Synthesis of Vicinal anti-Amino Alcohols from N-tert-Butanesulfinyl Aldimines and Cyclopropanols

Abstract

The stereoselective synthesis of vicinal amino alcohols derivatives from 1-substituted cyclopropanols and chiral N-tert-butanesulfinyl imines is described. Cyclopropanols are easily prepared from carboxylic esters upon reaction with ethylmagnesium bromide in the presence of titanium tetraisopropoxide and undergo carbon–carbon bond cleavage by means of diethylzinc to produce, upon base deprotonation, enolized zinc homoenolates, which react with chiral sulfinyl imines in a highly regio- and stereoselective manner.

1. Introduction

The allylation of imines is a matter of significant synthetic interest. When allylation is executed in a stereoselective fashion, it provides access to enantioenriched homoallyl amines, which serve as invaluable building blocks.¹ These compounds frequently feature as intermediates in numerous synthetic methodologies. The catalytic enantioselective allylation has been accomplished by employing substoichiometric quantities of chiral Lewis acids and/or bases.² However, stereoselective allylations are more commonly conducted using stoichiometric amounts of chiral reagents, particularly when operating on a larger scale. Stereoselectivity in these processes can be attributed to either the chiral imine (substrate diastereocontrol) or chiral allylating reagents (reagent diastereocontrol).³ Diastereoselective allylations of imines necessitate consideration of two critical factors: the face selectivity, influenced by the chiral substrate or reagent, and regioselectivity, which comes into play when substituted allylic reagents are involved. In the latter case, the formation of a contiguous stereocenter with a relative anti- or syn-configuration, facilitated through an ordered acyclic or cyclic transition state, is also feasible, with the metal playing a pivotal role in the governing transition state. Hydroxyallylation of imines holds special significance as it leads to the formation of vicinal allylic amino alcohols. This chemical motif is highly versatile and intriguing, garnering significant attention in the realms of natural product chemistry and drug discovery. Its unique structural features bestow compounds bearing this motif with a wide array of biological activities, rendering them promising candidates for pharmaceutical and medicinal applications. The most straightforward method for achieving hydroxy allylation of imines involves the use of hydroxy allyl organometallic compounds.⁴ Among these, 3-acyloxyallyl bromides have proven to be easily manageable and highly efficient precursors of these oxidofunctionalized allyl organometallic compounds.⁵ In this context, Norrby and Madsen established a protocol for the synthesis of vicinal amino alcohols. This method utilized a Barbier-type reaction between an imine and 3-benzoyloxyallyl bromide in the presence of zinc metal. The resulting addition products underwent debenzylation to yield amino alcohols in good yields, with diastereomeric ratios favoring the anti-isomer at greater than 85:15 (Scheme 1a).⁶ Similarly, Xu and Lin successfully developed a diastereoselective α-hydroxyallylation approach for the asymmetric synthesis of various β-amino-α-vinyl alcohols. They achieved this by employing highly diastereoselective Zn-promoted benzoyloxyallylation of chiral N-tert-butanesulfinyl imines with 3-bromopropenyl benzoate at room temperature, resulting in a wide range of vinylic amino alcohol derivatives in excellent yields. The diastereomeric ratios reached up to 99:1 in favor of the anti-isomers (Scheme 1b).⁷ This methodology was applied in a key step of the synthesis of the marine alkaloid ecteinascidin 743, a compound known for its potent cytostatic properties and antitumor activity. Ecteinascidin 743 is currently utilized in the treatment of soft-tissue sarcoma and ovarian cancer.⁸

Scheme 1. Hydroxyallylation of Imines and Carbonyl Compounds.

Concurrently, cyclopropanols have gained significant attention in organic synthesis as precursors of three-carbon building blocks.⁹ These easily accessible compounds¹⁰ contain strained three-membered rings that readily undergo carbon–carbon bond cleavage to release energy. Depending on the conditions used to promote ring opening, intermediates such as organometallic homoenolates, β-keto radicals, and O-protonated ketones are formed. Homoenolates are of particular interest due to the presence of two closely located carbon atoms with nucleophilic (carbon–metal bond) and electrophilic (carbonyl group) character. Transition metal derivatives of homoenolates have been employed in cross-coupling reactions.¹¹ On the other hand, the direct diastereoselective synthesis of anti-1,2-diols, with oxygen atoms bonded to secondary and allylic tertiary carbon atoms, as reported by Sekiguchi and Yoshikai, is of significant importance. The zinc homoenolate, formed upon the opening of the cyclopropanol, is in equilibrium under relatively strong basic conditions with an enolized homoenolate. The enolized homoenolate acts as an oxyallyl nucleophile, reacting with the aldehyde to serve as an oxygen-substituted allylating reagent. The resulting vicinal diols exhibit high diastereoselectivity, favoring the anti-isomers (Scheme 1c).¹² Importantly, enolized homoenolates can also function as enolates, depending on the reaction conditions and the electrophilic partner.¹³

Given our research group’s expertise in the diastereoselective allylation of N-tert-butanesulfinyl imines,¹⁴ and considering the bibliographic antecedents previously commented, we deemed it worthwhile to investigate the allylation of these chiral imines using zinc enolized homoenolates formed by the cleavage of 1-substituted cyclopropanols. We aimed to determine the influence of the tert-butanesulfinyl group on the stereoselectivity of the process. Starting cyclopropanols can be synthesized from carboxylic esters and ethylmagnesium bromide using the Kulinkovich protocol.¹⁵ Since sulfinyl imines are typically prepared from a carbonyl compound and tert-butanesulfinamide, the expected outcome is the formation of vicinal amino alcohol derivatives resulting from the coupling of two carbon atoms, ostensibly with the same polarity if considering their precursors. This transformation can be viewed as an umpolung reaction with respect to the enolized homoenolate (Scheme 1d).

Results and Discussion

The study of the allylation of N-tert-butanesulfinyl imines began with the optimization of the reaction conditions. For this purpose, we selected the (Rs)-tert-butanesulfinamide 1a derived from 3-phenylpropanal and 1-phenylcyclopropanol (2b) as the model substrates. Initially, we tested the conditions described by Sekiguchi and Yoshikai for selectively obtaining anti-1,2-diols (Scheme 1c).¹² The reaction was conducted with 2 equiv of Et₂Zn and 1 equiv of bipyridine as a base in THF at 23 °C for 1 h. Unfortunately, the reaction did not proceed under these conditions, and our analysis using ¹H NMR indicated the presence of only the starting imine 1a (Table 1, entry 1). Conversely, we repeated the same conditions but raised the temperature to 60 °C. Fortunately, we obtained allylation products 3ab and 4ab in a 4:1 ratio, with complete consumption of the starting imine 1a (Table 1, entry 2). Similar results were obtained when Et₃N was used as the base (Table 1, entry 3). However, when the reaction was carried out at 40 °C, we did not obtain the desired reaction products 3ab and 4ab. Instead, we observed the starting imine 1a and what appeared to be decomposition products of the starting materials (Table 1, entry 4). We noted that, apparently, the autocondensation product of imine 1a was the sole reaction product when EtONa in EtOH was used as the base (Table 1, entry 5). Complete decomposition of the starting materials occurred when DBU and Cs₂CO₃ were used as bases (Table 1, entries 6 and 7). When the reaction was conducted using pyridine or DIPEA as bases, we obtained the allylation products 3ab and 4ab with excellent conversions but poorer diastereoselectivity (Table 1, entries 8 and 9). Subsequently, we performed the reaction similarly to entry 3 but with the addition of 3 equiv of CuCN·2LiCl. Surprisingly, under these conditions, we obtained a diastereomeric mixture of 3ab and 4ab, with a reversed diastereoselectivity, where diastereoisomer 4ab became the major component in an almost 1:3 ratio (Table 1, entry 10). Lastly, we conducted the reaction under the same conditions as in entry 10 but in the absence of a base. Unfortunately, we observed only decomposition products (Table 1, entry 11).

Table 1. Optimization of the Reaction Conditions^a.

Entry	Reaction conditions	1a/3ab/4ab ratiob
1	Bpy (1 equiv), Et2Zn (2 equiv), 23 °C	100/0/0
2	Bpy (1 equiv), Et2Zn (2 equiv), 60 °C	0/82/18
3	Et3N (1 equiv), Et2Zn (2 equiv), 60 °C	0/83/17
4	Et3N (1 equiv), Et2Zn (2 equiv), 40 °C	100/0/0c
5	EtONa (2M, EtOH, 1 equiv), Et2Zn (2 equiv), 60 °C	--d
6	DBU (1 equiv), Et2Zn (2 equiv), 60 °C	--c
7	Cs2CO3 (1 equiv), Et2Zn (2 equiv), 60 °C	--c
8	Pyridine (1 equiv), Et2Zn (2 equiv), 60 °C	0/74/26
9	DIPEA (1 equiv), Et2Zn (2 equiv), 60 °C	0/60/40
10	Et3N (1 equiv), CuCN·2LiCl (0.5M, 3 equiv), Et2Zn (2 equiv), 60 °C	0/26/74
11	CuCN·2LiCl (0.5M, 3 equiv), Et2Zn (2 equiv), 60 °C	--c

^aReactions were carried out with 0.2 mmol of 1a and 2b.

^bRatio determined by analysis of the ¹H NMR spectrum of the crude reaction mixture.

^cTotal decomposition of the starting material 1a took place, and the expected products 3/4 were not observed.

^dAutocondensation product of imine 1a seems to be the reaction product.

With the optimized conditions in hand (Table 1, entry 3), in order to obtain diastereoisomer 3 as the major reaction product, we initially explored the reaction of various cyclopropanols 2 with sulfinyl imine 1a (Scheme 2). Alkyl and aryl cyclopropanol derivatives 2 participated in the hydroxyallylation with imine 1a, yielding the corresponding products 3ab–ai in moderately isolated yields. The scope of the reaction was explored at a 0.3 mmol scale, with the exception of 1-phenylcyclopropanol (2b), for which the reaction was also conducted on a 1.0 mmol-scale. This resulted in the production of the amino alcohol derivative 3ab with an 56% isolated yield, a little bit lower to that achieved at the 0.3 mmol scale. In Scheme 2, diastereomeric ratios of diastereoisomers 3 (always the major isomer) and 4 are provided in parentheses. Unfortunately, the reactions with 1-benzhydrylcyclopropan-1-ol (2h) did not yield the expected 1,2-aminoalcohol 3ah. Instead, only decomposition products were observed. Regarding the configuration of compounds 3, it was determined through crystal X-ray analysis (see the Supporting Information) of solid compounds 3ab and 3ai.¹⁶ The configurations of the remaining compounds 3 were assigned by analogy, assuming that they all were formed through the same stereochemical pathway. The allylation occurred via nucleophilic attack on the Si face of imines with R_S configuration, resulting in vicinal amino alcohols with a relative anti-configuration.

Scheme 2. Hydroxyallylation of Imine 1a with Different 1-Substituted Cyclopropanols 2^,,

Reactions were carried out with 0.3 mmol of 1a and 2.

Ratio determined by analysis of the ¹H NMR spectrum of the crude reaction mixture.

Reaction was carried out with 1.0 mmol of 1a and 2.

It is worth noting that hydroxyallylations can also be carried out under the same reaction conditions outlined in Scheme 2, using cyclopropanol (2a) as the hydroxyallylation agent. Interestingly, in the work of Sekiguchi and Yoshikai, all the examples presented involve substituted cyclopropanols.¹² The reaction products obtained in these cases are secondary allylic alcohols with a sulfonamide group in the neighboring position. The isolated yields, indicated in parentheses in Scheme 3 for the major reaction product 3, were moderate, as were the diastereomeric ratios in the case of imines derived from benzaldehyde (1b), isobutyraldehyde (1c), and O-TBS-protected hydroxyacetaldehyde (1d). In contrast, better diastereoselectivity, albeit with lower yield, was observed in the case of the imine derived from 3-phenylpropanal (1a) (Scheme 3).

Scheme 3. Hydroxyallylation of Imines 1 with Cyclopropanol 2a^,

Reactions were carried out with 0.3 mmol of 1 and 2a.

Ratio determined by analysis of the ¹H NMR spectrum of the crude reaction mixture.

We proceeded to investigate the reaction’s scope using the same cyclopropanols 2 and sulfinyl imine 1a. However, we applied the reaction conditions outlined in entry 10 of Table 1, aiming to favor the formation of diastereoisomers 4 as the major reaction products. The only deviation from the conditions previously employed in Scheme 2 was the addition of 3 equiv of CuCN·2LiCl (0.5 M in THF) (Scheme 4). Consequently, we consistently obtained the corresponding products 4ab–ai in moderately isolated yields as the primary components of the reaction products, with aminoalcohol derivatives 3 appearing as minor isomers (diastereomeric ratios are indicated in parentheses). Moreover, as observed with the prior conditions, the reaction failed to occur with 1-benzhydrylcyclopropan-1-ol (2h). Additionally, in the case of cyclopropanol 2f (3-bromopropyl derivative), the reaction did not yield the expected product 4af. An unexpected outcome arose in the hydroxyallylation involving 1-(2-bromophenyl)cyclopropanol (2i), as the predominant reaction product was the anti-isomer 3ai, the same one produced when working without copper cyanide. The configuration of compounds 4 was established after a simple sulfur atom epimerization of the sulfinyl unit in compound 3ae (vide infra). In this scenario, the nucleophilic attack of the allylic reagent occurred preferentially on the Re face of imines with R_S configuration, resulting in 1,2-aminoalcohol derivatives 4 with relative anti-configurations. The formation of syn-isomers resulting from an attack on the Si face of the imine could be an alternative possibility.

Scheme 4. Hydroxyallylation of Imine 1a with Different 1-Substituted Cyclopropanols 2 in the Presence of CuCN·2LiCl^,

Reactions were carried out with 0.3 mmol of 1a and 2.

Ratio determined by analysis of the ¹H NMR spectrum of the crude reaction mixture.

To expand the range of the reaction, we also investigated the reaction of 1-phenylcyclopropanol (2b) with various sulfinyl imines 1 under the reaction conditions outlined in Schemes 2 (Method A) and 4 (Method B). We observed slightly higher diastereoselectivities and yields when employing the reaction conditions of Method A. This consistently led to the formation of the anti-diastereoisomer 3 as the major component of the reaction mixture, resulting from the nucleophilic attack on the Si face of imines with R_S configuration (Scheme 5). In contrast, anti-diastereoisomers resulting from the nucleophilic attack on the Re face of imines with R_S configuration predominated when using the reaction conditions of Method B, producing compounds 4. Surprisingly, there was an exception to this general rule. When 1-phenylcyclopropanol (2b) reacted with the imine derived from benzaldehyde 1b under the conditions of Method B, it yielded the anti-isomer 3bb in fairly good yield with an 8:1 diastereomeric ratio. This anomalous result may be elucidated by considering steric or π–π stacking interactions between the two adjacent phenyl groups, potentially directing the process predominantly through the primary operating mechanism under the reaction conditions of Method A (see Figure 1a).

Scheme 5. Hydroxyallylation of Imines 1a, 1b, and 1e with Cyclopropanol 2b in the Presence and Absence of CuCN·2LiCl^,

Reactions were carried out with 0.3 mmol of 1 and 2b.

Ratio determined by analysis of the ¹H NMR spectrum of the crude reaction mixture.

Figure 1.

Speculative working models for explaining the stereochemical outcomes of the hydroxyallylations.

We determined the configuration of vicinal amino alcohol derivatives 4 by conducting a straightforward epimerization of the sulfur atom within the sulfinyl group under acidic conditions, employing a nonprotic solvent such as dichloromethane.¹⁷ We selected the anti-isomer 3ae as our model substrate. Under these conditions, the sulfinyl group was removed from the sulfinamide, resulting in the formation of the hydrochloride derivative 5ae and racemic tert-butanesulfinyl chloride. Subsequent addition of triethylamine led to the generation of sulfonamide derivatives as a mixture of diastereoisomers, 3ae and ent-4ae (Scheme 6). We analyzed the ¹H NMR spectrum of the crude reaction mixture and identified two distinct sets of signals: one corresponding to the starting anti-isomer 3ae and another set perfectly matching the signals of compound 4ae. This unequivocally confirmed the anti-relative configuration of amino alcohol derivatives 4, as the ¹H NMR spectra of ent-4ae and 4ae were entirely identical (see Supporting Information). Furthermore, a simple TLC experiment revealed identical R_f values for 4ae and the epimerized product of 3ae (ent-4ae).

Scheme 6. Epimerization of the Sulfur Atom of Amino Alcohol Derivative 3ae.

It is important to emphasize that amino alcohol derivatives 3 and 4, featuring various functionalities within their structures, hold significant potential for applications in synthesis as precursors to both carbo- and heterocyclic compounds, as well as others with potential biological activity. In this context, we present three examples of direct transformations of these amino alcohols in Scheme 7. To illustrate, the ring-closing metathesis of diene amino alcohol 3eb yielded the aminocycloheptenol derivative 6 in 55% yield (Scheme 7a). Conversely, the bromo-substituted compound 3af was converted into hydroxy vinyl piperidine 7, nearly quantitatively, through the removal of the sulfinyl group under acidic conditions, followed by a basic workup (Scheme 7b). Lastly, cross-metathesis involving the selectively protected amino diol derivative 3da and pentadec-1-ene resulted in N-tert-butanesulfinyl 1-O-TBS protected l-sphingosine 8 in 60% yield (Scheme 7c).

Scheme 7. Synthetic Transformations of Amino Alcohol Derivatives 3.

The stereochemical outcomes of these reactions were elucidated by considering the formation of an enolized zinc homoenolate with a Z configuration, featuring a stabilizing interaction between the oxygen of the enolate and the zinc-bound homoenolate, which interacts with the chiral sulfinyl imine 1. The formation of the enolized zinc homoenolate is supported by DFT calculations.¹² These calculations, conducted for the reaction of this organometallic intermediate with aldehydes, anticipate that the allylation proceeds through a chairlike Zimmerman–Traxler transition state. In this transition state, the larger alkyl or aryl group of the aldehyde occupies an axial position, while the R¹ group of the enolate is positioned equatorially. In the case of N-tert-butanesulfinyl imines 1, under the reaction conditions of Method A, we propose a working model A in which the zinc homoenolate coordinates with both the nitrogen of the imine and the oxygen of the sulfinyl group, forming a bicyclic environment composed of a 4-membered ring (N–S–O–Zn), and a chairlike 6-membered ring. In this configuration, the R¹ group of the enolate assumes a pseudoequatorial position, while the R² and sulfinyl groups of the imine are diaxially disposed. In this scenario, hydroxyallylation occurs at the Si face of the imine with R_S configuration, yielding the anti-diastereoisomer 3, consistent with experimental observations (Figure 1a). The formation of other anti-diastereoisomers 4 under the reaction conditions of Method B could be explained by considering an acyclic model. When hydroxyallylation is conducted in the presence of a large excess of copper cyanide, the formation of cyclic intermediates could be avoided due to the formation of zinc–copper couple intermediates with saturated coordination spheres, avoiding the formation of cyclic intermediates. Consequently, the addition to the imine may occur through an open transition state. The most stable configuration of the imine assumes an s-cis conformation, with the Re face of N-tert-butanesulfinyl imines 1 (with R_S configuration) being the less hindered face. In this manner, the configuration of the stereogenic center bonded to the nitrogen in the hydroxyallylated product is the opposite of that obtained when using Method A. Regarding the relative anti-configuration, it can be explained by considering an open transition state (Transition State B) that minimizes destabilizing dipole interactions with the nitrogen of the imine and the oxygen of the enolate in an antiperiplanar disposition, thereby accounting for the preferential formation of anti-diastereoisomer 4 (Figure 1b). As a result, both reaction pathways illustrated in Figure 1 could be operating to varying extents under the reaction conditions for Methods A and B, which explains why mixtures of diastereoisomers 3 and 4 were consistently obtained.

Conclusions

In conclusion, our investigation into the hydroxyallylation of N-tert-butanesulfinyl imines with cyclopropanols has provided valuable insights into the diastereoselective formation of vicinal amino alcohols. Notably, our research not only fine-tuned the reaction conditions for this transformation but also showcased the method’s versatility across a wide range of substrates. Furthermore, by unraveling the stereochemical outcomes of these reactions, we gained significant understanding of the mechanistic intricacies governing the preferential formation of anti-diastereoisomers as the predominant reaction products. These densely functionalized amino alcohol derivatives hold promise for diverse synthetic applications, exemplified by their direct conversion into various valuable carbo- and heterocyclic compounds. This work offers new avenues for the efficient synthesis of complex molecules with potential biological activities. As such, it holds great potential in the realms of medicinal chemistry and natural product synthesis.

Experimental Section

General Remarks

Reagents and solvents were purchased from commercial suppliers and used as received. (R)-tert-Butanesulfinamide was a gift of Medalchemy (>99% ee by chiral HPLC on a Chiracel AS column, 90:10 n-hexane/i-PrOH, 1.2 mL/min, λ = 222 nm). Optical rotations were measured using a Jasco P-1030 polarimeter with a thermally jacketed 5 cm cell at approximately 23 °C, and concentrations (c) are given in g/100 mL. Low-resolution mass spectra (EI) were obtained with an Agilent GC/MS5973N spectrometer at 70 eV, and fragment ions in m/z with relative intensities (%) in parentheses. High-resolution mass spectra (HRMS) were also carried out in the electron impact mode (EI) at 70 eV and on a Finnigan MAT95S spectrometer equipped with a time-of-flight (TOF) analyzer and the samples were ionized by ESI techniques and introduced through an ultrahigh pressure liquid chromatography (UPLC) model. NMR spectra were recorded at 300 or 400 MHz for ¹H NMR and at 75 or 100 MHz for ¹³C NMR with a Bruker AV300 Oxford or a Bruker AV400 spectrometers, respectively, using CDCl₃ as solvent, and TMS as internal standard (0.00 ppm). The data are reported as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved, br s = broad signal, coupling constant(s) in Hz, integration. ¹³C NMR spectra were recorded with ¹H-decoupling at 100 MHz and referenced to CDCl₃ at 77.16 ppm. DEPT-135 experiments were performed to assign CH, CH₂, and CH₃. TLCs were performed on prefabricated Merck aluminum plates with silica gel 60 coated with fluorescent indicator F₂₅₄ and were visualized with phosphomolybdic acid (PMA) stain. The R_f values were calculated under these conditions. Flash chromatography was carried out on handpacked columns of silica gel 60 (230–400 mesh). Compounds 1a [R = Ph(CH₂)₂],¹⁸1b (R = Ph),¹⁹1c (R = i-Pr),¹⁹1d (R = TBSOCH₂),²⁰ and 1e [R = CH₂=CH(CH₂)₃]²¹ were prepared from the corresponding aldehyde and (R)-tert-butanesulfinamide according to previously published procedures. Compound 2a was commercially available. Compounds 2b (R = Ph),²²2c [R = CH₃(CH₂)₉],²³2d [R = Br(CH₂)₆], 2e [R = Br(CH₂)₅],²⁴2f [R = Br(CH₂)₃],²⁵2g [R = CH₂=CH(CH₂)₃], 2h (R = Ph₂CH), and 2i (R = 2-BrC₆H₄)²⁶ were prepared from the corresponding ethyl ester and ethylmagnesium bromide in the presence of titanium tetraisopropoxide.¹⁵

General Procedure for the Reaction of Sulfinyl Imines 1 and Cyclopropanols 2 and Synthesis of Compounds 3 (Method A)

To a solution of corresponding cyclopropanol 2 (0.3 mmol) in dry THF (1.8 mL) was sequentially added Et₃N (42 μL, 0.3 mmol), a 1 M solution of Et₂Zn in toluene (0.6 mL, 0.6 mmol), and the corresponding sulfinyl imine imine 1 (0.3 mmol). The reaction mixture was stirred at 60 °C (oil bath) for 15 h. Then, the reaction was cooled to room temperature and hydrolyzed with a saturated aqueous solution of NH₄Cl (5.0 mL), extracted with AcOEt (3 × 10 mL), the combined organic phases dried over anhydrous MgSO₄, and the solvents evaporated (15 Torr). The residue was purified by column chromatography (silica gel, hexane/EtOAc) to yield pure compounds 3.

(R_S,3S,4R)-4-Amino-N-(tert-butanesulfinyl)-6-phenylhex-1-en-3-ol (3aa)

Following the general procedure, compound 3aa (24.8 mg, 0.085 mmol, 28%) was obtained as a yellow solid; mp 66–68 °C (hexane/CH₂Cl₂); [α]²³_D = +33.3 (c = 0.99, CH₂Cl₂); R_f = 0.30 (hexane/EtOAc, 1:1); ¹H NMR (300 MHz, CDCl₃) δ 7.40–7.19 (m, 5H), 5.89 (ddt, J = 15.8, 10.6, 4.6 Hz, 1H), 5.43–5.36 (m, 1H), 5.29 (dt, J = 10.6, 1.6 Hz, 1H), 4.34–4.20 (m, 1H), 3.47–3.34 (m, 1H), 2.90 (dddt, J = 18.9, 14.1, 9.3, 4.4 Hz, 2H), 2.79–2.62 (m, 2H), 1.32 (s, 9H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 141.4 (C), 136.5 (CH), 128.5 (CH), 128.3 (CH), 126.0 (CH), 117.0 (CH₂), 75.0 (CH), 60.8 (CH), 56.3 (C), 32.1 (CH₂), 31.2 (CH₂), 22.9 (CH₃); LRMS (EI) m/z 295 (M⁺, < 1%), 150 (14), 134 (20), 117 (19), 104 (24), 91 (86), 70 (19), 57 (37), 43 (100); HRMS (EI-TOF) Calcd for C₁₆H₂₅NO₂S [M⁺] 295.1606, found 295.1613.

(R_S,3R,4R)-4-Amino-N-(tert-butanesulfinyl)-3,6-diphenylhex-1-en-3-ol (3ab)

Following the general procedure, compound 3ab (68.5 mg, 0.19 mmol, 65%) was obtained as a white solid. The reaction was also performed with 1.0 mmol of cyclopropanol 2b (134.2 mg, 1.0 mmol), 1.0 mmol of sulfinyl imine 1a (237.4 mg), 1.0 mmol of Et₃N (101.2 mg, 139 μL), and 2.0 mmol of a 1 M solution of Et₂Zn in toluene (2.0 mL), in 6.0 mL of dry THF. After stirring the reaction at 60 °C (oil bath) for 15 h, it was cooled to room temperature and hydrolyzed with a saturated aqueous solution of NH₄Cl (15.0 mL), extracted with AcOEt (3 × 15 mL), the combined organic phases dried over anhydrous MgSO₄, and the solvents evaporated (15 Torr). The residue was purified by column chromatography (silica gel, hexane/EtOAc, 4:1) to yield pure compound 3ab (208.1 mg, 0.56 mmol, 56%) as a white solid; mp 130–133 °C (hexane/CH₂Cl₂); [α]²³_D = −7.9 (c = 1.24, CH₂Cl₂); R_f = 0.25 (hexane/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃) δ 7.43–7.09 (m, 8H), 7.03–6.79 (m, 2H), 6.45 (dd, J = 17.1, 10.7 Hz, 1H), 5.83–5.54 (m, 2H), 5.21 (s, 1H), 3.66 (d, J = 10.3 Hz, 1H), 3.44 (td, J = 10.7, 2.0 Hz, 1H), 2.73 (ddd, J = 13.5, 8.8, 4.4 Hz, 1H), 2.51–2.33 (m, 1H), 1.71–1.54 (m, 2H), 1.34 (s, 9H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 143.3 (C), 140.9 (C), 137.3 (CH), 128.5 (CH), 128.5 (CH), 127.7 (CH), 126.9 (CH), 126.2 (CH), 119.8 (CH₂), 78.8 (C), 67.4 (CH), 56.8 (C), 34.4 (CH₂), 32.7 (CH₂), 23.1 (CH₃); LRMS (EI) m/z 297 (M⁺–C₄H₉O, 2%), 239 (12), 238 (78), 234 (34), 164 (52), 143 (55), 133 (53), 117 (100), 91 (98), 57 (40), 55 (36); HRMS (EI-TOF) Calcd for C₁₈H₂₀NO₂S [M⁺–C₄H₉] 314.1215, found 314.1212.

(R_S,3R,4S)-3-Amino-N-(tert-butanesulfinyl)-1-phenyl-4-vinyltetradecan-4-ol (3ac)

Following the general procedure, compound 3ac (60.7 mg, 0.14 mmol, 48%) was obtained as a yellow wax; [α]²³_D = −2.1 (c = 1.80, CH₂Cl₂); R_f = 0.54 (hexane/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.04 (m, 5H), 5.77 (dd, J = 17.2, 10.6 Hz, 1H), 5.46–5.33 (m, 2H), 4.67 (s, 1H), 3.56 (d, J = 10.2 Hz, 1H), 3.22–3.04 (m, 1H), 2.85 (ddd, J = 13.7, 9.1, 4.6 Hz, 1H), 2.62–2.47 (m, 1H), 1.55–1.41 (m, 4H), 1.31 (s, 9H), 1.29–1.16 (m, 16H), 0.88 (t, J = 6.9 Hz, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 141.45 (C), 140.1 (CH), 128.7 (CH), 128.65 (CH), 126.3 (CH), 118.0 (CH₂), 76.7 (C), 65.4 (CH), 56.7 (C), 38.3 (CH₂), 34.8 (CH₂), 33.0 (CH₂), 32.1 (CH₂), 30.2 (CH₂), 29.8 (CH₂), 29.7 (CH₂), 29.7 (CH₂), 29.5 (CH₂), 23.1 (CH₃), 22.8 (CH₂), 14.3 (CH₃); LRMS (EI) m/z 379 (M⁺–C₄H₈, 1%), 361 (3), 298 (15), 238 (70), 197 (27), 182 (15), 164 (31), 157 (11), 134 (44), 117 (79), 91 (100), 57 (77), 55 (27), 43 (27), 41 (25); HRMS (EI-TOF) Calcd for C₂₆H₄₅NO₂S [M⁺] 435.3171, found 435.3168.

(R_S,3R,4S)-3-Amino-10-bromo-N-(tert-butanesulfinyl)-1-phenyl-4-vinyldecan-4-ol (3ad)

Following the general procedure, compound 3ad (60.5 mg, 0.13 mmol, 44%) was obtained as a yellow oil; [α]²³_D = +9.5 (c = 0.80, CH₂Cl₂); R_f = 0.29 (hexane/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃) δ 7.38–7.07 (m, 5H), 5.77 (dd, J = 17.2, 10.6 Hz, 1H), 5.49–5.24 (m, 2H), 4.68 (s, 1H), 3.56 (d, J = 10.2 Hz, 1H), 3.38 (t, J = 6.9 Hz, 2H), 3.20–3.05 (m, 1H), 2.93–2.72 (m, 1H), 2.63–2.45 (m, 1H), 1.81 (dt, J = 14.5, 6.9 Hz, 2H), 1.60 (s, 4H), 1.55–1.44 (m, 3H), 1.31 (s, 9H), 1.37–1.26 (m, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 141.4 (C), 139.9 (CH), 128.7 (CH), 128.7 (CH), 128.6 (CH), 126.35 (CH), 118.1 (CH₂), 76.7 (C), 65.4 (CH), 56.8 (C), 38.2 (CH₂), 34.8 (CH₂), 34.1 (CH₂), 32.9 (CH₂), 32.8 (CH₂), 29.3 (CH₂), 28.2 (CH₂), 23.15 (CH₃), 22.7 (CH₂); LRMS (EI) m/z 322 [M⁺(⁸¹Br)–C₄H₁₀NO₂S, 12%], 320 [M⁺(⁷⁹Br)–C₄H₁₀NO₂S, 12%], 239 (10), 238 (63), 221 (14), 219 (14), 182 (15), 164 (33), 157 (16), 134 (33), 117 (75), 91 (100), 67 (13), 57 (60), 55 (29), 41 (24); HRMS (EI-TOF) Calcd for C₁₈H₂₇NO₂S [M⁺–C₄H₉Br] 321.1762, found 321.176.

(R_S,3R,4S)-3-Amino-9-bromo-N-(tert-butanesulfinyl)-1-phenyl-4-vinylnonan-4-ol (3ae)

Following the general procedure, compound 3ae (52.0 mg, 0.12 mmol, 39%) was obtained as a yellow oil; [α]²³_D = +6.7 (c = 2.30, CH₂Cl₂); R_f = 0.35 (hexane/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃) δ 7.39–7.08 (m, 5H), 5.78 (dd, J = 17.2, 10.6 Hz, 1H), 5.50–5.30 (m, 2H), 4.73 (s, 1H), 3.58 (d, J = 10.2 Hz, 1H), 3.38 (t, J = 6.8 Hz, 2H), 3.20–3.07 (m, 1H), 2.93–2.80 (m, 1H), 2.63–2.48 (m, 1H), 2.02–1.93 (m, 2H), 1.87–1.73 (m, 2H), 1.63–1.45 (m, 4H), 1.40–1.33 (m, 2H), 1.33 (s, 9H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 141.3 (C), 139.8 (CH), 128.7 (CH), 128.7 (CH), 126.3 (CH), 118.2 (CH₂), 76.6 (C), 65.3 (CH), 56.8 (C), 38.05 (CH₂), 34.8 (CH₂), 34.1 (CH₂), 32.8 (CH₂), 32.8 (CH₂), 28.6 (CH₂), 23.1 (CH₃), 22.0 (CH₂); LRMS (EI) m/z 308 [M⁺(⁸¹Br)–C₄H₁₀NO₂S, 13%], 306 [M⁺(⁷⁹Br)–C₄H₁₀NO₂S, 13%], 238 (61), 207 (14), 205 (14), 182 (14), 164 (34), 157 (19), 134 (29), 117 (74), 91 (100), 67 (12), 57 (53), 55 (35), 41 (19); HRMS (EI-TOF): Calcd for C₁₇H₂₆NO₂S [M⁺–C₄H₈Br] 308.1684, found 308.1695.

(R_S,3R,4S)-3-Amino-7-bromo-N-(tert-butanesulfinyl)-1-phenyl-4-vinylheptan-4-ol (3af)

Following the general procedure, compound 3af (51.2 mg, 0.12 mmol, 41%) was obtained as a yellow oil; [α]²³_D = +6.1 (c = 1.20, CH₂Cl₂); R_f = 0.20 (hexane/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃) δ 7.34–7.08 (m, 6H), 5.71 (dd, J = 17.1, 10.6 Hz, 1H), 5.35–5.00 (m, 2H), 3.99–3.76 (m, 3H), 3.28 (ddd, J = 9.6, 7.0, 2.7 Hz, 1H), 2.97–2.81 (m, 1H), 2.55 (ddd, J = 13.7, 10.2, 6.7 Hz, 1H), 2.30–2.13 (m, 1H), 1.96–1.79 (m, 3H), 1.79–1.61 (m, 2H), 1.29 (s, 9H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 142.2 (C), 140.0 (CH), 128.6 (CH), 128.5 (CH), 126.0 (CH), 114.35 (CH₂), 87.8 (C), 68.9 (CH), 61.1 (CH₂), 56.5 (C) 35.45 (CH₂), 33.9 (CH₂), 32.95 (CH₂), 25.2 (CH₂), 23.2 (CH₃); LRMS (EI) m/z 279 (M⁺–C₄H₉Br, 24%), 239 (12), 238 (73), 216 (12), 187 (19), 182 (26), 164 (67), 134 (46), 118 (11), 117 (100), 104 (17), 99 (18), 97 (92), 91 (92), 79 (13), 57 (46), 55 (65), 41 (21); HRMS (EI-TOF): Calcd for C₁₅H₂₁NOS [M⁺–C₄H₉BrO] 263.1344, found 263.1337.

(R_S,3R,4S)-3-Amino-N-(tert-butanesulfinyl)-1-phenyl-4-vinyldec-9-en-4-ol (3ag)

Following the general procedure, compound 3ag (36.2 mg, 0.09 mmol, 32%) was obtained as a yellow oil; [α]²³_D = −4.6 (c = 1.13, CH₂Cl₂); R_f = 0.41 (hexane/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃) δ 7.43–6.97 (m, 5H), 5.89–5.62 (m, 2H), 5.51–5.22 (m, 2H), 5.05–4.85 (m, 2H), 4.67 (s, 1H), 3.56 (d, J = 10.2 Hz, 1H), 3.13 (m, 1H), 2.85 (m, 1H), 2.55 (m, 1H), 1.98 (m, 4H), 1.57–1.39 (m, 4H), 1.31 (s, 9H), 1.33–1.25 (m, 2H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 141.4 (C), 140.0 (CH), 139.15 (CH), 128.7 (CH), 128.65 (CH), 128.7 (CH), 128.6 (CH), 128.5 (CH), 128.4 (CH), 126.3 (CH), 118.1 (CH₂), 114.4 (CH₂), 76.7 (C), 65.4 (CH), 56.8 (C), 38.1 (CH₂), 34.8 (CH₂), 33.8 (CH₂), 33.0 (CH₂), 29.5 (CH₂), 23.1 (CH₃), 22.4 (CH₂); LRMS (EI) m/z 321 (M⁺+1–C₄H₈, 1%), 320 (2), 238 (54), 182 (13), 164 (32), 139 (17), 134 (31), 117 (75), 91 (100), 83 (14), 57 (53), 55 (41), 41 (28); HRMS (EI-TOF) Calcd for C₁₈H₂₇NO₂S [M⁺–C₄H₈] 321.1762, found 321.1759.

(R_S,3R,4R)-4-Amino-3-(2-bromophenyl)-N-(tert-butanesulfinyl)-6-phenylhex-1-en-3-ol (3ai)

Following the general procedure, compound 3ai (66.2 mg, 0.15 mmol, 49%) was obtained as a white solid; mp 38–40 °C (hexane/CH₂Cl₂); [α]²³_D = −5.0 (c = 1.10, CH₂Cl₂); R_f = 0.19 (hexane/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃) δ 7.58 (dd, J = 7.9, 1.4 Hz, 1H), 7.38–7.04 (m, 7H), 6.96 (dd, J = 7.9, 1.6 Hz, 1H), 6.52 (dd, J = 16.9, 10.6 Hz, 1H), 5.90–5.54 (m, 2H), 5.18 (s, 1H), 4.60 (td, J = 9.9, 3.2 Hz, 1H), 3.75 (d, J = 9.9 Hz, 1H), 2.83–2.69 (m, 1H), 2.54–2.40 (m, 1H), 1.63–1.45 (m, 2H), 1.32 (s, 9H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 141.1 (C), 137.65 (CH), 136.25 (CH), 130.8 (CH), 129.2 (CH), 128.6 (CH), 128.5 (CH), 127.0 (CH), 126.2 (CH), 121.9 (C), 120.1 (CH₂), 79.7 (C), 62.3 (CH), 56.6 (C), 35.1 (CH₂), 32.9 (CH₂), 23.1 (CH₃); LRMS (EI) m/z 314 [M⁺(⁸¹Br)–C₄H₉NO₂S, 16%], 312 [M⁺(⁷⁹Br)–C₄H₉NO₂S, 16%], 239 (12), 238 (74), 182 (22), 164 (55), 134 (18), 132 (49), 117 (100), 91 (99), 77 (13), 57 (40), 55 (13), 41 (11); HRMS (EI-TOF) Calcd for C₁₈H₂₀NO₂S [M⁺–C₄H₈Br] 314.1215, found 314.1212.

(R_S,1R,2S)-1-Amino-N-(tert-butanesulfinyl)-1-phenylbut-3-en-2-ol (3ba)

Following the general procedure, compound 3ba (40.8 mg, 0.153 mmol, 51%) was obtained as a yellow solid; mp 52–54 °C (hexane/CH₂Cl₂); [α]²³_D = +27.8 (c = 0.98, CH₂Cl₂); R_f = 0.31 (hexane/EtOAc, 1:1); ¹H NMR (300 MHz, CDCl₃) δ 7.34–7.18 (m, 6H), 5.55 (ddd, J = 17.2, 10.5, 4.8 Hz, 1H), 5.32 (dq, J = 17.3, 1.6 Hz, 1H), 5.23–5.14 (m, 1H), 4.57 (dd, J = 7.4, 4.2 Hz, 1H), 4.50–4.41 (m, 1H), 4.11 (d, J = 7.4 Hz, 1H), 1.12 (s, 9H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 138.3 (C), 135.6 (CH), 128.5 (CH), 127.8 (CH) 127.1 (CH), 117.8 (CH₂), 74.7 (CH), 60.7 (CH), 56.9 (C), 22.9 (CH₃); LRMS (EI) m/z 267 (M⁺, < 1%), 210 (12), 154 (37), 130 (25), 104 (15), 77 (11), 57 (32), 43 (100); HRMS (EI-TOF) Calcd for C₁₄H₂₁NO₂S (M⁺) 267.1293; found 267.1279.

(R_S,1R,2R)-1-Amino-N-(tert-butanesulfinyl)-1,2-diphenylbut-3-en-2-ol (3bb)

Following the general procedure, compound 3bb (87.6 mg, 0.26 mmol, 85%) was obtained as a white solid; mp 192–195 °C (hexane/CH₂Cl₂); [α]²³_D = +25.9 (c = 2.44, CH₂Cl₂); R_f = 0.18 (hexane/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃) δ 7.44–7.10 (m, 8H), 6.95–6.84 (m, 2H), 6.35 (dd, J = 17.1, 10.7 Hz, 1H), 5.55–5.33 (m, 2H), 4.66 (d, J = 5.6 Hz, 1H), 4.11 (d, J = 5.3 Hz, 1H), 3.87 (s, 1H), 1.20 (s, 9H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 142.5 (C), 138.4 (CH), 137.5 (C), 129.0 (CH), 128.3 (CH), 128.0 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 126.7 (CH), 117.4 (CH₂), 79.0 (C), 68.5 (CH), 22.8 (CH₃); LRMS (EI) m/z 269 (M⁺–C₄H₉OH, 1%), 210 (31), 206 (40), 154 (100), 136 (30), 133 (47), 106 (41), 105 (27), 77 (23), 57 (29), 55 (30); HRMS (EI-TOF) Calcd for C₁₆H₁₆NO₂S [M⁺–C₄H₉] 286.0902, found 286.0914.

(R_S,3S,4R)-4-Amino-N-(tert-butanesulfinyl)-5-methylhex-1-en-3-ol (3ca)

Following the general procedure, compound 3ca (30.0 mg, 0.13 mmol, 43%) was obtained as a yellow solid; mp 35–37 °C (hexane/CH₂Cl₂); [α]²³_D = +31.6 (c = 1.05, CH₂Cl₂); R_f = 0.35 (hexane/EtOAc, 1:1); ¹H NMR (300 MHz, CDCl₃) δ 5.93 (ddd, J = 18.1, 10.3, 3.9 Hz, 1H), 5.49 (dt, J = 17.3, 1.9 Hz, 1H), 5.41 (dd, J = 10.9, 4.3 Hz, 1H), 4.70 (dt, J = 15.2, 7.1 Hz, 1H), 4.52 (br s, 1H), 1.28 (s, 9H), 1.05 (d, J = 6.7 Hz, 3H), 1.01 (d, J = 6.7 Hz, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 133.4 (CH), 119.8 (CH₂), 71.10 (CH) 61.9 (CH), 29.7 (C), 27.6 (CH), 22.4 (CH₃), 19.7 (CH₃), 19.5 (CH₃); LRMS (EI) m/z 233 (M⁺, < 1%), 207 (20), 183 (27), 152 (11), 108 (24), 77 (11), 57 (3), 43 (100); HRMS (EI-TOF) Calcd for C₇H₁₃NOS [M⁺–C₄H₁₀O] 159.0718, found 159.0713.

(R_S,3S,4R)-4-Amino-N-(tert-butanesulfinyl)-5-[(tert-butyldimethylsilyl)oxy]pent-1-en-3-ol (3da)

Following the general procedure, compound 3da (53.30 mg, 0.159 mmol, 53%) was obtained as a yellow oil; [α]²³_D = +31.6 (c = 1.05, CH₂Cl₂); R_f = 0.21 (hexane/EtOAc, 2:1); ¹H NMR (300 MHz, CDCl₃) δ 5.91 (ddd, J = 17.2, 10.6, 5.0 Hz, 1H), 5.37 (dt, J = 17.2, 1.7 Hz, 1H), 5.24 (dt, J = 10.6, 1.6 Hz, 1H), 4.28 (br s, 1H), 3.99 (dd, J = 10.3, 3.5 Hz, 2H), 3.83 (dd, J = 10.2, 4.5 Hz, 1H), 3.33 (dt, J = 4.8, 3.9 Hz, 1H), 1.23 (s, 10H), 0.89 (s, 9H), 0.09 (s, 6H), 0.08 (s, 6H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 137.5 (CH), 116.3 (CH₂), 73.9 (CH), 63.8 (CH₂), 59.9 (CH), 56.2 (C), 25.8 (CH₃), 22.7 (CH₃), 18.1 (C), −5.5 (CH₃), −5.6 (CH₃); LRMS (EI) m/z 335 (M⁺, < 1%), 279 (32), 261 (7), 204 (21), 173 (28), 156 (13), 141 (44), 116 (64), 100 (18), 83 (64), 73 (99), 57 (100), 41 (34); HRMS (EI-TOF) Calcd for C₇H₁₃NOS [M⁺–C₃H₅O] 278.1581, found 278.1576.

(R_S,3R,4R)-4-Amino-N-(tert-butanesulfinyl)-3-phenylnona-1,8-dien-3-ol (3eb)

Following the general procedure, compound 3eb (73.5 mg, 0.22 mmol, 73%) was obtained as a white solid; mp 106–109 °C (hexane/CH₂Cl₂); [α]²³_D = −62.4 (c = 0.86, CH₂Cl₂); R_f = 0.29 (hexane/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃) δ 7.54–7.18 (m, 5H), 6.48 (dd, J = 17.0, 10.7 Hz, 1H), 5.76–5.54 (m, 3H), 5.22 (s, 1H), 4.90–4.79 (m, 2H), 3.56 (d, J = 10.3 Hz, 1H), 3.48–3.37 (m, 1H), 1.99–1.84 (m, 1H), 1.85–1.71 (m, 1H), 1.54–1.35 (m, 1H), 1.28 (s, 9H), 1.25–1.05 (m, 3H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 143.6 (C), 138.2 (CH), 137.3 (CH), 128.5 (CH), 127.65 (CH), 126.9 (CH₂), 119.6 (CH), 114.85 (CH₂), 78.8 (C), 68.5 (CH), 56.7 (C), 32.9 (CH₂), 32.0 (CH₂), 25.9 (CH₂), 23.0 (CH₃); LRMS (EI) m/z 261 (M⁺–C₄H₉OH, 2%), 203 (12), 202 (96), 198 (32), 169 (10), 156 (26), 146 (79), 133 (100), 130 (20), 128 (29), 105 (35), 98 (21), 94 (16), 81 (55), 77 (30), 57 (85), 55 (83), 41 (34); HRMS (EI-TOF) Calcd for C₁₅H₂₁NO₂S [M⁺–C₄H₈] 279.1293, found 279.1295.

General Procedure for the Reaction of Sulfinyl Imines 1 and Cyclopropanols 2 in the Presence of CuCN·LiCl and Synthesis of Compounds 4 (Method B)

To a solution of corresponding cyclopropanol 2 (0.3 mmol) in dry THF (1.8 mL) was sequentially added Et₃N (42 μL, 0.3 mmol), a 1 M solution of Et₂Zn in toluene (0.6 mL, 0.6 mmol), and a 0.5 M solution of CuCN·LiCl in THF (1.8 mL, 0.9 mmol). The reaction mixture was stirred at 23 °C for 15 min. After that, the corresponding sulfinyl imine 1 (0.3 mmol) was added to the reaction mixture and continued stirring at 60 °C (oil bath) for 15 h. Then, the reaction was cooled to room temperature and hydrolyzed with a saturated aqueous solution of NH₄Cl (5.0 mL), extracted with AcOEt (3 × 10 mL), the combined organic phases dried over anhydrous MgSO₄, and the solvents evaporated (15 Torr). The residue was purified by column chromatography (silica gel, hexane/EtOAc) to yield pure compounds 4.

(R_S,3S,4S)-4-Amino-N-(tert-butanesulfinyl)-3,6-diphenylhex-1-en-3-ol (4ab)

Following the general procedure, compound 4ab (72.1 mg, 0.20 mmol, 68%) was obtained as a yellow oil; [α]²³_D = −24.2 (c = 1.70, CH₂Cl₂); R_f = 0.28 (hexane/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃) δ 7.43–7.14 (m, 10H), 6.04 (dd, J = 17.0, 10.7 Hz, 1H), 5.43 (dd, J = 17.0, 1.6 Hz, 1H), 5.17 (dd, J = 10.7, 1.6 Hz, 1H), 4.82 (s, 1H), 3.69–3.61 (m, 1H), 3.48 (d, J = 3.2 Hz, 1H), 2.97–2.83 (m, 1H), 2.66–2.55 (m, 1H), 2.28–2.16 (m, 2H), 1.06 (s, 9H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 144.5 (C), 141.5 (C), 140.3 (C), 137.3 (CH), 128.9 (CH), 128.7 (CH), 128.6 (CH), 127.2 (CH), 126.9 (CH), 126.15 (CH), 125.7 (CH), 114.8 (CH₂), 79.1 (C), 64.2 (CH), 55.8 (C), 32.45 (CH₂), 29.8 (CH₂), 28.3 (CH₂), 22.7 (CH₃); LRMS (EI) m/z 297 (M⁺–C₄H₉O, 1%), 239 (11), 238 (69), 234 (33), 182 (16), 164 (56), 143 (49), 134 (34), 133 (63), 117 (97), 105 (22), 91 (100), 57 (44), 55 (39); HRMS (EI-TOF) Calcd for C₁₈H₂₀NO₂S [M⁺–C₄H₉] 314.1215, found 314.1203.

(R_S,3S,4R)-3-Amino-N-(tert-butanesulfinyl)-1-phenyl-4-vinyltetradecan-4-ol (4ac)

Following the general procedure, compound 4ac (52.28 mg, 0.12 mmol, 40%) was obtained as a yellow wax; [α]²³_D = −48.3 (c = 0.38, CH₂Cl₂); R_f = 0.29 (hexane/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.03 (m, 5H), 5.71 (dd, J = 17.3, 10.8 Hz, 1H), 5.36–5.12 (m, 2H), 3.37 (d, J = 7.2 Hz, 1H), 3.11 (ddd, J = 10.4, 7.2, 2.2 Hz, 1H), 2.97 (ddd, J = 13.9, 9.1, 4.6 Hz, 1H), 2.88 (s, 1H), 2.70 (dt, J = 13.9, 8.4 Hz, 1H), 1.58–1.41 (m, 2H), 1.30 (s, 9H), 1.28–1.14 (m, 12H), 0.92–0.84 (m, 5H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 141.75 (C), 140.1 (CH), 128.8 (CH), 128.6 (CH), 128.5 (CH), 126.8 (CH), 115.3 (CH₂), 77.5 (C), 64.2 (CH), 56.7 (C), 38.3 (CH₂), 32.5 (CH₂), 32.4 (CH₂), 32.05 (CH₂), 30.2 (CH₂), 29.7 (CH₂), 29.7 (CH₂), 29.45 (CH₂), 23.2 (CH₂), 23.2 (CH₃), 22.8 (CH₂), 14.3 (CH₃); LRMS (EI) m/z 379 (M⁺–C₄H₈, 2%), 298 (13), 238 (57), 197 (18), 182 (16), 181 (22), 164 (34), 134 (38), 117 (100), 91 (99), 57 (75), 55 (28), 43 (33), 41 (27); HRMS (EI-TOF) Calcd for C₂₆H₄₅NO₂S [M⁺] 435.3171, found 435.3181.

(R_S,3S,4R)-3-Amino-10-bromo-N-(tert-butanesulfinyl)-1-phenyl-4-vinyldecan-4-ol (4ad)

Following the general procedure, compound 4ad (52.3 mg, 0.11 mmol, 38%) was obtained as a yellow wax; [α]²³_D = −29.5 (c = 0.90, CH₂Cl₂); R_f = 0.14 (hexane/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃) δ 7.46–7.09 (m, 5H), 5.72 (dd, J = 17.2, 10.8 Hz, 1H), 5.39–5.14 (m, 2H), 3.47 (d, J = 7.1 Hz, 1H), 3.40 (t, J = 6.6 Hz, 2H), 3.17–3.06 (m, 1H), 3.06–2.87 (m, 3H), 2.82–2.59 (m, 3H), 1.90–1.72 (m, 5H), 1.32 (s, 9H), 1.44–1.01 (m, 4H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 141.7 (C), 139.9 (CH), 128.8 (CH), 128.7 (CH), 128.6 (CH), 128.6 (CH), 128.4 (CH), 126.1 (CH), 115.5 (CH₂), 77.4 (C), 64.4 (CH), 56.8 (C), 38.0 (CH₂), 34.1 (CH₂), 32.8 (CH₂), 32.5 (CH₂), 29.85 (CH₂), 29.2 (CH₂), 28.2 (CH₂), 23.2 (CH₃), 23.0 (CH₂); LRMS (EI) m/z 322 [M⁺(⁸¹Br)–C₄H₁₀NO₂S, 10%], 320 [M⁺(⁷⁹Br)–C₄H₁₀NO₂S, 10%], 238 (53), 221 (11), 219 (10), 182 (14), 164 (37), 157 (17), 134 (26), 117 (77), 91 (100), 67 (13), 57 (58), 55 (28), 41 (25); HRMS (EI-TOF) Calcd for C₁₈H₂₈NO₂S [M⁺–C₄H₈Br] 322.1841, found 322.1838.

(R_S,3S,4R)-3-Amino-9-bromo-N-(tert-butanesulfinyl)-1-phenyl-4-vinylnonan-4-ol (4ae)

Following the general procedure, compound 4ae (50.7 mg, 0.11 mmol, 38%) was obtained as a colorless wax; [α]²³_D = −40.3 (c = 2.10, CH₂Cl₂); R_f = 0.18 (hexane/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.16 (m, 5H), 5.72 (dd, J = 17.3, 10.8 Hz, 1H), 5.38–5.15 (m, 2H), 3.47 (d, J = 7.1 Hz, 1H), 3.39 (t, J = 6.8 Hz, 2H), 3.11 (ddd, J = 10.5, 7.2, 2.1 Hz, 1H), 3.05–2.90 (m, 2H), 2.77–2.62 (m, 2H), 2.13–1.94 (m, 1H), 1.91–1.70 (m, 4H), 1.66–1.41 (m, 4H), 1.32 (s, 9H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 141.7 (C), 139.8 (CH), 128.8 (CH), 128.7 (CH), 128.6 (CH), 128.4 (CH), 126.1 (CH), 115.6 (CH₂), 77.3 (C), 64.3 (CH), 56.8 (C), 37.9 (CH₂), 34.0 (CH₂), 32.9 (CH₂), 32.5 (CH₂), 32.3 (CH₂), 28.6 (CH₂), 23.2 (CH₃), 22.4 (CH₂); LRMS (EI) m/z [M⁺(⁸¹Br)–C₄H₁₀NO₂S, 12%], 306 [M⁺(⁷⁹Br)–C₄H₁₀NO₂S, 12%, 238 (53), 205 (10), 182 (14), 164 (39), 157 (21), 134 (22), 117 (83), 91 (100), 67 (13), 57 (55), 55 (32), 41 (19); HRMS (EI-TOF) Calcd for C₁₇H₂₅NO₂S [M⁺–C₄H₉Br] 307.1606, found 307.1615.

(R_S,3S,4R)-3-Amino-N-(tert-butanesulfinyl)-1-phenyl-4-vinyldec-9-en-4-ol (4ag)

Following the general procedure, compound 4ag (39.6 mg, 0.10 mmol, 35%) was obtained as a yellow wax; [α]²³_D = −45.7 (c = 1.11, CH₂Cl₂); R_f = 0.20 (hexane/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃) δ 7.33–7.12 (m, 5H), 5.91–5.61 (m, 2H), 5.36–5.14 (m, 2H), 5.02–4.84 (m, 2H), 3.45 (d, J = 7.3 Hz, 1H), 3.16–3.02 (m, 1H), 3.00–2.88 (m, 2H), 2.86 (s, 1H), 2.76–2.59 (m, 2H), 2.11–1.94 (m, 4H), 1.89–1.68 (m, 2H), 1.64–1.39 (m, 2H), 1.30 (s, 9H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 141.7 (C), 140.0 (CH), 139.0 (CH), 128.8 (CH), 128.7 (CH), 128.6 (CH), 128.55 (CH), 128.4 (CH), 126.1 (CH), 115.4 (CH₂), 114.5 (CH₂), 77.4 (C), 64.35 (CH), 56.8 (C), 38.1 (CH₂), 33.8 (CH₂), 32.6 (CH₂), 32.4 (CH₂), 29.45 (CH₂), 23.2 (CH₃), 22.7 (CH₂); LRMS (EI) m/z 321 (M⁺–C₄H₈, 1%), 238 (42), 182 (12), 164 (33), 139 (11), 136 (14), 134 (21), 117 (81), 108 (10), 104 (12), 91 (100), 67 (12), 57 (49), 55 (35), 41 (25); HRMS (EI-TOF) Calcd for C₁₈H₂₇NO₂S [M⁺–C₄H₈] 321.1766, found 321.1764.

(R_S,3S,4S)-4-Amino-N-(tert-butanesulfinyl)-3-phenylnona-1,8-dien-3-ol (4eb)

Following the general procedure, compound 4eb (61.1 mg, 0.18 mmol, 61%) was obtained as a yellow wax; [α]²³_D = +11.4 (c = 0.92, CH₂Cl₂); R_f = 0.29 (hexane/EtOAc, 3:1); ¹H NMR (400 MHz, CDCl₃) δ 7.53–7.29 (m, 5H), 6.12 (ddd, J = 17.0, 10.7, 1.4 Hz, 1H), 5.89–5.70 (m, 1H), 5.48 (dd, J = 17.0, 1.6 Hz, 1H), 5.19 (dd, J = 10.7, 1.6 Hz, 1H), 5.09–4.89 (m, 2H), 4.78 (d, J = 1.4 Hz, 1H), 3.74–3.58 (m, 1H), 3.40 (d, J = 3.1 Hz, 1H), 2.16–1.94 (m, 2H), 1.97–1.80 (m, 2H), 1.32–1.17 (m, 2H), 1.02 (s, 9H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 144.8 (C), 140.5 (CH), 138.6 (CH), 128.9 (CH), 127.2 (CH), 125.8 (CH), 114.9 (CH₂), 114.7 (CH₂), 79.2 (C), 65.3 (CH), 55.7 (C), 33.6 (CH₂), 26.3 (CH₂), 26.0 (CH₂), 22.7 (CH₃); LRMS (EI) m/z 335 (M⁺, < 1%), 202 (39), 146 (44), 133 (59), 115 (10), 105 (23), 81 (28), 70 (15), 55 (44), 43 (100); HRMS (EI-TOF) Calcd for C₁₉H₂₉NO₂S [M⁺] 335.1928, found 335.1923.

Synthesis of (R_S,1R,7R)-7-Amino-N-(tert-butanesulfinyl)-1-phenylcyclohept-2-en-1-ol (6) from Amino Alcohol Derivative 3eb

A solution of compound 3eb (0.022 g, 0.065 mmol), Hoveyda–Grubbs second generation catalyst (4.34 mg, 0.007 mmol, 10 mol %), and 1,7-octadiene (44 μL, 0.3 mmol) in dry CH₂Cl₂ (2.0 mL) was stirred at 40 °C (oil bath) for 17 h. Then the solvent was evaporated (15 Torr). The residue was purified by column chromatography (silica gel, hexane/EtOAc) to give compound 6 (10.1 mg, 0.033 mmol, 55%) as a white solid; mp 64–66 °C (hexane/CH₂Cl₂); [α]²³_D = +38.7 (c = 0.83, CH₂Cl₂); R_f = 0.20 (hexane/EtOAc, 2:1); ¹H NMR (400 MHz, CDCl₃) δ 7.61–7.48 (m, 2H), 7.46–7.21 (m, 3H), 6.13 (ddd, J = 12.1, 7.7, 4.3 Hz, 1H), 5.82–5.64 (m, 1H), 4.90 (s, 1H), 3.98–3.80 (m, 2H), 2.29–2.02 (m, 2H), 1.78–1.64 (m, 1H), 1.57–1.42 (m, 3H), 1.28 (s, 9H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 141.85 (C), 137.5 (CH), 132.0 (CH), 128.6 (CH), 127.9 (CH), 127.25 (CH), 81.1 (C), 65.2 (CH), 56.0 (C), 31.4 (CH₂), 28.75 (CH₂), 22.9 (CH₃), 20.7 (CH₂); LRMS (EI) m/z 305 (M⁺, < 1%), 233 (20), 202 (13), 170 (100), 159 (25), 142 (29), 128 (11), 105 (40), 91 (20), 77 (23), 56 (38), 43 (26); HRMS (EI-TOF) Calcd for C₁₃H₁₇NO₂S [M⁺–C₄H₈] 250.0892, found 250.0890.

Synthesis of (2R,3S)-2-Phenethyl-3-vinylpiperidin-3-ol (7) from Amino Alcohol Derivative 3af

To a solution of compound 3af (0.012 g, 0.03 mmol) in MeOH (0.5 mL) was added a 2 M solution of HCl in Et₂O (115.0 μL, 0.23 mmol) at 0 °C. The reaction mixture was stirred at the same temperature for 30 min. After that, a 2 M aqueous solution of NaOH (2.0 mL, 2.0 mmol) was added to the reaction mixture at 0 °C, and after 10 min, it was extracted with CH₂Cl₂ (4 × 5 mL), the combined organic phases dried over anhydrous MgSO₄, and the solvents evaporated (15 Torr). To a solution of the resulting residue in CH₂Cl₂ (2.0 mL) was added a 2 M aqueous solution of NaOH (2.0 mL, 4.0 mmol), and the reaction mixture was stirred at 23 °C for 15 h. After that, the aqueous layer was extracted with CH₂Cl₂ (5 × 5 mL), and the combined organic layers were dried over anhydrous MgSO₄, and the solvents evaporated (15 Torr). The residue was purified by column chromatography (silica gel, hexane/EtOAc) to yield pure compound 7 (6.5 mg, 0.028 mmol, 93%) as a white solid; mp 39–41 °C (hexane/CH₂Cl₂); [α]²³_D = +8.6 (c = 0.45 CH₂Cl₂); R_f = 0.67 (hexane/EtOAc, 1:1); ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.07 (m, 5H), 5.72 (dd, J = 17.1, 10.6 Hz, 1H), 5.37–5.07 (m, 2H), 3.95–3.71 (m, 2H), 2.94 (ddd, J = 14.6, 10.3, 4.8 Hz, 1H), 2.75–2.47 (m, 2H), 1.95–1.73 (m, 4H), 1.71–1.63 (m, 2H), 1.25 (s, 1H); ¹³C{¹H} NMR (100 MHz, CDCl₃) δ 142.45 (C), 138.5 (CH), 128.5 (CH), 128.4 (CH), 125.8 (CH), 115.4 (CH₂), 88.5 (C), 67.6 (CH₂), 59.1 (CH), 35.2 (CH₂), 34.0 (CH₂), 33.5 (CH₂), 25.5 (CH₂); LRMS (EI) m/z 231 (M⁺, < 1%), 134 (100), 117 (35), 91 (94), 55 (25) 43 (15); HRMS (EI-TOF) Calcd for C₁₅H₁₉N [M⁺–H₂O] 214.1595, found 214.1587.

Synthesis of (R_S,2R,3S,E)-2-Amino-N-(tert-butanesulfinyl)-1-O-(tert-butyldimethylsilyl)-octadec-4-ene-1,3-diol (8) from Amino Diol Derivative 3da

To a solution of allylic amino alcohol derivative 3da (67.0 mg, 0.2 mmol), 1-pentadecene (84.0 mg, 108.4 μL, 0.4 mmol), and 1,7-octadiene (88.0 mg, 108.0 μL, 0.8 mmol) in anhydrous CH₂Cl₂ (1.0 mL) was added Hoveyda–Grubbs II catalyst (12.5 mg, 0.02 mmol). This mixture was stirred at 45 °C (oil bath) for 3 h. After that, the solvents evaporated (15 Torr). The residue was purified by column chromatography (silica gel, hexane/EtOAc) to yield pure compound 8 (62.0 mg, 1.20 mmol, 60%) as a colorless oil; [α]²³_D = −42.7 (c = 0.97 CH₂Cl₂); R_f = 0.48 (hexane/EtOAc, 2:1); ¹H NMR (300 MHz, CDCl₃) δ 5.81 (dtd, J = 15.4, 6.8, 1.5 Hz, 1H), 5.50 (ddt, J = 15.5, 5.2, 1.4 Hz, 1H), 4.42 (br s, 1H), 4.02 (d, J = 9.7 Hz, 1H), 3.82–3.70 (m, 2H), 3.58 (dd, J = 10.2, 6.5 Hz, 1H), 3.52–3.42 (m, 1H), 2.08 (dd, J = 7.8, 6.5 Hz, 2H), 1.27 (s, 22H), 1.25 (s, 9H), 0.91 (s, 9H), 0.90 (t, J = 6.6 Hz, 3H), 0.09 (s, 3H), 0.08 (s, 3H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 134.5 (CH), 127.7 (CH), 72.4 (CH), 64.3 (CH₂), 62.5 (CH), 55.8 (C), 32.5 (CH₂), 31.9 (CH₂), 29.7 (CH₂), 29.6 (CH₂), 29.6 (CH₂), 29.5 (CH₂), 29.4 (CH₂), 29.3 (CH₂), 29.3 (CH₂), 25.8 (CH₃), 22.7(CH₃), 22.6 (CH₂), 14.1 (CH₃), −5.5 (CH₃), −5.6 (CH₃); LRMS (EI) m/z 517 (M⁺, < 1%), 460 (7), 345 (19), 323 (100), 278 (89), 239 (16), 203 (16), 174 (65), 133 (11), 116 (47), 105 (10), 89 (57), 75 (78), 57 (88), 41 (32); HRMS (EI-TOF) Calcd for C₂₄H₅₀NO₃SSi [M⁺–C₄H₉] 460.3281, found 460.3286.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.4c00198.

• Experimental procedures and characterization data for compounds 1 and 2. Experimental epimerization conditions of the sulfur atom of amino alcohol derivative 3ae. Copies of ¹H, ¹³C NMR, and DEPT spectra for all the reported compounds (1, 2, 3, 4, 6, 7, and 8), and X-ray structures of compounds 3ab and 3ai. (PDF)

The authors declare no competing financial interest.