Nickel-Catalyzed Three-Component Cycloadditions of Enoates, Alkynes, and Aldehydes

Abstract

A method for the three-component cycloaddition of enoates, alkynes, and aldehydes has been developed. Building upon previous work by this group in which stoichiometrically generated metallacycles undergo alkylation, we report a catalytic, alkylative [3 + 2] cycloaddition. From simple starting materials, structurally complex cyclopentenones may be rapidly assembled. Computational investigation of the mechanism (ωB97X-D3/cc-pVTZ//ωB97X/6–31G(d)) identified three energetically feasible pathways. Based on the relative rates of ketene formation compared to isomerization to a seven-membered metallacycle, the most likely mechanism has been determined to occur “ketene-first”, with carbocyclization prior to aldol addition. Deuterium labeling studies suggest that formation of the seven-membered metallacycle becomes possible when an α-substituted enoate is used. This observed change in selectivity is due to the increased difficulty of phenoxide elimination with the inclusion of additional steric bulk of the α-substituent. The net transformation results in a [3 + 2] cycloaddition accompanied by an alkylation of the enoate substituent.

Graphical Abstract

INTRODUCTION

Methods for enabling [3 + 2] cycloadditions typically involve 1,3-dipolar cycloadditions,¹ cyclopropane ring openings,² vinyl carbenoid additions,³ cycloadditions of allyl, allenyl, or propargylsilanes accompanied by 1,2 silicon shifts,⁴ or organocatalytic processes accompanied by a 1,2 hydrogen transfer.⁵ As a complement to methods of this type, a number of metal-promoted processes have been developed utilizing the formal reductive [3 + 2] cycloaddition of α,β-unsaturated carbonyl derivatives with alkynes or allenes. By pairing a net two-electron reduction with the cycloaddition process, simple, readily available substrates may be utilized in the generation of five-membered carbocyclic ring systems. Early illustrations of reductive cycloadditions involved the stoichiometric generation of titanium,⁶ nickel,⁷ or iron metallacycles,⁸ followed by either protonation or alkylation of a metal enolate motif. During processes of this type, the protonation or alkylation occurs on the enoate or enal α-carbon (Scheme 1). In the stoichiometric nickel processes involving alkylation of the intermediate metallacycle, a broad range of electrophiles were utilized,^7c including aldehydes, alkyl halides, acyl chlorides, and enals as Michael acceptors. These alkylative processes, however, were restricted to intramolecular versions to enable synthesis of the well-defined metallacyclic species involved in the couplings.

Scheme 1.

Reductive Cycloaddition Methods

Catalytic versions of [3 + 2] reductive cycloadditions of enals and alkynes became possible with nickel catalysis by employing CH₃ OH and Et₃B as a key reagent combination.⁹ Methods involving enoate–alkyne cycloadditions utilizing either Et₃B or isopropanol as the terminal reductant then provided direct access to cyclopentenone products, and other types of nickel-catalyzed reductive cycloadditions have more recently been reported.¹⁰ Following this work, a highly attractive enantio- and regioselective reductive cycloaddition process was developed, providing access to highly enantioen-riched products,^11a and other types of highly attractive and versatile nickel-catalyzed reductive cycloadditions have been developed using dihaloprecursors.^11b,d Cobalt-catalyzed enone-allene cycloadditions provided a complementary outcome with access to products possessing an exocyclic double bond.^12a The cobalt-catalyzed method was further extended with access to [3.2.1] bicyclooctene products derived from cycloaddition of cyclic enones with alkynes.^12b Hydrogen-mediated reductive cycloadditions of unsaturated carbonyls with 2 equiv of acetylene allowed six-membered ring construction by a novel [2 + 2 + 2] pathway utilizing rhodium catalysis.¹³ The above advances in catalytic reductive cycloaddition processes demonstrate the utility of the strategy in numerous contexts. However, alkylative versions, where a carbon electrophile is introduced to the enoate or enal α-position, have remained elusive since the initial demonstrations utilizing stoichiometrically generated metallacycles.^7c Herein, this void is addressed by the development of catalytic, alkylative [3 + 2] cycloadditions involving an aldol addition reaction as the key metallacycle alkylation step.

RESULTS AND DISCUSSION

Discovery and Optimization.

In our previous report of reductive cycloadditions of phenyl enoates with alkynes,^10a a catalyst prepared from Ni(COD)₂ with PBu₃ allowed efficient enoate–alkyne reductive cycloaddition utilizing Et₃B as the reductant with 2% methanol in THF. By replacing methanol with benzaldehyde and conducting the reaction in toluene, catalytic alkylative cycloaddition was observed (Table 1, entry 1). In efforts to optimize the yield and diastereoselectivity of this process, reactions with PBu₃ were compared against a number of N-heterocyclic carbene (NHC) ligands with a wide range of steric properties. Yields were very poor with the unhindered NHC’s IPrBAC and ITol (Table 1, entries 2–3), whereas IMes as ligand (Table 1, entry 4) afforded comparable yields with slightly lower selectivities compared to PBu₃. Yields were best with the bulkier ligand IPr, whereas the saturated analogue SIPr led to a lower chemical yield (Table 1, entries 5–6). Notably, with both of these bulkier ligands IPr and SIPr, a reversal of regiochemistry was noted compared with the outcome using PBu₃ or IMes. Stereochemical relationships of 1a and 1b were established by stereoselective Luche reduction and acetonide formation, followed by analysis of coupling constants and NOE relationships on the bicyclic derivatives.

Table 1.

Ligand Optimization in Three-Component Cycloadditions

entry	ligand	X mol %	% yielda	1a:1b:1c:1d
1	PBu3	20	57	69:26:5:0
2	IPrBAC·HCl	10	5	67:22:7:4
3	ITol·HCl	10	10	78:20:0:2
4	IMes·HCl	10	61	45:35:20:0
5	IPr·HCl	10	62	18:11:53:18
6	SIPr·HCl	10	36	12:3:64:23

^aCombined yield of the products 1a–1d.

Exploration of the Substrate Scope.

The scope of the three-component couplings was then expanded to include a range of enoate–alkyne–aldehyde combinations. While the PBu₃- and IMes-promoted procedures described above were satisfactory for some substrate combinations, in some instances, the reductive cycloaddition products (without aldehyde incorporation) were significant byproducts. In these cases, adding the enoate, alkyne, and Et₃B by syringe drive to a mixture of the catalyst and aldehyde served to minimize these byproducts and improve product yields. Additionally, precise assessment of inherent aldol diastereoselectivities was made difficult by the formation of small amounts of aldol elimination products. The alkylative cycloadditions of phenyl acrylate, lacking a β-substituent, was a representative case where slow addition of the enoate, alkyne, and reductant resulted in yield improvements (Scheme 2). Using IMes as ligand, the Et₃B-mediated cycloaddition of phenyl acrylate, phenyl propyne, and benzaldehyde proceeded in 35% isolated yield when all components were added at once, whereas the yield improved to 48% isolated yield (3:1 dr) of products 2a and 2b when the enoate, alkyne, and Et₃B reductant were added by syringe drive to a mixture of the Ni-IMes catalyst and benzaldehyde. In this case, only trace quantities of the minor regioisomer were detected.

Scheme 2.

Slow Addition Protocol with Phenyl Acrylate

Based on the above observations, three general procedures were utilized in other cycloaddition attempts: procedure A involves PBu₃ as ligand, procedure B involves IMes as ligand, and procedure C involves IMes as ligand with slow addition of the enoate, alkyne, and Et₃B. The use of PBu₃ as ligand (procedure A) typically provided the highest selectivity favoring the major regioisomer, whereas the use of IMes as ligand (procedure B) provided improvements in chemical yield at the expense of selectivity. The slow addition protocol (procedure C) provided only marginal improvements in most cases; however, two cases with a fully unsubstituted phenyl enoate or β-aryl enoate showed moderate improvements compared with the analogous procedure without syringe drive addition. The following examples describe the optimal procedure, in some cases comparing two of the protocols examined when comparable results were obtained.

The optimal outcomes of previously described couplings (Table 1 and Scheme 2) are summarized as the examples where the three general procedures were developed (Table 2, entries 1–3). α-Substitution of the enoate was tolerated with either PBu₃ or IMes as ligand, with slightly better diastereoselectivity being observed with PBu₃ (Table 2, entries 4–5). A β-aryl substituted enoate was incorporated most efficiently using the syringe drive protocol of procedure C (Table 2, entry 6). Additional examples demonstrated the breadth of the method by examining nonaromatic internal alkynes (Table 2, entry 7), an aliphatic aldehyde (Table 2, entry 8), and alkynes bearing silyloxy or ester functionality (Table 2, entries 9–10). The trans relative configuration of the cyclopentenone ring substituents was directly established by NOE analysis for the major products of the catalytic cycloadditions. In several representative cases (entries 1, 3, 6, and 8), the side chain stereochemistry was determined through ketone reduction and acetonide formation followed by NOE analysis. The relative configurations were consistent aside from the product derived from an aliphatic aldehyde (Table 2, entry 8), where the major product was epimeric at the secondary hydroxyl compared with all other examples.

Table 2.

Scope of Three-Component Cycloadditions

entry	Procedurea	% yieldb	isomer ratioc	major productd
1	A	57	69:26:5
2	B	61	45:35:20
3	C	48	69:25:6
4	A	54	61:39
5	B	50	52:36:11
6	C	50	65:29:6
7	B	52	58:42
8	A	52	63:37
9	B	57	54:37:9
10	B	47	54:33:13

^aProcedure A utilizes Ni(COD)₂ with PBu₃, procedure B utilizes Ni(COD)₂ with IMes, and procedure C utilizes Ni(COD)₂ with IMes with syringe drive addition of the enoate, alkyne, and borane over 10 min. See the Supporting Information for details.

^bCombined isolated yields of the products are given.

^cIsomer ratios indicate crude ratios (from ¹H NMR) of the major product depicted as the first product, followed by the product epimeric at the secondary hydroxyl center, then followed by regioisomers of the alkyne insertion.

^dComplete stereostructures for entries 1, 3, 6, and 8 were unambiguously determined through reduction and acetonide formation followed by NOE analysis. In other cases, the side chain stereochemistry was assigned by analogy. In all cases, the trans relative configuration of the cyclopentenone ring substituents was established directly on the products obtained by the catalytic cycloaddition. See Supporting Information for a description of structural and stereochemical determinations.

Computational Investigation of the Mechanism.

To provide deeper insight into the mechanism of the transformation, quantum chemical reaction path simulations were performed. As a starting point, prior work by our group suggests formation of a five-membered metallacycle (3) from enoate and alkyne would be facile,⁷ which is concurrent with mechanistic proposals of related processes.¹⁰ From this common intermediate, several different pathways were then postulated (Scheme 3).¹⁴ In the upper two pathways, metallacycle 3 isomerizes to seven-membered metallacycle 4, which is capable of reacting with electrophiles (i.e., aldehydes).^7a Such aldol-first mechanisms conceivably occur through an inner-sphere (Path A, black) or outer-sphere (Path B, blue) process, and carbocyclization could occur after aldol addition from species such as 5. Alternatively, Ogoshi has shown that cyclic C-enolate species such as 7 can form rapidly under aprotic conditions, via ketene intermediate 6 (Path C, red).^10b In this ketene-first mechanism, aldol addition occurs after carbocyclization.

Scheme 3.

Postulated Mechanisms for Cyclization

The simulation results for paths A–C are shown in Figure 1, which shows the detailed potential energy profile for the three-component cycloaddition. This reaction profile starts with complex I, a five-membered metallacycle analogous to 3 of Scheme 3. I can isomerize to rotamer II, from which it can branch into the aldol-first or ketene-first pathways, respectively (Figure S1). In the aldol-first pathway, II isomerizes to η−3 coordinated III-A (Figure S1), which can subsequently rearrange to form seven-membered metallacycle IV-A (TS-III-A). The aldol-first pathways A and B split at this point. In inner-sphere path A, ligation of benzaldehyde to IV-A yields complex V-A, which can then undergo an aldol reaction (TS-V-A) by a conventional six-membered transition state. In outer-sphere path B, a triethylborane–benzaldehyde complex directly adds to metallacycle IV-A (TS-IV-B). Both aldol adducts V-B and VI-A can then subsequently undergo carbocyclization (Figure S2). In the ketene-first pathway, extrusion of the phenoxide from II (TS-II-C) yields ketene complex III-C. Carbocylization of III-C to yield C-enolate IV-C is rapid and irreversible. Subsequently, benzaldehyde can coordinate to this complex, to ultimately undergo an aldol reaction (Figure S3). Phenoxide extrusion (TS-II-C) is thus the rate-limiting step in the ketene-first path. As this transition state is 1.4 kcal/mol lower in energy than TS-III-A, we predict that ketene-first pathway C is the major reaction pathway that occurs in solution.

Figure 1.

Comparison of Ketene-First and Aldol-First Mechanisms. Path A (black): inner-sphere aldol-first mechanism; Path B (blue): outer-sphere aldol-first mechanism; Path C (red): ketene-first mechanism. The key ground states and transition states that influence relative rates and selectivities are depicted. Other structures on the pathways are omitted for clarity, and the complete pathways with all relevant structures are available in the Supporting Information (Figures S1, S2, and S3). Free energies and enthalpies from ωB97X-D3/cc-pVTZ/Toluene are listed in kcal/mol, and enthalpy values are listed in italics.

Evidence of Metallacycle Formation with α-Substituted Enoates.

Considering the similarity of transition state energies of the competing pathways (TS-II-C, TS-III-A, and TS-IV-B), an aldol-first pathway is inherently plausible, and a minor perturbation from the system studied in Figure 1 can push the reaction to use a different path. For instance, in the case of α-substituted enoates (and only in the case of α-substitution), small amounts of linear products can be isolated in addition to the desired carbocycle. To better understand this outcome, the coupling of PhCDO, phenyl methacrylate, and phenyl propyne led to the production of products 10 (46%, >97% D) and 12 (23%, >97% D) (Scheme 4). The formation of product 12, which maintains the phenyl ester functionality, is best explained by a pathway involving the aldol addition of 8 to produce 9, followed by β-hydride elimination to form 11, and reductive elimination to form 12. This redox neutral pathway was previously described in the absence of Et₃B,¹⁵ but as this example demonstrates, the phenyl ester may be maintained under conditions optimized for the reductive cycloaddition with Et₃B. The formation of species such as 12 implies that, in the α-substituted system, ketene formation does not fully outcompete isomerization to a seven-membered metallacycle and that an inner-sphere or outer-sphere aldol-first process is involved in the production of intermediate 9 in the production of 12. The pathway leading to 10, however, is not clarified by this result and may involve an aldol-first or ketene first mechanism.

Scheme 4.

Linear Product Formation with α-Substituted Enoates

Computational analysis of the first steps with an α-substituted enoate support this explanation (Figure 2). With the inclusion of additional steric bulk near the ester, phenoxide extrusion becomes more difficult by 2.8 kcal/mol (α-TS-II-C vs TS-II-C). Isomerization to the seven-membered metallacycle is also more challenging in the α-substituted system, but only by 0.8 kcal/mol (α-TS-III-A vs TS-III-A). In this system, metallacycle formation now is predicted to outcompete ketene formation by 0.6 kcal/mol (α-TS-II-C vs α-TS-III-A) and is now the major reaction path. The relative abundance of seven-membered metallacyclic intermediates such as α-IV-A explains why linear products such as 12 are observed in reactions involving α-substituted enoates, but not with their β-substituted counterparts.

Figure 2.

Ketene Formation is Disfavored with α-Substituted Enoates. Path A (black): formation of the seven-membered metallacycle; Path C (red): formation of the ketene complex. The key ground states and transition states that influence relative rates and selectivities are depicted. Other structures on the pathways are omitted for clarity, and the complete pathways with all relevant structures are available in the Supporting Information (Figure S4). Free energies and enthalpies ωB97X-D3/cc-pVTZ/Toluene in kcal/mol, with enthalpy values in italics.

CONCLUSION

In summary, a cascade reaction allowing the reductive combination of enoates, alkynes, and aldehydes to provide access to highly functionalized cyclopentenone products has been described. The sequence allows the formal [3 + 2] cycloaddition of the phenyl enoate and alkyne accompanied by alkylation of the enoate α-carbon with an aldehyde. Nickel catalysts supported by either phosphines or N-heterocyclic carbenes promote the transformation. Computational and experimental results suggest that the ketene-first pathway is preferred, and insights into switching the selectivity from a ketene-first path to an aldol-first path have been provided. The detailed computational analysis demonstrates the precarious balance that exists between different possible addition pathways involving nickel ester enolates. A ketene-first pathway is dominant in most cases, based on the preference for phenoxide extrusion to proceed faster than intermolecular aldol addition. This selectivity can be reversed (favoring aldol addition first) when an α-substituted enoate is used, since isomerization to a seven-membered metallacycle is computationally predicted to precede phenoxide extrusion to form a ketene complex. The ability of this process to build considerable complexity from three simple and widely available starting materials suggests that the design principles and the understanding of the competing pathways available to nickel enoates may find use in other catalytic sequences.

EXPERIMENTAL SECTION

General Information.

All reagents were used as received unless otherwise noted. Solvents were purified under nitrogen using a solvent purification system (Innovative Technology, Inc. Model # SPS-400–3 and PS-400–3. Enoates were distilled prior to use. Ni(COD)₂ (Strem Chemicals, Inc., used as received), 1,3-Bis(2,4,6-trimethyl-phenyl)-imidazolium chloride (IMes·HCl), and potassium tert-butoxide were stored and weighed in an inert atmosphere glovebox. Tri-N-butylphosphine was freshly distilled and used under an inert atmosphere. Aldehydes were freshly distilled using a Buchi GKR-51 Kuegelrhor. All reactions were conducted in flame-dried or oven-dried (120 °C) glassware under a nitrogen atmosphere. ¹H and ¹³C spectra were obtained in CDCl₃ at rt (25 °C), unless otherwise noted. Chemical shifts of ¹H NMR spectra were recorded in parts per million (ppm) on the δ scale from an internal standard of residual chloroform (7.26 ppm). Chemical shifts of ¹³C NMR spectra were recorded in ppm from the central peak of CDCl₃ (77.0 ppm) on the δ scale. HPLC purification was conducted using either a Shimadzu LC-8A HPLC with a Grace PN 81116 Alltima Silica 5 μm 250 mm × 10 mm prep column or a Waters Delta 600 Agilent Zorbax RX-SIL Prep HT 7 μm 21.2 mm × 250 mm column.

General Procedure A.

Ni(COD)₂ (8 mg, 0.03 mmol, 0.1 equiv) was added to a vial in a glovebox, and the vial was then fitted with a rubber septum, removed from the glovebox, and attached to a nitrogen-filled Schlenk line. Toluene (1.5 mL) was then added to the vial, and the catalyst was allowed to stir for a few minutes before tri-n-butylphosphine (15 μL, 0.06 mmol, 0.2 equiv) was added dropwise turning the pale yellow catalyst solution to bright yellow. Next, enoate (0.3 mmol, 1 equiv) was weighed out into a separate vial and the vial was placed under a nitrogen atmosphere and purged three times with nitrogen. Alkyne (0.45 mmol 1.5 equiv) and aldehyde (0.45 mmol, 1.5 equiv) were then added to the substrate vial via syringe, and the vial was purged with nitrogen twice more. Toluene (0.5 mL) was added to the combined substrates, and this solution was transferred by cannula to the catalyst solution washing twice with toluene (0.5 mL), resulting in a red reaction mixture. Triethylborane (217 μL, 1.5 mmol, 5 equiv) was then added immediately to the reaction via syringe, and the reaction was placed in a preheated 90 °C oil bath and stirred for 2 h before quenching with 1.5 mL of saturated NH₄Cl.

General Procedure B.

Ni(COD)₂ (8 mg, 0.03 mmol, 0.1 equiv), IMes·HCl (10 mg, 0.03 mmol, 0.1 equiv), and t-BuOK (3 mg, 0.03 mmol, 0.1 equiv) were added sequentially to a flame-dried vial in a glovebox. The vial was then fitted with a rubber septum, removed from the glovebox, and attached to a nitrogen-filled Schlenk line. Toluene (1.5 mL) was then added to the catalyst, resulting in a black-yellow or brown solution after 10 min of stirring. The rest of the procedure is identical to procedure A.

General Procedure C.

Ni(COD)₂ (8 mg, 0.03 mmol, 0.1 equiv), IMes·HCl (10 mg, 0.03 mmol, 0.1 equiv), and t-BuOK (3 mg, 0.03 mmol, 0.1 equiv) were added sequentially to a flame-dried vial in a glovebox. The vial was then fitted with a rubber septum, removed from the glovebox, and attached to a nitrogen-filled Schlenk line. Toluene (2.0 mL) was then added to the catalyst, resulting in a black-yellow or brown solution after 10 min of stirring. Next, enoate (0.3 mmol, 1 equiv) was weighed out into a separate vial, and the vial was placed under a nitrogen atmosphere and purged three times with nitrogen. Alkyne (0.45 mmol 1.5 equiv) was then added to the substrate vial, and the vial was purged twice more with nitrogen. Toluene (0.5 mL) was added to the substrate vial followed by addition of triethylborane (217 μL, 1.5 mmol, 5 equiv) by syringe. The substrate and reducing agent solution was drawn up into a syringe, and the vial was washed with toluene twice (0.25 mL) resulting in a substrate solution volume of 1.0 mL. Aldehyde (0.45 mmol, 1.5 equiv) was then added via syringe to the stirred catalyst solution, and the vial was placed in a preheated 90 °C oil bath followed by a 10 min addition of the 1 mL solution of substrates and reducing agent with a syringe drive. The reaction was stirred for 2 h before quenching with 1.5 mL of saturated NH₄Cl.

General Workup Procedure.

The reaction is quenched with 1.5 mL of saturated NH₄Cl and then washed into a separatory funnel. The organic and aqueous layers are then separated, and the aqueous layer is extracted twice with methylene chloride (2 mL). The organic layers were then combined and washed with 10 mL of 0.5 M NaOH followed by brine (10 mL). The organic layers are then dried with Na₂SO₄ and filtered through a pad of silica washing with 50/50 EtOAc/Hex. The solution was then concentrated to yield the crude isolate. Product ratios reported in Table 2 of the manuscript and within each experimental below were determined on crude reaction mixtures by ¹H NMR analysis.

Relative Stereochemistry Determinations.

The purified diastereomer (1 equiv) and CeCl₃ (1 equiv) were dissolved in 1 mL of MeOH. This solution was cooled to 0 °C, and NaBH₄ (4.5 equiv) was added in portions. The reaction was stirred until completion of the reaction was confirmed by TLC. The reaction was quenched with 1 mL of NH₄Cl and extracted 3× with EtOAc. The organic layers were washed with brine and dried over Na₂SO₄. Flash chromatography of the crude isolate separated the product diastereomers.

Each diastereomer was dissolved in 1 mL of DMP (dimethoxypropane), and a 1 mol % PTSA was added as a 1 mg/100 μL solution. After 30 min, the reaction was quenched with 1 mL of sat. NaHCO₃ and extracted 3× with EtOAc. The organic layers were washed with brine and dried over Na₂SO₄. The crude product was purified by flash chromatography yield. Only one diastereomer will yield the desired acetonide. The other diastereomer will initially yield a ketal product, but this product is unstable and will rapidly decompose. NOE experiments are then performed on the acetonide product to determine the relative stereochemistry.

5-(Hydroxy(phenyl)methyl)-3,4-dimethyl-2-phenylcyclopent-2-enone (Table 1 and Table 2, Entries 1 and 2, Compounds 1a,b).

General Procedure A was followed using phenyl 3-butenoate (49 mg, 0.3 mmol, 1 equiv), 1-phenyl-1-propyne (56 μL, 0.45 mmol, 1.5 equiv), and benzaldehyde (46 μL, 0.45 mmol, 1.5 equiv). The reaction was then worked up using the general workup procedure, and NMR analysis of the crude isolate revealed the product in an isomeric ratio of 69:26:5. Column chromatography (5% to 20% EtOAc/Hex) yielded the products whose NMR data matched those previously published (50 mg combined, 57%).⁹

General Procedure B was followed using phenyl 3-butenoate (49 mg, 0.3 mmol, 1 equiv), 1-phenyl-1-propyne (56 μL, 0.45 mmol, 1.5 equiv), and benzaldehyde (46 μL, 0.45 mmol, 1.5 equiv). The reaction was then worked up using the general workup procedure, and NMR of the crude isolate revealed the product in an isomeric ratio of 45:35:20. Column chromatography (5% to 20% EtOAc/Hex) yielded the products whose NMR matched that previously published (54 mg combined, 61%).^10a

trans-5-Hydroxy(phenyl)methyl)-3-methyl-2-phenylcyclopent-2-enone (Major Diastereomer, Scheme 2 and Table 2, Entry 3, Compound 2a).

General Procedure C was followed using phenyl acrylate (44 mg, 0.3 mmol, 1 equiv), 1-phenyl-1-propyne (56 μL, 0.45 mmol, 1.5 equiv), and benzaldehyde (46 μL, 0.45 mmol, 1.5 equiv). The reaction was then worked up using the general workup procedure and purified by column chromatography (10% to 30% EtOAc/Hex) to yield an impure mixture of isomers (69:25:6). Purification of the products on the Shimadzu HPLC yielded the products as a mixture of diastereomers (84:16) (40 mg, 48%). The diastereomers could be separated after additional HPLC runs revealing the major diastereomer as a white solid and the minor as an oil. ¹H NMR (700 MHz, CDCl₃): δ 7.28–7.42 (m, 10H), 5.47 (t, J = 3.9 Hz, 1H), 2.94 (m, 1H), 2.73 (d, J = 18.2 Hz, 1H), 2.58 (d, J = 4.9 Hz, 1H), 2.45 (dd, J = 18.9 Hz, J = 7.4 Hz, 1H), 2.14 (s, 3H). ¹³C{¹H} NMR (176 MHz, CDCl₃): δ 207.8, 172.8, 142.4, 140.2, 131.5, 129.1, 128.4, 128.2, 127.7, 127.4, 125.6, 71.9, 52.8, 33.0, 18.4. IR (thin film) ν: 3441, 3056, 2907, 1695, 1635, 1597, 1494, 1448, 1380, 1346, 1209, 1135, 1006, 964, 912, 762, 744, 701, 668, 586 cm⁻¹. HRMS (ESI-TOF) (m/z): [M + H]⁺ calcd for C₁₉H₁₉O₂, 279.1380; found, 279.1377. NOE relationships of the dimethylketal derived from reduction of this compound were determined according to the general procedure.

cis-5-Hydroxy(phenyl)methyl)-3-methyl-2-phenylcyclopent-2-enone (Minor Diastereomer, Scheme 2 and Table 2, Entry 3, Compound 2b).

¹H NMR (700 MHz, CDCl₃): δ 7.30–7.45 (m, 10H), 4.98 (s, 1H), 4.74 (d, 9.8 Hz, 1H), 2.91 (ddd, J = 9.8 Hz, 7.0 Hz, 2.8 Hz), 2.49 (dd, J = 19.3 Hz, J = 7.3 Hz, 1H), 2.26 (d, J = 18.9 Hz, 1H), 2.14 (s, 3H). ¹³C{¹H} NMR (176 MHz, CDCl₃): δ 210.3, 172.7, 141.5, 139.5, 130.1, 129.1, 128.6, 128.4, 128.2, 128.0, 75.7, 51.3, 35.7, 18.3. IR (thin film) ν: 3442, 1676, 1635, 1494, 1429, 1381, 1346, 1205, 1140, 1040, 911, 737, 701 cm⁻¹. HRMS (ESI-TOF) (m/z): [M + Na]⁺ calcd for C₁₉H₁₈O₂Na, 301.1199; found, 301.1199.

5-(Hydroxy(phenyl)methyl)-3,5-dimethyl-2-phenylcyclopent-2-enone (Major Diastereomer, Table 2, Entries 4 and 5).

General Procedure A was followed using phenyl methacrylate (49 mg, 0.3 mmol, 1.0 equiv), 1-phenyl-1-propyne (56 μL, 0.45 mmol, 1.5 equiv), and benzaldehyde (46 μL, 0.45 mmol, 1.5 equiv). The reaction was worked up using the general workup procedure, and the NMR revealed the isomeric ratio of the crude to be 61:39. This crude isolate was then subjected to column chromatography (10% to 20% EtOAc/Hex), and 48 mg combined (54%) of product were isolated. The diastereomers could be separated with additional flash chromatography revealing the major diastereomer as a white solid and the minor as a colorless oil. ¹H NMR (700 MHz, CDCl₃): δ 7.28–7.42 (m, 10H), 4.97 (d, J = 4.9 Hz, 1H), 3.12 (d, J = 18.2 Hz, 1H), 2.70 (d, J = 4.2 Hz, 1H), 2.13 (s, 3H), 2.10 (d, J = 18.2 Hz, 1H), 1.15 (s, 3H). ¹³C{¹H} NMR (176 MHz, CDCl₃): δ 211.3, 171.2, 141.0, 138.5, 131.7, 129.1, 128.2, 128.1, 127.8, 127.6, 127.2, 76.8, 52.3, 41.7, 22.9, 18.3. IR (thin film) ν: 3443, 2928, 1689, 1639, 1495, 1380, 1044, 909, 744, 700 cm⁻¹. HRMS (ESI-TOF) (m/z): [M + H]⁺ calcd for C₂₀H₂₁O₂, 293.1536; found, 293.1533.

General Procedure B was followed using phenyl methacrylate (49 mg, 0.3 mmol, 1.0 equiv), 1-phenyl-1-propyne (56 μL, 0.45 mmol, 1.5 equiv), and benzaldehyde (46 μL, 0.45 mmol, 1.5 equiv). The reaction was then worked up using the general workup procedure, and NMR spectroscopy revealed a 46:36:12:6 distribution of isomers. Column chromatography (10 to 20%) of the crude concentrate yielded the product as an oil in a 52:36:11 ratio (44 mg, 50%).

5-(Hydroxy(phenyl)methyl)-3,5-dimethyl-2-phenylcyclopent-2-enone (Minor Diastereomer, Table 2, Entries 4 and 5).

¹H NMR (700 MHz, CDCl₃): δ 7.38–7.40 (m, 4H), 7.26–7.34 (m, 4H), 7.18 (d, J = 7.7 Hz, 2H), 4.85 (s, 1H), 3.95 (s, 1H), 2.86 (d, J = 19.6 Hz, 1H), 2.15 (d, J = 18.9 Hz, 1H), 2.08 (s, 3H), 1.32 (s, 3H). ¹³C{¹H}NMR (176 MHz, CDCl₃): δ 212.4, 171.0, 140.0, 138.0, 131.3, 129.0, 128.2, 127.9, 127.8, 127.7, 127.3, 76.7, 51.2, 43.3, 18.9, 18.1. IR (thin film) ν: 3443, 2929, 1688, 1638, 1495, 1452, 1381, 1046, 739, 700 cm⁻¹. HRMS (ESI-TOF) (m/z): [M + H]⁺ calcd for C₂₀H₂₁O₂, 293.1536; found, 293.1532.

5-(Hydroxy(phenyl)methyl)-3-methyl-2,4-diphenylcyclopent-2-enone (Major Diastereomer, Table 2, Entry 6).

General Procedure C was followed using phenylcinnamate (67 mg, 0.3 mmol, 1 equiv), 1-phenyl-1-propyne (56 μL, 0.45 mmol, 1.5 equiv), and benzaldehyde (46 μL, 0.45 mmol, 1.5 equiv). The reaction was then worked up using the general workup procedure and purified by column chromatography (10% to 20% EtOAc/Hex) to yield an impure mixture of isomers (65:29:6). Further column chromatography and HPLC purification on the Waters HPLC yielded the major diastereomer as a white solid (28 mg) and the minor diastereomer as a colorless oil (10 mg) and mixture of isomers (15 mg, 50:29:15:6) (53 mg, 50%). ¹H NMR (700 MHz, CDCl₃): δ 7.44 (t, J = 7.4 Hz, 2H), 7.34–7.39 (m, 5H), 7.28 (t, J = 7.7 Hz, 2H), 7.23 (t, J = 7.7 Hz, 1H), 7.12–7.13 (m, 3H), 6.70–6.72 (m, 2H), 5.51 (t, J = 4.2 Hz, 1H), 3.88 (d, J = 2.1 Hz, 1H), 2.92 (t, J = 3.2 Hz, 1H), 2.68 (d, 4.9 Hz, 1H), 1.91 (s, 3H). ¹³C{¹H} NMR (176 MHz, CDCl₃): δ 207.4, 174.4, 141.6, 141.2, 141.1, 131.4, 129.2, 128.6, 128.3, 128.2, 127.9, 127.4, 127.3, 126.7, 125.6, 72.2, 62.5, 50.3, 16.8. IR (thin film) ν: 3445, 3026, 1682, 1630, 1495, 1379, 1149, 1054, 908, 763, 728, 698, 602, 574 cm⁻¹. HRMS (ESI-TOF) (m/z): [M + H]⁺ calcd for C₂₅H₂₃O₂, 355.1693; found, 355.1693. NOE relationships of the acetonide derived from reduction of this compound were determined according to the general procedure above.

5-(Hydroxy(phenyl)methyl)-3-methyl-2,4-diphenylcyclopent-2-enone (Minor Diastereomer, Table 2, Entry 6).

¹H NMR (700 MHz, CDCl₃): δ 7.45–7.47 (m, 2H), 7.38–7.39 (m, 3H), 7.26–7.30 (m, 5H), 7.10–7.13 (m, 3H), 6.52 (d, J = 7.0 Hz, 2H), 4.82 (d, J = 9.8 Hz, 1H), 4.75 (s, 1H), 3.45 (s, 1H), 2.85 (dd, J = 9.8 Hz, J = 2.8 Hz, 1H), 1.91 (s, 3H). ¹³C{¹H} NMR (176 MHz, CDCl₃): δ 209.7, 174.5, 140.7, 140.2, 140.1, 130.8, 129.2, 128.7, 128.5, 128.4, 128.3, 128.2, 127.4, 127.3, 126.9, 75.9, 61.4, 52.7, 16.9. IR (thin film) ν: 3449, 3028, 2916, 1679, 1635, 1599, 1494, 1454, 1377, 1334, 1203, 1146, 1039, 912, 761, 735, 699, 572 cm⁻¹. HRMS (ESI-TOF) (m/z): [M + H]⁺ calcd for C₂₅H₂₃O₂, 355.1693; found, 355.1693.

trans-5-(Hydroxy(phenyl)methyl)-4-methyl-2,3-dipropyl-cyclopent-2-enone (Major Diastereomer, Table 2, Entry 7).

General Procedure B was followed using phenyl 3-butenoate (49 mg, 0.3 mmol, 1 equiv), 4-octyne (66 μL, 0.45 mmol, 1.5 equiv), and benzaldehyde (46 μL, 0.45 mmol, 1.5 equiv). The reaction was then worked up using the general workup procedure, and NMR revealed two diastereomers (58:42). The crude reaction mixture was subjected to column chromatography (10% to 20% EtOAc/Hex) to yield an impure and unseparated diastereomers. Further column chromatography (0.5% MeOH/CH₂Cl₂) resulted in purification and partial separation of the product diastereomers yielding 14 mg of the minor diastereomer, 16 mg of the major diastereomer, and 15 mg of both diastereomers (58:42) all as colorless oils (44 mg combined, 52%). ¹H NMR (700 MHz, CDCl₃): δ 7.32–7.33 (m, 4H), 7.25–7.26 (m, 1H), 5.33 (t, J = 4.2 Hz, 1H), 2.83 (d, J = 5.6 Hz, 1H), 2.75 (q, J = 7.0 Hz, 1H), 2.40 (ddd, J = 14.0 Hz, 9.1 Hz, 7.7 Hz, 1H), 2.31 (t, J = 2.8 Hz, 1H), 2.23 (ddd, J = 14.0 Hz, 9.1 Hz, 4.9 Hz, 1H), 2.08–2.16 (m, 2H), 1.48–1.56 (m, 1H), 1.39 (sext, J = 7.7 Hz, 2H), 1.28–1.36 (m, 1H), 0.86 (t, J = 5.6 Hz, 3H), 0.86 (t, J = 6.0 Hz, 3H), 0.80 (d, J = 7.0 Hz, 3H). ¹³C{¹H} NMR (176 MHz, CDCl₃): δ 209.6, 178.8, 142.1, 140.0, 128.2, 127.3, 125.6, 72.3, 60.0, 35.8, 30.3, 25.1, 21.8, 20.7, 18.1, 14.1, 14.0. IR (thin film) ν: 3402, 2959, 1684, 1635, 1450, 1372, 1084, 701, 556 cm⁻¹. HRMS (ESI-TOF) (m/z): [M + H]⁺ calcd for C₁₉H₂₇O₂, 287.2006; found, 287.2007.

5-(Hydroxy(phenyl)methyl)-4-methyl-2,3-dipropylcyclopent-2-enone (Minor Diastereomer, Table 2, Entry 7).

¹H NMR (700 MHz, CDCl₃): δ 7.29–7.39 (m, 5H), 5.09 (s, 1H), 4.57 (d, J = 9.8 Hz, 1H), 2.43 (ddd, 14.0 Hz, 9.1 Hz, 7.0 Hz, 1H), 2.32 (q, J = 7.0 Hz, 1H), 2.23 (ddd, J = 14.0 Hz, 9.1 Hz, 4.9 Hz, 1H) 2.11–2.20 (m, 3H), 1.52–1.57 (m, 1H), 1.42 (quind, J = 7.0 Hz, 3.5 Hz, 2H), 1.36–1.39 (m, 1H), 0.93 (t, J = 7.7 Hz, 3H), 0.90 (t, J = 7.7 Hz, 3H), 0.63 (d, J = 7.0 Hz, 3H). ¹³C{¹H} NMR (176 MHz, CDCl₃): δ 211.7, 178.8, 141.6, 139.2, 128.4, 128.1, 126.9, 75.9, 59.1, 38.4, 30.3, 25.0, 21.8, 20.8, 17.5, 14.2, 14.0. IR (thin film) ν: 3436, 2961, 2872, 1676, 1630, 1454, 1383, 1048, 703 cm⁻¹. HRMS (ESI-TOF) (m/z): [M + H]⁺ calcd for C₁₉H₂₇O₂, 287.2006; found, 287.2007.

5-(1-Hydroxy-2-methylpropyl)-3,4-dimethyl-2-phenylcyclopent-2-enone (Major Diastereomer, Table 2, Entry 8).

General Procedure A was followed using phenyl 3-butenoate (49 mg, 0.3 mmol, 1 equiv), 1-phenyl-1-propyne (56 μL, 0.45 mmol, 1.5 equiv), and isobutyr-aldehyde (41 μL, 0.45 mmol, 1.5 equiv). Procedural Note: This reaction was conducted in a sealed tube instead of a vial. The reaction was worked up using the general workup procedure, and NMR of the crude reaction revealed a 37:63 ratio of isomers. The crude isolate was subjected to column chromatography (5% to 20% EtOAc/Hex) followed by purification on a Waters HPLC (97:3 Hex/(20% i-PrOH/Hex) yielding 18 mg of the major diastereomer as a colorless oil and 22 mg of the minor diastereomer as a white solid (40 mg combined, 52%). ¹H NMR (700 MHz, CDCl₃): δ 7.41 (t, J = 7.7 Hz, 2H), 7.33 (t, J = 6.3 Hz, 1H), 7.28 (d, J = 7.7 Hz, 2H), 4.39 (s, 1H), 3.58 (d, J = 9.1 Hz, 1H), 2.53 (q, J = 6.5 Hz, 1H), 2.22 (d, J = 9.8 Hz, 1H), 2.15 (s, 3H), 1.86 (quint, J = 6.3 Hz, 1H), 1.33 (d, J = 7.0 Hz, 3H), 1.10 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 7.0 Hz, 3H). ¹³C{¹H} NMR (176 MHz, CDCl₃): δ 210.5, 176.0, 139.2, 131.2, 129.1, 128.3, 127.8, 76.6, 55.4, 41.5, 31.4, 20.4, 18.0, 15.9, 14.9. IR (thin film) ν: 3455, 2963, 1675, 1635, 1598, 1493, 1419, 1380, 1342, 1270, 1154, 1003, 733, 699 cm⁻¹. HRMS (ESI-TOF) (m/z): [M + H]⁺ calcd for C₁₇H₂₃O₂, 259.1693; found, 259.1694.

5-(1-Hydroxy-2-methylpropyl)-3,4-dimethyl-2-phenylcyclopent-2-enone (Minor Diastereomer, Table 2, Entry 8).

¹H NMR (700 MHz, CDCl₃): δ 7.40 (t, J = 7.7 Hz, 2H), 7.27–7.35 (m, 3H), 3.90 (ddd, J = 8.5 Hz, J = 5.5 Hz, J = 2.5 Hz, 1H), 2.95 (q, J = 5.4 Hz, 1H), 2.37 (t, J = 2.8 Hz, 1H), 2.15 (s, 3H), 1.90 (dsept, J = 2.5 Hz, J = 6.5 Hz, 1H), 1.73 (d, J = 5.0 Hz, 1H), 1.33 (d, J = 7.0 Hz, 3H), 1.10 (d, J = 7.0 Hz, 3H), 1.00 (d, J = 7.0 Hz, 3H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 208.1, 176.2, 139.9, 131.9, 129.2, 128.2, 127.6, 76.8, 56.8, 38.5, 31.8, 19.7, 19.1, 18.6, 15.9. IR (thin film) ν: 3439, 2961, 1685, 1635, 1598, 1444, 1379, 1341, 1152, 1079, 997, 751, 700 cm⁻¹. HRMS (ESI-TOF) (m/z): [M + H]⁺ calcd for C₁₇H₂₃O₂, 259.1693; found, 259.1698. NOE relationships of the acetonide derived from reduction of this compound were established according to the general procedure above.

trans-3-(3-((tert-Butyldimethylsilyl)oxy)propyl)-5-(hydroxy-(phenyl)methyl)-4-methyl-2-phenylcyclopent-2-enone (Major Diastereomer, Table 2, Entry 9).

General Procedure B was followed using phenyl 3-butenoate (49 mg, 0.3 mmol, 1 equiv), tert-butyldimethyl((5-phenylpent-4-yn-1-yl)oxy)silane (123 mg, 0.45 mmol, 1.5 equiv), and benzaldehyde (46 μL, 0.45 mmol, 1.5 equiv). The reaction was worked up using the general workup procedure and subjected to column chromatography yielding a crude mixture of isomers (54:37:9). These isomers were able to be further purified and separated using the Shimadzu HPLC yielding 19 mg of pure minor diastereomer as a colorless oil, 44 mg of pure major diastereomer as a white solid, and an additional 14 mg of mixed isomers (22:68:10) as a colorless oil (77 mg, 57%). ¹H NMR (700 MHz, CDCl₃): δ 7.35–7.41 (m, 6H), 7.31 (t, J = 7.0 Hz, 1H), 7.28 (t, J = 7.0 Hz, 1H), 7.22 (d, J = 6.8 Hz, 2H), 5.44 (d, J = 1.4 Hz, 1H), 3.56 (dt, J = 10.5 Hz, 5.6 Hz, 1H), 3.47 (ddd, J = 10.5 Hz, 7.0 Hz, 5.6 Hz, 1H), 2.96 (qd, J = 7.0 Hz, 2.8 Hz, 1H), 2.75 (s, 1H), 2.68 (ddd, J = 7.0 Hz, 10.5 Hz, 5.6 Hz, 1H), 2.49 (t, J = 2.8 Hz, 1H), 2.37 (ddd, J = 13.3 Hz, 10.0 Hz, 4.4 Hz, 1H), 1.69 (dtt, J = 16.1 Hz, 7.7 Hz, 5.6 Hz, 1H), 1.50 (dquin, J = 18.2 Hz, 5.6 Hz, 1H), 0.89 (d, J = 7.7 Hz, 3H), 0.84 (s, 9H), −0.01 (s, 3H), −0.02 (s, 3H). ¹³C{¹H} NMR (176 MHz, CDCl₃): δ 207.4, 180.1, 142.0, 140.1, 131.7, 129.1, 128.3, 128.2, 127.7, 127.4, 125.6, 72.2, 62.3, 60.6, 35.9, 30.6, 25.8, 25.3, 18.2, 17.9, −5.4, −5.5. IR (thin film) ν: 3446, 2955, 2856, 1684, 1630, 1597, 1495, 1471, 1360, 1255, 1152, 1099, 959, 835, 776, 702 cm⁻¹. HRMS (ESI-TOF) (m/z): [M + H]⁺ calcd for C₂₈H₃₉O₃Si, 451.2663; found, 451.2672.

trans-3-(3-((tert-Butyldimethylsilyl)oxy)propyl)-5-(hydroxy-(phenyl)methyl)-4-methyl-2-phenylcyclopent-2-enone (Minor Diastereomer, Table 2, Entry 9).

¹H NMR (700 MHz, CDCl₃): δ 7.38–7.44 (m, 6H), 7.33–7.35 (m, 2H), 7.25 (d, J = 7.0 Hz, 2H), 5.01 (s, 1H), 4.74 (d, J = 9.8 Hz, 1H), 3.57 (dt, J = 5.6 Hz, 10.5 Hz, 1H), 3.52 (ddd, J = 9.8 Hz, 7.0 Hz, 5.6 Hz, 1H), 2.71 (ddd, J = 13.3 Hz, 10.5 Hz, 5.6 Hz, 1H), 2.53 (qd, J = 7.0 Hz, 4.2 Hz, 1H), 2.36–2.41 (m, 2H), 1.70 (dtt, J = 16.8 Hz, 7.7 Hz, 5.6 Hz, 1H), 1.50–1.56 (m, 1H), 0.84 (s, 9H), 0.75 (d, J = 7.0 Hz, 3H), −0.01 (s, 3H), −0.01 (s, 3H). ¹³C{¹H} NMR (176 MHz, CDCl₃): δ 209.0, 180.2, 141.4, 139.3, 131.1, 129.1, 128.5, 128.4, 128.2, 127.9, 126.9, 75.7, 62.4, 59.5, 38.5, 30.6, 25.8, 25.5, 18.2, 17.2, −5.4, −5.4. IR (thin film) ν: 3443, 2927, 2855, 1679, 1631, 1597, 1494, 1471, 1360, 1256, 1149, 1099, 956, 834, 775, 700 cm⁻¹. HRMS (ESI-TOF) (m/z): [M + H]⁺ calcd for C₂₈H₃₉O₃Si, 451.2663; found, 451.2662.

Methyl-3-trans-4-(hydroxy(phenyl)methyl)-5-methyl-3-oxo-2-phenylcyclopent-1-en-1-yl)propanoate (Major Diastereomer, Table 2, Entry 10).

General Procedure B was followed using phenyl 3-butenoate (49 mg, 0.3 mmol, 1 equiv), methyl-5-phenylpent-4-ynoate (85 mg, 0.45 mmol, 1.5 equiv), and benzaldehyde (46 μL, 0.45 mmol, 1.5 equiv). The reaction was worked up using the general workup procedure, and NMR spectroscopy revealed a 54:33:13 mixture of isomers. This product was further purified using column chromatography (10 to 40% EtOAc/Hex) yielding impure unseparated isomers. These isomers could be further purified and separated using the Waters HPLC (85:15 (Hex/(i-PrOH/Hex)) yielding 13 mg of pure major diastereomer as a white solid, 13 mg of the pure minor diastereomer, as a colorless oil, and 25 mg of mixed isomers (62:17:14:7) as a colorless oil (51 mg, 47%). ¹H NMR (500 MHz, CDCl₃): δ 7.27–7.43 (m 8H), 7.20–7.22 (m, 2H), 5.45 (dd, J = 5.0 Hz, J = 3.5 Hz, 1H), 3.63 (s, 3H), 2.91–2.97 (m, 2H), 2.59–2.66 (m, 2H), 2.51 (t, J = 3.0 Hz, 1H), 2.44 (ddd, J = 16.0 Hz, 10.0 Hz, 5.5 Hz, 1H), 2.32 (ddd, J = 15.5 Hz, 8.5 Hz, 7.0 Hz, 1H), 0.90 (d, J = 7.5 Hz, 3H). ¹³C{¹H} NMR (176 MHz, CD₃CN): δ 207.0, 177.9, 173.5, 144.5, 141.4, 133.4, 130.2, 129.2, 129.1, 128.6, 127.9, 126.5, 72.2, 62.0, 52.3, 36.3, 32.1, 24.8, 18.5. IR (thin film) ν: 3465, 2959, 1736, 1699, 1493, 1443, 1345, 1197, 765, 703. HRMS (ESI-TOF) (m/z): [M + H]⁺ calcd for C₂₃H₂₅O₄, 365.1747; found, 365.1750.

Methyl-3-trans-4-(hydroxy(phenyl)methyl)-5-methyl-3-oxo-2-phenylcyclopent-1-en-1-yl)propanoate (Minor Diastereomer, Table 2, Entry 10).

¹H NMR (400 MHz, CDCl₃): δ 7.34–7.44 (m, 8H), 7.22 (d, J = 6.8 Hz, 2H), 4.83 (s, 1H), 4.75 (d, J = 9.6 Hz, 1H), 3.63 (s, 3H), 2.98 (ddd, J = 14.6 Hz, 9.1 Hz, 7.1 Hz, 1H), 2.62 (ddd, J = 14.8 Hz, 9.2 Hz, 5.6 Hz, 1H), 2.52 (qd, J = 6.8 Hz, 2.4 Hz, 1H), 2.39–2.47 (m, 2H), 2.33 (ddd, J = 16.0 Hz, 9.4 Hz, 7.0 Hz, 1H), 0.78 (d, J = 7.2 Hz, 3H). ¹³C{¹H} NMR (133 MHz, CDCl₃): δ 209.3, 177.2, 172.2, 141.2, 140.2, 130.8, 129.0, 128.6, 128.5, 128.3, 128.2, 126.9, 75.5, 59.5, 51.9, 38.4, 31.4, 24.0, 17.5. IR (thin film) ν: 3454, 2961, 1734, 1695, 1635, 1597, 1493, 1436, 1345, 1199, 1048, 913, 765, 736, 702 cm⁻¹. HRMS (ESI-TOF) (m/z): [M + Na]⁺ calcd for C₂₃H₂₄O₄Na, 387.1569; found, 387.1571.

5-(1-Deutero,1-hydroxy(phenyl)methyl)-3,5-dimethyl-2-phenyl-cyclopent-2-enone (Major Diastereomer, Scheme 4, Compound 10).

General Procedure B was followed using phenyl methacrylate (49 mg, 0.3 mmol, 1.0 equiv), 1-phenyl-1-propyne (56 μL, 0.45 mmol, 1.5 equiv), and D-benzaldehyde (46 μL, 0.45 mmol, 1.5 equiv). The reaction was then worked up using the general workup procedure, and the crude was subjected to column chromatography (10% to 20% EtOAc/Hex). Further purification on the Waters HPLC yielded the pure major diastereomer as a white solid (25 mg) and the minor diastereomer as a colorless oil (15 mg) (40 mg, 46%). ¹H NMR (400 MHz, CDCl₃): δ 7.26–7.42 (m, 10H), 3.12 (d, J = 18.4 Hz, 1H), 2.69 (s, 1H), 2.08–2.12 (m, 4H), 1.14 (s, 3H). ¹³C{¹H} NMR (176 MHz, CD₃CN): δ 211.3, 172.3, 143.0, 138.7, 133.6, 130.2, 129.1, 128.8, 128.5, 128.5, 128.4, 77.0 (t, J = 22.4), 53.1, 41.7, 22.9, 18.3. IR (thin film) ν: 3445, 3056, 1688, 1638, 1598, 1494, 1446, 1380, 1345, 1221, 1117, 1057, 901, 779, 743 cm⁻¹. HRMS (ESI-TOF) (m/z): [M + H]⁺ calcd for C₂₀H₂₀O₂D, 294.1599; found, 294.1598.

5-(1-Deutero,1-hydroxy(phenyl)methyl)-3,5-dimethyl-2-phenyl-cyclopent-2-enone (Minor Diastereomer, Scheme 4, Compound 10).

¹H NMR (400 MHz, CDCl₃): δ 7.37 (t, J = 6.8 Hz, 4H), 7.27–7.34 (m, 4H), 7.16 (d, J = 7.2 Hz, 2H), 3.92 (s, 1H), 2.84 (d, J = 19.2 Hz, 1H), 2.13 (d, J = J = 19.2 Hz, 1H), 2.06 (s, 3H), 1.31 (s, 3H). ¹³C{¹H} NMR (176 MHz, CD₃CN): δ 211.5, 172.6, 142.3, 139.3, 133.2, 130.0, 128.9, 128.5, 128.3, 128.3, 127.8, 77.2 (J = 22.1 Hz), 53.6, 42.3, 21.6, 17.8. IR (thin film) ν: 3443, 3056, 2928, 1684, 1637, 1597, 1495, 1447, 1380, 1345, 1232, 1089, 1058, 1031, 904, 873, 776, 737, 701, 666, 546 cm⁻¹. HRMS (ESI-TOF) (m/z): [M + H]⁺ calcd for C₂₀H₂₀O₂D, 294.1599; found, 294.1592.

(E)-5-Deutero-phenyl-2-benzoyl-2,4-dimethyl-5-phenylpent-4-enoate (Scheme 4, Compound 12).

General Procedure B was followed using phenyl methacrylate (49 mg, 0.3 mmol, 1.0 equiv), 1-phenyl-1-propyne (56 μL, 0.45 mmol, 1.5 equiv), and D-benzaldehyde (46 μL, 0.45 mmol, 1.5 equiv). The reaction was then worked up using the general workup procedure, and the crude was subjected to column chromatography (10% to 20% EtOAc/Hex). Further column chromatography (2.5% Acetone/Hex) of the impure isolate yielded the pure product as a white solid (26 mg, 23%). ¹H NMR (500 MHz, CDCl₃): δ 8.03 (d, J = 8.0 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.8 Hz, 2H), 7.33 (t, J = 7.8 Hz, 2H), 7.17–7.29 (m, 6H), 6.74 (d, J = 8.0 Hz, 2H), 3.22 (d, J = 14.0 Hz, 1H), 3.13 (d, J = 14.0 Hz, 1H), 1.89 (s, 3H), 1.80 (s, 3H). ¹³C{¹H}NMR (176 MHz, CDCl₃): δ 197.0, 172.9, 150.3, 137.6, 135.9, 133.5, 132.9, 130.6 (t, J = 22.8 Hz) 129.4, 129.0, 128.8, 128.6, 128.1, 126.4, 126.1, 121.0, 57.5, 47.4, 21.6, 19.6. IR (thin film) ν: 3057, 1753, 1684, 1597, 1492, 1446, 1378, 1304, 1192, 1089, 1024, 1001, 969, 936, 796, 748 cm⁻¹. HRMS (ESI-TOF) (m/z): [M + H]⁺ calcd for C₂₆H₂₄O₃D, 386.1861; found, 386.1861.

Computational Details.

Density functional calculations were performed using Q-Chem 3.1.0.0,¹⁶ for geometry optimization and frequency calculations, and ORCA 4.0.0.2,¹⁷ for single-point calculations. All geometries for intermediates and transition states were optimized using the ωB97X density functional¹⁸ and 6–31G(d) basis set.¹⁹ Energies were refined by applying the ωB97X-D3 density functional²⁰ with the cc-pVTZ basis²¹ and the SMD implicit solvent model²² with toluene as the solvent (ε = 2.4). Transition state geometries and minimum energy reaction paths were found using the single-²³ and double-ended²⁴ growing string methods. Found transition states were subsequently reoptimized after the initial search. All energies listed are Gibbs free energies with enthalpy and entropy corrections at 363 K. Entropy corrections were scaled to 50% to account for the difference in entropy between the gas and solvated phases.²⁵ The effects of low frequency oscillations were reassigned to 50 cm⁻¹ to prevent the highly anharmonic vibrations from overly influencing the free energy. All intermediates and transition states were confirmed to have the appropriate number of imaginary frequencies: one for transition states, and none for intermediates. All geometry optimizations, frequency calculations, were performed with an SCF convergence tolerance of 10⁻⁶. Single-point calculations were performed with an SCF convergence tolerance of 10⁻⁸.