³C{¹H}NMR (151 MHz, CDCl₃): δ 190.7, 168.4, 144.9, 131.3 (q, ²J_CF = 31.8 Hz), 129.4, 127.0, 125.5, 124.1 (q, ¹J_CF = 272.3 Hz), 123.4, 117.6, 114.5 (q, ³J_cf = 3.9 Hz), 110.4 (q, ³J_cf = 3.9 Hz), 109.2, 70.5, 66.1, 41.0, 36.5, 21.33, 21.27. ¹⁹F NMR (471 MHz, CDCl₃): δ −61.9 (s). HRMS (ESI-TOf) m/z: [M + H]⁺ calcd for C₂₃H₂₈F₃N₂O₅ 469.1945, found 469.1944.

Diisopropyl 2-((3-Chlorophenyl)amino)-2-(2-oxo-2-(pyridin-3-yl)ethyl)malonate (27r).

The general procedure was followed using 3-acetylpyridine (0.45 mL, 4.1 mmol), KHMDS (1 M solution in THF) (4.43 mL, 4.4 mmol), and 3-chlorophenyl iminomalonate (0.86 g, 2.7 mmol) as starting materials to afford the ketone adduct as a viscous gummy oily liquid (0.71 g, 60%). The compound was purified by flash column chromatography (R_f = 0.20 (30% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 9.05 (s, 1H), 8.67 (s, 1H), 8.07 (d, J = 7.7 Hz, 1H), 7.32–7.27 (m, 1H), 6.95 (t, J = 8.0 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H), 6.44 (d, J = 7.8 Hz, 1H), 5.52 (s, 1H), 5.07 (hept, J = 6.3 Hz, 2H), 4.06 (s, 2H), 1.16 (d, J = 6.2 Hz, 6h), 1.08 (d, J = 6.2 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 195.0, 167.8, 153.6, 149.2, 145.1, 135.0, 134.6, 131.5, 130.0, 123.3, 118.4, 114.0, 112.2, 70.6, 65.6, 40.6, 21.15, 21.11. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₆ClN₂O₅ 433.1525, found 433.1525.

Diisopropyl 2-((3-Chlorophenyl)amino)-2-(2-oxo-2-(pyridin-2-yl)ethyl)malonate (27s).

The general procedure was followed using 2-acetylpyridine (0.43 mL, 3.8 mmol), KHMDS (1 M solution in THF) (4.10 mL, 4.1 mmol), and 3-chlorophenyl iminomalonate (0.80 g, 2.5 mmol) as starting materials to afford the ketone adduct as a yellow solid (mp 110–113 °C) (0.61 g, 55%). The compound was purified by flash column chromatography (R_f = 0.62 (30% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 8.68–8.55 (m, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.77 (t, J = 7.1 Hz, 1H), 7.48–7.36 (m, 1H), 7.00 (t, J = 7.8 Hz, 1h), 6.65 (d, J = 7.8 Hz, 1H), 6.54 (d, J = 7.5 Hz, 1H), 5.57 (s, 1H), 5.13 (hept, J = 6.2 Hz, 2H), 4.43 (s, 2H), 1.23 (d, J = 6.1 Hz, 6h), 1.14 (d, J = 6.1 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 197.6, 168.1, 152.5, 148.7, 145.5, 136.6, 134.4, 129.8, 127.2, 121.4, 118.2, 114.3, 112.5, 70.3, 65.9, 40.0, 21.2, 21.1. HRMS (ESI-TOF)m/z: [M + H]⁺ calcd for C₂₂H₂₆ClN₂O₅ 433.1525, found 433.1527.

Diisopropyl 2-((4-Bromophenyl)amino)-2-(2-oxo-2-(pyridin-3-yl)ethyl)malonate (27t).

The general procedure was followed using 3-acetylpyridine (0.37 mL, 3.3 mmol), KHMDS (1 M solution in THF) (3.59 mL, 3.5 mmol), and 4-bromophenyl iminomalonate (0.80 g, 2.2 mmol) as starting materials to afford the ketone adduct as a yellow solid (mp 127–130 °C) (0.58 g, 54%). The compound was purified by flash column chromatography (R_f = 0.21 (30% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 9.05 (s, 1H), 8.70 (d, J = 4.1 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.31 (dd, J = 7.8, 4.9 Hz, 1H), 7.15 (d, J = 8.6 Hz, 2H), 6.47 (d, J = 8.6 Hz, 2H), 5.46 (s, 1H), 5.08 (hept, J = 6.2 Hz, 2H), 4.06 (s, 2h), 1.17 (d, J = 6.3 Hz, 6H), 1.10 (d, J = 6.3 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 195.1, 168.0, 153.6, 149.3, 143.0, 135.0, 131.8, 131.6,123.4, 115.9, 110.5, 70.7, 65.8, 40.5, 21.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₆BrN₂O₅ 477.1020, found 477.1017.

General Procedure for the Asymmetric Reduction of Ketone Adducts via CBS Reduction (Figure 7).

In a thick-walled flame-dried reaction vial, Mannich ketone adduct (1.0 equiv) was dissolved in anhydrous THF (0.2 M) under argon and cooled to –15 °C using a NESLAB CC 100 immersion cooler with isopropanol as bath solvent. To this cooled reaction mixture was added (S)-(–)-2-methyl-CBS-oxazaborolidine solution (1 M solution in toluene) (0.15 equiv) dropwise and the mixture stirred for 5 min. Then BH₃·DMS solution (2 M solution in THF) (2.0 equiv) was added slowly dropwise to the reaction mixture and continued stirring for 75 h at −15 °C or until complete consumption of the starting material ketone. Then the reaction was cooled to 0 °C and quenched using saturated NH₄Cl solution or methanol (3 mL).

Workup and Purification.

After quenching, the reaction mixture was diluted with brine (10 mL), and the organic layer was separated. The aqueous layer was then extracted with EtOAc twice (2 × 20 mL), and the combined organic layers were washed with brine (20 mL) once, dried over anhydrous Na₂SO₄, and concentrated. The crude product was purified by automated flash column chromatography.

Diisopropyl (R)-2-(2-Hydroxy-2-phenylethyl)-2-((4-methoxyphenyl)amino)malonate (28a).

The general procedure was followed using 27a (0.1 g, 0.2 mmol) (S)-(–)-2-methyl-CBS-oxazaborolidine solution (1 M solution in toluene) (0.035 mL, 0.03 mmol), and BH₃·DMS solution (2 M solution in THF) (0.23 mL, 0.4 mmol) as starting materials to afford the alcohol as a beige viscous oily liquid (0.075g, 75%). The compound was purified by flash column chromatography (R_f = 0.33 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.35–7.31 (m, 4H), 7.28–7.24 (m, 1H), 6.82 (d, J = 8.9 Hz, 2H), 6.76 (d, J = 9.0 Hz, 2H), 5.16 (s, 1H), 5.11 (hept, J = 6.3 Hz, 1H), 4.95 (hept, J = 6.3 Hz, 1H), 4.85 (d, J = 10.0 Hz, 1H), 3.98 (s, 1H), 3.74 (s, 3H), 2.74–2.62 (m, 2H), 1.29 (d, J = 6.3 Hz, 3H), 1.19 (d, J = 6.3 Hz, 3H), 1.13 (d, J = 6.3 Hz, 3H), 1.02 (d, J = 6.3 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 169.1, 168.4, 154.1, 144.1, 137.5, 128.3, 127.3, 125.5, 118.8, 114.5, 70.9, 70.2, 69.9,69.0, 55.5, 41.7, 21.5, 21.36, 21.32, 21.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₃₂NO₆ 430.2224, found 430.2228. HPLC analysis: Chiralpak IC, 20% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 13.6 min, t_minor = 15.2 min, ee 94%, er 97:3; [α]_D²⁰ = +42.3 (C = 1, CHCl₃).

Determination of Absolute Configuration of Chiral Alcohol Using Mosher Ester Analysis.

Preparation of (S)- and (R)-MTPA Esters.16

To a stirred solution of the alcohol (28a, 10 mg, 0.023 mmol) and dry pyridine (5.8 μL, 0.07 mmol, 3.1 equiv) in dry DCM (0.5 mL, 0.046 M) at room temperature was added S-(+)-MTPA-Cl (8.2 μL, 0.04 mmol, 1.9 equiv). The reaction progress was monitored by thin-layer chromatography (TLC) on silica gel. After 5 h of stirring at room temperature, the reaction mixture was quenched by the addition of water (~1 mL) and ethyl acetate (~3 mL). The aqueous layer was extracted with two additional portions of ethyl acetate (~3 mL), and the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by column chromatography to give the R-MTPA ester. ¹H NMR (600 MHz, CDCl₃): 7.37 (ddd, J = 8.5,4.0, 2.1 Hz, 1H), 7.34–7.28 (m, 7H), 7.26 (s, 2H), 6.70 (d, J = 8.9 Hz, 2H), 6.53 (d, J = 8.9 Hz, 2H), 6.08 (t, J = 6.7 Hz, 1H), 4.87–4.80 (m, 2H), 4.64 (dp, J = 12.6, 7.2, 6.3 Hz, 1H), 3.73 (s, 3H), 3.37 (s, 3H), 3.06 (dd, J = 15.5, 7.0 Hz, 1H), 2.94 (dd, J = 15.5, 6.4 Hz, 1H), 1.19 (d, J = 6.3 Hz, 3H), 1.01 (d, J =5.7 Hz, 6H), 0.95 (d, J = 6.2 Hz, 3H). In an entirely analogous fashion, the S-MTPA ester was prepared using R-(–)-MTPA-Cl. ¹H NMR (600 MHz, CDCl₃): 7.37–7.29 (m, 2H), 7.26 (h, J = 4.6 Hz, 4H), 7.21 (d, J = 7.7 Hz, 2H), 7.18 (dd, J = 7.6, 1.7 Hz, 2H), 6.73 (d, J = 8.9 Hz, 2H), 6.61 (d, J = 8.9 Hz, 2H), 5.95 (t, J = 6.6 Hz, 1H), 4.99 (s, 1H), 4.95 (hept, J = 12.5, 6.3 Hz, 1H), 4.65 (hept, J = 6.3 Hz, 1H), 3.74 (s, 3H), 3.40 (s, 3H), 3.08 (dd, J = 15.6,7.2 Hz, 1H), 2.91 (dd, J = 15.6, 6.1 Hz, 1H), 1.11 (d, J = 6.3 Hz, 3H), 1.05 (d, J = 6.2 Hz, 3H), 0.98 (d, J = 6.3 Hz, 3H), 0.95 (d, J = 6.2 Hz, 3H).

Diisopropyl (R)-2-((3,5-Dimethylphenyl)amino)-2-(2-hydroxy-2-phenylethyl)malonate (28b).

The general procedure was followed using 27b (0.5 g, 1.18 mmol), (S)-(–)-2-methyl-CBS-oxazaborolidine solution (1 M solution in toluene) (0.18 mL, 0.18 mmol), and BH₃·DMS solution (2 M solution in THF) (1.18 mL, 2.3 mmol) as starting materials to afford the alcohol as a brown viscous gummy substance (0.42g, 83%). The compound was purified by flash column chromatography (R_f = 0.47 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.36–7.30 (m, 4H), 7.29–7.23 (m, 1H), 6.49 (s, 1H), 6.42 (s, 2H), 5.35 (s, 1H), 5.09 (hept, J = 6.3 Hz, 1H), 5.02 (hept, J = 6.3 Hz, 1H), 4.84 (t, J = 6.3 Hz, 1H), 3.42 (s, 1H), 2.75 (d, J = 6.4 Hz, 2H), 2.23 (s, 6H), 1.26 (dd, J = 17.6, 6.3 Hz, 6h), 1.11 (d, J = 6.3 Hz, 3h), 1.05 (d, J = 6.3 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 169.0, 168.8, 144.24, 144.22, 138.6, 128.2, 127.2, 125.5, 121.6, 113.8, 70.6, 70.1, 70.0, 68.0, 41.7, 21.5,21.3,21.2, 21.1. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₅H₃₄NO₅ 428.2431, found 428.2431. HPLC analysis: Chiralpak IC, 20% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 8.8 min, t_minor = 9.4 min, ee 97%, er 98.4:1.6; [α]_D²⁰ = +32.7 (C = 1, CHCl₃).

Diisopropyl (R)-2-(2-(4-Bromophenyl)-2-hydroxyethyl)-2-((3,5-1dimethylphenyl)amino)malonate (28c).

The general procedure was followed using 27c (0.27 g, 0.53 mmol), (S)-(–)-2-methyl-CBS-oxazaborolidine solution (1 M solution in toluene) (0.08 mL, 0.08 mmol), and BH₃·DMS solution (2 M solution in THF) (0.53 mL, 1.07 mmol) as starting materials to afford the alcohol as a pale yellow foamy solid (0.22g, 81%). The compound was purified by flash column chromatography (R_f = 0.55 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.43 (d, J = 8.4 Hz, 2H), 7.16 (d, J =8.3 Hz, 2H), 6.49 (s, 1H), 6.38 (s, 2H), 5.32 (s, 1H), 5.08 (hept, J = 6.2 Hz, 1h), 5.00 (hept, J = 6.2 Hz, 1H), 4.78 (dd, J = 8.3, 3.9 Hz, 1H), 3.60 (s, 1H), 2.74–2.63 (m, 2H), 2.22 (s, 6H), 1.27 (d, J = 6.3 Hz, 3H), 1.23 (d, J = 6.3 Hz, 3H), 1.11 (d, J = 6.3 Hz, 3H), 1.04 (d, J = 6.3 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 168.9, 168.7, 144.0, 143.2, 138.7, 131.3, 127.2, 121.8, 120.9, 113.8, 70.2, 70.1, 70.0, 68.0, 41.6, 21.5, 21.3, 21.2, 21.1. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₅H₃₃BrNO₅ 506.1537, found 506.1536. HPLC analysis: Chiralpak IC, 20% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major =8.1 min, t_minor = 8.7 min, ee 94%, er 97:3; [α]_D²⁰ = +26.8 (C = 1, CHCl₃).

Diisopropyl (R)-2-(Benzo[d][1,3]dioxol-5-ylamino)-2-(2-hydroxy-2-phenylethyl)malonate (28d).

The general procedure was followed using 27d (0.32 g, 0.73 mmol), (S)-(–)-2-methyl-CBS-oxazaborolidine solution (1 M solution in toluene) (0.11 mL, 0.11 mmol), and BH₃·DMS solution (2 M solution in THF) (0.73 mL, 1.46 mmol) as starting materials to afford the alcohol as a pale yellow waxy solid (0.28g, 90%). The compound was purified by flash column chromatography (R_f = 0.35 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.26–7.20 (m, 4H), 7.19–7.14 (m, 1H), 6.54 (d, J = 8.3 Hz, 1H), 6.36 (d, J = 2.2 Hz, 1H), 6.17 (dd, J = 8.3, 2.3 Hz, 1h),5.77 (s,2H), 5.12 (s, 1H), 5.00 (hept, J = 6.2 Hz, 1H), 4.91 (hept, J = 6.3 Hz, 1H), 4.74 (dd, J = 9.5, 2.8 Hz, 1H), 3.58 (s, 1H), 2.66–2.52 (m, 2H), 1.19 (d, J = 6.3 Hz, 3H), 1.14 (d, J = 6.3 Hz, 3h), 1.05 (d, J = 6.3 Hz, 3H), 0.99 (d, J = 6.3 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 169.0, 168.5, 148.0, 144.1, 141.6, 139.0, 128.3, 127.3, 125.5, 109.0, 108.2, 100.7, 99.9, 70.7, 70.2, 70.0, 68.7, 41.5, 21.5, 21.34, 21.30. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₃₀NO₇ 444.2017, found 444.2022. HPLC analysis: Chiralpak IB, 20% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 14.0 min, t_minor =15.3 min, ee 96%, er 98:2; [α]_D²⁰ = +36.2 (C = 1, CHCl₃).

Diisopropyl (R)-2-(2-Hydroxy-2-phenylethyl)-2-((3-(trifluoromethyl)phenyl)amino)malonate (28e).

The general procedure was followed using 27e (0.40 g, 0.87 mmol), (S)-(–)-2-methyl-CBS-oxazaborolidine solution (1 M solution in toluene) (0.13mL, 0.13 mmol), and BH₃·DMS solution (2 M solution in THF) (0.87 mL, 1.75 mmol) as starting materials to afford the alcohol as a colorless viscous gummy substance (0.385g, 94%). The compound was purified by flash column chromatography (R_f = 0.43 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.33 (t, J = 7.3 Hz, 2H), 7.31–7.25 (m, 4H), 7.07 (d, J = 7.5 Hz, 1H), 6.99 (s, 1H), 6.88 (d, J = 7.8 Hz, 1H), 5.77 (s, 1H), 5.13 (hept, J = 6.3 Hz, 1h), 5.06 (hept, J = 6.4 Hz, 1H), 4.84 (s, 1h), 2.85–2.72 (m, 3H), 1.33 (d, J = 6.2 Hz, 3H), 1.26 (d, J = 6.2 Hz, 3h), 1.17 (d, J = 6.2 Hz, 3H), 1.07 (d, J = 6.2Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 169.0, 168.6, 144.9, 144.0, 131.5 (q, ²J_CF = 31.9 Hz), 129.7, 128.4, 127.5, 125.5, 124.0 (q, ¹J_CF = 272.3 Hz), 117.5, 115.3 (q, ³J_cf = 3.6 Hz), 111.5 (q, ³J_cf = 3.6 Hz), 70.6, 70.3, 70.2, 67.2, 41.4, 21.33, 21.30, 21.2, 21.1. ¹⁹F NMR (471 MHz, CDCl₃): δ −61.9 (S). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₂₉F₃NO₅ 468.1992, found 468.1993. HPLC analysis: Chiralpak IB, 2% IP/hexanes, continuous flow at 0.4 mL/min, 230 nm; t_major = 21.1 min, t_minor = 18.8 min, ee 92%, er 4:96; [α] _D²⁰ = +6.2 (C = 1, CHCl₃).

Diisopropyl (R)-2-((3,5-Dimethylphenyl)amino)-2-(2-hydroxy-2-(naphthalen-2-yl)ethyl)malonate (28f).

The general procedure was followed using 27f (0.6 g, 1.26 mmol), (S)-(–)-2-methyl-CBS-oxazaborolidine solution (1 M solution in toluene) (0.19 mL, 0.19 mmol), and BH₃·DMS solution (2 M solution in THF) (1.26 mL, 2.52 mmol) as starting materials to afford the alcohol as a pale yellow foamy solid (0.44g, 73%). The compound was purified by flash column chromatography (R_f = 0.51 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.87–7.75 (m, 4H), 7.51–7.44 (m, 2H), 7.41 (dd, J = 8.5, 1.8 Hz, 1H), 6.52 (s, 1H),6.45 (s,2H), 5.41 (s, 1H),5.11 (hept, J = 6.4 Hz, 1H), 5.07–4.99 (m, 2H), 3.55 (s, 1H), 2.91–2.79 (m,2H), 2.25 (s, 6H), 1.29 (dd, J = 14.3, 6.3 Hz, 6H), 1.13 (d, J = 6.2 Hz, 3h), 1.07 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 169.0, 168.9, 144.2, 141.6, 138.7, 133.2, 132.8, 128.0, 127.9, 127.5, 125.9, 125.6, 124.1, 123.9, 121.7, 113.8, 70.7, 70.2, 70.1, 68.1, 41.7, 21.5, 21.4, 21.3, 21.27, 21.21. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₉H₃₆NO₅ 478.2588, found 478.2589. HPLC analysis: Chiralpak IB, 2% IP/hexanes, continuous flow at 0.4 mL/min, 230 nm; t_major = 26.7 min, t_minor = 25.4 min, ee 98%, er 1:99; [α]_D²⁰ = +18.8 (C = 1, CHCl₃).

Diisopropyl (R)-2-(2-Hydroxy-2-(naphthalen-1-yl)ethyl)-2-(ptolylamino)malonate (28g).

The general procedure was followed using 27g (0.64g, 1.40 mmol), (S)-(–)-2-methyl-CBS-oxazaborolidine solution (1 M solution in toluene) (0.21 mL, 0.21 mmol), and BH₃·DMS solution (2 M solution in THF) (1.40 mL, 2.80 mmol) as starting materials to afford the alcohol as a beige solid (mp 95–98 °C) (0.47g, 73%). The compound was purified by flash column chromatography (R_f = 0.48 (20% EtOAc/hexanes). ¹HNMR (600 MHz, CDCl₃): δ 7.84 (d, J = 8.2 Hz, 1H), 7.75 (t, J = 8.5 Hz, 2H), 7.66 (d, J = 8.5 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.29–7.22 (m, 1h), 7.03 (d, J =8.1 Hz, 2h), 6.75 (d, J = 8.3 Hz, 2h), 5.68 (d, J = 10.7 Hz, 1H), 5.47 (s, 1H), 5.14–5.04 (m, 2H), 3.31 (s, 1H), 3.00 (d, J = 15.4 Hz, 1H), 2.79 (dd, J = 15.4, 10.8 Hz, 1H), 2.31 (s, 3H), 1.29 (dd, J = 15.6, 6.3 Hz, 6H), 1.12 (dd, J = 21.7, 6.3 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 169.3, 141.8, 140.0, 133.5, 129.8, 129.7, 128.8, 128.6, 127.125.5, 125.4, 125.2, 122.9, 122.8, 116.0, 70.2, 70.1, 67.9, 67.2, 40.6, 21.4, 21.36, 21.31, 20.4. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₈H₃₄NO₅ 464.2431, found 464.2434. HPLC analysis: Chiralpak ID, 91% IP/hexanes, continuous flow at 0.4 mL/min, 250 nm; t_major = 12.8 min, t_minor = 11.7 min, ee 83%, er 8.6:91.4; [α]_D²⁰ = +28.5 (C =1, CHCl₃).

Diisopropyl (R)-2-(2-Hydroxy-2-phenylethyl)-2-(phenylamino)- malonate (28h).

The general procedure was followed using 27h (0.45 g, 1.13 mmol), (S)-(–)-2-methyl-CBS-oxazaborolidine solution (1 M solution in toluene) (0.17 mL, 0.17 mmol), and BH₃·DMS solution (2 M solution in THF) (1.13 mL, 2.27 mmol) as starting materials to afford the alcohol as a colorless viscous oily liquid (0.37g, 82%). The compound was purified by flash column chromatography (R_f = 0.42 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.34–7.23 (m, 5H), 7.18 (dd, J = 8.4, 7.5 Hz, 2H), 6.82 (t, J = 7.3 Hz, 1H), 6.77 (d, J = 7.7 Hz, 2h), 6.77 (d, J = 7.7 Hz, 1H), 5.05 (ddt, J = 20.7, 12.6, 6.3 Hz, 2H), 4.84 (dt, J = 6.5, 3.2 Hz, 1H), 3.16 (s, 1H), 2.79–2.71 (m, 2H), 1.25 (dd, J = 6.3, 1.9 Hz, 6h), 1.06 (dd, J = 11.3, 6.3 Hz, 6H). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 169.0, 168.9, 144.3, 144.1, 129.1, 128.3, 127.3, 125.5, 119.6, 115.6, 70.5, 70.2, 67.9, 41.7, 21.5, 21.3, 21.25, 21.22. HRMS (eSI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₃₀NO₅ 400.2118, found 400.2120. HPLC analysis: Chiralpak IC, 14% IP/hexanes, continuous flow at 0.4 mL/min, 250 nm; t_major = 14.8 min, t_minor = 16.3 min, ee 97%, er 98.4:1.6; [α]_D²⁰ = +26.2 (c = 1, CHCl₃).

Diisopropyl (R)-2-(benzo[d][1,3]dioxol-5-ylamino)-2-(2-(furan-2- yl)-2-hydroxyethyl)malonate (28i).

The general procedure was followed using 27i (0.53 g, 1.24 mmol), (S)-(–)-2-methyl-CBS-oxazaborolidine solution (1 M solution in toluene) (0.18 mL, 0.18 mmol), and BH₃·DMS solution (2 M solution in THF) (1.24 mL, 2.48 mmol) as starting materials to afford the alcohol as a pale yellow wax (0.39g, 77%). The compound was purified by flash column chromatography (R_f= 0.26 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.33 (dd, J = 1.8, 0.9 Hz, 1H), 6.59 (d, J = 8.3 Hz, 1H), 6.38 (d, J = 2.3 Hz, 1H), 6.29 (dd, J = 3.1, 1.8 Hz, 1h), 6.24–6.16 (m, 2H), 5.83 (s, 2H), 5.14 (s, 1H), 5.00 (ddt, J = 15.7, 12.5, 6.3 Hz, 2H), 4.88 (dd, J = 10.0, 2.6 Hz, 1H), 3.35 (s, 1H), 2.88–2.74 (m, 2h), 1.21 (d, J = 6.4 Hz, 6H), 1.08 (dd, J = 16.5, 6.3 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 168.8, 168.7, 155.9, 148.0, 141.8, 141.4, 139.0, 110.0, 108.6, 108.2, 105.6, 100.7, 99.6, 70.2, 70.1, 68.1, 64.3, 37.9, 21.36, 21.30, 21.27, 21.25. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₈NO₈ 434.1809, found 434.1811. HPLC analysis: Chiralpak IB, 20% IP/hexanes, continuous flow at 0.8 mL/min, 250 nm; t_major =14.1 min, t_minor = 10.3 min, ee 92%, er 4:96; [α]_D²⁰ = +12.0 (c = 1, CHCl₃).

Diisopropyl-(R)-2-((4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)amino)-2-(2-(furan-2-yl)-2-hydroxyethyl)malonate (28j).

The general procedure was followed using 27j (0.55 g, 1.00 mmol), (S)-(–)-2-methyl-CBS-oxazaborolidine solution (1M solution in toluene) (0.15 mL, 0.15 mmol) and BH₃·DMS solution (2M solution in THF) (1.00 mL, 2.01 mmol) as starting materials to afford the alcohol as a colorless viscous oily liquid (0.40g, 73%). Compound was purified by flash column chromatography (R_f = 0.37 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.33 (s, 1H), 6.98 (d, J = 8.1 Hz, 2H), 6.66 (d, J = 8.1 Hz, 2H), 6.32–6.28 (m, 1H), 6.22 (d, J = 2.9 Hz, 1H), 5.28 (s, 1H), 5.01 (pd, J = 6.1, 2.1 Hz, 2H), 4.90–4.85 (m, 1H), 3.70 (t, J = 7.1 Hz, 2H), 3.03 (s, 1H), 2.94–2.83 (m, 2H), 2.69 (t, J = 7.1 Hz, 2H), 1.22 (dd, J = 10.3, 6.3 Hz, 6H), 1.05 (dd, J = 28.9, 6.2 Hz, 6H), 0.86 (s, 9H), −0.03 (s, 6H). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 169.0, 168.9, 155.9, 142.4, 141.8, 130.2, 129.7, 115.7, 110.0, 105.7, 70.3, 70.1, 67.5, 64.7, 64.3, 38.6, 37.9, 25.8, 21.4, 21.3, 21.26, 21.25, 18.2, −5.4. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₉H₄₆NO₇Si 548.3038; found 548.3040. HPLC Analysis: Chiralpak IC, 20% IP/hexanes, continuous flow at 0.5mL/min, 250 nm; t_major = 13.7 min, t_minor = 8.4 min, ee 94%, er 3:97; [α]_D²⁰ = +1.5 (C = 1, CHCl₃).

Diisopropyl-(R)-2-(benzo[d][1,3]dioxol-5-ylamino)-2-(2-hydroxy-2-(thiophen-2-yl)ethyl)malonate (28k).

The general procedure was followed using 27k (0.51 g, 1.15 mmol), (S)-(–)-2-methyl-CBS-oxazaborolidine solution (1M solution in toluene) (0.17 mL, 0.17 mmol) and BH₃·DMS solution (2M solution in THF) (1.15 mL, 2.31 mmol) as starting materials to afford the alcohol as a dark brown colored foamy gummy substance (0.39g, 75%). Compound was purified by flash column chromatography (R_f = 0.32 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.22 (dd, J = 5.0, 1.2 Hz, 1H), 6.95 (dd, J = 5.0, 3.5 Hz, 1H), 6.91 (d, J = 3.4 Hz, 1H), 6.62 (d, J = 8.3 Hz, 1H), 6.43 (d, J = 2.3 Hz, 1H), 6.24 (dd, J = 8.3, 2.3 Hz, 1H), 5.86 (s, 2H), 5.16 (s, 1H), 5.12–5.04 (m, 2H), 4.99 (hept, J = 6.2 Hz, 1H), 3.71 (s, 1H), 2.86–2.75 (m, 2H), 1.25 (d, J = 6.3 Hz, 3H), 1.22 (d, J = 6.3 Hz, 3H), 1.12 (d, J = 6.3 Hz, 3H), 1.08 (d, J = 6.3 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 168.8, 168.4, 148.1, 148.0, 141.7, 138.8, 126.5, 124.3, 122.9, 109.1, 108.3, 100.8, 99.9, 70.3, 70.2, 68.6, 67.0, 41.7, 21.5, 21.37, 21.33. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₂H₂₈NO₇S 450.1581; found 450.1581. HPLC Analysis: Chiralpak IC, 20% IP/hexanes, continuous flow at 0.8mL/min, 250 nm; t_major = 12.3 min, t_minor = 10.6 min, ee 90%, er 5:95; [α]_D²⁰ = +20.3 (C = 1, CHCl₃).

Diisopropyl (R)-2-(2-(4-bromophenyl)-2-hydroxyethyl)-2-(pyridin-3-ylamino)malonate (28l).

The general procedure was followed using 27l (0.53 g, 1.11 mmol), (S)-(–)-2-methyl-CBS-oxazaborolidine solution (1 M solution in toluene) (0.16 mL, 0.16 mmol), and BH₃·DMS solution (2 M solution in THF) (1.11 mL, 2.22 mmol) as starting materials to afford the alcohol as a white foamy solid (0.37g, 69%). The compound was purified by flash column chromatography (R_f = 0.30 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 8.04 (s, 1H), 7.91 (d, J = 5.2 Hz, 1H), 7.38 (d, J =8.1 Hz, 2H), 7.19 (dd, J =8.1, 5.7 Hz, 1H), 7.06 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 8.2 Hz, 1H), 6.00 (s, 1H), 5.11 (hept, J = 6.3 Hz, 1H), 5.02 (hept, J = 6.4 Hz, 1H),4.69 (d, J = 9.5 Hz, ¹H), 2.70–2.48 (m, 4H), 1.29 (d, J = 6.2 Hz, 3H), 1.20 (t, J = 6.3 Hz, 6h), 1.06 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 168.3, 167.6, 142.6, 142.1, 136.9, 134.5, 131.5, 127.1, 125.2, 121.8, 121.4, 71.3, 70.9, 69.4, 66.3, 40.4, 21.3, 21.29, 21.27. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₈BrN₂O₅ 479.1176, found 479.1173. HPLC analysis: Chiralpak ID, 90% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 11.1 min, t_minor = 9.8 min, ee 82%, er 9:91; [α]_D²⁰ = −14.7 (C = 1, CHCl₃).

Diisopropyl (R)-2-((4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1 phenyl)amino)-2-(2-hydroxy-2-(pyridin-4-yl)ethyl)malonate (28m).

The general procedure was followed using 27m (0.5 g, 0.89 mmol), (S)-(–)-2-methyl-CBS-oxazaborolidine solution (1 M solution in toluene) (0.13 mL, 0.13 mmol), and BH₃·DMS solution (2 M solution in THF) (0.9 mL, 1.8 mmol) as starting materials to afford the alcohol as a beige foamy solid (0.32g, 65%). The compound was purified by flash column chromatography (R_f = 0.20 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 8.44 (d, J = 6.3 Hz, 2H), 7.33 (d, J = 6.3 Hz, 2H), 7.01 (d, J = 8.3 Hz, 2H), 6.64 (d, J =8.3 Hz, 2H), 5.30 (s, 1H), 5.08 (hept, J = 6.2 Hz, 1H), 4.97 (hept, J = 6.2 Hz, 1H), 4.88 (d, J =10.2 Hz, 1H), 4.03 (s, 1H), 3.71 (t, J = 7.0 Hz, 2H), 2.69 (t, J = 6.9 Hz, 2H), 2.57 (dd, J = 15.2, 10.6 Hz, 2H), 1.25 (d, J = 6.3 Hz, 3H), 1.20 (d, J = 6.3 Hz, 3H), 1.08 (d, J = 6.3 Hz, 3H), 1.01 (d, J = 6.3 Hz, 3H), 0.85 (s, 9H), −0.03 (s, 6H). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 168.5, 168.3, 157.1, 147.1, 141.7, 131.2, 129.9, 121.9, 115.9, 70.65, 70.60, 68.8, 67.8, 64.4, 40.8, 38.5, 25.8, 21.5, 21.28, 21.21, 21.1, 18.2, −5.4. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₃₀H₄₇N₂O₆Si 559.3198, found 559.3197. HPLC analysis: Chiralpak IC, 15% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 16.2 min, t_minor = 18.2 min, ee 72%, er 86:14; [α]_D²⁰ = +5.5 (C = 1, CHCl₃).

General Procedure for the Synthesis of Racemic Alcohols from Ketone Adducts (Figure 7).

In a thick-walled flame-dried reaction vial, Mannich ketone adduct (1.0 equiv) was dissolved in anhydrous THF (0.2 M) under argon. Then BH₃·DMS solution (2 M solution in THF) (2.0 equiv) was added slowly dropwise to the reaction mixture at room temperature under constant stirring. Then the reaction mixture was heated to 50 °C and stirring was continued until the complete consumption of the starting material ketone. Then the reaction was cooled to 0 °C and quenched using saturated NH₄Cl solution or methanol (3 mL).

Workup and Purification.

After quenching, the reaction mixture was diluted with brine (10 mL) and the organic layer was separated. The aqueous layer was then extracted with EtOAc twice (2 × 20 mL), and the combined organic layers were washed with brine (20 mL) once, dried over anhydrous Na₂SO₄, and concentrated. The crude product was purified by automated flash column chromatography.

Diisopropyl 2-((1R,2R)-1-Hydroxy-1-phenylpropan-2-yl)-2-((4–1 methoxyphenyl)amino)malonate (28n).

The general procedure was followed using 27n (0.34 g, 0.77 mmol) and BH₃·DMS solution (2 M solution in THF) (0.78 mL, 1.55 mmol) as starting materials to afford the alcohol as a dark yellowish brown viscous oily liquid (0.21g, 61%). The reaction was finished in 3.5 h. The compound was purified by flash column chromatography (R_f = 0.39 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.33 (dt, J = 15.3, 7.6 Hz, 4H), 7.22 (t, J = 7.2 Hz, 1H), 6.81–6.74 (m, 4H), 5.51 (s, 1H), 5.10 (hept, J = 6.2 Hz, 2H), 4.96 (hept, J = 6.0 Hz, 1H), 3.74 (s, 3H), 3.37 (s, 1H), 2.86 (q, J = 7.0 Hz, 1H), 1.26 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.17 (d, J = 6.3 Hz, 3H), 0.94 (dd, J = 14.0, 6.7 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 169.9, 168.5, 153.9, 143.6, 138.4, 127.9, 126.6, 125.5, 118.7, 114.5, 72.3, 71.9, 70.5, 69.8, 55.6, 43.8, 21.5, 21.45, 21.40, 21.1, 7.5. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₅H₃₄NO₆ 444.2381, found 444.2386. HPLC analysis: racemic mixture.

Diisopropyl 2-((1R, 2R)-2-Hydroxycyclohexyl)-2-((4–1 methoxyphenyl)amino)malonate (28o).

The general procedure was followed using 27o (0.31 g, 0.77 mmol) and BH₃·DMS solution (2 M solution in THF) (0.77 mL, 1.54 mmol) as starting materials to afford the alcohol as a yellow viscous oily liquid (0.207g, 66%). The reaction was finished in 14 h. The compound was purified by flash column chromatography (R_f = 0.32 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 6.69 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 8.8 Hz, 2H), 5.03 (hept, J = 5.9 Hz, 1H), 5.03 (hept, J = 5.9 Hz, 2H), 4.26 (s, 1H), 3.69 (s, 3H), 3.10 (s, 1H), 2.50 (d, J = 11.7 Hz, 1H), 1.82 (q, J = 13.0 Hz, 3H), 1.65 (dq, J = 26.3, 12.7, 11.4 Hz, 2H), 1.36 (dt, J = 45.4, 13.8 Hz, 3H), 1.22 (d, J = 6.2 Hz, 3H), 1.14 (d, J = 6.2 Hz, 3H), 1.08 (d, J = 6.2 Hz, 3H), 0.91 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl3): δ 169.6, 168.8, 153.4, 138.7, 117.5, 114.3, 72.1, 70.1, 69.7, 66.6, 55.5, 45.7, 33.4, 26.4, 23.0, 21.4, 21.3, 21.2, 21.1, 19.6. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₃₄NO₆ 408.2381, found 408.2381. HPLC analysis: racemic mixture.

Diisopropyl 2-(Benzo[d][1,3]dioxol-5-ylamino)-2-((1S,2R)-1-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)malonate (28p).

The general procedure was followed using 27p (0.34 g, 0.72 mmol) and BH₃·DMS solution (2 M solution in THF) (0.72 mL, 1.45 mmol) as starting materials to afford the alcohol as a beige foamy solid (0.178g, 52%). The reaction was finished in 12 h. The compound was purified by flash column chromatography (R_f = 0.27 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.28 (d, J = 5.9 Hz, 1H), 7.24 (t, J = 6.9 Hz, 1H), 7.21–7.16 (m, 2H), 6.60 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 2.1 Hz, 1h), 6.19 (dd, J = 8.3, 2.1 Hz, 1H), 5.85 (d, J = 3.0 Hz, 2H), 5.25–5.14 (m, 2H), 5.09 (s, 1H), 5.00 (hept, J = 6.1, 5.6 Hz, 1H), 2.97 (qd, J = 16.8, 15.7, 7.7 Hz, 3h), 2.38 (s, 1h), 2.27 (d, J = 10.3 Hz, 1H), 2.15–2.04 (m, 1H), 1.33 (d, J = 6.2 Hz, 3H), 1.29 (d, J = 6.2 Hz, 3H), 1.21 (d, J = 6.2 Hz, 3H), 1.00 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 170.0, 168.3, 148.0, 140.9, 139.8, 137.8, 136.8, 130.3, 128.8, 128.0, 126.0, 108.3, 108.0, 100.6, 99.0, 70.76, 70.72, 69.5, 67.8, 44.6, 30.5, 21.6, 21.46, 21.40, 21.3, 20.6. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₆H₃₂NO₇ 470.2173, found 470.2172. HPLC analysis: racemic mixture.

General Procedure for the Cyclization of Chiral Alcohols to the Corresponding Azetidines and Tetrahydroquinolines (Figure 9).

This procedure was adopted from the literature procedure.^30,31 In a thick-walled, flame-dried reaction vial, chiral alcohol (1.0 equiv) was dissolved in anhydrous toluene (0.05 M) under argon. To this reaction mixture was added PPh₃ (2.2 equiv) in one portion followed by the addition of 2,4,5-tribromoimidazole (1.1 equiv) and continued stirring for 48 h or in general until the complete consumption of starting material by heating at 80 °C. After the complete consumption of starting material was confirmed, the heating was stopped and the reaction mixture was brought to room temperature.

Workup and Purification.

After the reaction mixture was brought to room temperature, the solids that were separated out were filtered and the solids were washed with ethyl acetate twice (2 × 5 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by automated flash column chromatography.

Note: For the substrates that we made, the reaction times ranged from 48 to 96 h.

Diisopropyl (R)-4-(4-Bromophenyl)-1-(3,5-dimethylphenyl)-azetidine-2,2-dicarboxylate (30c) and Diisopropyl (S)-4-(4-Bromophenyl)-5,7-dimethyl-3,4-dihydroquinoline-2,2(1H)-dicarboxylate (31c).

The general procedure was followed using 28c (0.20 g, 0.39 mmol), PPh₃ (0.23 g, 0.87 mmol), and 2,4,5-tribromoimidazole (0.13 g, 0.43 mmol) as starting materials to afford azetidine (30c) as a white wax (0.093 g) (R_f = 0.40 (10% EtOAc/hexane)) and tetrahydroquinoline (31c) as a pale yellow viscous oily liquid (0.048 g) (R_f = 0.35 (10% EtOAc/hexane)) in a ratio of 1.9:1 after isolation (0.14 g in total, 72%). The reaction was finished in 48 h. The compound was purified by column chromatography to separate azetidine and tetrahydroqinoline. Azetidine (30c). ¹H NMR (500 MHz, CDCl₃): δ 7.49 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 6.46 (s, 1H), 6.32 (s, 2H), 5.27 (hept, J = 6.2 Hz, 1H), 5.11 (t, J = 7.6 Hz, 1H), 5.03 (hept, J = 6.2 Hz, 1H), 3.14 (dd, J = 11.1, 8.4 Hz, 1H), 2.46 (dd, J = 11.2, 7.0 Hz, 1H), 2.17 (s, 6H), 1.36 (t, J = 6.1 Hz, 6H), 1.21 (d, J = 6.2 Hz, 3H), 1.07 (d, J = 6.3 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 169.6, 168.5, 147.0, 141.6, 138.0, 131.8, 127.5, 121.7, 121.4, 111.5, 72.0, 69.7, 69.2, 61.5, 36.3, 21.68, 21.66, 21.64, 21.48, 21.32. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₅H₃₁BrNO₄ 488.1431, found 488.1460. HPLC analysis: Chiralpak IE, 3% IP/hexanes, continuous flow at 0.4 mL/min, 250 nm; t_major = 13.5 min, t_minor = 12.9 min, ee 86%, er 7:93; [α]_D²⁰ = −23.8 (C = 1, CHCl₃).

Tetrahydroquinoline (31c).

¹H NMR (500 MHz, CDCl₃): δ 7.31 (d, J =8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2h), 6.49 (s, 1H), 6.42 (s, 1H), 5.02 (hept, J = 6.2 Hz, 1H), 4.76 (s, 1H), 4.43 (hept, J = 6.2 Hz, 1H), 4.21 (dd, J = 6.5, 4.2 Hz, 1H), 2.77–2.64 (m,2H), 2.24(s,3H), 1.79 (s, 3H), 1.21 (d, J = 6.3 Hz, 6H), 1.06 (d, J = 6.2 Hz, 3H), 0.83 (d, J = 6.3 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 169.5, 168.6, 143.3, 142.8, 137.4, 137.3, 131.1, 130.2, 122.2, 119.8, 116.9, 114.1, 69.8, 69.7, 63.2, 37.5, 35.1, 21.46, 21.42, 21.1, 21.0, 20.9, 19.4. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₅H₃₁BrNO₄ 488.1431, found 488.1455. HPLC analysis: Chiralpak IF, 5% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 15.7 min, t_minor = 16.5 min, ee 84%, er 92:8; [α]_D²⁰ = +65.6 (C = 1.04, CHCl₃).

Diisopropyl (R)-4-Phenyl-1-(3-(trifluoromethyl)phenyl)azetidine-2,2-dicarboxylate (30e).

The general procedure was followed using 28e (0.27 g, 0.58 mmol), PPh₃ (0.34 g, 1.29 mmol), and 2,4,5-tribromoimidazole (0.19 g, 0.64 mmol) as starting materials to afford only azetidine as a beige viscous oily liquid (0.084 g, 31%). In this reaction, the starting material was not totally consumed even after stirring at 80 °C for 62 h and at 100 °C for 34 h. The compound was purified by flash chromatography (R_f = 0.39 (10% EtOAc/hexanes). Azetidine (30e). ¹H NMR (600 MHz, CDCl₃): δ 7.47 (d, J = 7.3 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 7.14 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 7.7 Hz, 1H), 5.29 (hept, J = 6.2 Hz, 1H), 5.19 (t, J = 7.7 Hz, 1H), 5.04 (hept, J = 6.2 Hz, 1H), 3.15 (dd, J = 11.3, 8.4 Hz, 1H), 2.67 (dd, J =11.3, 7.1 Hz, 1H), 1.38 (dd, J = 6.2, 2.1 Hz, 6H), 1.21 (d, J = 6.3 Hz, 3H), 1.07 (d, J = 6.3 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 169.2, 168.2, 147.6, 141.4, 130.8 (q, ²J_CF = 31.8 Hz), 129.0, 128.9, 128.1, 125.9, 124.2 (q, ¹J_CF = 272.3 Hz), 116.5, 115.8 (q, ³J_CF = 3.7 Hz), 110.6 (q, ³J_CF = 3.7 Hz), 72.2, 70.3, 69.8, 62.7, 36.5, 21.61, 21.60, 21.5, 21.2. ¹⁹F NMR (471 MHz, CDCl₃): δ −61.86 (t, J = 0.8 Hz). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₂₇F₃NO₄ 450.1887, found 450.1889. HPLC analysis: Chiralpak IA, 2% IP/hexanes, continuous flow at 0.4 mL/min, 250 nm; t_major =11.4 min, t_minor = 10.7 min, ee 26%, er 37:63; [α]_D²⁰ = +4.0 (C = 1, CHCl₃).

Diisopropyl (R)-1-(3,5-dimethylphenyl)-4-(naphthalen-2-yl)-azetidine-2,2-dicarboxylate (30f) and Diisopropyl (S)-5,7-dimethyl-4-(naphthalen-2-yl)-3,4-dihydroquinoline-2,2(1H)-dicarboxylate (31f).

The general procedure was followed using 28f (0.10 g, 0.20 mmol), PPh₃ (0.12 g, 0.46 mmol), and 2,4,5-tribromoimidazole (0.070 g, 0.23 mmol) as starting materials to afford azetidine (30f) as a beige viscous oily liquid (0.018g) (R_f = 0.33 (10% EtOAc/hexanes) and tetrahydroquinoline (31f) as beige foam (0.051 g) (R_f = 0.28 (10% EtOAc/hexanes) in a ratio of 1:2.8 after isolation (0.070 g in total, 73%). Reaction took 48 h to finish. The compound was purified by column chromatography to separate azetidine and tetrahydroqinoline.

Azetidine (30f).

¹H NMR (600 MHz, CDCl₃): δ 7.93 (s, 1H), 7.85 (t, J = 8.7 Hz, 3H), 7.59 (d, J =8.3 Hz, 1H), 7.51–7.44 (m, 2H), 6.44 (s, 1H), 6.39 (s, 2H), 5.29 (dq, J =18.5, 6.9, 6.0 Hz, 2H), 5.06 (hept, J = 6.0 Hz, 1H), 3.20 (dd, J = 11.0, 8.5 Hz, 1H), 2.57 (dd, J = 11.2,7.1 Hz, 1H), 2.15 (s, 6H), 1.37 (dd, J = 15.0, 6.2 Hz, 6H), 1.23 (d, J = 6.2 Hz, 3H), 1.08 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 169.8, 168.8, 147.5, 140.1, 138.0, 133.4, 133.1, 128.6, 128.0, 127.7, 126.1, 125.8, 124.5, 123.8, 121.5, 111.6, 72.2, 69.7, 69.2, 62.4, 36.5, 21.76, 21.72, 21.5, 21.3. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₉H₃₄NO₄ 460.2482, found 460.2479. HPLC analysis: Chiralpak IE, 3% IP/hexanes, continuous flow at 0.4 mL/min, 250 nm; t_major = 17.4 min, t_minor = 16.0 min, ee 60%, er 20:80; [α]_D²⁰ = −14.7 (C = 1, CHCl₃).

Tetrahydroquinoline (31f).

¹H NMR (600 MHz, CDCl₃): δ 7.79–7.66 (m, 3H), 7.43–7.37 (m, 2H), 7.35 (s, 1H), 7.28 (d, J = 7.5 Hz, 1H), 6.56 (s, 1H), 6.45 (s, 1H), 5.04 (hept, J = 5.8 Hz, 1H), 4.83 (s, 1H), 4.43 (t, J =5.3 Hz, 1H), 4.13 (hept, J = 6.3 Hz, 1H), 2.87–2.78 (m, 2H), 2.29 (s, 3H), 1.81 (s, 3H), 1.22 (d, J = 6.2 Hz, 6H), 0.94 (d, J = 6.1 Hz, 3H), 0.48 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl3): δ 169.5, 168.8, 143.0, 141.7, 137.7, 137.1, 133.2, 132.1, 127.8, 127.7, 127.3, 126.89, 126.85, 125.7, 125.2, 122.2, 117.5, 114.1, 69.6, 69.5, 63.4, 38.3, 35.4, 21.45, 21.41, 21.0, 20.5, 19.6. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₉H₃₄NO₄ 460.2482, found 460.2486. HPLC analysis: Chiralpak IA, 20% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 15.8 min, t_minor = 9.6 min, ee 62%, er 19:81; [α]_D²⁰ = +66.8 (C = 1, CHCl₃).

Diisopropyl (R)-1,4-Diphenylazetidine-2,2-dicarboxylate (30h) and Diisopropyl (S)-4-Phenyl-3,4-dihydroquinoline-2,2(1H)-dicarboxylate (31h).

The general procedure was followed using 28h (0.10 g, 0.25 mmol), PPh₃ (0.144 g, 0.055 mmol) and 2,4,5-tribromoimidazole (0.084 g, 0.27 mmol) as starting materials to afford azetidine (30h) as beige viscous oily liquid (0.055g) (R_f = 0.4 (10% EtOAc/hexanes) and tetrahydroquinoline (31h) as yellow viscous oily liquid (0.013 g) (R_f = 0.34 (10% EtOAc/hexanes) in the ratio of 4.2:1 after isolation (0.070 g in total, 71%). Reaction took 48 h to finish. The compound was purified by column chromatography to separate azetidine and tetrahydroqinoline.

Azetidine (30h).

¹H NMR (500 MHz, CDCl₃): C-phenyl group: δ 7.46–7.49 (m, 2H, H-2/H-6), 7.34–7.38 (m, 2H, H-3/H-5), 7.26–7.31 (m, 1H, H-4); N-phenyl group: 7.08–7.13 (m, 2H, H-3′/H-5′), 6.75–6.79 (m, 1H, H-4′), 6.69–6.73 (m, 2H, H-2′/H-6′); isopropoxy group 1:5.26 (hept, J = 6.3 Hz, 1H, methine), 1.35 (d, 3H, methyl), 1.34 (d, 3H, methyl); isopropoxy group 2:5.00 (hept, J = 6.3 Hz, 1H, methine), 1.20 (d, J = 6.3 Hz, 3H, methyl), 0.99 (d, J = 6.3 Hz, 3H, methyl); 5.15 (dd, 1H, benzylicproton); 3.13 (dd, J = 11.3, 8.3 Hz, 1H, CH₂ proton cis to the benzylic proton); 2.56 (dd, J = 11.3,7.2 Hz, 1H, CH₂ proton cis to the adjacent phenyl group). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 169.80 (carbonyl); 168.71 (other carbonyl); 147.43 (quaternary aromatic); 142.29 (other quaternary aromatic); C-phenyl group: 128.80 (C-3/C-5), 127.84 (C-4), 125.97 (C-2/C-6) N-phenyl group: 128.52 (C-3′/C-5′), 119.50 (C-4′), 113.75 (C-2′/C-6′); 72.24 (quaternary aliphatic carbon); isopropoxy group 1:69.37 (methine), 21.71 (methyl correlating with methyl ¹H signal at δ 1.34 in HSQC spectrum), 21.66 (methyl correlating with methyl ¹H signal at δ 1.35 in HSQC spectrum); isopropoxy group 2:69.86 (methine), 21.71 (methyl correlating with methyl ¹H signal at δ 1.20 in HSQC spectrum), 21.34 (methyl correlating with methyl ¹H signal at δ0.99 in HSQC spectrum); 62.43 (benzylic CH), 36.54 (CH₂). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₂₈NO₄ 382.2013, found 382.2021. HPLC analysis: Chiralpak IA, 2% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 12.6 min, t_minor = 14.7 min, ee 82%, er 91:9; [α]_D²⁰ = +14.8 (C = 1, CHCl₃).

Tetrahydroquinoline (31h).

¹H NMR (500 MHz, CDCl₃): δ 7.33 (t, J = 7.4 Hz, 2H), 7.28–7.25 (m, 1H), 7.21 (d, J = 7.1 Hz, 2H), 7.03 (dt, J = 8.2,4.1 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 6.60 (q, J = 3.1, 1.9Hz, 2H), 5.6 (ddq, J = 31.0, 12.5, 6.3 Hz, 2H), 4.91 (s, 1H), 4.13 (dd, J = 11.9, 5.3 Hz, 1H), 2.84 (ddd, J = 13.4, 5.3, 1.5 Hz, 1H), 2.25 (dd, J = 13.3, 12.0 Hz, 1H), 1.38–1.12 (m, 12H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 169.7, 168.9, 144.2, 142.2, 129.0, 128.8, 128.5, 127.3, 126.7, 123.9, 118.4, 114.8, 70.0, 69.6, 64.8, 40.7, 35.6, 21.54, 21.52, 21.47, 21.43. HRMS (ESI-TOF) m/z: calcd for [M + H]⁺ C₂₃H₂₈NO₄ 382.2013, found 382.2034. HPLC analysis: Chiralpak IF, 3% IP/hexanes, continuous flow at 0.4 mL/min, 250 nm; t_major = 23.7 min, t_minor = 22.7 min, ee 80%, er 10:90; [α]_D²⁰ = +37.0 (C = 1, CHCI₃).

Determination of Stereochemistry of the Azetidines.

The stereochemistry of the two phenyl groups was established through a series of experiments. First, a COSY experiment (p. S174 enabled one set of three aromatic ¹H signals to be assigned to one phenyl group and the other set of three aromatic signals to be assigned to the other phenyl group. The single-intensity multiplets at δ 7.26–7.31 and δ 6.75–6.79 clearly resulted from the para protons, each of which exhibits a 3-contour pattern in the HSQC spectrum (at δ 127.84 and δ 119.50, respectively) from two (equal) ortho J couplings (p. S175). The two other three-contour patterns in the HSQC spectrum, at δ 128.80 and δ 128.52, result from two ortho J couplings and clearly are from the two pairs of phenyl C-3/C-5 carbons. The two 2-contour patterns in the HSQC spectrum, at δ 125.97 and δ 113.75, result from just one ortho J coupling and are clearly from the two pairs of phenyl C-2/C-6 carbons. The HSQC correlations thus establish that the signals at δ 7.46–7.49 result from one set of H-2/H-6 protons, that the signals at δ 6.69–6.73 result from the other set of H-2/H-6 protons, that the signals at δ 7.34–7.38 result from one set of H-3/H-5 protons, and that the signals at δ 7.08–7.13 result from the other set of H-3/H-5 protons.

With these secure assignments for the phenyl protons closest to the azetidine ring, NOE experiments then enabled the proximity of these phenyl protons to each other and to the benzylic (δ 5.15) and CH₂ (δ 3.13 and δ 2.56) protons to be probed. The absence of any NOE between protons on different phenyl rings with a mixing time of 0.10 or 0.20 s (SI pp S176 and S177) strongly indicated that the two phenyl rings were not near each other, i.e., they had a trans orientation. If the rings were cis to each other, H-2/H-6 on one ring would be near H-2′/H-6′ on the other ring; H-3/H-5 on one ring would be near H-3′/H-5′ on the other ring; and strong NOE cross peaks would result, even at very short mixing times. A weak NOE between H-2/H-6 and H-2′/H-6′ is detected with a mixing time of 0.40 or 0.70 s (SI pp S178 and S179). Increasing the mixing time from 0.10 to 0.20 to 0.40 to 0.70 s results in a steadily increasing NOE between the H-2/H-6 protons at δ 7.46–7.49 and the CH₂ proton at δ 2.56. In contrast, the H-2′/H-6′ protons at δ 6.69–6.73 do not show an NOE with this CH₂ proton at any mixing time. Clearly, the CH₂ proton at δ 2.56 is cis to the adjacent C-phenyl group and trans to the more remote N-phenyl group.

Pictorial representation of NOE correlation in 30h:

General Procedure for the Cyclization of Chiral Alcohols to the Corresponding γ-Lactones (Figures 10 and 11).

Method A:

In a thick-walled flame-dried reaction vial, chiral alcohol (28) (1.0 equiv) was dissolved in anhydrous toluene (0.2 M) under argon. To this reaction mixture was added TsOH·H₂O (0.20 equiv) in one portion and stirring was continued for 1 h by heating to 70 °C. After confirming the complete consumption of starting material, the reaction was quenched using water (2 mL).

Note: This reaction can be heated to 110 °C and the reaction will be finished in less than 1 h without a change in the diastereoselectivity.

Workup and Purification.

After quenching, the reaction mixture was diluted with brine (3 mL), and the organic layer was separated. The aqueous layer was then extracted with EtOAc twice (2 × 10 mL), and the combined organic layers were washed with brine (10 mL) once, dried over anhydrous Na₂SO₄, and concentrated. The crude product was purified by automated flash column chromatography.

Method B:

In a thick-walled flame-dried reaction vial, chiral alcohol (1.0 equiv) was dissolved in anhydrous toluene (0.1 M) under argon. To this reaction mixture was added DBU (1 M solution in EtOAc) (1.1 equiv) dropwise and stirring was continued for 1 h at room temperature. After confirming the complete consumption of starting material, the reaction was quenched using water (2 mL).

Workup and Purification.

After quenching, the reaction mixture was diluted with brine (2 mL), and the organic layer was separated. The aqueous layer was then extracted with EtOAc twice (2 × 5 mL), and the combined organic layers were washed with brine (10 mL) once, dried over anhydrous Na₂SO₄, and concentrated. The crude product was purified by column chromatography.

Isopropyl (3S,5R) −2-Oxo-5-phenyl-3- (phenylamino)-tetrahydrofuran-3-carboxylate (24a) and Isopropyl (3R,5R)-2-Oxo-5-phenyl-3-(phenylamino)tetrahydrofuran-3-carboxylate (24b).

The general procedure (Method A) was followed using 28h (0.29 g, 0.72 mmol) and TsOH·H₂O (0.027 g, 0.14 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 2:1, by crude ¹HNMR) (0.21 g, 86%) which were separated by using flash column chromatography. 24a. Physical state: white solid (mp 79–81 °C). R_f = 0.52 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.45–7.39 (m, 4H), 7.39–7.35 (m, 1H), 7.18 (t, J = 7.9 Hz, 2H), 6.82 (t, J = 7.3 Hz, 1H), 6.64 (d, J = 8.0 Hz, 2H), 5.77 (dd, J =10.3, 6.1 Hz, 1H), 5.10–5.02 (m, 2H), 3.57 (dd, J = 13.1, 6.1 Hz, 1H), 2.59 (dd, J =13.0, 10.5 Hz, 1H), 1.27 (d, J =6.3 Hz, 3H), 1.02 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 171.9, 167.6, 144.2, 137.8, 129.2, 128.9, 128.8, 125.7, 119.6, 114.8, 80.1, 71.1, 67.2, 42.8, 21.4, 21.0. HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for C₂₀H₂₁NO₄Na 362.1363, found 362.1365. HPLC analysis: Chiralpak ID, 90% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 13.9 min, t_minor = 14.9 min, ee 94%, er 97:3; [α]_D²⁰ = −8.2 (C = 1, CHCl₃).

24b.

Physical state: white solid (mp 132–134 °C). R_f = 0.46 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.46–7.34 (m, 5H), 7.23 (t, J = 7.7 Hz, 2H), 6.88 (t, J = 7.3 Hz, 1H), 6.67 (d, J = 7.9 Hz, 2H), 5.71 (t, J =7.5 Hz, 1H), 5.01 (hept, J = 6.0 Hz, 1H), 4.81 (s, 1H), 3.14 (dd, J = 13.8, 8.1 Hz, 1H), 3.06(dd, J = 13.8, 7.0 Hz, 1H), 1.08 (dd, J = 19.6, 6.2 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 172.4, 168.2, 143.7, 138.8, 129.3, 128.6, 128.5, 125.4, 120.0, 115.6, 78.9, 71.0, 66.3, 39.4, 21.1, 21.0. HRMS (ESI-TOF) m/z: [M + Na]⁺ calcd for 1 C₂₀H₂₁NO₄Na 362.1363, found 362.1365. HPLC analysis: Chiralpak ID, 40% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 16.5 min, t_minor = 15.5 min, ee 90%, er 5:95; [α]_D²⁰ = −3.7 (C = 1, CHCl₃).

Isopropyl (3S,5R)-3-((4-Methoxyphenyl)amino)-2-oxo-5-phenyltetrahydrofuran-3-carboxylate (24c) and Isopropyl (3R,5R)-3-((4-Methoxypheny)amino)-2-oxo-5-phenyitetrahydrofuran-3-carboxylate (24d).

The general procedure (Method A) was followed using 28a (0.48 g, 1.11 mmol) and TsOH·H₂O (0.042 g, 0.22 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 2:1, by crude ¹HNMR) (0.40 g, 98%) which were separated by using flash column chromatography. 24c. Physical state: beige waxy solid; R_f = 0.41 (20% EtOAc/hexanes). ¹H NMR (500 MHz, CDCl₃): δ 7.33–7.42 (m, phenyl, 5H), 6.75 (m, AA′ part of AA′BB′ pattern, 2H, H-3′/H-5′), 6.63 (m, BB′ part of AA′BB′ pattern, 2H, H-2′/H-6′), 5.70 (dd, J = 10.4, 6.1 Hz, 1H, benzylic), 5.04 (hept, J = 6.3 Hz, 1H, isopropoxy methine), 4.77 (s, broad, NH), 3.72 (s, 3H, methoxy), 3.48 (dd, J = 13.0, 6.1 Hz, 1H, one H of CH₂), 2.55 (dd, J = 13.0, 10.4 Hz, 1H, other H of CH₂), 1.26 (d, J = 6.3 Hz, 3H, one isopropyl methyl), 1.04 (d, J = 6.2 Hz, 3H, other isopropyl methyl); ¹³C NMR{¹H} (126 MHz, CDCl₃): 172.3 (ring carbonyl), 167.9 (isopropoxy carbonyl), 153.9 (C-4′ of p-disubstituted aromatic ring), 138.0 (phenyl C-1), 137.8 (C-1′ of p-disubstituted aromatic ring), 129.0 (phenyl C-4, J_CH = 161.3 Hz), 128.9 (phenyl C-3/C-5, J_CH ≈ 161.3 Hz), 125.9 (phenyl C-2/C-6, J_CH = 158.6 Hz), 117.4 (C-2′/C-6′ of p-disubstituted aromatic ring, J_CH = 157.5 Hz), 114.7 (C-3′/C-5′ of p-disubstituted aromatic ring, J_CH = 159.8 Hz), 80.1 (benzylic CH, J_CH = 154.9 Hz), 71.2 (isopropyl CH, J_CH = 149.5 Hz), 68.1 (quaternary aliphatic carbon), 55.6 (methoxy, J_CH = 143.4 Hz), 42.8 (CH₂, J_CH = 139.3 Hz with ¹H at δ 3.48, J_CH = 134.8 Hz with ¹H at δ 2.55), 21.5 [isopropyl methyl (correlating with methyl ¹H signal at δ 1.26 in HSQC spectrum), J_CH = 127.1 Hz with ¹H at δ 1.26], 21.3 [other isopropyl methyl (correlating with methyl ¹H signal at δ 1.04 in HSQC spectrum), J_CH = 127.3 Hz with ¹H at δ 1.04]. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₄NO₅ 370.1649, found 370.1646; HPLC analysis: Chiralpak ID, 90% IP/hexanes, continuous flow at 0.7 mL/min, 250 nm; t_major = 12.6 min, t_minor = 13.8 min, ee 93%, er 96.5:3.5; [α]_D²⁰ = −6.5 (C =1, CHCI₃).

The evidence for C-attack by the initial enolate followed by formation of a 5-membered-ring lactone (rather than N-attack by the initial enolate followed by formation of a 6-membered-ring lactone) was the generation of a quaternary aliphatic carbon, as shown by the presence of a signal at δ 68.1 in the standard ¹³C spectrum (p. S190) and the absence of this signal in the DEPT-135 ¹³C spectrum (SI p S191) and in the DEPT-90 ¹³C spectrum (both optimized for ¹J_CH = 145 Hz). Additional confirmation that the signal at δ 68.1 resulted from a quaternary carbon was provided by the absence of this signal in DEPT-135 ¹³C spectra optimized for ¹J_CH =125 Hz and ¹J_CH =170 Hz and by the absence of a large ¹J_CH coupling for the signal at δ 68.1 in a ¹H-coupled ¹³C spectrum. (Just two small couplings, each ≈4.4 Hz, were observed, apparently from equal ²J_CH couplings with the adjacent CH₂ protons.) Detailed chemical shift assignments could be made through a combination of ¹H (SI p S189), ¹³C (with and without ¹H decoupling), DEPT-135 ¹³C, DEPT-90 ¹³C, NOE (SI pp S192–S195), HSQC (SI p S197), and HMBC (SI p S196) experiments (with key parameters the same as for 27n).

The stereochemistry of phenyl and H on the benzylic carbon relative to the substituents on the quaternary aliphatic carbon and relative to the two inequivalent CH₂ protons was established through NOE experiments with various mixing times (0.2, 0.3, 0.5, 0.7 s). An NOE experiment with a relatively short mixing time will minimize spin diffusion effects³² and thus enable a more secure identification of the interacting protons provided that cross peaks with sufficient signal-to-noise are generated. However, even with the longest mixing time, there is no NOE between any of the phenyl protons and an isopropyl methyl group, establishing that these protons are not near each other; similarly, there is no NOE between any of the phenyl protons and the more deshielded CH₂ proton (δ 3.48). In contrast, with the shortest mixing time, NOE is detected between phenyl protons and the more shielded CH₂ proton (δ 2.55), establishing their cis relationship, and between phenyl protons and the benzylic proton (δ 5.70). NOE is also detected between the methoxy protons (δ 3.72) and the aromatic protons at δ 6.75, while NOE is detected between the aromatic protons at δ 6.63 and NH and each of the CH₂ protons. These observations enabled secure assignments of the aromatic protons at δ 6.75 (H-3′/H-5′) and at δ 6.63 (H-2′/H-6′).

Pictorial representation of NOE correlation in 24c:

24d.

Physical state: beige waxy solid. R_f = 0.36 (20% EtOAc/hexanes). ¹H NMR (500 MHz, CDCl₃): δ 7.33–7.42 (m, phenyl, 5H), 6.81 (m, AA′ part of AA′BB′ pattern, 2H, H-3′/H-5′), 6.74 (m, BB′ part of AA′BB′ pattern, 2H, H-2′/H-6′), 5.56 (dd, J ≈ 7.7, 7.6 Hz, 1H, benzylic), 5.02 (hept, J = 6.3 Hz, 1H, isopropoxy methine), 4.50 (s, broad, NH), 3.76 (s, 3H, methoxy), 3.04 (dd, J ≈ 13.8, 7.7 Hz, 1H, one H of CH₂), 2.99 (dd, J ≈ 13.8, 7.6 Hz, 1H, other H of CH₂), 1.13 (d, J = 6.3 Hz, 3H, one isopropyl methyl), 1.12 (d, J = 6.3 Hz, 3H, other isopropyl methyl). ¹³C{¹H} NMR (126 MHz, CDCl₃): 172.9 (ring carbonyl), 168.6 (isopropoxy carbonyl), 154.7 (C-4′ of p-disubstituted aromatic ring), 138.8 (phenyl C-1), 136.9 (C-1′ of p-disubstituted aromatic ring), 128.7 (phenyl C-3/C-5), 128.6 (phenyl C-4), 125.6 (phenyl C-2/C-6), 119.6 (C-2′/C-6′ of p-disubstituted aromatic ring), 114.7 (C-3′/C-5′ of p-disubstituted aromatic ring), 79.1 (benzylic CH), 71.0 (isopropyl CH), 67.5 (quaternary aliphatic carbon), 55.6 (methoxy), 39.6 (CH₂), 21.34 [isopropyl methyl (correlating with methyl ¹H signal at δ 1.13 in HSQC spectrum)], 21.26 [other isopropyl methyl (correlating with methyl ¹H signal at δ 1.12 in HSQC spectrum)]. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₄NO₅ 370.1649, found 370.1648. HPLC analysis: Chiralpak ID, 90% IP/hexanes, continuous flow at 0.7 mL/min, 250 nm; t_major =11.0 min, t_minor = 13.9 min, ee 93%, er 3.4:96.6; [α]_D²⁰ = −3.7 (C = 1, CHCl₃).

The evidence for C-attack by the initial enolate followed by formation of a 5-membered-ring lactone (rather than N-attack by the initial enolate followed by formation of a 6-membered-ring lactone) was the generation of a quaternary aliphatic carbon, as shown by the presence of a signal at δ 67.5 in the standard ¹³C spectrum (SI p S199) and the absence of this signal in the DEPT-135 ¹³C spectrum (SI p S200) and in the DEPT-90 ¹³C spectrum (both optimized for ¹J_CH = 145 Hz). Detailed chemical shift assignments could be made through a combination of ¹H (SI p S198), ¹³C, DEPT-135 ¹³C, DEPT-90 ¹³C, NOE (SI p S201–S204), HSQC (SI p S206), and HMBC (SI p S205) experiments (with key parameters the same as for 27n).

The stereochemistry of phenyl and H on the benzylic carbon relative to the substituents on the quaternary aliphatic carbon and relative to the two inequivalent CH₂ protons was established through NOE experiments with various mixing times (0.2, 0.3, 0.5, 0.7 s). Compared to 24c, the critical difference for 24d is that with a mixing time of just 0.3 s, NOE is clearly detected between phenyl protons and an isopropyl methyl group, establishing that these protons can be near each other. With a mixing time of 0.3 s, NOE is also detected between phenyl protons and the more shielded CH₂ proton (δ 2.99), establishing their cis relationship, and between phenyl protons and the benzylic proton (δ 5.56). NOE is also detected between the methoxy protons (δ 3.76) and the aromatic protons at δ 6.81, while NOE is detected between the aromatic protons at δ 6.74 and NH and each of the more deshielded CH₂ protons. These observations enabled secure assignments of the aromatic protons at δ 6.81 (H-3′/H-5′) and at δ 6.74 (H-2′/H-6′).

Pictorial representation of NOE correlation in 24d:

Isopropyl (3S,5R)-3-((3,5-Dimethylphenyl)amino)-2-oxo-5-phenyltetrahydrofuran-3-carboxylate (24e) and Isopropyl (3R,5R)-3-((3,5-Dimethylphenyl)amino)-2-oxo-5-phenyltetrahydrofuran-3-carboxylate (24f).

The general procedure (method A) was followed using 28b (0.35 g, 0.82 mmol) and TsOH·H₂O (0.031 g, 0.16 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.2:1, by crude ¹HNMR) (0.26 g, 86%) which were separated by using flash column chromatography. 24e. Physical state: beige solid (mp 106–108 °C). R_f = 0.57 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.46–7.4] (m, 4H), 7.38 (ddd, J =8.5, 5T, 2.4 Hz, 1H), 6.48 (s, 1H), 6.28 (s, 2H), 5.78 (dd, J = 10.3, 6.3 Hz, 1H), 5.11 (hept, J = 6.2 Hz, 1H), 4.96(s, 1H), 3.49 (dd, J = 13.2, 6.3 Hz, 1H), 2.64 (dd, J = 13.2, 10.3 Hz, 1H), 2.23 (s, 6H), 1.31 (d, J = 6.3 Hz, 3H), 1.11 (d, J = 6.3 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 172.0, 167.7, 143.8, 138.7, 138.0, 128.8, 128.7, 125.6, 121.4, 112.8, 79.8, 71.7, 67.1, 42.2, 21.4, 21.2, 21.0. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₆NO₄ 368.1856, found 368.1859. HPLC analysis: Chiralpak ID, 90% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 12.9 min, t_minor = 15.5 min, ee 96%, er 97.8:2.2; [α]_D²⁰ = −6.7 (C = 1, CHCl₃). 24f. Physical state: pale yellow waxy solid; R_f = 0.52 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.47–7.41 (m, 4H), 7.39 (ddd, J = 8.5, 5.3, 2.1 Hz, 1H), 6.56 (s, 1H), 6.32 (s, 2H), 5.72 (t, J =7.6 Hz, 1H), 5.05 (hept, J = 6.3 Hz, 1H), 4.74 (s, 1H), 3.17 (dd, J = 13.8, 8.1 Hz, 1H), 3.08 (dd, J = 13.8, 7.1 Hz, 1H), 2.28 (s, 6H), 1.13 (dd, J = 16.4, 6.3 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 172.5, 168.3, 143.6, 138.9, 138.8, 128.6, 128.4, 125.4, 122.0, 113.6, 78.9, 70.9, 66.3, 39.5, 21.4, 21.1, 21.0. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₆NO₄ 368.1856, found 368.1859; HPLC analysis: Chiralpak ID, 90% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 14.5 min, t_minor = 12.8 min, ee 96%, er 2:98; [α]_D²⁰ = −3.3 (C = 1, CHCl₃).

Isopropyl (3S,5R)-3-(Benzo[d][1,3]dioxol-5-ylamino)-2-oxo-5-phenyltetrahydrofuran-3-carboxylate (24g) and Isopropyl (3R,5R)-3-(Benzo[d][1,3]dioxol-5-ylamino)-2-oxo-5-phenyltetrahydrofuran-3-carboxylate (24h).

The general procedure (method A) was followed using 28d (0.27 g, 0.61 mmol) and TsOH·H₂O (0.023 g, 0.12 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.8:1, by crude ¹HNMR) (0.206 g, 87%) which were separated by using flash column chromatography. 24g. Physical state: beige solid (mp 91–94 °C); R_f = 0.39 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.38 (td, J = 12.3, 10.2, 5.2 Hz, 5H), 6.62 (d, J = 8.3 Hz, 1H), 6.29 (d, J = 2.2 Hz, 1H), 6.07 (dd, J = 8.3, 2.2 Hz, 1H), 5.85 (s, 2H), 5.70 (dd, J = 10.3, 6.1 Hz, 1H), 5.06 (hept, J = 6.2 Hz, 1H), 4.79 (s, 1H), 3.49 (dd, J = 13.0, 6.1 Hz, 1H), 2.53 (dd, J = 13.0, 10.4 Hz, 1H), 1.27 (d, J =6.3 Hz, 3H), 1.09 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 172.0, 167.6, 148.3, 141.5, 139.3, 137.8, 128.9, 128.8, 125.7, 108.3, 107.5, 100.8, 98.8, 80.0, 71.1, 67.9, 42.8, 21.4, 21.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₂NO₆ 384.1442, found 384.1440. HPLC analysis: Chiralpak ID, 80% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 22.5 min, t_minor = 21.2 min, ee 96%, er 2:98; [α]_D²⁰ = −9.2 (C = 1, CHCl₃). 24h: Physical state: beige solid (mp 78–80 °C); R_f = 0.31 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.38 (dq, J = 14.5, 7.5 Hz, 5H), 6.67 (d, J =8.3 Hz, 1H), 6.38 (d, J = 2.1 Hz, 1H), 6.17 (dd, J = 8.3, 2.1 Hz, 1H), 5.90 (s, 2H), 5.61 (t, J = 7.6 Hz, 1H), 5.02 (hept, J = 6.2 Hz, 1H), 4.53 (s, 1H), 3.12–2.93 (m, 2H), 1.12 (d, J = 6.1 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 172.5, 168.3, 148.3, 142.3, 138.7, 138.4, 128.6, 128.5, 125.4, 109.7, 108.3, 100.9, 100.5, 78.9, 71.0, 67.2, 39.5, 21.2, 21.1. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₂NO₆ 384.1442, found 384.1441. HPLC analysis: Chiralpak ID, 80% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 18.6 min, t_minor = 20.02 min, ee 96%, er 98:2; [α]_D²⁰ = −4.0 (C = 1, CHCl₃).

Isopropyl (3S,5R)-2-Oxo-5-phenyl-3-((3-(trifluoromethyl)phenyl)-amino)tetrahydrofuran-3-carboxylate (24i) and Isopropyl (3R,5R)-2-Oxo-5-phenyl-3-((3-(trifluoromethyl)phenyl)amino)-tetrahydrofuran-3-carboxylate (24j).

The general procedure (method A) was followed using 28e (0.35 g, 0.76 mmol) and TsOH·H₂O (0.029 g, 0.15 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.7:1, by crude ¹HNMR) (0.285 g, 92%) which were separated by using flash column chromatography. 24i. Physical state: white solid (mp 79–81 °C). R_f = 0.50 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.45–7.35 (m, 5H), 7.31–7.23 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.83 (s, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.80 (dd, J = 10.3, 6.2 Hz, 1H), 5.25 (s, 1H), 5.09 (hept, J = 6.2 Hz, 1H), 3.55 (dd, J = 13.1, 6.2 Hz, 1H), 2.56 (dd, J = 13.0, 10.4Hz, 1H), 1.28 (d, J =6.3 Hz, 3H), 1.06 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 171.5, 167.2, 144.6, 137.6, 131.6 (q, ²J_CF = 32.0 Hz), 129.8, 129.0, 128.9, 125.7, 124.0 (q, ¹J_CF = 272.4 Hz), 117.9, 116.0 (q, ³J_CF = 3.8 Hz), 110.8 (q, ³J_CF = 3.8 Hz), 80.2, 71.6, 67.0, 42.6, 21.4, 21.0. ¹⁹F NMR (471 MHz, CDCl₃): δ −61.9 (S). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₁F₃NO₄ 408.1417, found 408.1420. HPLC analysis: Chiralpak ID, 10% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 15.8 min, t_minor = 14.8 min, ee 93%, er 3.6:96.4; [α]_D²⁰ = −7.2 (C = 1, CHCl ₃). 24j. Physical state: colorless viscous oily liquid. R_f =0.40 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.40 (dq, J = 13.3, 6.9 Hz, 5H), 7.31 (d, J = 7.9 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.87 (s, 1H), 6.82 (d, J =8.1 Hz, 1H), 5.74 (t, J = 7.5 Hz, 1H), 5.07–4.96 (m, 2H), 3.17–3.05 (m, 2H), 1.07 (dd, J = 14.4, 6.3 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 171.9, 167.8, 144.2, 138.5, 131.6 (q, ² J_CF = 32.0 Hz), 129.8, 128.8, 128.7, 125.4, 124.0 (q, ¹J_CF = 272.4 Hz), 118.2, 116.4 (q, ³J_CH = 3.9 Hz), 111.7 (q, ³J_CH = 3.9 Hz), 78.9, 71.4, 66.0, 39.7, 21.1, 21.0. ¹⁹F NMR (471 MHz, CDCl ₃): δ −61.9 (S). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₁H₂₁F₃NO₄ 408.1417, found 408.1420. HPLC analysis: Chiralpak ID, 15% IP/hexanes, continuous flow at 0.6 mL/min, 250 nm; t_major = 16.1 min, t_minor = 12.6 min, ee 93%, er 3.4:96.6; [α]_D²⁰ = −4.3 (C = 1, CHCl ₃).

Isopropyl (3S,5R)-3-((3,5-Dimethylphenyl)amino)-5-(naphthalen-2-yl)-2-oxotetrahydrofuran-3-carboxylate (24k) and Isopropyl (3R,5R)-3-((3,5-Dimethylphenyl)amino)-5-(naphthalen-2-yl)-2-oxo-tetrahydrofuran-3-carboxylate (24l).

The general procedure (method A) was followed using 28f (0.32 g, 0.66 mmol) and TsOH·H₂O (0.025 g, 0.13 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.8:1, by crude ¹HNMR) (0.25 g, 90%) which were separated by using flash column chromatography. 24k. Physical state: white foamy solid. R_f = 0.42 (15% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.93–7.89 (m, 2H), 7.87 (d, J = 6.3 Hz, 2H), 7.55–7.51 (m, 2H), 7.50 (d, J = 7.7 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 6.30 (s, 2H), 5.94 (dd, J = 10.1, 6.4 Hz, 1H), 5.13 (hept, J = 6.1 Hz, 1H), 4.99 (s, 1H), 3.55 (dd, J = 13.2, 6.3 Hz, 1H), 2.73 (dd, J = 13.1, 10.5 Hz, 1H), 2.22 (s, 6H), 1.34 (d, J = 6.2 Hz, 3H), 1.13 (d, J =6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 172.1, 167.8, 143.9, 138.8, 135.3, 133.3, 133.0, 128.9, 128.0, 127.7, 126.63, 126.60, 125.0, 122.9, 121.5, 112.9, 80.0, 71.2, 67.2, 42.2, 21.5, 21.3, 21.1. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₆H₂₈NO₄ 418.2013, found 418.2007. HPLC analysis: Chiralpak IB, 10% IP/hexanes, continuous flow at 0.4 mL/min, 230 nm; t_major = 19.3 min, t_minor = 22.9 min, ee 95%, er 97.3:2.6; [α]_D²⁰ = −14.2 (C = 1, CHCl₃). 24l. Physical state: brown viscous gummy liquid. R_f = 0.37 (15% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.92 (d, J = 8.5 Hz, 1H), 7.87 (t, J =10.0 Hz, 3H), 7.57–7.46 (m, 3H), 6.56 (s, 1H), 6.33 (s, 2H), 5.86 (t, J =7.5 Hz, 1H), 5.02 (hept, J = 6.4 Hz, 1H), 4.77 (s, 1H), 3.22 (dd, J = 13.7, 8.2 Hz, 1h), 3.15 (dd, J = 13.8, 7.1 Hz, 1H), 2.28 (s, 6H), 1.07 (d, J = 6.2 Hz, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 172.6, 168.3, 143.6, 138.9, 136.1, 133.1, 132.9, 128.7, 127.9, 127.6, 126.5, 126.4, 124.6, 122.8, 122.0, 113.7, 79.1, 70.9, 66.3, 39.4, 21.4, 21.1, 21.0. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₆H₂₈NO₄ 418.2013, found 418.2017. HPLC analysis: Chiralpak IC, 20% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 21.3 min, t_minor = 17.7 min, ee 95%, er 2.6:97.3; [α]_D²⁰ = −8.2 (C = 1, CHCl₃).

Isopropyl (3S,5R)-5-(Naphthalen-1-yl)-2-oxo-3-(p-tolylamino)-tetrahydrofuran-3-carboxylate (24m) and Isopropyl (3R,5R)-5-(Naphthalen-1-yl)-2-oxo-3-(p-tolylamino)tetrahydrofuran-3-carboxylate (24n).

The general procedure (method A) was followed using 28g (0.42 g, 0.90 mmol) and TsOH·H₂O (0.034 g, 0.18 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.7:1, by crude ¹HNMR) (0.333 g, 91%) which were separated by using flash column chromatography. 24m. Physical State: Yellow foamy gummy substance. R_f = 0.55 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 8.03 (d, J = 8.4Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.87 (d, J =8.2 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.54 (dt, J = 20.6, 7.6 Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 6.61 (d, J = 8.3 Hz, 2h), 6.56 (dd, J = 10.3, 6.0 Hz, 1H), 5.16 (hept, J = 6.2 Hz, 1H), 5.02 (s, 1H), 3.81 (dd, J = 13.1, 6.0 Hz, 1H), 2.68 (dd, J = 13.0, 10.6 Hz, 1H), 2.26 (s, 3H), 1.37 (d, J = 6.3 Hz, 3h), 1.13 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 171.9, 167.8, 141.6, 133.5, 129.64, 129.61, 129.0, 128.96, 128.91, 126.6, 125.9, 125.3, 122.2, 121.8, 115.2, 77.4, 71.1, 67.5, 42.2, 21.4, 21.1, 20.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₅H₂₆NO₄ 404.1856, found 404.1854. HPLC analysis: Chiralpak IB, 9% IP/hexanes, continuous flow at 0.4 mL/min, 230 nm; t_major = 21.8 min, t_minor = 20.4 min, ee 80%, er 9.7:90.3; [α]_D²⁰ = +4.3 (C = 1, CHCl₃). 24n. Physical State: Pink foamy gummy substance. R_f = 0.48 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.96–7.92 (m, 1H), 7.88 (d, J =8.1 Hz, 1H), 7.77–7.72 (m, 1H), 7.69 (d, J = 7.0 Hz, 1H), 7.58–7.50 (m, 3H), 7.08 (d, J = 7.9 Hz, 2H), 6.67 (d, J = 8.1 Hz, 2H), 6.39 (t, J = 7.3 Hz, 1H), 4.98 (hept, J = 6.3 Hz, 1H), 4.86 (s, 1H), 3.36 (dd, J = 13.7, 8.6 Hz, 1H), 3.09 (dd, J = 13.7, 6.3 Hz, 1H), 2.30 (s, 3H), 1.11 (d, J = 6.2 Hz, 3h), 1.03 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 173.0, 168.3, 141.3, 134.6, 133.8, 130.0, 129.7, 129.33, 129.30, 128.9, 126.7, 126.0, 125.3, 122.5, 122.2, 116.3, 76.8, 71.1, 66.3, 39.3, 21.35, 21.33, 20.58, 20.57. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₅H₂₆NO₄ 404.1856, found 404.1857. HPLC analysis: Chiralpak ID, 85% IP/hexanes, continuous flow at 0.6 mL/min, 250 nm; t_major = 13.4 min, t_minor = 12.6 min, ee 80%, er 10:90; [α]_D²⁰ = +0.8 (C = 1, CHCl₃).

Isopropyl (3S,5R)-5-(4-Bromophenyl)-3-((3,5-dimethylphenyl)-amino)-2-oxotetrahydrofuran-3-carboxylate (24o) and Isopropyl(3R,5R)-5-(4-Bromophenyl)-3-((3,5-dimethylphenyl)amino)-2-oxo-tetrahydrofuran-3-carboxylate (24p).

The general procedure (method A) was followed using 28c (0.37 g, 0.72 mmol) and TsOH·H₂O (0.027 g, 0.14 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.7:1, by crude ¹HNMR) (0.277 g, 85%) which were separated by using flash column chromatography. 24o. Physical state: white solid (mp 120–122 °C); R_f = 0.59 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.54 (d, J =8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 6.47 (s, 1H), 6.24 (s, 2H), 5.70 (dd, J = 10.2, 6.3 Hz, 1H), 5.08 (hept, J = 6.2 Hz, 1H), 4.92 (s, 1H), 3.48 (dd, J = 13.2, 6.3 Hz, 1H), 2.55 (dd, J = 13.2, 10.3 Hz, 1H), 2.21 (s, 6H), 1.29 (d, J = 6.3 Hz, 3H), 1.08 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 171.8, 167.6, 143.8, 138.8, 137.1, 131.9, 127.3, 122.8, 121.6, 112.9, 79.0, 71.2, 67.1, 42.1, 21.4, 21.3, 21.0. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₅BrNO₄ 446.0961, found 446.0961. HPLC analysis: Chiralpak ID, 90% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 14.4 min, t_minor = 17.3 min, ee 94%, er 97:3; [α]_D²⁰ = −12.2 (C = 1, CHCl₃). 24p. Physical state: beige solid (mp 145–148 °C); R_f = 0.54 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.54 (d, J = 8.4 Hz, 2H), 7.28 (d, J =8.4 Hz, 2H), 6.53 (s, 1H), 6.27 (s, 2H), 5.63 (t, J = 7.5 Hz, 1H), 5.02 (hept, J = 6.2 Hz, 1H), 4.69 (s, 1H), 3.13 (dd, J = 13.8, 8.2 Hz, 1H), 3.00 (dd, J = 13.8, 7.0 Hz, 1H), 2.24 (s, 6H), 1.12 (d, J = 6.3 Hz, 3H), 1.07 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 172.3, 168.2, 143.5, 138.9, 138.0, 131.8, 127.1, 122.4, 122.1, 113.6, 78.2, 71.1, 66.2, 39.4, 21.4, 21.2, 21.0. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₅BrNO₄ 446.0961, found 446.0965. HPLC analysis: Chiralpak ID, 90% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 13.8 min, t_minor = 12.4 min, ee 94%, er 3:97; [α]_D²⁰ = −5.2 (C = 1, CHCl₃).

Isopropyl (3S,5R)-3-(Benzo[d][1,3]dioxol-5-ylamino)-5-(furan-2-yl)-2-oxotetrahydrofuran-3-carboxylate (24q) and Isopropyl (3R,5R)-3-(Benzo[d][1,3]dioxol-5-ylamino)-5-(furan-2-yl)-2-oxotetrahydrofuran-3-carboxylate (24r).

The general procedure (method B) was followed using 28i (0.073 g, 0.16 mmol) and DBU (1 M solution in ethyl acetate) (0.185 mL, 0.18 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.2:1, by crude ¹HNMR) (0.054 g, 86%) which were separated by using flash column chromatography. 24q. Physical state: brown viscous oily liquid; R_f = 0.35 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.48 (d, J = 1.9 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 3.3 Hz, 1H), 6.41 (dd, J = 3.4, 1.8 Hz, 1H), 6.31 (d, J = 2.5 Hz, 1H), 6.08 (dd, J = 8.2, 2.4 Hz, 1H), 5.87 (s, 2H), 5.70 (dd, J = 10.5, 6.3 Hz, 1H), 5.06 (hept, J = 6.4 Hz, 1H), 4.81 (s, 1H), 3.27 (dd, J = 13.1, 6.3 Hz, 1H), 2.96 (dd, J = 13.1, 10.5 Hz, 1H), 1.27 (d, J =6.3 Hz, 3H), 1.10 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 171.3, 167.7, 149.0, 148.4, 144.1, 141.4, 139.1, 111.1, 110.7, 108.4, 107.2, 100.8, 98.5, 73.0, 71.3, 67.4, 37.8, 21.5, 21.3. HRMS (ESI-TOF) m/z: [M + h]⁺ calcd for C₁₉H₂₀NO₇ 374.1234. found 374.1234. HPLC analysis: Chiralpak IC, 20% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 24.7 min, t_minor = 26.8 min, ee 82%, er 91:9; [α]_D²⁰= −7.3 (C = 1, CHCl₃). 24r. Physical state: dark brown viscous oily liquid; R_f = 0.29 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.47 (d, J = 1.9 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.52 (d, J = 3.3 Hz, 1H), 6.43–6.35 (m, 2H), 6.18 (dd, J = 8.3, 2.3 Hz, 1H), 5.90 (s, 2H), 5.57 (t, J = 7.7 Hz, 1H), 5.07 (hept, J = 6.3 Hz, 1H), 4.48 (s, 1H), 3.35 (dd, J = 13.9, 7.7 Hz, 1H), 2.88 (dd, J = 13.9, 7.8 Hz, 1H), 1.25 (d, J = 6.3 Hz, 3H), 1.16 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 172.0, 168.2, 149.7, 148.3, 143.7, 142.5, 138.3, 110.7, 110.2, 110.1, 108.4, 101.0, 100.8, 72.6, 71.1, 67.2, 35.4, 21.5, 21.3. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₉H₂₀NO₇ 374.1234, found 374.1249. HPLC analysis: Chiralpak IC, 35% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 24.5 min, t_minor = 21.7 min, ee 86%, er 7:93; [α]_D²⁰ = −5.2 (C =1, CHCl₃).

Isopropyl (3S,5R)-3-((4-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-phenyl)amino)-5-(furan-2-yl)-2-oxotetrahydrofuran-3-carboxylate (24s) and Isopropyl (3R,5R)-3-((4-(2-((tert-Butyldimethylsilyl)oxy)-ethyl)phenyl)amino)-5-(furan-2-yl)-2-oxotetrahydrofuran-3-carboxylate (24t).

The general procedure (method B) was followed using 28j (0.211 g, 0.38 mmol) and DBU (1 M solution in ethyl acetate) (0.423 mL, 0.42 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.2:1, by crude ¹HNMR) (0.15 g, 80%) which were separated by using flash column chromatography. 24s. Physical state: pale yellow viscous oily liquid. R_f =0.58 (20% EtOAc/hexanes); ¹H NMR (600 MHz, CDCl₃): δ 7.48 (s, 1H), 7.04 (d, J = 8.1 Hz, 2H), 6.58 (d, J = 8.2 Hz, 2H), 6.54 (d, J = 2.9 Hz, 1H), 6.41 (s, 1H), 5.73 (dd, J = 10.4, 6.4 Hz, 1H), 5.05 (hept, J = 7.3, 6.6 Hz, 1H), 4.96 (s, 1H), 3.74 (t, J = 7.1 Hz, 2H), 3.28 (dd, J = 13.2, 6.3 Hz, 1H), 3.03–2.95 (m, 1H), 2.72 (t, J = 7.0 Hz, 2H), 1.27 (d, J = 6.2 Hz, 3H), 1.07 (d, J = 6.2 Hz, 3H), 0.88 (s, 9H), −0.00 (s, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 171.3, 167.8, 149.1, 144.1, 142.1, 130.2, 129.9, 114.8, 111.0, 110.7, 72.9, 71.3, 66.9, 64.7, 38.6, 37.6, 25.9, 21.4, 21.2, 18.3, −5.3, −5.4. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₆H₃₈NO₆Si 488.2463, found 488.2464. HPLC analysis: Chiralpak IB, 2% IP/hexanes, continuous flow at 0.4 mL/min, 230 nm; t_major = 19.4 min, t_minor = 20.9 min, ee 90%, er 95:5; [α]_D²⁰ = −5 (C = 1, CHCl₃). 24t. Physical state: pale yellow viscous oily liquid; R_f = 0.52 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.47 (s, 1H), 7.05 (d, J = 8.1 Hz, 2H), 6.61 (d, J = 8.2 Hz, 2H), 6.53 (d, J = 2.7 Hz, 1H), 6.41 (s, 1H), 5.63 (t, J = 7.6 Hz, 1H), 5.05 (hept, J =6.3 Hz, 1H), 4.65 (s, 1H), 3.74 (t, J = 7.0 Hz, 2H), 3.39 (dd, J = 13.8, 7.4 Hz, 1H), 2.93 (dd, J = 13.8, 8.0 Hz, 1H), 2.73 (t, J =6.9 Hz, 2H), 1.23 (d, J = 6.2 Hz, 3H), 1.11 (d, J = 6.2 Hz, 3H), 0.87 (s, 9H), −0.01 (s, 6H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 172.0, 168.2, 149.8, 143.6, 141.8, 131.3, 129.9, 116.3, 110.6, 110.0, 72.6, 71.0, 66.4, 64.6, 38.6, 35.3, 25.9. 21.4, 21.2, 18.3, −5.41. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₆H₃₈NO₆Si 488.2463, found 488.2465. HPLC analysis: Chiralpak ID, 15% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 18.5 min, t_minor = 17.2 min, ee 90%, er 5:95; [α]_D²⁰ = −4.3 (C = 1, CHCl ₃).

Isopropyl (3S,5R)-3-(benzo[d][1,3]dioxol-5-ylamino)-2-oxo-5-(thiophene-2-yl)tetrahydrofuran-3-carboxylate (24u) and Isopropyl (3R,5R)-3-(Benzo[d][1,3]dioxol-5-ylamino)-2-oxo-5-(thiophene-2-yl)tetrahydrofuran-3-carboxylate (24v).

The general procedure (method B) was followed using 28k (0.288 g, 0.64 mmol) and DBU (1 M solution in ethyl acetate) (0.704 mL, 0.70 mmol) as starting materials to afford the diastereomeric mixture of γ-lactones (diastereomeric ratio = 1.5:1, by crude ¹HNMR) (0.237 g, 95%) which were separated by using flash column chromatography. 24u. Physical state: yellow viscous oily liquid; R_f = 0.33 (20% EtOAc/hexanes); ¹H NMR (600 MHz, CDCl₃): δ 7.38 (d, J = 4.5 Hz, 1H), 7.17 (d, J = 3.2 Hz, 1H), 7.04–7.00 (m, 1H), 6.64 (d, J = 8.3 Hz, 1H), 6.30 (d, J = 2.2 Hz, 1H), 6.07 (dd, J = 8.3, 2.2 Hz, 1H), 5.93 (dd, J = 10.3, 6.1 Hz, 1H), 5.86 (s, 2H), 5.05 (hept, J = 6.2 Hz, 1H), 4.81 (s, 1H), 3.45 (dd, J = 13.1, 6.1 Hz, 1H), 2.74 (dd, J = 13.1, 10.5 Hz, 1H), 1.26 (d, J = 6.3 Hz, 3H), 1.09 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 171.2, 167.5, 148.3, 141.4, 139.9, 139.0, 127.2, 127.1, 127.0, 108.3, 107.3, 100.8, 98.7, 75.8, 71.2, 67.8, 42.1, 21.4, 21.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₉H₂₀NO₆S 390.1006, found 390.1011. HPLC analysis: Chiralpak IC, 25% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 21.1 min, t_minor = 24.9 min, ee92%, er 96:4; [α]_D²⁰ = −8.7 (C = 1, CHCL₃). 24v. Physical state: beige waxy solid; R_f = 0.25 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.37 (d, J = 4.9 Hz, 1H), 7.14 (d, J = 3.2 Hz, 1H), 7.03–7.00 (m, 1H), 6.67 (d, J =8.3 Hz, 1H), 6.38 (d, J = 2.0 Hz, 1H), 6.17 (dd, J = 8.2, 2.0 Hz, 1H), 5.89 (s, 2H), 5.80 (t, J = 7.6 Hz, 1H), 5.06 (hept, J = 6.2 Hz, 1H), 4.51 (s, 1H), 3.16 (dd, J = 13.9, 7.6 Hz, 1H), 3.05 (dd, J =13.9, 7.6 Hz, 1H), 1.21 (d, J = 6.3 Hz, 3H), 1.15 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl3): δ 171.8, 168.2, 148.3, 142.4, 140.8, 138.2, 126.9, 126.6, 126.4, 110.0, 108.3, 100.9, 100.7, 75.3, 71.1, 67.4, 39.3, 21.3, 21.1. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₉H₂₀NO₆S 390.1006, found 390.1008. HPLC analysis: Chiralpak IB, 40% IP/hexanes, continuous flow at 0.5 mL/min, 250 nm; t_major = 16.2 min, t_minor = 19.1 min, ee 90%, er 95:5; [α]_D²⁰ = −4.7 (C = 1, CHCl₃).

Isopropyl (3S,4S,5R)-3-((4-Methoxyphenyl)amino)-4-methyl-2-oxo-5-phenyltetrahydrofuran-3-carboxylate (24w).

The general procedure (method A) was followed using 28n (0.18 g, 0.40 mmol) and TsOH·H₂O(0.015 g, 0.08 mmol) as starting materials to afford the fully substituted γ-lactone as a single diastereomer 24w (0.13 g, 84%) which was purified by using flash column chromatography. Physical state: beige viscous gummy substance. R_f = 0.51 (20% EtOAc/hexanes). ¹H NMR (500 MHz, CDCl₃): δ 7.31–7.43 (m, phenyl, 5H), 6.75 (m, AA′ part of AA′BB′ pattern, 2H, H-3′/H-5′), 6.57 (m, BB′ part of AA′BB′ pattern, 2H, H-2′/H-6′), 6.00 (d, J = 5.2 Hz, 1H, benzylic H), 4.93 (hept, J = 6.3 Hz, 1H, isopropyl CH), 4.71 (s, broad, NH), 3.78 (qd, J = 7.5, 5.2 Hz, 1H, ring H-C−CH₃), 3.73 (s, 3H, methoxy), 1.19 (d, J = 6.3 Hz, 3H, isopropyl CH₃), 0.82 (d, J = 6.2 Hz, 3H, other isopropyl CH₃), 0.61 (d, J = 7.5 Hz, ring H−C−CH₃). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 172.1, 167.1, 153.3, 138.6, 135.5, 128.5, 128.0, 125.2, 115.1, 114.7, 82.5, 71.5, 70.7, 55.5, 43.8, 21.4, 21.0, 9.9. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₂₆NO₅ 384.1805, found 384.1808.

The stereochemistry of the methyl group on the 5-membered ring was established with two NOE experiments with very short mixing times [0.1 s (SI p S266) and 0.2 s (SI p S267)]. This methyl group is clearly cis to the adjacent phenyl substituent. With a mixing time of just 0.1 s:

• The benzylic proton (δ 6.00) has a significantly stronger NOE with the adjacent methine proton (δ 3.78) than with the adjacent methyl group (δ0.61).

• NH (δ 4.71) exhibits NOE with the adjacent methyl group (δ0.61) but not with the adjacent methine proton (δ 3.78).

• The protons on the monosubstituted phenyl ring (downfield of δ 7.3) exhibit a much stronger NOE with the adjacent methyl group (δ0.61) than with the adjacent methine proton (δ 3.78).

In addition, the very shielded nature of the methyl protons of ring H–C–CH₃ is consistent with these observations. With the monosubstituted phenyl ring and the ring methyl group cis to each other, the ring methyl group is nearly above the monosubstituted phenyl ring, which would be expected to result in a shielding effect.

NOE is also detected between the methoxy protons (δ 3.73) and the aromatic protons at δ 6.75 and between the NH proton (δ 4.71) and the aromatic protons at δ 6.57. These observations enabled secure assignments of the aromatic protons at δ 6.75 (H-3′/H-5′) and at δ 6.57 (H-2′/H-6′).

The same observations were made with a mixing time of 0.2 s.

Pictorial representation of NOE correlation in 24w:

Isopropyl (3R,3aR,7aR)-3-((4-Methoxyphenyl)amino)-2-oxoocta-hydrobenzofuran-3-carboxylate (24x).

The general procedure (method A) was followed using 28o (0.149 g, 0.36 mmol) and TsOH·H₂O (0.014 g, 0.07 mmol) as starting materials to afford the fully substituted γ-lactone as a single diastereomer 24x (0.12 g, 95%) which was purified by using flash column chromatography. Physical state: pale brown viscous oily liquid. R_f = 0.50 (20% EtOAc/hexanes). ¹H NMR (500 MHz, CDCl₃): δ 6.74 (m, AA′ part of AA′BB′ pattern, 2H, H-3′/H-5′), 6.57 (m, BB′ part of AA′BB′ pattern, 2H, H-2′/H-6′), 4.88 (m, 1H, bridgehead methine next to oxygen≡H-1), 4.87 (hept, J = 6.3 Hz, 1H, isopropyl methine), 4.57 (s, broad, NH), 3.73 (s, 3H, methoxy), 3.29–3.23 (m, 1H, bridgehead methine next to quaternary carbon≡H-2), 2.31–2.25 (m, 1H), 1.76–1.56 (overlapping m, 4H), 1.41–1.18 (overlapping m, 3H), 1.15 (d, J = 6.3 Hz, 3H, isopropyl methyl), 0.80 (d, J = 6.2 Hz, 3H, other isopropyl methyl). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 173.0 (carbonyl), 166.9 (carbonyl), 153.2 (C-4′), 139.0 (C-1′), 115.2 (C-2′/C-6′), 114.8 (C-3′/C-5′), 77.8 (C-1), 72.2 (quaternary aliphatic carbon), 70.4 (isopropyl CH), 55.7 (methoxy), 43.0 (C-2), 27.3 (C-6), 23.0 (C-4), 22.0 (C-3), 21.4 [isopropyl methyl (correlating with methyl ¹H signal at δ 1.15 in HSQC spectrum)], 21.1 [other isopropyl methyl (correlating with methyl ¹H signal at δ0.80 in HSQC spectrum)], 19.4 (C-5). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₉H₂₆NO₅ 348.1805, found 348.1804. As with 24y, the key issue for 24x was determining the stereochemistry of the fusion of the 6-and 5-membered rings, i.e., the relative orientation of H-1 and H-2. The severe overlap of the heptet from the isopropyl methine proton and the multiplet from the bridgehead methine proton next to oxygen (H-1) complicates the analysis. However, detailed chemical shift assignments could be made through a combination of ¹H (SI p S268), ¹³C (SI p S269), COSY (SI p S271), NOE (SI p S273–S276), and HSQC (SI p S272) experiments. Indeed, the pair of diastereotopic protons associated with each methylene carbon could be assigned as follows: C-3 CH₂ (next to bridgehead methine next to quaternary carbon): δ 1.65 and δ 1.27 with δ 22.0, C-4 CH2: δ 1.73 and δ 1.27 with δ 23.0, C-5 CH₂: δ 1.59 and δ 1.34 with δ 19.4, C-6 CH₂ (next to bridgehead methine next to oxygen): δ 2.28 and δ 1.66 with δ 27.3. NOE experiments with various mixing times (0.15, 0.30, 0.50 s) were used to establish the relative orientation of H-1 and H-2. With the shortest mixing time, prominent cross peaks were detected between the multiplet centered at δ 4.88 (H-1) and the multiplets centered at δ 3.26 (H-2) and δ 2.28 (one of the H-6 protons). These multiplets can be differentiated from the cross peaks between the heptet centered at δ 4.87 (isopropyl CH) and the doublets centered at δ 1.15 and δ0.80 (SI p S274). As with 24y, the prominent cross peak between H-1 and H-2 with a very short mixing time indicated cis ring fusion. NOE is also detected between the aromatic protons at δ 6.57 and each of H-2 and NH and between the methoxy protons (δ 3.73) and the aromatic protons at δ 6.74. These observations enabled secure assignments of the aromatic protons at δ 6.57 (H-2′/H-6′) and at δ 6.74 (H-3′/H-5′). NOE is not detected between H-2′/H-6′ and the more remote H-1, even with a mixing time of 0.50 s. In general, lengthening the mixing time increased the intensity of various cross peaks and simply reinforced the analysis.

The NOE experiments also exhibited a cross peak at δ 4.57/δ 1.27 indicating spatial proximity between the amine proton at δ 4.57 and methylene proton at δ 1.27. This is consistent with interaction between the amine proton and one of the H-3 protons; the cross peak becomes noticeably stronger as the mixing time is lengthened from 0.15 to 0.30 s to 0.50 s and is consistent with a cis relationship of the 3-CH₂ group and the −NH-C₆H₄-OCH₃ group. The absence of any cross peak between the amine proton and ring junction H-2 at the three mixing times is consistent with a trans relationship of ring junction H-2 and the −NH-C₆H₄-OCH₃ group.

Pictorial representation of NOE correlation in 24x:

Isopropyl (3R,3aR,9bS)-3-(Benzo[d][1,3]dioxol-5-ylamino)-2-oxo-2,3,3a,4,5,9b-hexahydronaphtho[1,2-b]furan-3-carboxylate (24y).

The general procedure (method A) was followed using 28p (0.134 g, 0.28 mmol) and TsOH·H₂O (0.011 g, 0.05 mmol) as starting materials to afford the fully substituted γ-lactone as a single diastereomer 24y (0.099 g, 85%) which was purified by using flash column chromatography. Physical state: white foam. R_f = 0.51 (20% EtOAc/hexanes). ¹H NMR (500 MHz, CDCl₃): δ 7.46 (m, 1H, H-5), 7.26–7.33 (m, 2H, H-7 and H-6), 7.18 (m, 1H, H-8), 6.65 (d, J =8.3 Hz, 1H, H-5′), 6.28 (d, J = 2.4 Hz, 1H, H-2′), 6.05 (dd, J = 8.3, 2.4 Hz, 1H, H-6′), 5.88 (d, J = 1.4 Hz, 1H, one H of-OCH₂O−), 5.87 (d, J = 1.4 Hz, 1H, other H of-OCH2O−), 5.78 (d, J = 5.0 Hz, 1H, H-4), 4.98 (hept, J = 6.3 Hz, 1H, isopropyl methine), 4.70 (s, broad, NH), 3.60 (ddd, J = 13.5, 5.0, 4.7 Hz, 1H, H-3), 2.72–2.86 (m, 2H, H-1ax, H-1eq), 1.86 (dddd, J ≈ 13.6, 4.7, 3.6, 3.6 Hz, 1H, H-2ax or H-2eq), 1.51 (dddd, J = 13.6, 13.6, 13.5, 4.7 Hz, 1H, H-2eq or H-2ax), 1.21 (d, J = 6.3 Hz, 3H, isopropyl methyl), 0.90 (d, J = 6.2 Hz, 3H, other isopropyl methyl). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 171.3, 167.2, 148.4, 140.9, 140.4, 137.9, 131.1, 130.0, 129.2, 128.6, 126.6, 108.5, 105.1, 100.7, 96.9, 78.0, 71.3, 70.7, 43.6, 27.8, 21.4, 21.1, 19.9. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₂₄NO₆ 410.1598, found 410.1599. The key issue was determining the stereochemistry of the fusion of the 6- and 5-membered rings, i.e., the relative orientation of H-4 and H-3. H-4 gave a distinctive, deshielded doublet at δ 5.78 (SI p S277). Detailed ¹H chemical shift assignments could be made through COSY (SI p S280) and NOE (p. S281–S285) experiments. In particular, COSY confirmed that only the multiplet at δ 3.60 correlated with H-4 and thus resulted from H-3. COSY indicated that H-3 also correlated with the protons at δ 1.86 and δ 1.51, thus confirming their assignments as H-2.

NOE experiments with various mixing times (0.15, 0.30, 0.50 s) were used to establish the relative orientation of H-4 and H-3. With the shortest mixing time, a cross peak was not detected between the signals at δ 5.78 (H-4) and the H-2 proton at δ 1.51; a weak cross peak was detected between H-4 and the other H-2 proton (at δ 1.86), which established their closer spatial proximity. A significantly stronger cross peak was detected between the signals at δ 5.78 (H-4) and δ 3.60 (H-3), which strongly suggested a cis relationship and thus cis ring fusion. With this very short mixing time, the cross peak between H-4 and H-3 was stronger than (1) the cross peak between H-4 and the signal at δ 7.46 (thus identified as H-5), (2) the cross peak between the other benzylic protons (H-1) and the signal at δ 7.18 (thus identified as H-8), (3) the cross peaks between H-3 and the signals at δ 6.28 and δ 6.05 (consistent with their assignments as H-2′ and H-6′ on the other aromatic ring on the basis of the magnitude of their J values), and (4) the cross peaks between NH and H-2′ and H-6′. Thus, the relatively strong cross peak between H-4 and H-3 with a very short mixing time indicated cis ring fusion. Lengthening the mixing time increased the intensity of various cross peaks and simply reinforced the analysis.

With mixing times of 0.30 and 0.50 s, very weak cross peaks were also observed between H-4 (δ 5.78) and each of the isopropyl methyl groups (δ 1.21 and δ 0.90) and between the 2-CH₂ protons (δ 1.86 and δ 1.51) and the amine NH (δ 4.70). These cross peaks were also observed with mixing times of 0.70 and 1.00 s. The cross peaks clearly indicate a cis relationship between H-4 and the isopropoxycarbonyl group and a cis relationship between 2-CH₂ and the -NH-C₆H₄–OCH₃ group.

Pictorial representation of NOE correlation in 24y:

General procedure for the synthesis of aziridine-2,2,3-triesters, Figure 12.

To a solution of methyl bromoacetate (2.0 equiv) in anhydrous THF (0.2 M) in a flame-dried reaction vial under argon was added LiHMDS (1 M solution in THF) (2.1 equiv) dropwise over 3 minutes via syringe at −41 °C. After stirring for 45 min, a solution of diisopropyl iminomalonate 25 (1.0 equiv) in anhydrous THF (0.2M) was added dropwise via syringe. After stirring for another 2 h at −41 °C and confirming the completion of the reaction by thin layer chromatography, the reaction was quenched with saturated aqueous NH₄Cl and warmed to room temperature. The reaction mixture was then diluted with brine (10 mL) and extracted with ethyl acetate thrice (3 × 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The crude product was purified by automated flash column chromatography to afford the N-aryl aziridine.

2,2-diisopropyl-3-methyl-(R)-1-phenylaziridine-2,2,3-tricarboxylate (33a).

The general procedure was followed using diisopropyl phenyl iminomalonate (0.3 g, 1.08 mmol), bromomethyl ester (0.206 mL, 2.16 mmol) and LiHMDS (1M solution in THF) (2.27 mL, 2.27 mmol) were used as starting materials to afford aziridine-2,2,3-triester as pale yellow colored viscous oily liquid (0.3 g, 79%). Compound was purified by flash chromatography (R_f = 0.45 (20% EtOAc/hexanes). ¹H NMR (500 MHz, CDCl₃): δ 7.22–7.26 (m, 2H, H-3/H-5), 7.02–7.06 (m, 1H, H-4), 6.95–6.98 (m, 2H, H-2/H-6), 5.22 (hept, J = 6.3 Hz, 1H, isopropyl CH), 4.86 (hept, J = 6.3 Hz, 1H, other isopropyl CH), 3.81 (s, 4H, methoxy and aziridine ring methine), 1.34 (d, J = 6.3 Hz, 3H, one isopropyl CH₃), 1.31 (d, J = 6.3 Hz, 3H, second isopropyl CH₃), 1.13 (d, J = 6.3 Hz, 3H, third isopropyl CH₃), 0.96 (d, J = 6.3 Hz, 3H, fourth isopropyl CH₃). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 166.9 (carbonyl), 163.7 (carbonyl), 162.6 (carbonyl), 146.1 (sp² C–N), 129.0 (C-2/C-6 or C-3/C-5), 124.1 (C-4), 119.5 (C-3/C-5 or C-2/C-6), 71.0 (isopropyl CH), 70.0 (other isopropyl CH), 53.1 (quaternary aliphatic), 52.8 (methoxy), 45.6 (aziridine ring CH), 21.6 (overlapping signals for two isopropyl CH₃), 21.5 (third isopropyl CH₃), 21.1 (fourth isopropyl CH₃). HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₈H₂₄NO₆ 350.1598; Found 350.1598.

The singlets for the methoxy protons and the aziridine ring proton completely overlap and give a sharp signal with a half-height linewidth of 0.63 Hz. Additional support for this assignment comes from ¹³C satellites exhibiting ¹J_CH values that are reasonable for these functional groups; the identification of these satellites is supported by the expected very small, negative, one-bond ¹³C vs. ¹²C isotope effect on the ¹H chemical shift [¹ΔH(¹³/¹²C)] that is also observed for each type of proton. One pair of satellites exhibits ¹J_CH = 148.0 Hz (consistent with methoxy) with ¹ΔH(¹³/¹²C) = −0.0025 ppm. A weaker pair of satellites exhibits ¹J_CH = 176.6 Hz (consistent with aziridine ring H) with ¹ΔH(¹³/¹²C) = −0.0020 ppm.

Comparing the standard and DEPT-135 ¹³C spectra provided a secure assignment of the quaternary aromatic carbon (δ 146.1) and of the quaternary aliphatic carbon (δ 53.1) in the aziridine ring (through the absence of these signals in the DEPT-135 ¹³C spectrum). Comparing the DEPT-135 and DEPT-90 ¹³C spectra provided a secure assignment of the methoxy carbon (δ 52.8) and aziridine ring methine carbon (δ 45.6), as the methoxy carbon signal appeared in only the DEPT-135 ¹³C spectrum while the aziridine ring methine carbon signal appeared in both spectra).

In principle, two isomers are possible: the phenyl group can be cis or trans to the aziridine ring methine proton. If both isomers are present and inversion about the nitrogen is very fast, just one set of signals (representing the average environment) will be present, as is observed with N-(p-methoxyphenyl)-2,2-dimethylaziridine above the coalescence temperature T_c of −26 °C.³³ In general, conjugation of the nitrogen lone pair with an aromatic ring system is known to decrease the barrier to inversion about nitrogen.^33–35 The electron-donating nature of the p-methoxy substituent (present in 33b) raises the barrier to inversion relative to an unsubstituted phenyl group (as is present in 33a); T_c = −49 °C for N-phenyl-2,2-dimethylaziridine.³³ The single pair of ¹H and ¹³C spectra of 33a does not indicate whether (1) cis and trans isomers are present with very fast inversion about the nitrogen or (2) just one isomer of 33a formed when the enolate reacted with the diisopropyl iminomalonate. However, one can reasonably conclude that slow inversion about the nitrogen is not occurring with a mixture of cis and trans isomers of 33a, as only one set of ¹³C signals and only one set of ¹H signals are observed. (This aspect will be further considered in the discussion of 33h.)

2,2-diisopropyl-3-methyl-(R)-1-(4-methoxyphenyl)aziridine-2,2,3-tricarboxylate (33b).

The general procedure was followed using diisopropyl p-methoxyphenyl iminomalonate (1 g, 3.25 mmol), bromomethyl ester (0.618 mL, 6.50 mmol) and LiHMDS (1 M solution in THF) (6.8 mL, 6.8 mmol) were used as starting materials to afford aziridine-2,2,3-triester as brown colored viscous oily liquid (0.758 g, 62%). The compound was purified by flash chromatography (R_f = 0.19 (20% EtOAc/hexanes). ¹H NMR (500 MHz, CDCl₃): δ 6.90 (m, AA′ part of AA′BB′ pattern, 2H), 6.77 (m, BB′ part of AA′BB′ pattern, 2H), 5.21 (hept, J = 6.3 Hz, 1H, isopropyl CH), 4.87 (hept, J = 6.3 Hz, 1H, other isopropyl CH), 3.80 (s, 3H, methoxy), 3.78 (s, 1H, aziridine ring CH), 3.75 (s, 3H, methoxy), 1.34 (d, J = 6.3 Hz, 3H, one isopropyl CH₃), 1.30 (d, J = 6.3 Hz, 3H, second isopropyl CH₃), 1.14 (d, J = 6.3 Hz, 3H, third isopropyl CH₃), 1.02 (d, J = 6.3 Hz, 3H, fourth isopropyl CH₃). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 167.0 (carbonyl), 163.8 (carbonyl), 162.6 (carbonyl), 156.4 (sp² C–O), 139.2 (sp² C–N), 120.5 (C-2/C-6 or C-/C-5), 114.2 (C-3/C-5 or C-2/C-6), 70.9 (isopropyl CH), 69.9 (other isopropyl CH), 55.4 (methoxy), 53.4 (quaternary aliphatic), 52.8 (methoxy), 45.8 (aziridine ring CH), 21.64 (isopropyl CH₃), 21.62 (second isopropyl CH₃), 21.5 (third isopropyl CH₃), 21.2 (fourth isopropyl CH₃). HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₉H₂₆NO₇ 380.1704; Found 380.1706.

Of the five N-aryl aziridines 33a–e, only 33b has two methoxy groups. The methoxy protons in 33a, 33c, 33d, and 33e give signals from δ 3.795–3.811 (dilute solutions in CDCl₃). Thus, it is reasonable to assign the singlet in 33b at δ 3.80 to the ester and the singlet at δ 3.75 to the ether.

As with 33a, the combination of standard, DEPT-135, and DEPT-90 ¹³C experiments provided a secure assignment of the quaternary aliphatic carbon (δ 53.4) in the aziridine ring, the aziridine ring methine carbon (δ 45.8), and the methoxy carbons (δ 55.4 and δ 52.8). The methoxy carbon signals can reasonably be assigned to the ether (δ 55.4) and ester (δ 52.8) functional groups in light of the signal for the ester in 33a, 33c, 33d, and 33e appearing at δ 52.8 or δ 52.9.

The single pair of ¹H and ¹³C spectra of 33b does not indicate whether (1) cis and trans isomers are present with very fast inversion about the nitrogen or (2) just one isomer of 33b formed when the enolate reacted with the diisopropyl iminomalonate. However, as with 33a, one can reasonably conclude that slow inversion about the nitrogen is not occurring with a mixture of cis and trans isomers of 33b, as only one set of ¹³C signals and only one set of ¹H signals are observed.

2,2-diisopropyl-3-methyl-(R)-1-(benzo[d][1,3]dioxol-5-yl)aziridine-2,2,3-tricarboxylate (33c).

The general procedure was followed using diisopropyl p-methoxyphenyl iminomalonate (0.45 g, 1.40 mmol), bromomethyl ester (0.266 mL, 2.80 mmol) and LiHMDS (1 M solution in THF) (2.9 mL, 2.94 mmol) were used as starting materials to afford aziridine-2,2,3-triester as brown colored viscous oily liquid (0.346 g, 63%). Compound was purified by flash chromatography (R_f = 0.23 (20% EtOAc/hexanes). ¹H NMR (500 MHz, CDCl₃): δ 6.66 (dd, ³J = 8.3 Hz, ⁵J ~ 0.3 Hz, 1H, H-5), 6.52 (dd, ⁴J = 2.3 Hz, ⁵J ~ 0.3 Hz, 1H, H-2), 6.41 (dd, ³J = 8.3 Hz, ⁴J = 2.3 Hz, 1H, H-6), 5.91 (AB quartet whose protons have virtually identical chemical shifts, J ~ 1.4 Hz, -OCH₂O–), 5.20 (hept, J = 6.3 Hz, 1H, isopropyl CH), 4.93 (hept, J = 6.3 Hz, 1H, other isopropyl CH), 3.79 (s, 3H, methoxy), 3.75 (s, 1H, aziridine ring CH), 1.33 (d, J = 6.3 Hz, 3H, one isopropyl CH₃), 1.30 (d, J = 6.3 Hz, 3H, second isopropyl CH₃), 1.17 (d, J = 6.2 Hz, 3H, third isopropyl CH₃), 1.08 (d, J = 6.3 Hz, 3H, fourth isopropyl CH₃). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 166.8 (methoxycarbonyl), 163.7 (isopropoxycarbonyl), 162.5 (other isopropoxycarbonyl), 148.0 (C-3 or C-4), 144.3 (C-4 or C-3), 140.8 (C-1), 111.8 (C-6), 108.1 (C-5), 101.5 (C-2), 101.3 (−OCH₂O–), 71.0 (isopropyl CH, correlating with methine ¹H signal at δ 4.93 in HSQC spectrum), 70.0 (other isopropyl CH, correlating with methine ¹H signal at δ 5.20 in HSQC spectrum), 53.4 (quaternary aliphatic), 52.8 (methoxy), 46.0 (aziridine ring CH), 21.65 (isopropyl CH₃, correlating with methyl ¹H signal at δ 1.17 in HSQC spectrum), 21.61 (second isopropyl CH₃, correlating with methyl ¹H signal at δ 1.30 in HSQC spectrum), 21.5 (third isopropyl CH₃, correlating with methyl ¹H signal at δ 1.33 in HSQC spectrum), 21.3 (fourth isopropyl CH₃, correlating with methyl ¹H signal at δ 1.08 in HSQC spectrum). HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₉H₂₄NO₈ 394.1496; Found 394.1489.

As with 33a, the combination of standard, DEPT-135, and DEPT-90 ¹³C experiments provided a secure assignment of the quaternary aliphatic carbon (δ 53.4) in the aziridine ring, the methoxy carbon (δ 52.8), and the aziridine ring methine carbon (δ 46.0). These experiments also provided a secure assignment of the -OCH₂O- carbon (δ 101.3), which has a chemical shift very similar to that of one of the aromatic CH carbons (δ 101.5).

In light of the unambiguous assignments for H-2, H-5, and H-6 in the 1D ¹H spectrum, the ¹H–¹³C HSQC spectrum immediately provided the C-2, C-5, and C-6 assignments. It also enabled pairwise ¹H/¹³C assignments for each of the two isopropyl CH groups and for each of the four isopropyl CH₃ groups (SI p S299–S304). The ¹H–¹³C HMBC spectrum (SI p S295) unambiguously differentiated the two quaternary aromatic carbons bonded to oxygen from the quaternary aromatic carbon bonded to nitrogen. Only the two more deshielded quaternary aromatic carbons (δ 148.0 and δ 144.3) correlate with the -OCH₂O- protons at δ 5.91, while only the most shielded quaternary aromatic carbon (δ 140.8) correlates with the aziridine ring methine proton at δ 3.75 (a ³J_ch correlation in each case; SI p S296). In addition, the HMBC experiment indicated that

• the methoxy ¹H signal at δ 3.79 correlated with the carbonyl signal at δ 166.8 (but not with either of the other carbonyl signals), which clearly established that the signal at δ 166.8 resulted from the methoxycarbonyl group (SI p S296).

• the more deshielded isopropyl methine ¹H signal at δ 5.20 correlated with the carbonyl signal at δ 163.7 (but not with either of the other carbonyl signals) and that the more shielded isopropyl methine ¹H signal at δ 4.93 correlated with the carbonyl signal at δ 162.5 (but not with either of the other carbonyl signals) (SI p S296). Each of these seven-contour cross peaks displays a very noticeable tilt resulting from the six ³J_hh couplings experienced by the methine proton.³⁶ Acquiring the spectrum under conditions of high digital resolution in the ¹³C dimension (0.074 ppm) enables the individual contours to be readily observed. The separation between contours in the ¹³C dimension = ³J_hh; the separation between contours in the ¹H dimension = ³J_ch. Tilted correlations are also observed for the correlations involving the isopropyl methyl carbons SI p S297). Similarly, the relatively large ³J_h-5,h-6 coupling enables tilted correlations to be observed for correlations involving H-5 and H-6.

• the two more deshielded isopropyl methyl doublets at δ 1.33 and δ 1.30 correlated with the more shielded isopropyl methine carbon at δ 70.0 (page S381) and that the two more shielded isopropyl methyl doublets at δ 1.17 and δ 1.08 correlated with the more deshielded isopropyl methine carbon at δ 71.0 (page S313) Tilted correlations are again observed, exhibiting ³J_hh in the ¹³C dimension and ²J_CH in the ¹H dimension.

The single pair of ¹H and ¹³C spectra of 33c does not indicate whether (1) cis and trans isomers are present with very fast inversion about the nitrogen or (2) just one isomer of 33c formed when the enolate reacted with the diisopropyl iminomalonate. However, as with 33a and 33b, one can reasonably conclude that slow inversion about the nitrogen is not occurring with a mixture of cis and trans isomers of 33c, as only one set of ¹³C signals and only one set of ¹H signals are observed.

2,2-diisopropyl-3-methyl-(R)-1-(4-bromophenyl)aziridine-2,2,3-tricarboxyiate (33d).

The general procedure was followed using diisopropyl p-bromophenyl iminomalonate (0.36 g, 1.01 mmol), bromomethyl ester (0.192 mL, 2.02 mmol) and LiHMDS (1 M solution in THF) (2.12 mL, 2.12 mmol) were used as starting materials to afford aziridine-2,2,3-triester as yellow viscous oily liquid (0.311 g, 72%). The compound was purified by flash chromatography (R_f = 0.32 (20% EtOAc/hexanes). ¹H NMR (500 MHz, CDCl₃): δ 7.36 (m, AA′ part of AA′BB′ pattern, 2H), 6.85 (m, BB′ part of AA′BB′ pattern, 2H), 5.21 (hept, J = 6.3 Hz, 1H, isopropyl CH), 4.90 (hept, J = 6.3 Hz, 1H, other isopropyl CH), 3.81 (s, 3H, methoxy), 3.75 (s, 1H, aziridine ring CH), 1.34 (d, J = 6.3 Hz, 3H, one isopropyl CH₃), 1.30 (d, J = 6.3 Hz, 3H, second isopropyl CH₃), 1.16 (d, J = 6.3 Hz, 3H, third isopropyl CH₃), 1.04 (d, J = 6.3 Hz, 3H, fourth isopropyl CH₃). ¹³C{¹H} NMR (126 MHz, CDO₃): δ 166.6 (carbonyl), 163.4 (carbonyl), 162.3 (carbonyl), 145.3 (sp² C–N), 132.0 (C-2/C-6 or C-3/C-5), 121.2 (C-3/C-5 or C-2/C-6), 116.9 (sp² C–Br), 71.3 (isopropyl CH), 70.2 (other isopropyl CH), 53.0 (quaternary aliphatic), 52.9 (methoxy), 45.7 (aziridine ring CH), 21.7 (isopropyl CH₃), 21.6 (second isopropyl CH₃), 21.5 (third isopropyl CH₃), 21.2 (fourth isopropyl CH₃). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₂₃BrNO₆ 428.0703, found 428.0705.

As with 33a and 33c the combination of standard, DEPT-135, and DEPT-90 ¹³C experiments provided a secure assignment of the quaternary aliphatic carbon (δ 53.0) in the aziridine ring, the methoxy carbon (δ 52.9), and the aziridine ring methine carbon (δ 45.7).

The single pair of ¹H and ¹³C spectra of 33d does not indicate whether (1) cis and trans isomers are present with very fast inversion about the nitrogen or (2) just one isomer of 33d formed when the enolate reacted with the diisopropyl iminomalonate. However, as with 33a–c, one can reasonably conclude that slow inversion about the nitrogen is not occurring with a mixture of cis and trans isomers of 33d, as only one set of ¹³C signals and only one set of ^LH signals are observed.

2.2-diisopropyl-3-methyl-(R)-1-(3-chlorophenyl)aziridine-2,2,3-tricarboxylate (33e).

The general procedure was followed using diisopropyl m-chlorophenyl iminomalonate (0.32 g, 1.02 mmol), bromomethyl ester (0.195 mL, 2.05 mmol) and LiHMDS (1 M. solution in THF) (2.1 mL, 2.15 mmol) were used as starting materials to afford aziridine-2,2,3-triester as pale yellow viscous oily liquid (0.297 g, 75%). The compound was purified by flash chromatography (R_f = 0.36 (20% EtOAc/hexanes). ¹H NMR (500 MHz, CDCl₃): δ 7.18 (ddd, ³J_h-5,h-4 = 8.0 Hz, ³J_h-5,h-6 = 8.0 Hz, ⁵J_H-5,H-2 ~ 0.3 Hz, 1H, H-5), 7.03 (ddd, ³J_h-4,h-5 = 8.0 Hz, ⁴J_H-4,H-2 = 2.0 Hz, ⁴J_H-4,H-6 ~ 0.95 Hz, 1H, H-4), 6.97 (ddd, ⁴J_H-2,H-4 = 2.0 Hz, ⁴J_H-2,H-6 = 2.0 Hz, ⁵J_H-2,H-5 ~ 0.3 Hz, 1H, H-2), 6.85 (ddd, ³J_H‑6,H‑5 = 8.1 Hz, ⁴J_H‑6,H‑2 = 2.2 Hz, ⁴J_H‑6,H‑4 ~ 0.93 Hz, 1H, H-6), 5.21 (hept, J = 6.3 Hz, 1H, isopropyl CH), 4.92 (hept, J = 6.3 Hz, 1H, other isopropyl CH), 3.81 (s, 3H, methoxy), 3.78 (s, 1H, aziridine ring CH), 1.34 (d, J = 6.3 Hz, 3H, one isopropyl CH₃), 1.31 (d, J = 6.3 Hz, 3H, second isopropyl CH₃), 1.17 (d, J = 6.3 Hz, 3H, third isopropyl CH₃), 1.05 (d, J = 6.3 Hz, 3H, fourth isopropyl CH₃).; ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 166.5 (carbonyl), 163.4 (carbonyl), 162.3 (carbonyl), 147.5 (sp² C–N), 134.6 (sp² C–Cl), 1 130.1 (C-5), 124.3 (C-4), 119.8 (C-2), 117.8 (C-6), 71.4 (isopropyl CH), 70.2 (other isopropyl CH), 53.0 (quaternary aliphatic), 52.9, (methoxy), 45.7 (aziridine ring CH), 21.64 (isopropyl CH3), 21.59 (second isopropyl CH₃), 21.49 (third isopropyl CH₃), 21.18 (fourth isopropyl CH₃). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₂₃ClNO₆ 384.1208, found 384.1211.

While H-2 and H-5 in the aromatic ring have distinctive coupling patterns, H-4 and H-6 have very similar coupling patterns and cannot be confidently differentiated just on the basis of chemical shift. However, literature ¹³C chemical shift data on 3-chloroaniline,³⁷ 3-chloro-N,N-1 dimethylaniline,³⁸ and a more elaborate 3-chloro-N,N-dialkylaniline³⁹ clearly show that C-6 is considerably more shielded than C-4 (with C-6 ranging from δ 113.9–110.4 vs C-4 ranging from δ 119.5–115.9), that C-2 is essentially in between (ranging from δ 115.8–112.0), and that C-5 is much more deshielded (ranging from δ 130.1–129.9). ¹H chemical shift data were also reported for 3-chloroaniline³⁷ and the elaborate derivative,³⁹ and in both cases, H-6 is more shielded than H-4, and H-5 is significantly more deshielded than either.

An HSQC experiment on 33e gave the following correlations for the four aromatic CH groups: δ_c130.1/δ_h7.18, δ_c124.3/δ_h7.03, δ_c119.8/δ_h6.97, and δ_c117.8/δ_h6.85 (page S326). The δ_c130.1/δ_h7.18 correlation clearly results from C-5/H-5. The δ_c119.8/δ_h6.97 correlation clearly results from C-2/H-2. In light of the literature chemical shift data,^37–39 the δ_c124.3/δ_h7.03 correlation can reasonably be assigned to C-4/H-4, and the δ_c117.8/δ_h6.85 correlation (the most shielded aromatic ¹³C and ¹H nuclei) can reasonably be assigned to C-6/H-6. Highly expanded plots of the correlations for the two isopropyl CH groups, the methoxy and aziridine CH groups, and the four isopropyl CH₃ groups are shown on pages S312–S314.

As with 33a, 33c and 33d, the combination of standard, DEPT-135, and DEPT-90 ¹³C experiments provided a secure assignment of the quaternary aliphatic carbon (δ 53.0) in the aziridine ring, the methoxy, carbon (δ 52.9), and the aziridine ring methine carbon (δ 45.7). In the standard ¹³C spectrum, two signals of different intensity appear for C–Cl (page S309), reflecting the ¹Δ¹³C(³⁷/³⁵Cl) isotope effect (4 ppb shielding upon replacement of ³⁵Cl with ³⁷Cl).^40,41

The single pair of ¹H and ¹³C spectra of 33e does not indicate whether (1) cis and trans isomers are present with very fast inversion about the nitrogen or (2) just one isomer of 33e formed when the enolate reacted with the diisopropyl iminomalonate. However, as with 33a–d, one can reasonably conclude that slow inversion about the nitrogen is not occurring with a mixture of cis and trans isomers of 33e, as only one set of ¹³C signals and only one set of ¹H signals are observed.

2,2-diisopropyl-3-methyl-(R)-1-phenethylaziridine-2,2,3-tricarboxylate (33f).

The general procedure was followed using diisopropyl Phenethyl iminomalonate (0.31 g, 1.01 mmol), bromomethyl ester (0.193 mL, 2.03 mmol) and LiHMDS (1 M solution in THF) (2.13 mL, 2.13 mmol) were used as starting materials to afford aziridine-2,2,3-triester as pale yellow colored viscous oily liquid (0.194 g, 51%). Compound was purified by flash chromatography (R_f = 0.29 (20% EtOAc/hexanes). ¹H NMR (500 MHz, CDCl₃): δ 7.29–7.16 (m, phenyl, 5H), 5.12 (hept, J = 6.3 Hz, 1H, isopropyl CH), 5.11 (hept, J = 6.3 Hz, 1H, other isopropyl CH), 3.70 (s, 3H, methoxy), 3.07 (s, 1H, aziridine ring CH), 3.06–2.99 (m, 3H, CH₂), 2.87–2.77 (m, 1H, CH₂), 1.29 (d, J = 6.3 Hz, 6H, overlapping doublets for two isopropyl CH₃), 1.27 (d, J = 6.2 Hz, 3H, third isopropyl CH₃), 1.22 (d, J = 6.3 Hz, 3H, fourth isopropyl CH₃). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 167.5 (carbonyl), 164.1 (carbonyl), 163.6 (carbonyl), 138.9 (C-1), 128.8 (C-2/C-6 or C-3/C-5), 128.4 (C-3/C-5 or C-2/C-6), 126.4 (C-4), 71.0 (isopropyl CH), 69.5 (other isopropyl CH), 53.1 (N–CH₂), 52.4 (methoxy), 51.8 (quaternary aliphatic), 47.8 (aziridine ring CH), 35.7 (phenyl C-CH₂), 21.73 (isopropyl CH₃), 21.55 (second isopropyl CH₃), 21.54 (third isopropyl CH₃), 21.49 (fourth isopropyl CH₃). HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₈NO₆ 378.1911; Found 378.1909.

As with 33a and 33c-e, the combination of standard, DEPT-135, and DEPT-90 ¹³C experiments provided a secure assignment of the quaternary aliphatic carbon (δ 51.8) in the aziridine ring, the methoxy carbon (δ 52.4), and the aziridine ring methine carbon (δ 47.8). The presence of inverted signals at δ 53.1 and δ 35.7 in the DEPT-135 ¹³C spectrum and their absence in the DEPT-90 ¹³C spectrum enabled their identification as CH₂ signals. Their large chemical shift difference allowed the N–CH₂ and phenyl C–CH₂ assignments to easily be made.

Inversion about the nitrogen is known to be much slower, in general, in N-alkylaziridines than in N-arylaziridines.

In contrast to the coalescence temperature T_c = −49 °C for N-phenyl-2,2-dimethylaziridine (15 vol % solution in CF₂Cl₂),³³ T_c = +60 °C for N-isopropyl-2,2-dimethylaziridine (1M in CDCl₃),⁴² and T_c = +76 °C for N-methyl-2,2-dimethylaziridine (1M in CDCl₃).⁴² Solvent has a noticeable effect, as the T_c values for N-isopropyl-2,2-dimethylaziridine and N-methyl-2,2-dimethylaziridine are significantly lower (+38 °C and +48 °C, respectively) in 1 M C₆H₁₂. The effect of substituents on the aziridine ring on the rate of inversion seems to vary widely with the nature of the N-substituent. Relatively little change in T_c occurs with N-phenyl (T_c = −40 °C for N-phenylaziridine in CS₂),³⁵ but a large increase in T_c occurs with N-methyl (T_c = +108 °C for N-methylaziridine, 1M in C₆H₁₂). We are not aware of any studies with several much bulkier C-substituents such as are in aziridines 33a-h and therefore do not know their effect on T_c.

T_c is the same within experimental error (+95 °C) for N-cyclohexylaziridine and N-(2-phenylethyl)aziridine.³⁴ Since the latter compound has the same N-substituent as in 33f, it seems reasonable to conclude that inversion about the nitrogen in 33f is slow at ambient temperature and that a set of signals for each isomer would be observed if both isomers of 33f were present. However, the ¹H and ¹³C spectra of 33f clearly exhibit signals for only one isomer. To confirm that only one isomer is present and undergoing slow inversion about the nitrogen, spectra would have to be obtained at much lower temperatures to determine if only one set of ¹H signals and only one set of ¹³C signals continue to be observed.

The N-alkyl substituent in 33f has a noticeable effect on the ¹H chemical shifts of the aziridine ring methine proton and the C-substituents on the aziridine ring and on the ¹³C chemical shifts of the aziridine ring carbons and their substituents, as shown in Table S7 (see SI page No. S25). Not surprisingly, the effect is most noticeable for the nuclei closest to the aziridine N: the two carbons in the aziridine ring and especially for the aziridine ring proton.

Even with the aziridine N-substituent apparently cis to one isopropoxycarbonyl group and trans to the other in 33f, the two isopropyl methine protons have nearly the same chemical shift. In contrast, the environments for the two isopropyl methine protons in N-arylaziridines 33a-e are noticeably different, as the isopropyl methine ¹H chemical shifts differ by 0.27–0.36 ppm in 33a-e. Still, it does not seem possible to rigorously conclude from the single pair of ¹H and ¹³C spectra for each of 33a-e whether (1) cis and trans isomers are present with very fast inversion about the nitrogen or (2) just one isomer formed when the enolate reacted with the diisopropyl iminomalonate.

The N-alkyl substituent also has a striking effect on some of the ¹³C linewidths. Four of the signals are much shorter because they are much broader: the most shielded carbonyl, the N–CH₂, the aziridine ring methine carbon, and the aziridine ring quaternary carbon (Table S8) (see SI Page No. S26). Indeed, significant signal averaging is required to clearly detect these signals above the baseline noise in the standard, DEPT-135, and DEPT-90 ¹³C experiments.

In 33f, the signal for the aziridine ring quaternary carbon is significantly sharper (ν_1/2 = 1.09 Hz) than the signals for the other two N–C carbons (ν_1/2= 4.6 and 6.5 Hz) but is still broader than every other signal except for the most shielded carbonyl (ν_1/2 = 2.7 Hz). In contrast, in 33a-e:

• the signal for the aziridine ring quaternary carbon is very sharp (ν_1/2 = 0.34−0.38 Hz, three times narrower than the corresponding signal in 33f),

• the signal for the quaternary aromatic carbon bonded to aziridine N is sharp (ν_1/2 = 0.55−0.62 Hz, seven times narrower than the corresponding signal in 33f),

• the signal for the aziridine ring methine carbon is almost as sharp (ν_1/2 = 0.75–0.81 Hz, eight times narrower than the corresponding signal in 33f), and

• the signal for the most shielded carbonyl carbon is very sharp (ν_1/2 = 0.34–0.37 Hz, seven times narrower than the corresponding signal in 33f).

Relaxation of the quadrupolar ¹⁴N appears to be significantly faster with the N-alkyl substituent in 33f than with any of the N-aryl substituents in 33a-33e.

2,2-diisopropyl-3-methyl-(R)-1-(1-(tert-butoxycarbonyl)-piperidin-4-yl)aziridine-2,2,3-tricarboxylate (33g).

The general procedure was followed using diisopropyl-1-(tert-butoxycarbonyl)-piperidin-4-yl iminomalonate (0.4 g, 1.04 mmol), bromomethyl ester (0.198 mL, 2.08 mmol) and LiHMDS (1M solution in THF) (2.18 mL, 2.18 mmol) were used as starting materials to afford aziridine-2,2,3-triester as pale yellow colored viscous oily liquid (0.183 g, 39%). Compound was purified by flash chromatography (R_f = 0.4 (30% EtOAc/hexanes). ¹H (500 MHz, CDCl₃): δ 5.12 (hept, J = 6.3 Hz, 1H, isopropyl CH), 5.10 (hept, J = 6.3 Hz, 1H, other isopropyl CH), 3.93 (br s, 2H, a CH₂ proton on each N–CH₂), 3.72 (s, 3H, methoxy), 3.22 (s, 1H, aziridine ring CH), 3.00 (m, 2H, a CH₂ proton on each N–CH₂), 2.61 (m, 1H, N–CH in 6-membered ring), 1.75–1.50 (m, 4H, –CH₂-CH–CH₂-), 1.45 (s, 9H, t-butoxy), 1.29 (d, J = 6.3 Hz, 3H, isopropyl CH₃), 1.28 (d, J = 6.3 Hz, 3H, second isopropyl CH₃), 1.26 (d, J = 6.3 Hz, 3H, third isopropyl CH₃), 1.22 (d, J = 6.3 Hz, 3H, fourth isopropyl CH₃). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 167.3 (carbonyl), 163.8 (carbonyl), 163.6 (carbonyl), 154.6 (N-Boc carbonyl), 79.2 (t-butoxy quaternary), 70.7 (isopropyl CH), 69.2 (other isopropyl CH), 55.9 (N–CH in 6-membered ring), 52.3 (methoxy), 51.8 (aziridine ring quaternary), 46.4 (aziridine ring CH), 41.6, 41.3, 40.7, and 40.5 (N–CH₂), 30.8 (CH-CH₂), 28.2 (t-butoxy methyl), 21.37 (isopropyl CH₃), 21.34 (second isopropyl CH₃), 21.32 (third isopropyl CH₃), 21.30 (fourth isopropyl CH₃). HRMS (ESI-TOF) m/z: [M + H]⁺ Calcd for C₂₂H₃₇N₂O₈ 457.2544; Found 457.2548.

As with 33a and 33c-f, the combination of standard, DEPT-135, and DEPT-90 ¹³C experiments provided a secure assignment of the t-butoxy quaternary carbon (δ 79.2) and the aziridine ring quaternary carbon (δ 51.8), the methoxy carbon (δ 52.3), and the 6-membered ring methine carbon (δ 55.9) and the aziridine ring methine carbon (δ 46.4). The presence of inverted signals at δ 41.6, 41.3, 40.7, 40.5, and 30.8 in the DEPT-135 ¹³C spectrum and their absence in the DEPT-90 ¹³C spectrum enabled their identification as CH₂ signals. The large chemical shift differences for signals with the same multiplicity allowed assignments for the pair of quaternary aliphatic carbons, the pair of ring methine carbons, and the pair of methylene carbons to easily be made.

The severe broadening of the CH₂ signals is obvious. We believe that the four broad signals near 41 ppm result from a combination of two factors: (1) inversion at nitrogen in the 6-membered ring occurring on a time scale comparable to the reciprocal of the frequency difference (in Hz) between the chemical shift of a given N–CH₂ in the conformer with t-Boc equatorial and the chemical shift of that N–CH₂ in the conformer with t-Boc axial (2) the presence of two diastereotopic N–CH₂ carbons because of the chiral center in the aziridine ring. For the two diastereotopic CH-CH₂ carbons, just one broad signal is observed at δ 30.8. The much higher sensitivity of the 600 MHz spectrometer’s cryoprobe optimized for ¹³C detection greatly facilitated detecting these extremely broad CH₂ signals.

The ¹³C signals that are so broad in 33f narrow by approximately a factor of two in 33g (Table S8) (see SI page No. S26). In light of the very slow inversion about nitrogen for N-cyclohexylaziridine,³⁴ it seems reasonable to conclude that inversion about the aziridine nitrogen in 33g is slow at ambient temperature and that a set of signals for each isomer would be observed if both isomers of 33g were present. However, as with 33f, the ¹H and ¹³C spectra of 33g clearly exhibit signals for only one isomer.

2,2-diisopropyl-3-methyl-(R)-1-cyclopentylaziridine-2,2,3-tricarboxylate (33h).

The general procedure was followed using diisopropyl cyclopentyl iminomalonate (0.27 g, 1.002 mmol), bromomethyl ester (0.190 mL, 2.005 mmol) and LiHMDS (1 M solution in THF) (2.11 mL, 2.10 mmol) were used as starting materials to afford aziridine-2,2,3-triester as colorless viscous oily liquid (0.15 g, 44%). The Compound was purified by flash chromatography (R_f = 0.15 (10% EtOAc/hexanes). ¹H (500 MHz, CDCl₃): δ 5.12 (hept, J = 6.3 Hz, 1H, isopropyl CH), 5.10 (hept, J = 6.3 Hz, 1H, other isopropyl CH), 3.72 (s, 3H, methoxy), 3.21 (s, 1H, aziridine ring CH), 2.94 (m, 1H, N–CH in 5-membered ring), 1.94–1.63 (m, 5H, ring CH₂ protons), 1.63–1.45 (m, 3H, ring CH₂ protons), 1.28 (d, J = 6.3 Hz, 3H, isopropyl CH₃), 1.270 (d, J = 6.3 Hz, 3H, second isopropyl CH₃), 1.268 (d, J = 6.3 Hz, 3H, third isopropyl CH₃), 1.21 (d, J = 6.3 Hz, 3H, fourth isopropyl CH₃). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 167.9 (methoxycarbonyl, ν_1/2 = 0.51 Hz), 164.3 (isopropoxycarbonyl, ν_1/2 = 0.47 Hz), 163.8 (other isopropoxycarbonyl, ν_1/2 = 0.93 Hz), 70.6 (isopropyl CH, ν_1/2 = 0.89 Hz, correlating with methine ¹H signal at δ 5.12 in HSQC spectrum), 69.3 (other isopropyl CH, ν_1/2 = 0.90 Hz, correlating with methine ¹H signal at δ 5.10 in HSQC spectrum), 62.5 (N–CH in 5-membered ring, ν_1/2 = 2.2 Hz), 52.8 (aziridine ring quaternary, ν_1/2 = 0.48 Hz), 52.4 (methoxy, ν_1/2 = 0.87 Hz), 47.8 (aziridine ring CH, ν_1/2 = 2.5 Hz), 32.7 (–CH₂-CH-CH₂-, ν_1/2 = 0.63 Hz), 32.3 (–CH₂-CH-CH₂-, ν_1/2 = 0.63 Hz), 24.6 (–CH₂-CH₂-CH-, ν_1/2 = 0.51 Hz), 24.5 (–CH-CH₂-CH₂-, ν_1/2 = 0.50 Hz), 21.59 (isopropyl CH₃, ν_1/2 = 0.63 Hz, correlating with methyl ¹H signal at δ 1.270 in HSQC spectrum), 21.553 (second isopropyl CH₃, correlating with methyl ¹H signal at δ 1.21 in HSQC spectrum), 21.548 (third isopropyl CH₃, correlating with methyl ¹H signal at δ 1.28 in HSQC spectrum), 21.49 (fourth isopropyl CH₃, ν_1/2 = 0.65 Hz, correlating with methyl ¹H signal at δ 1.268 in HSQC spectrum). HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₁₇H₂₈NO₆ 342.1911; Found 342.1936.

As with the other aziridines, the combination of standard, DEPT-135, and DEPT-90 ¹³C experiments differentiated among the CH₃, CH₂, CH, and quaternary carbons. A ¹H–¹³C HSQC experiment (SI p S325) provided secure assignments and critical additional information:

• The correlation at δ_H3.72/δ_C52.4 (SI p S326) clearly results from methoxy because the ¹H singlet at δ 3.72 results from three protons and because the ¹³C signal at δ 52.4 appears in a DEPT-135 ¹³C spectrum but is strongly attenuated in a DEPT-90 ¹³C spectrum.

• The correlation at δ_H3.21/δ_C47.8 (SI p S326) clearly results from the aziridine ring CH because the ¹H singlet at δ 3.21 results from one proton and because the ¹³C signal at δ 47.8 is strong in DEPT-135 and DEPT-90 ¹³C spectra.

• The correlation at δ_H2.94/δ_C62.5 (SI p S326) clearly results from the cyclopentyl ring CH because the ¹H multiplet at δ 2.94 results from one proton and because the ¹³C signal at δ 62.5 is strong in DEPT-135 and DEPT-90 ¹³C spectra.

• At each of the four different CH₂ ¹³C frequencies (δ 32.7, 32.3, 24.6, and 24.5), a different pattern of contours appears (SI p S327). Each CH₂ group is clearly different, consistent with the presence of two pairs of diastereotopic CH₂ groups because of the chiral center in the aziridine ring. The pattern is consistent with the relative intensities for the CH₂ signals in the ¹H spectrum: signals for five CH₂ protons downfield of δ 1.65 and signals for three CH₂ protons upfield of δ 1.65.

There are striking differences in the ¹³C spectra of 33g and 33h (SI p S319 and S322). First, the ¹³C signals that are relatively broad in 33f and narrow by about a factor of 2 in 33g continue to narrow in 33h (Table S9) (See SI p S11). The CH2 signals greatly sharpen in 33h and have half-height line widths comparable to many of the other signals. The two methylene carbons adjacent to the methine are diastereotopic because of the chiral center in the aziridine ring and give distinct signals at δ 32.7 and δ 32.3. The remaining two methylene carbons are diastereotopic for the same reason; because they are further from the chiral center, they exhibit a smaller chemical shift difference (δ 24.6 and δ 24.5).

An alternative explanation for these pairs of CH2 signals seems much less plausible—the presence of two diastereomers: one with the cyclopentyl group cis to the aziridine ring proton, the other with the cyclopentyl group trans to the aziridine ring proton, and very slow interconversion of the diastereomers (through inversion about nitrogen) because of the rigidity of the three-membered ring with an N-alkyl substituent. This explanation seems much less plausible because pairs of signals would then be expected for all carbons, which is clearly not observed. (A previous report⁴³ has clearly shown different ¹³C chemical shifts for a wide range of cis- and trans-N-alkyl-2,3- disubstituted aziridines).

Because of the aziridine ring quaternary carbon′s proximity to the N-substituent and the 3-methoxycarbonyl substituent and because of the extreme sensitivity of ¹³C chemical shifts to even remote changes in stereochemistry,⁴⁴ the chemical shift of the aziridine ring quaternary carbon should be particularly sensitive to the presence of cis and trans isomers. Because the signal for this carbon in 33h is very sharp (v_1/2 = 0.48 Hz with 0.20 Hz of line broadening applied), observing a pair of signals from the aziridine ring quaternary carbon in the two diastereomers—if they were present—should be particularly easy. Such a pair is not seen. Clearly, only one isomer of33h is present. Note that in N-aryl aziridines 33a-e, the signal for the aziridine ring quaternary carbon is even sharper (with v_1/2 ranging from 0.34 to 0.38 Hz), which would make observing a pair of signals even easier; however, each of 33a-e exhibits just one aziridine ring quaternary carbon signal. Again, as noted earlier, the single pair of ¹H and ¹³C spectra for each of 33a-e does not indicate whether (1) cis and trans isomers are present with very fast inversion about the nitrogen or (2) just one isomer of 33a-e formed when the enolate reacted with the diisopropyl iminomalonate.

The ¹H spectra support the presence of only one isomer for each of N-alkyl aziridines 33f-h, as just one methoxy singlet and just one aziridine ring methine ¹H singlet are observed (as is also the case for N-aryl aziridines 33a-e. In 33a, these singlets happen to coincide within our ability to measure.) Remarkably, the ¹H half-height line widths of the methoxycarbonyl and aziridine ring methine proton singlets are remarkably similar in 33a-h (Table S9) (see SI p S11); the modest broadening in 33g might result from the relatively slow inversion about nitrogen in the 6-membered ring. Still, it does not seem possible to rigorously conclude from the single pair of ¹H and ¹³C spectra for each of 33a-e whether (1) cis and trans isomers are present with very fast inversion about the nitrogen or (2) just one isomer formed when the enolate reacted with the diisopropyl iminomalonate.

We note that the much smaller chemical shift range in ¹H NMR and the presence of multiplets for the other signals make ¹H NMR a less sensitive probe for the presence of cis and trans isomers. Still, one could reasonably expect the chemical shift of the aziridine ring methine proton to be sensitive to whether it is cis or trans to the adjacent substituent on nitrogen. (For 33a, the probability of the cis and trans isomers both being present and both methoxy ¹H singlets and both aziridine ring methine ¹H singlets all occurring at the same frequency in the slow inversion limit seems extraordinarily low.) Indeed, ¹H spectra of N-substituted aziridines have been reported with different ¹H chemical shifts for the cis and trans isomers.⁴³

Thus, with only one diastereomer of 33h formed when the enolate reacted with the diisopropyl iminomalonate, determining the stereochemistry was the next goal. NOE experiments have been previously used to determine the relative orientation of substituents on N-substituted aziridines.^45–47 NOE experiments with mixing times of 0.6 and 1.0 s (SI p S328 and S329) clearly showed NOE between the aziridine ring proton at δ 3.21 and the cyclopentyl methine proton at δ 2.94. No cross peak was evident between the methoxy protons at δ 3.72 and the cyclopentyl methine proton at δ 2.94. These observations are consistent with the cyclopentyl ring cis to the aziridine ring proton and trans to the methoxycarbonyl group, which is clearly the sterically less hindered diastereomer.

A ¹H–¹³C HMBC experiment (SI p S324) indicated that

• the methoxy ¹H signal at δ 3.72 correlated with the carbonyl signal at δ 167.9 (but not with either of the other carbonyl signals), which clearly established that the signal at δ 167.9 resulted from the methoxycarbonyl group;

• the more deshielded isopropyl methine ¹H signal at δ 5.12 correlated with the carbonyl signal at δ 163.8 (but not with either of the other carbonyl signals) and that the more shielded isopropyl methine ¹H signal at δ 5.10 correlated with the carbonyl signal at δ 164.3 (but not with either of the other carbonyl signals);

• the two more shielded isopropyl methyl doublets at δ 1.21 and δ 1.268 correlated with the more shielded isopropyl methine carbon at δ 69.3; and

• the two more deshielded isopropyl methyl doublets at δ 1.270 and δ 1.28 correlated with the more deshielded isopropyl methine carbon at δ 70.6.

It was not clear which isopropoxycarbonyl group is cis to the aziridine ring proton and which is trans.

Finally, we note the sensitivity of the ¹H and ¹³C chemical shifts of various functional groups to the presence of an N-aryl or an N-alkyl substituent on the aziridine (Table S7) (see SI p. S11). In general, small, but clearly noticeable, differences are observed for the two types of substituents. However, the chemical shift difference is large for the isopropyl methine protons as well as for the aziridine ring methine proton.

General Procedure for the Addition of Nitrile Carbanions onto Iminomalonates, Figure 13.

Ina thick-walled, flame-dried, 25 mL round-bottom flask, the corresponding acetonitrile (1.35 equiv) was dissolved in DME (0.23M) and cooled to −78 °C. KHMDS (1.0M in THF) (1.35 equiv) was added dropwise to this solution. Usually the solution turned yellow and slowly to reddish yellow. After 1hof stirring, a solution of the iminomalonate (1 equiv) in of DME (0.13M) was added slowly in a dropwise manner. The reaction mixture was stirred for 2 h. After confirming the complete consumption of starting material by TLC, saturated aqueous solution of ammonium chloride was added (5 mL) to quench the reaction and the reaction mixture was allowed to warm to room temperature. The organic layer was separated. The aqueous layer was extracted twice with diethyl ether (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude reaction mixture was purified by automated flash chromatography.

Note: For gram-scale reaction (for the synthesis of 35a) for acetonitrile-derived carbanion generation, the reaction mixture should be stirred for 2 h, after which the iminomalonate was added and the reaction mixture was stirred for another 3 h. The rest of the workup procedure is same as mentioned in the procedure described above.

Diisopropyl2-(Cyano(phenyl)methyl)-2-(phenylamino)malonate (35a).

The general procedure was followed using 2-phenylacetonitrile (0.079 g, 0.675 mmol), KHMDS (1 M solution in THF) (0.68 mL, 0.675 mmol) and phenyl iminomalonate (0.138 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow viscous oily liquid (0.107 g, 54%). The compound was purified by flash column chromatography (R_f = 0.24 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.26 (td, J = 6.1, 5.0, 3.1 Hz, 1H), 7.21 (t, J = 7.4 Hz, 2H), 7.19–7.16 (m, 2H), 7.12–7.08 (m, 2H), 6.74 (t, J = 7.4 Hz, 1H), 6.57 (d, J = 7.8 Hz, 2H), 5.10 (hept, J = 6.2 Hz, 1H), 5.01 (p, J = 6.3 Hz, 1H), 4.93 (s, 1H), 4.87 (s, 1h), 1.39 (d, J =6.3 Hz, 3H), 1.18 (d, J = 6.3 Hz, 3H), 1.15 (d, J = 6.2 Hz, 3H), 0.95 (d, J = 6.3 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 166.7, 166.0, 143.3, 130.7, 129.5, 129.3, 128.9, 128.4, 119.4, 118.8, 114.8, 72.3, 71.2, 70.4, 40.0, 21.6, 21.3, 21.2, 21.1. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₂₇N₂O₄ 395.1965, found 395.1990.

Note: For gram-scale reaction, the general procedure was followed using 2-phenylacetonitrile (0.808 g, 6.91 mmol), KHMDS (1 M solution in THF) (6.91 mL, 6.91 mmol), and phenyl iminomalonate) (1.42 g, 5.12 mmol) as starting materials. The rest of the procedure is same as mentioned in the procedure described above.

Diisopropyl 2-(Cyano(phenyl)methyl)-2-((4-methoxyphenyl)-amino)malonate (35b).

The general procedure was followed using 2-phenylacetonitrile (0.079 g, 0.675 mmol), KHMDS (1 M solution in THF) (0.68 mL, 0.675 mmol), and p-methoxyphenyl iminomalonate (0.154 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a bright yellow viscous oily liquid (0.140 g, 66%). The compound was purified by flash column chromatography (R_f = 0.35 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.33–7.22 (m, 5H), 6.72 (d, J = 8.8 Hz, 2H), 6.59 (d, J = 8.8 Hz, 2H), 5.10 (hept, J = 6.2 Hz, 1H), 5.01 (hept, J = 6.7 Hz, 1H), 4.84 (s, 1h), 4.74 (s, 1H), 3.72 (s, 3h), 1.40 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.16 (d, J = 6.2 Hz, 3H), 1.0 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 166.9, 166.2, 153.5, 137.2, 130.8, 129.7, 129.0, 128.4, 119.1, 117.0, 114.8, 72.1, 71.23, 71.20, 55.6, 40.5, 21.6, 21.4, 21.3, 21.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₂₉N₂O₃ 425.2100, found 425.2065.

Diisopropyl 2-(Cyano(4-fluorophenyl)methyl)-2-(phenylamino)-malonate (35c).

The general procedure was followed using 2-(4-fluorophenyl)acetonitrile (0.091 g, 0.675 mmol), KHMDS (1 M solution in THF) (0.68 mL, 0.675 mmol) and phenyl iminomalonate (0.138 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow viscous oily liquid (0.150 g, 73%). The compound was purified by flash column chromatography (R_f = 0.24 (20% EtOAc/hexanes). ¹HNMR (600 MHz, CDCl₃): δ 7.22 (dd, J = 8.6, 5.2 Hz, 2H), 7.15 (t, J = 7.9 Hz, 2H), 6.96 (t, J =8.6 Hz, 2H), 6.80 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 7.9 Hz, 2H), 5.15 (hept, J = 6.3 Hz, 1H), 5.05 (hept, J = 6.3 Hz, 1H), 4.99 (s, 1H), 4.92 (s, 1H), 1.44 (d, J = 6.3 Hz, 3H), 1.23 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 0.99 (d, J = 6.3 Hz, 3H). ¹³C{¹H} (151 MHz, CDCl₃): δ 166.7, 166.0, 163.0 (d, ¹J_CF = 248.9 Hz), 143.2, 131.4 l (d, ³J_cf = 8.3 Hz), 129.4, 126.5 (d, ⁴J_cf = 3.4 Hz), 119.7, 118.7, 115. Five (d, ²J_cf = 21.8 Hz), 114.9, 72.5, 71.4, 70.5, 39.4, 21.6, 21.4, 21.3, 21.2. ¹⁹F NMR (471 MHz, CDCl₃): δ –111.3 (tt, J = 8.4, 5.1 Hz). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₂₆FN₂O₄ 413.1832, found 413.1866.

Diisopropyl 2-((4-Chlorophenyl)(cyano)methyl)-2-(phenylamino)malonate (35d).

The general procedure was followed using 2-(4-chlorophenyl)acetonitrile (0.102 g, 0.675 mmol), KHMDS (1 M solution in THF) (0.68 mL, 0.675 mmol), and phenyl iminomalonate (0.138 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow viscous oily liquid (0.131 g, 61%). The compound was purified by flash column chromatography (R_f = 0.24 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.27 (d, J = 8.5 Hz, 2H), 7.18 (dd, J = 17.6, 8.2 Hz, 4H), 6.83 (t, J = 7.3 Hz, 1h), 6.62 (d, J = 7.9 Hz, 2H), 5.17 (hept, J = 6.3 Hz, 1H), 5.08 (hept, J = 6.2 Hz, 1H), 5.01 (s, 1H), 4.93 (s, 1H), 1.46 (d, J = 6.3 Hz, 3H), 1.25 (d, J = 6.3 Hz, 3H), 1.23 (d, J = 6.2 Hz, 3H), 1.01 (d, J = 6.3 Hz, 3H). ¹³C{¹H} (151 MHz, CDCl₃): δ 166.5, 165.8, 143.1, 135.1, 130.9, 129.4, 129.2, 128.6, 119.6, 118.4, 114.8, 72.5, 71.4, 70.3, 39.4, 21.6, 21.3, 21.2, 21.1. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₂₆ClN₂O₄ 429.1576, found 429.1582.

Diisopropyl 2-(Cyano(4-fluorophenyl)methyl)-2-((4-methoxyphenyl)amino)malonate (35e).

The general procedure was followed using 2-(4-fluorophenyl)acetonitrile (0.091 g, 0.675 mmol), KHMDS (1 M solution in THF) (0.68 mL, 0.675 mmol), and p-methoxyphenyl iminomalonate (0.154 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow viscous oily liquid (0.130 g, 59%). The compound was purified by flash column chromatography (R_f = 0.35 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.26 (dd, J =8.2 Hz, 2H), 6.96 (t, J =8.5 Hz, 2H), 6.72 (d, J =8.8 Hz, 2H), 6.57 (d, J =8.8 Hz, 2H), 5.10 (hept, J = 6.2 Hz, 1H), 5.01 (hept, J = 6.1 Hz, 1H), 4.85 (s, 1H), 4.77 (s, 1H), 3.72 (s, 3h), 1.39 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.16 (d, J = 6.2 Hz, 3H), 0.99 (d, J = 6.3 Hz, 3H). ¹³C{¹H} (151 MHz, CDCl₃): δ 166.8, 166.1, 163.0 (d, ¹J_CF = 248.9 Hz), 153.6, 137.0,131.5 (d, ³J_CF = 8.3 Hz), 126.6 (d, ⁴J_cf = 3.3 Hz), 118.9, 117.0, 115.5 (d, ²J_cf = 21.9 Hz), 114.7, 72.2, 71.3, 71.1, 55.5, 39.9, 21.6, 21.4, 21.3, 21.2. ¹⁹F NMR (471 MHz, CDCl₃): δ –111.3 (tt, J = 8.4, 5.2 Hz). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₂₈FN₂O₅ 443.1973, found 443.1972.

Diisopropyl 2-((4-Chloro-2-fluorophenyl)(cyano)methyl)-2-((4- methoxyphenyl)amino)malonate (35f).

The general procedure was followed using 2-(4-chloro-2-fluorophenyl)acetonitrile (0.114 g, 0.675 mmol), KHMDS (1 M solution in THF) (0.68 mL, 0.675 mmol), and p-methoxyphenyl iminomalonate (0.154 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a bright yellow viscous oily liquid (0.167 g, 70%). The compound was purified by flash column chromatography (R_f = 0.35 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.34 (t, J =8.1 Hz, 1H), 7.08 (ddd, J = 23.2, 9.1, 1.9 Hz, 2H), 6.74–6.72 (m, 2H), 6.69–6.67 (m, 2H), 5.16–5.09 (m, 2H), 4.98 (hept, J =6.1 Hz, 1H), 4.74 (s, 1H), 3.73 (s, 3H), 1.38 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.12 (d, J = 6.2 Hz, 3H), 1.00 (d, J = 6.2 Hz, 3H). ¹³c{¹H} (151 MHz, CDCl₃): δ 166.5,166.2,160.2 (d, ¹J_CF = 253.2 Hz), 153.9, 137.1,136.2 (d, ³J_cf = 10.5 Hz), 132.2 (d,^{4 or 3}J_cf = 3.4 Hz), 124.9 (d, ^{3 or 4}J_cf = 3.5 Hz), 118.0, 117.6, 117.5 (d, ²J_cf = 13.9 Hz), 116.5 (d, ²J_cf = 25.8 Hz), 114.6, 72.3, 71.8, 71.2, 55.6, 34.8, 21.5, 21.2, 21.1. ¹⁹F NMR (471 MHz, CDCl₃): δ –110.4 (t, J = 8.9 Hz). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₂₇ClFN₂O₅ 477.1594, found 477.1586.

Diisopropyl 2-(Cyano(phenylthio)methyl)-2-((4-methoxyphenyl)- amino)malonate (35g).

The general procedure was followed using 2-(phenylthio)acetonitrile (0.100 g, 0.675 mmol), KHMDS (1 M solution in THF) (0.68 mL, 0.675 mmol), and p-methoxyphenyl iminomalonate (0.154 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellowish brown viscous oily liquid (0.178 g, 78%). The compound was purified by flash column chromatography (R_f = 0.35 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.44–7.38 (m, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.29 (t, J = 7.3 Hz, 2h), 6.81 (d, J = 8.9 Hz, 2h), 6.76 (d, J = 8.9 Hz, 2H), 5.16 (hept, J = 6.2 Hz, 1H), 5.09 (hept, J = 6.2 Hz, 1H), 5.01 (s, 1H),4.59(s, 1H), 3.74 (s, 3h), 1.28 (d, J = 6.3 Hz, 3H), 1.25 (d, J = 6.3 Hz, 3H), 1.20 (d, J =6.3 Hz, 3H), 1.16 (d, J = 6.3 Hz, 3H). ¹³C{¹H} (151 MHz, CDCl₃): 166.6, 165.4, 154.6, 136.0, 134.4, 130.7, 129.5, 129.3, 119.6, 117.6, 114.6, 72.1, 71.7, 70.4, 55.5, 42.4, 21.3, 21.2, 21.1. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₂₉N₂O₅S 457.1785, found 457.1794.

Diisopropyl 2-(Cyano(phenyl)methyl)-2-((3-(trifluoromethyl)- phenyl)amino)malonate (35h).

The general procedure was followed using 2-phenylacetonitrile (0.079 g, 0.675 mmol), KHMDS (1 M solution in THF) (0.68 mL, 0.675 mmol), and m-trifluoromethyl- phenyl iminomalonate (0.172 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow viscous oily liquid (0.141 g, 61%). The compound was purified by flash column chromatography (R_f = 0.36 (10% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.287.14 (m, 6H), 6.95 (d, J = 7.7 Hz, 1H), 6.69 (dd, J = 8.2, 2.1 Hz, 1H), 6.57 (s, 1H), 5.22 (s, 1H), 5.12 (hept, J = 6.5 Hz, 1H), 4.95 (hept, J = 6.3 Hz, 1H), 4.84 (s, 1H), 1.37 (d, J = 6.3 Hz, 3H), 1.16 (d, J = 6.3 Hz, 3H), 1.14 (d, J = 6.3 Hz, 3H), 0.91 (d, J = 6.3 Hz, 3H). ¹³C{¹H} (151 MHz, CDCl₃): δ 166.0, 165.9, 144.0, 131.6 (q, ²J_CF = 32.1 Hz), 130.4, 129.8, 129.7, 129.2, 128.6, 123.9 (q, ¹J_CF = 272.4 Hz), 118.7, 117.8, 115.9 (q, ³J_cf = 3.8 Hz), 111.3 (q, ³J_cf = 3.8 Hz), 72.7, 71.8, 70.7, 40.8, 21.6, 21.4, 21.3, 21.1. ¹⁹F NMR (471 MHz, CDCl₃): δ −61.9 (S). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₂₆ F₃N₂O₄463.1823, found 463.1815.

Diisopropyl 2-(Cyano(4-fluorophenyl)methyl)-2-((3-(trifluoromethyl)phenyl)amino)malonate (35i).

The general procedure was followed using 2-(4-fluorophenyl)acetonitrile (0.091 g, 0.675 mmol), KHMDS (1 M solution in THF) (0.68 mL, 0.675 mmol), and m-trifluoromethylphenyl iminomalonate (0.172 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow viscous oily liquid (0.146 g, 61%). The compound was purified by flash column chromatography (R_f = 0.36 (10% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.32 (dd, J = 8.4, 5.2 Hz, 2H), 7.22 (t, J = 7.9 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.97 (t, J = 8.5 Hz, 2H), 6.73 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 5.33 (s, 1H), 5.19 (hept, J = 6.2 Hz, 1H), 5.00 (hept, J = 6.1 Hz, 1H), 4.91 (s, 1H), 1.43 (d, J =6.3 Hz, 3H), 1.22 (d, J =5.7 Hz, 3H), 1.21 (d, J = 5.7 Hz, 3H), 0.94 (d, J = 6.2 Hz, 3H). ¹³C{¹H} (151 MHz, CDCl₃): δ 165.9, 165.8, 163.2 (d, ¹J_CF = 249.5 Hz), 144.0, 131.8 (d, ³J_cf = 8.4 Hz), 131.7 (q, ²J_cf = 32.1 Hz), 129.7, 126.2 (d, ⁴J_cf =3.3 Hz), 123.9 (q, ¹J_CF = 272.4Hz), 118.5, 118.0, 116.1 (q, ³J_CF = 3.9 Hz), 115.8 (d, ²J_cf = 21.9 Hz), 111.2 (q, ³J_cf = 3.7 Hz), 72.8, 71.9, 70.7, 40.4, 21.5, 21.3, 21.2, 21.0. ¹⁹F NMR(471 MHz, CDCl₃): δ –62.04 (S), –110.9 (tt, J = 8.4, 5.2 Hz). HRMS (ESI-TOF) m/z: [M + H]⁺calcd for C₂₄H₂₅F₄N₂O₄ 481.1787, found 481.1785.

Diisopropyl 2-(cyano(phenyl)methyl)-2-(pyridin-3-ylamino)-malonate (35j).

The general procedure was followed using 2-phenylacetonitrile (0.079 g, 0.675 mmol), KHMDS (1 M solution in THF) (0.68 mL, 0.675 mmol) and 3-pyridyl iminomalonate (0.139 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow viscous oily liquid (0.126 g, 64%). Compound was purified by flash column chromatography (R_f = 0.32 (40% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 8.02 (s, 1H), 7.95 (s, 1H), 7.30–7.23 (m, 5H), 7.00 (m, 1H), 6.81 (d, J = 7.4 Hz, 1H), 5.14 (s, 1H), 5.13 (hept, J = 6.2 Hz, 1H), 5.00 (hept, J = 6.2 Hz, 1H), 4.85 (s, 1H), 1.39 (d, J = 6.3 Hz, 3H), 1.20 (d, J = 6.3 Hz, 3H), 1.15 (d, J = 6.2 Hz, 3H), 0.96 (d, J = 6.3 Hz, 3H). ¹³C{¹H} (151 MHz, CDCl₃): δ 165.9, 165.8, 140.9, 138.3, 130.3, 129.7, 129.2, 128.7, 120.4, 118.7, 72.6, 71.8, 70.6, 40.8, 21.5, 21.4, 21.3, 21.2. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₂H₂₆N₃O₄ [M+H]⁺ 396.2122; found 396.2101.

Diisopropyl 2-(cyano(4-fluorophenyl)methyl)-2-(pyridin-3-ylamino)malonate (35k).

The general procedure was followed using 2-(4-fluorophenyl)acetonitrile (0.091 g, 0.675 mmol), KHMDS (1 M solution in THF) (0.68 mL, 0.675 mmol) and 3-pyridyl iminomalonate (0.139 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow viscous oily liquid (0.124 g, 60%). Compound was purified by flash column chromatography (R_f = 0.32 (40% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 8.05 (d, J = 4.3 Hz, 1H), 8.01–7.94 (m, 1H), 7.30 (dd, J = 7.6, 5.6 Hz, 2H), 7.00 (dt, J = 16.8, 5.9 Hz, 3H), 6.82–6.74 (m, 1H), 5.18 (s, 1H), 5.12 (hept, J = 6.2 Hz, 1H), 5.01 (hept, J = 6.1 Hz, 1H), 4.86 (s, 1H), 1.40 (d, J = 6.3 Hz, 3H), 1.22 (d, J = 6.2 Hz, 3H), 1.18 (d, J = 6.2 Hz, 3H), 0.98 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 165.8, 165.7, 163.2 (d, ¹J_CF = 249.7 Hz), 141.1, 139.9, 138.3, 131.6 (d, ³J_CF = 8.4 Hz), 126.2 (d, ⁴J_CF = 3.3 Hz), 123.4, 120.4, 118.5, 115.8 (d, ²J_CF = 21.8 Hz), 72.8, 72.0, 70.7, 40.3, 21.5, 21.4, 21.3, 21.2. ¹⁹F NMR (471 MHz, CDCl₃): δ −110.6 (tt, J = 8.4, 5.1 Hz). HRMS (ESI-TOF) m/z: [M+H]⁺ calcd for C₂₂H₂₅FN₃O₄ [M+H]⁺ 414.2034; found 414.2027.

Diisopropyl 2-((4-chloro-2-fluorophenyl)(cyano)methyl)-2-((3-(trifluoromethyl)phenyl)amino)malonate (35l).

The general procedure was followed using 2-(4-chloro-2-fluorophenyl)acetonitrile (0.114 g, 0.675 mmol), KHMDS (1 M solution in THF) (0.68 mL, 0.675 mmol) and m-trifluoromethylphenyl iminomalonate (0.172 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow oily liquid (0.172 g, 67%). The compound was purified by flash column chromatography (R_f = 0.35 (10% EtOAc/hexanes). ¹H NMR (500 MHz, CDCl₃): δ 7.33 (dd, ³J_HH = 8.4 Hz, ⁴J_HF = 7.8 Hz, 1H, H-6’); 7.27 (dd, ³J_HH = 8.0 Hz, ³J_HH = 7.9 Hz, 1H, H-5); 7.11 (ddd, ³J_HH = 8.4 Hz, ⁴J_HH = 2.1 Hz, ⁵J_HH ≈ 0.7 Hz, 1H, H-5′); 7.065 (m, 1H, H-4); 7.062 (dd, ³J_HF = 9.7 Hz, ⁴J_HH = 2.1 Hz, 1H, H-3′); 6.88 (dd, ³J_HH = 8.2 Hz, ⁴J_HH = 2.4 Hz, 1H, H-6); 6.82 (s with unresolved long-range couplings, 1H, H-2); 5.22 (s, broad, NH); 5.16 [d, ⁵J_HH (with H-5′) ≈ 0.7 Hz, 1H, H–C–CN]; isopropoxy group 1:5.19 (hept, J = 6.3 Hz, 1H, methine), 1.41 (d, J = 6.3 Hz, 3H, methyl), 1.16 (d, J = 6.3 Hz, 3H, methyl); isopropoxy group 2:5.03 (hept, J = 6.3 Hz, 1H, methine), 1.24 (d, J = 6.3 Hz, 3H, methyl), 1.01 (d, J = 6.3 Hz, 3H, methyl). ¹³C{¹H} NMR (126 MHz, CDCl₃): δ 160.2 (d, ¹J_CF = 253.4 Hz, C-2′); 143.9 (s, C-1); 136.6 (d, ³J_CF = 10.5 Hz, C-4′); 132.0 (d, ³J_CF = 3.4 Hz, C-6′); 131.6 (q, ²J_CF = 32.2 Hz, C-3); 129.8 (s, C-5); 125.1 (d, ⁴J_CF = 3.7 Hz, C-5′); 123.9 (q, ¹J_CF = 272.4 Hz, CF₃); 118.1 (q, ⁵J_CF = 1 Hz, C-6); 117.6 (s, nitrile); 117.1 (d, ²J_CF = 14.0 Hz, C-1′); 116.6 (d, ²J_CF = 25.6 Hz, C-3′); 116.4 (q, ³J_CF = 3.9 Hz, C-4); 111.7 (q, ³J_CF = 3.9 Hz, C-2); 70.4 (broadened—unresolved long-range J_CF coupling, quaternary aliphatic carbon); 34.5 (d, ³J_CF = 1.7 Hz, N≡C–CH); isopropoxy group 1:165.7 (s, carbonyl), 72.9 [s, CH (correlating with methine ¹H signal at δ 5.19 in HSQC spectrum)], 21.5 [s, CH₃ (correlating with methyl ¹H signal at δ 1.41 in HSQC spectrum)], 21.23 [s, CH₃ (correlating with methyl ¹H signal at δ 1.16 in HSQC spectrum)]; isopropoxy group 2:165.9 (s, carbonyl), 72.4 [s, CH (correlating with methine ¹H signal at δ 5.03 in HSQC spectrum)], 21.22 [d, J_CF = 1 Hz, CH₃ (correlating with methyl ¹H signal at δ 1.24 in HSQC spectrum)], 21.1 [s, CH₃ (correlating with methyl ¹H signal at δ 1.01 in HSQC spectrum)]. ¹⁹F NMR (471 MHz, CDCl₃): δ −62.03 (broad singlet with shoulders from unresolved long-range J_HF couplings that are not recognizable in the ¹H spectrum, CF₃; satellite ¹J_CF = 272.4 Hz), δ−110.5 [broad dd, J ≈ 8 Hz, J ≈ 8 Hz from ³J_HF with H-3′ and ⁴J_HF with H-6′ (see above), ring CF; satellite ¹J_CF = 253 Hz)]. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₄ClF₄N₂O₄ 515.1447; found 515.1441.

Detailed chemical shift assignments could be made through a combination of ¹H (p. S384), ¹³C (SI p S370), DEPT-135 ¹³C (SI p S371), COSY (SI p S373), HSQC (SI p S375–S379), HMBC (SI p S374), and ¹⁹F (SI p S372) spectra. The ¹H–¹³C HSQC spectra also enabled ¹H–¹⁹F couplings to be readily recognized and the corresponding J_HF values to be measured because of the distinctive effect that coupling to a passive spin (¹⁹F) has on the appearance of a ¹H–¹³C HSQC spectrum, i.e., splitting the contour into two contours separated by the value of J_CF in the ¹³C dimension and by the value of J_HF in the ¹H dimension (SI pp S393 and S394).⁴⁸ For example, SI p S393 shows a highly expanded plot of part of the aromatic region in the HSQC spectrum and the corresponding regions in the 1D ¹H and ¹³C spectra. The correlations for C-4/H-4 and C-3′/H-3′ are shown. The two contours at δ_C116.41 separated in the ¹H dimension by about 7.2 Hz and centered at δ_H7.065 result from C-4 and H-4 on the CF₃-substituted ring. The separation between the contours results from ³J(H-4,H-5). The 1D ¹³C spectrum (left side) indicates that C-4 is a quartet with ³J_CF = 3.9 Hz. This splitting is too small to detect in the HSQC spectrum, where the ¹³C FID digital resolution is 5.2 Hz (1.3 Hz after zero-filling). The ⁴J_HF splitting is much too small to detect in the ¹H dimension, where the ¹H digital resolution is 2.1 Hz. In contrast, the 1D ¹³C spectrum indicates that C-3′ is a doublet at δ 116.62 with ²J_CF = 25.6 Hz. The corresponding contours in the HSQC spectrum are offset by ±12.8 Hz in the ¹³C dimension; the separation of the contours in the ¹³C dimension is ²J_CF. The contours in the ¹H dimension are centered at δ 7.062 and separated by 9.7 Hz (³J_HF). The ⁴J_HH coupling between H-3′ and H-5′ (2.1 Hz) is too small to detect in the ¹H dimension of the HSQC spectrum. The severely overlapping ¹H signals for H-4 and H-3′ in the 1D ¹H spectrum (top) make this region difficult to interpret by sight, but the HSQC results enable the four relatively prominent signals to be recognized as a doublet (³J_HF) of doublets (⁴J_HH) for H-3′. The same doublet of doublets centered at δ 7.062 is observed in a 400 MHz ¹H spectrum, providing further support for the interpretation. SI p S379 shows a highly expanded plot of the C-6′/H-6′ correlation in the HSQC spectrum and the corresponding regions in the 1D ¹H and ¹³C spectra. The ¹H spectrum (top) is a doublet of doublets with similar J values that are attributed to ³J_HH = 8.4 Hz and ⁴J_HF = 7.8 Hz. Three equidistant contours (separation ≈ 8.3 Hz) are correspondingly observed in the ¹H dimension in the HSQC spectrum. In the ¹³C dimension, the most shielded and the most deshielded contours differ by 3.4 Hz, the value of ³J_CF observed for the doublet in the 1D ¹³C spectrum (left side). There is no detectable ⁵J_HF between H-5′ and the ring fluorine. Thus, the broad doublet of doublets (with the central peaks clearly overlapping) observed for the ring fluorine in the ¹⁹F spectrum can be attributed to ³J_HF with H-3’ and ⁴J_HF with H-6′. The 1D ¹³C spectrum exhibited a completely unexpected splitting of one of the isopropyl methyl signals (SI p S370) that was also evident on 400 and 600 MHz spectrometers. In contrast, the 1D ¹³C spectrum of the analogous compound 35o without the ring fluorine (i.e., a 4-chlorophenyl group) exhibits the expected four singlets for the four different isopropyl methyl carbons. Thus, in the 2-fluoro-4-chlorophenyl compound (35l), there is an unexpected coupling between one methyl carbon and the ring fluorine. A ¹³C–¹⁹F J coupling through eight bonds would not be expected. A through-space ¹³C–¹⁹F coupling of a single methyl carbon with the ring fluorine is also hard to explain. Additional work is required to determine the origin of this unexpected ¹³C–¹⁹F interaction in 35l.

Diisopropyl-2-(cyano(phenylthio)methyl)-2-((3-(trifluoromethyl)phenyl)amino)malonate (35m).

The general procedure was followed using 2-(phenylthio)acetonitrile (0.100 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and m-trifluoromethylphenyl iminomalonate (0.172 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow colored viscous oily liquid (0.180 g, 73%). Compound was purified by flash column chromatography (R_f = 0.36 (10% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.44 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.32–7.26 (m, 3H), 7.09 (d, J = 7.7 Hz, 1H), 6.98 (s, 1H), 6.94 (d, J = 8.1 Hz, 1H), 5.50 (s, 1H), 5.19 (hept, J = 6.2 Hz, 1H), 5.15 (hept, J = 6.2 Hz, 1H), 4.68 (s, 1H), 1.32 (d, J = 6.3 Hz, 3H), 1.29 (d, J = 6.3 Hz, 3H), 1.19 (d, J = 6.2 Hz, 3H), 1.17 (d, J = 6.2 Hz, 3H). ¹³C{¹H} (151 MHz, CDCl₃): δ 166.0, 165.0, 143.2, 134.4, 132.4, 132.1, 131.7 (q, ²J_CF = 32.1 Hz), 130.4, 129.8, 129.7, 129.5, 129.4, 128.9, 123.9 (q, ¹J_CF = 272.4 Hz), 118.4, 117.3, 116.6 (q, ³J_CF = 3.8 Hz), 116.5, 112.7 (q, ³J_CF = 3.8 Hz), 72.7, 72.3, 69.7, 41.9, 21.34, 21.32, 21.2, 21.1. ¹⁹F NMR (471 MHz, CDCl₃): δ −62.0 (S). HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₆F₃N₂O₄S 495.1599; found 495.1595.

Diisopropyl-2-((4-chloro-2-fluorophenyl)(cyano)methyl)-2-(pyridin-3-ylamino)malonate (35n).

The general procedure was followed using 2-(4-chloro-2-fluorophenyl)acetonitrile (0.114 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and p-pyridyl iminomalonate (0.139 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellow colored viscous oily liquid (0.152 g, 68%). Compound was purified by flash column chromatography (R_f = 0.32 (40% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 8.06–8.03 (m, 2H), 7.32 (t, J = 8.1 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.08–7.03 (m, 3H), 5.16 (hept, J = 6.2 Hz, 1H), 5.12 (s, 1H), 5.07 (s, 1H), 5.01 (hept, J = 6.3 Hz, 1H), 1.38 (d, J = 6.3 Hz, 3H), 1.22 (d, J = 6.3 Hz, 3H), 1.12 (d, J = 6.3 Hz, 3H), 1.00 (d, J = 6.2 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ 165.7, 165.5, 160.0 (d, ¹J_CF = 253.2 Hz), 141.3, 139.7, 138.5, 136.5 (d, ³J_CF = 10.5 Hz), 131.8 (d, ^{4 or 3} J_CF = 3.3 Hz), 125.1 (d, ^{3 or 4}J_CF = 3.5 Hz), 123.3, 120.8, 117.6, 117.0 (d, ²J_CF = 13.9 Hz), 116.7 (d, ²J_CF = 25.6 Hz), 72.8, 72.3, 70.2, 34.3, 21.4, 21.2, 21.1. ¹⁹F NMR (471 MHz, CDCl₃): δ −110.6 (t, J = 8.3 Hz). HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₂H₂₄ClFN₃O₄ 448.1434; found 448.1438.

Diisopropyl-2-((4-chlorophenyl)(cyano)methyl)-2-((3-(trifluoromethyl)phenyl)amino)malonate (35o).

The general procedure was followed using 2-(4-chlorophenyl)acetonitrile (0.102 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and m-trifluoromethylphenyl iminomalonate (0.172 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a yellowish grey colored viscous oily liquid (0.149 g, 60%). Compound was purified by flash column chromatography (R_f = 0.36 (10% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.31–7.24 (m, 5H), 7.05 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.62 (s, 1H), 5.35 (s, 1H), 5.21 (hept, J = 6.1 Hz, 1H), 5.04 (hept, J = 6.2 Hz, 1H), 4.93 (s, 1H), 1.45 (d, J = 6.3 Hz, 3H), 1.25 (d, J = 6.3 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H), 0.98 (d, J = 6.2 Hz, 3H). ¹³C{¹H} (151 MHz, CDCl₃): δ 165.8, 165.7, 143.9, 135.5, 131.5 (q, ²J_CF = 32.1 Hz), 131.1, 129.7, 128.9, 128.8, 123.8 (q, ¹J_CF = 272.5 Hz), 118.2, 117.9, 116.2 (q, ³J_CF = 3.7 Hz), 111.2 (q, ³J_CF = 3.7 Hz), 72.9, 71.9, 70.6, 40.4, 21.5, 21.3, 21.2, 21.0. ¹⁹F NMR (471 MHz, CDCl₃): δ −62.0 (S). HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₅ClF₃N₂O₄ 497.1480; found 497.1477.

Diisopropyl-2-((4-chlorophenyl)(cyano)methyl)-2-((4-methoxyphenyl)amino)malonate (35p).

The general procedure was followed using 2-(4-chlorophenyl)acetonitrile (0.102 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and p-methoxyphenyl iminomalonate (0.154 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a dark brown colored viscous oily liquid (0.146 g, 64%). Compound was purified by flash column chromatography (R_f = 0.35 (20% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.27 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 6.74 (d, J = 8.7 Hz, 2H), 6.60 (d, J = 8.7 Hz, 2H), 5.13 (hept, J = 6.2 Hz, 1H), 5.03 (hept, J = 6.2 Hz, 1H), 4.85 (s, 1H), 4.77 (s, 1H), 3.75 (s, 3H), 1.41 (d, J = 6.2 Hz, 3H), 1.23 (d, J = 6.2 Hz, 3H), 1.19 (d, J = 6.1 Hz, 3H), 1.02 (d, J = 6.2 Hz, 3H). ¹³C{¹H} (151 MHz, CDCl₃): δ 166.7, 166.0, 153.7, 136.9, 135.2, 131.0, 129.3, 128.7, 118.7, 117.0, 114.8, 72.3, 71.4, 71.1, 55.6, 40.0, 21.6, 21.4, 21.3, 21.2. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₄H₂₈ClN₂O₅ 459.1681; found 459.1674.

Diisopropyl-2-((4-chlorophenyl)(cyano)methyl)-2-(pyridin-3-ylamino)malonate (35q).

The general procedure was followed using 2-(4-chlorophenyl)acetonitrile (0.102 g, 0.675 mmol), KHMDS (1M solution in THF) (0.68 mL, 0.675 mmol) and 3-pyridyl iminomalonate (0.139 g, 0.5 mmol) as starting materials to afford the nitrile adduct as a brown colored viscous oily liquid (0.159 g, 74%). Compound was purified by flash column chromatography (R_f = 0.31 (40% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 8.06 (d, J = 4.1 Hz, 1H), 8.00 (d, J = 2.8 Hz, 1H), 7.31–7.24 (m, 2H), 7.24–7.20 (m, 2H), 7.03 (dd, J = 8.3, 4.7 Hz, 1H), 6.82 (ddd, J = 8.4, 2.9, 1.1 Hz, 1H), 5.18 (s, 1H), 5.15 (hept, J = 6.2 Hz, 1H), 5.01 (hept, J = 6.2 Hz, 1H), 4.84 (s, 1H), 1.39 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.17 (d, J = 6.2 Hz, 1H), 0.98 (d, J = 6.2 Hz, 3H). ¹³C{¹H} (151 MHz, CDCl₃): δ 165.6, 165.4, 140.9, 139.7, 138.1, 135.3, 130.9, 128.8, 128.7, 123.3, 120.4, 118.1, 72.6, 71.8, 70.4, 40.2, 21.4, 21.2, 21.1, 21.0. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₂H₂₅ClN₃O₄ 430.1671; found 430.1662.

General procedure for the cyclization of nitrile addition products to corresponding γ-lactams, Figure 14.

Method A:

In a thick-walled flame dried 25 mL round bottom flask, the acetonitrile addition product (1 equiv) was dissolved in of anhydrous methanol (0.07 M) at room temperature. Raney Nickel (600 mg), washed with water and ethanol, was added to this. The mixture was then stirred for 3 days under a hydrogen atmosphere (in form of a balloon). After confirming the complete consumption of the starting material by TLC, the reaction was stopped and the mixture was passed through a small pad of celite and the celite pad was rinsed with ethyl acetate (10 mL). All the solvent was removed under reduced pressure followed by automated flash chromatography.

Method B:

In a thick wall flame dried 25 mL round bottom flask; the acetonitrile addition product (1.0 equiv) was dissolved in of dry THF (0.83 M) at room temperature. BH₃^.Me₂S (10 equiv) was added dropwise in this solution followed by reflux for 1 hour. After confirming the complete consumption of the starting material by TLC, the reaction mixture was brought to room temperature and 1 mL of water was added slowly dropwise to the reaction mixture. Evolution of hydrogen was noticed. The mixture was again refluxed for 6 hours. The reaction mixture was then allowed to cool to room temperature and ethyl acetate (10 mL) was added. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (2 X 10 mL). The combined organic layer was then dried over anhydrous sodium sulphate. All the solvent was removed under reduced pressure followed by automated flash chromatography.

Isopropyl-2-oxo-4-phenyl-3-(phenylamino)pyrrolidine-3-carboxylate (36a).

The general procedure, Method A was followed using diisopropyl 2-(cyano(phenyl)methyl)-2-(phenylamino)malonate, 35a (0.197 g, 0.5 mmol) to afford the nitrile adduct as a white colored solid (m.p. 198–203 °C) (0.101 g, 60%). Compound was purified by flash column chromatography (R_f = 0.33 (40% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.22–7.14 (m, 5H), 7.03 (t, J = 7.9 Hz, 2H), 6.66 (t, J = 7.3 Hz, 1H), 6.50 (d, J = 7.8 Hz, 2H), 6.47 (s, 1H), 4.94 (hept, J = 6.2 Hz, 1H), 4.68 (s, 1H), 4.52 (d, J = 5.9 Hz, 1H), 4.10 (dd, J = 9.7, 6.6 Hz, 1H), 3.50 (d, J = 9.7 Hz, 1H), 1.16 (d, J = 6.3 Hz, 3H), 0.82 (d, J = 6.3 Hz, 3H). ¹³C{¹H} (151 MHz, CDCl₃): δ 172.0, 169.4, 145.3, 139.1, 128.6, 128.2, 128.0, 127.4, 118.5, 114.3, 70.2, 69.8, 49.1, 47.6, 21.5, 21.0. HRMS (ESI-TOF): calc’d for C₂₀H₂₃N₂O₃ [M+H]⁺ 339.1703; found 339.1703.

Isopropyl-3-((4-methoxyphenyl)amino)-2-oxo-4-phenylpyrrolidine-3-carboxylate (36b).

The general procedure, Method A was followed using diisopropyl 2-(cyano(phenyl)methyl)-2-((4-methoxyphenyl)amino)malonate, 35b (0.212 g, 0.5 mmol) to afford the nitrile adduct as a white colored solid (m.p. 185–187 °C) (0.088 g, 48%). Compound was purified by flash column chromatography (R_f = 0.35 (40% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.23–7.15 (m, 5H), 6.76 (s, 1H), 6.63 (d, J = 8.7 Hz, 2H), 6.48 (d, J = 8.7 Hz, 2H), 4.95 (hept, J = 6.1 Hz, 1H), 4.47 (d, J = 5.5 Hz, 1H), 4.43 (s, 1H), 4.04 (dd, J = 9.6, 6.8 Hz, 1H), 3.68 (s, 3H), 3.50 (d, J = 9.7 Hz, 1H), 1.17 (d, J = 6.2 Hz, 3H), 0.88 (d, J = 6.2 Hz, 3H). ¹³C{¹H} (151 MHz, CDCl₃): δ 172.3, 169.6, 152.8, 139.1, 138.9, 128.2, 128.0, 127.3, 115.9, 114.2, 70.1, 70.0, 55.6, 49.2, 47.4, 21.5, 21.1. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₁H₂₅N₂O₄ 369.1809; found 369.1809.

Isopropyl-4-(4-fluorophenyl)-2-oxo-3-(phenylamino)pyrrolidine-3-carboxylate (36c).

The general procedure, Method A was followed using diisopropyl 2-(cyano(4-fluorophenyl)methyl)-2-(phenylamino)malonate, (35c) (0.206 g, 0.5 mmol) to afford the nitrile adduct as a white colored solid (m.p. 191–193 °C) (0.112 g, 63%). Compound was purified by flash column chromatography (R_f = 0.35 (40% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.16 (AA′ part of AA′BB′X spin system, 2H, H-2′/H-6′), 7.04 (m, 2H, H-3/H-5), 6.85 (BB′ part of AA′BB′X spin system, 2H, H-3′/H-5′), 6.67 (m, 1H, H-4), 6.47 (m, 2H, H-2/H-6), 6.46 (s, br, amide NH), 4.93 (hept, J = 6.3 Hz, 1H, isopropyl methine), 4.71 (s, br, amine NH), 4.53 (d, J = 6.5 Hz, 1H, benzylic H), 4.12 (dd, J = 9.8, 6.6 Hz, 1H, one of the CH₂ protons), 3.45 (ddd, J = 9.8, ≈1.7, ≈1.3 Hz, 1H, the other CH₂ proton), 1.16 (d, J = 6.3 Hz, 3H, isopropyl methyl), 0.81 (d, J = 6.3 Hz, 3H, other isopropyl methyl). ¹³C{¹H} (126 MHz, CDCl₃): δ 171.8 (carbonyl), 169.3 (carbonyl), 161.9 (d, ¹J_CF = 245.8 Hz, C-4′), 145.1 (C-1), 135.1 (d, ⁴J_CF = 3.4 Hz, C-1′), 129.5 (d, ³J_CF = 8.0 Hz, C-2′/C-6′), 128.7 (C-3/C-5), 118.6 (C-4), 115.1 (d, ²J_CF = 21.3 Hz, C-3′/C-5′), 114.2 (C-2/C-6), 70.4 (isopropyl methine), 69.7 (d, ⁶J_CF ≈ 0.8 Hz, quaternary aliphatic carbon), 48.2 (s, br, unresolved ⁵J_CF, benzylic CH), 47.9 (CH₂), 21.5 [isopropyl methyl (correlating with the methyl ¹H signal at δ 1.16 in HSQC spectrum)], 21.0 [other isopropyl methyl (correlating with the methyl ¹H signal at δ 0.81 in HSQC spectrum)]. ¹⁹F NMR (471 MHz, CDCl₃): δ −114.1 (X part of AA′BB′X spin system: tt, ³J_HF = 8.6 Hz, ⁴J_HF = 5.3 Hz). HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₂ FN₂O₃ 357.1609; found 357.1628.

The COSY spectrum (SI, p S408) immediately identifies the two pairs of coupled protons (H-2′/H-6′ and H-3′/H-5′) in the p-fluorophenyl ring and the three sets of coupled protons (H-2/H-6, H-3/H-5, and H-4) in the –NH-phenyl ring. In the cluster of signals centered at δ 6.85 (SI, p S505), the three tallest signals appear to result from splitting the two most prominent peaks of the BB′ part of the AA′BB′ pattern into two doublets (with the central components overlapping) exhibiting the ³J_HF = 8.6 Hz separation seen in the ¹⁹F spectrum (SI, p S407). The HSQC spectrum (SI, pp. S409 and S410) shows that the ¹H signal at δ 6.85 correlates with the ¹³C doublet centered at δ 115.1. This HSQC correlation for H-3′/C-3′ and H-5′/C-5′ exhibits the expected pair of tilted contours that reflect ³J_HF in the ¹H dimension and ²J_CF in the ¹³C dimension (SI, p S410). The relatively shielded aromatic carbon adjacent to CF is consistent with the corresponding carbon in 4-fluorotoluene, where C-3/C-5 gives a signal at δ 114.0.⁴⁹ In the cluster of signals centered at δ 7.16 (SI, p S411), the four tallest signals appear to result from splitting the two most prominent peaks of the AA′ part of the AA′BB′ pattern into two doublets exhibiting the ⁴J_HF = 5.3 Hz separation seen in the ¹⁹F spectrum. The HSQC spectrum shows that the ¹H signal at δ 7.16 correlates with the ¹³C doublet centered at δ 129.5. This HSQC correlation for H-2′/C-2′ and H-6′/C-6′ also exhibits the expected pair of tilted contours that reflect the smaller ⁴J_HF in the ¹H dimension and the smaller ³J_CF in the ¹³C dimension (SI, p S411). The relative intensities of the ¹H signals for the three aromatic multiplets of the –NH-phenyl group, the corresponding ¹³C chemical shifts, and the HSQC spectrum provided unambiguous assignments for these three types of CH groups. The single-intensity ¹H multiplet at δ 6.67 can result only from H-4, while the very shielded aromatic ¹³C signal at δ 114.2 clearly results from C-2/C-6 in light of ¹³C chemical shift data for aniline and N-substituted anilines.⁵³ Thus, the HSQC spectrum indicates that C-4 gives the signal at δ 118.6, while H-2/H-6 give the double-intensity multiplet at δ 6.47. By elimination, H-3/H-5 give the double-intensity multiplet at δ 7.04, and C-3/C-5 give the signal at δ 128.7. As expected, ordinary (i.e., untilted) contours are observed for the three HSQC correlations in the phenyl group of –NH-phenyl: at δ_H 6.47 / δ_C 114.2 for H-2/C-2 and H-6/C-6, at δ_H 7.04 / δ_C 128.7 for H-3/C-3 and H-5/C-5, and at δ_H 6.67 / δ_C 118.6 for H-4/C-4 (SI, pp. S409 and S412). The equal J values (9.8 Hz) exhibited by the multiplets at δ 4.12 and δ 3.45 indicated that these signals resulted from the CH₂ protons; by elimination, the multiplet at δ 4.53 resulted from the benzylic CH proton. The additional J coupling for the CH₂ proton at δ 3.45 (compared to that at δ 4.12) results from coupling with the amide proton, as shown by the COSY spectrum. The NOE observed with mixing times of 0.10, 0.20, and 0.40 s (SI, pp. S413–S415) between the –NH-phenyl H-2/H-6 protons at δ 6.47 and the amine proton at δ 4.71 is reasonable. The NOE observed between the –NH-phenyl H-2/H-6 protons at δ 6.47 and the benzylic proton at δ 4.53 suggests that –NH-phenyl and the benzylic proton have a cis relationship because it would be hard for the phenyl ring to approach the benzylic proton with the other stereochemistry. Similarly, the weak cross peak between the amine proton at δ 4.71 and the p-fluorophenyl H-2′/H-6′ protons at δ 7.16 suggests that the amine proton and p-fluorophenyl group have a trans relationship. With mixing times of 0.10, 0.20, and 0.40 s, the CH₂ proton at δ 3.45 exhibits an NOE with the p-fluorophenyl H-2′/H-6′ protons at δ 7.16 but not with the phenyl H-2/H-6 protons at δ 6.47. Thus, the CH₂ proton at δ 3.45 appears to be cis to the p-fluorophenyl group and trans to the –NH-phenyl group.

Finally, we note the clearly unequal peak heights for the two components of the ¹J_CF doublet centered at δ 161.9 in the standard ¹³C spectrum (SI, p. S405, 5.77s FID processed with just 0.2 Hz of line broadening). In contrast, the peak heights are essentially the same (at this level of S/N) for the long-range J_CF doublets. The unequal peak heights for the two components of the ¹J_CF doublet apparently result from ¹³C–¹⁹F cross-correlated relaxation, as previously shown for the ¹J_CF splitting in 1,3-difluorobenzene.⁵¹

Pictorial representation of NOE correlation in 36c:

Isopropyl-4-(4-chlorophenyl)-2-oxo-3-(phenylamino)pyrrolidine-3-carboxylate (36d).

The general procedure, Method B was followed using diisopropyl 2-((4-chlorophenyl)(cyano)methyl)-2-(phenylamino)malonate, (35d) (0.214 g, 0.5 mmol) and BH₃^.Me₂S (0.380 g, 5 mmol) to afford the nitrile adduct as a white colored solid (m.p. 184–186 °C) (0.069 g, 37%). Compound was purified by flash column chromatography (R_f = 0.35 (40% EtOAc/hexanes). ¹H NMR (600 MHz, CDCl₃): δ 7.13 (s, 4H, H-2′/H-6′, H-3′/H-5′), 7.05 (m, 2H, H-3/H-5), 6.68 (m, 1H, H-4), 6.47 (m, 2H, H-2/H-6), 6.43 (s, br, amide NH), 4.92 (hept, J = 6.3 Hz, 1H, isopropyl methine), 4.72 (s, br, amine NH), 4.53 (dd, J = 6.5, ≈0.8 Hz, 1H, benzylic H), 4.12 (dd, J = 9.8, 6.6 Hz, 1H, one of the CH₂ protons), 3.43 (ddd, J = 9.8, ≈1.7, ≈1.1 Hz, 1H, the other CH₂ proton), 1.16 (d, J = 6.3 Hz, 3H, isopropyl methyl), 0.79 (d, J = 6.3 Hz, 3H, other isopropyl methyl). ¹³C{¹H} (126 MHz, CDCl₃): δ 171.7 (carbonyl), 169.2 (carbonyl), 145.1 (C-1), 137.9 (C-1′), 133.1 (C-4′), 129.3 (C-2′/C-6′ or C-3′/C-5′), 128.8 (C-3/C-5), 128.4 (C-3′/C-5′ or C-2′/C-6′), 118.7 (C-4), 114.2 (C-2/C-6), 70.4 (isopropyl methine), 69.7 (quaternary aliphatic carbon), 48.3 (benzylic CH), 47.7 (CH₂), 21.5 [isopropyl methyl (correlating with methyl ¹H signal at δ 1.16 in HSQC spectrum)], 20.9 [other isopropyl methyl (correlating with methyl ¹H signal at δ 0.79 in HSQC spectrum)]. HRMS (ESI-TOF) m/z: [M+H]⁺ Calcd for C₂₀H₂₂ClN₂O₃ 373.1313; found 373.1309.

The ¹H spectrum indicated that the p-chlorophenyl ring provided a very unusual example of H-2′/H-6′ and H-3′/H-5′ having the same chemical shift (δ 7.13) and thus giving just a singlet that exhibits no correlations in the COSY spectrum (SI, p. S419). Consequently, an HSQC spectrum (SI, p. S420) indicated that two carbons (δ 129.3 and δ 128.4) exhibited correlations at this ¹H frequency. The equal J values (9.8 Hz) exhibited by the multiplets at δ 4.12 and δ 3.43 indicated that these signals resulted from the CH₂ protons; by elimination, the multiplet at δ 4.53 resulted from the benzylic CH proton. The additional J coupling for the CH₂ proton at δ 3.43 (compared to that at δ 4.12) results from coupling with the amide proton, as shown by a COSY spectrum. The relative intensities of the ¹H signals for the three aromatic multiplets of the –NH-phenyl group, the corresponding ¹³C chemical shifts, and the HSQC spectrum provided unambiguous assignments for these three types of CH groups. The single-intensity ¹H multiplet at δ 6.68 can result only from H-4, while the very shielded aromatic ¹³C signal at δ 114.2 clearly results from C-2/C-6 in light of ¹³C chemical shift data for aniline and N-substituted anilines (method B). Thus, the HSQC spectrum indicates that C-4 gives the signal at δ 118.7, while H-2/H-6 give the double-intensity multiplet at δ 6.47. By elimination, H-3/H-5 give the double-intensity multiplet at δ 7.05, and C-3/C-5 give the signal at δ 128.8. Thus, the NOE observed with mixing times of 0.10, 0.20, and 0.40 s (SI, pp. S421–S423) between the –NH-phenyl H-2/H-6 protons at δ 6.47 and the amine proton at δ 4.72 is reasonable. The NOE observed between the –NH-phenyl H-2/H-6 protons at δ 6.47 and the benzylic proton at δ 4.53 suggests that –NH-phenyl and the benzylic proton have a cis relationship because it would be hard for the phenyl ring to approach the benzylic proton with the other stereochemistry. Similarly, the weak cross peak between the amine proton at δ 4.72 and the p-chlorophenyl protons at δ 7.13 suggests that the amine proton and p-chlorophenyl group have a trans relationship. With mixing times of 0.10, 0.20, and 0.40 s, the CH₂ proton at δ 3.43 exhibits an NOE with the p-chlorophenyl protons at δ 7.13 but not with the –NH-phenyl H-2/H-6 protons at δ 6.47. Thus, the CH₂ proton at δ 3.43 appears to be cis to the p-chlorophenyl group and trans to the –NH-phenyl group.⁵²