Asymmetric Synthesis of Enantioenriched 6-Hydroxyl Butyrolactams

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Asymmetric Synthesis of Enantioenriched 6-Hydroxyl Butyrolactams Promoted by N-Heterocyclic Carbene Zhouli Hu, Ying Zhu, Zhenqian Fu, and Wei Huang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01490 • Publication Date (Web): 22 Jul 2019 Downloaded from pubs.acs.org on July 22, 2019

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The Journal of Organic Chemistry

Asymmetric Synthesis of Enantioenriched 6-Hydroxyl Butyrolactams Promoted by N-Heterocyclic Carbene Zhouli Hu,† Ying Zhu,† Zhenqian Fu,*,†,‡ and Wei Huang*,†,‡ †

Key Laboratory of Flexible Electronics & Institute of Advanced Materials, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University, 30 South Puzhu Road, Nanjing 211816, China ‡ Shaanxi Institute of Flexible Electronics (SIFE), Northwestern Polytechnical University (NPU), 127 West Youyi Road, Xi'an, 710072, China E-mail: [email protected]; [email protected].

ABSTRACT: Herein, an efficient route to 6-hydroxyl butyrolactams has been successfully developed via an NHC-catalyzed formal [3+2] annulation of bromoenals with α-amino ketones, followed by reduction. Remarkably, enantioenriched epineoclausenamide which is one of clausenamide derivatives, could be efficient prepared by this strategy.

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INTRODUCTION

Butyrolactams (γ-lactams), especially 6-hydroxyl butyrolactams, are among the most of privileged azaheterocycles, often found as the core structural scaffolds in numerous natural products and pharmaceuticals with a wide range of promising biological properties (Figure 1a).1-3 Among them, clausenamide and its stereoisomers, which are found in the aqueous extract of Clausen alassium (lour) skeels, a Chinese herb medicine, displayed several biological activities, such as nootropic activity, antiaging activity, hepatoprotective activity and against acute cerebral ischemia.4 Importantly, they have showed potential use in treatment of Alzheimer’s disease.5 However, these Clausena alkaloids are isolated from nature as racemates with a very lower yield.6 Owing to prevalence and importance of such alkaloids, considerable effort has been devoted to this field, and many elegant methods 7,8 for the synthesis of enantioenriched clausenamide and its stereoisomers have been successfully developed by the groups of Hartwig,8a Roberts,8b Tang,8c Wang,8d Shi,8e Yu,8f,8g Huang,8h and Tanda.8i Notably, some of them often suffer from the obtained product with a low diastereoselectivity, the use of equivalents of a chiral assisted reagent and at most 50% yield via a kinetic resolution. Further development of a novel and efficient method for the synthesis of these important compounds is of high demand. Retrosynthetic analysis showed that clausenamide and its stereoisomers could be prepared via a formal [3+2] annulation of α,β-unsaturated acyl intermediate with α-amino enolate intermediate for the synthesis of butyrolactams, followed by reduction and subsequently 3-hydoxylation (Figure 1). For total four stereocenters, two stereocenters would be generated from the asymmetric reaction and another two more

Figure 1. Representative examples of 6-hydroxyl butyrolactams and retrosynthetic analysis. stereocenters would be formed via further synthetic transformations. Thus, the formation of butyrolactams with excellent diastereoselectivities and enantioselectivities from the formal [3+2] annulation is the crucial step for this synthetic route.

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Over the past decade, N-heterocyclic carbene (NHC) has proven to be one of the most privileged organocatalysts and has enabled construction of structurally diverse carbo- and heterocycles from simple raw materials.9 As a part of our ongoing interest in carbene catalysis,10 and based on aforementioned retrosynthetic analysis for clausenamide and its stereoisomers, we envisaged that a new synthetic strategy for enantioenriched clausenamide and its stereoisomers might be achieved starting from a formal [3+2] annulation of αbromoenals with α-amino ketones promoted by NHC, followed by reduction and subsequently 3-hydroxylation (Figure 1b). Herein, we present an efficient route to 6-hydroxyl butyrolactams starting from formal [3+2] annulation of αbromoenals with α-amino ketone enabled by NHC organocatalyst under mild conditions. Notably, the Ye group11 has reported the use unsaturated carboxylic acids as unsaturated acyl azolium intermediates for the synthesis of 6-keto butyrolactams promoted by NHC (Figure 1c).

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A was used with Et3N as the base in THF at room temperature (entry 1). Notably, this reaction showed excellent chemoselectivity, and N-attack product 3a’ was not detected under reaction conditions.12 Gratifyingly, aminoindanol-derived triazolium pre-catalyst B could also realized this annulation to furnish the desired chiral γ-lactam 3a in 92% yield with good diastereoselectivity (11:1 dr) and excellent enantioselectivity (98% ee) (entry 2). Several bases, such as Cs2CO3, K2CO3, DBU, NaOAc, KOH, DIPEA, DMAP and DABCO, were next evaluated and Et3N was proved to the most effective choice (entries 2-10). Subsequent solvent screening revealed that dioxane was the most effective, resulting in the formation of 3a in 82% yield with >20:1 dr and 99% ee (entries 11-14). Scheme 1. Scope of reaction a

RESULTS AND DISCUSSION

Table 1. Screening reaction conditions a

Entrya

Yield drc ee b (%) (%)d 1 Et3N THF 85 11:1 A 2 Et3N THF 92 11:1 98 B 3 Cs2CO3 THF 45 4:1 93 B 4 K2CO3 THF 40 >20:1 96 B 5 DBU THF 54 6:1 97 B 6 NaOAc THF 60 >20:1 97 B 7 KOH THF 20 11:1 80 B 8 DIPEA THF 92 >20:1 88 B 9 DMAP THF 43 >20:1 96 B 10 DABCO THF 75 >20:1 96 B 11 Et3N dioxane 82 >20:1 99 B 12 Et3N DCM 82 >20:1 95 B 13 Et3N CH3CN 70 15:1 89 B 14 Et3N EA 80 >20:1 97 B a Standard conditions: α-bromocinnamaldehyde (0.36 mmol, 1.8 equiv), α-amino ketone (0.2 mmol), NHC precursor (10 mol %), base (3.0 equiv), solvent (0.1 M), rt, 12 h. b Isolated yields after column chromatography. c Determined via 1H NMR analysis of unpurified reaction mixtures. d Determined by HPLC using a chiral stationary phase.

a

The reaction of readily available α-bromocinnamaldehyde 1a and 4-methyl-N-(2-oxo-2-phenylethyl) benzenesulfonamide 2a was selected as a model reaction for optimizing the conditions. The key results are summarized in Table 1. To our delight, the desired γ-lactam 3a was obtained in 85% yield with 11:1 dr when the racemic triazolium N-Mes pre-catalyst

With acceptable optimized conditions in hand (Table 1, entry 11), we then evaluated the scope of the reaction for αbromoenals substrates by using α-amino ketone 2a as a model substrate (Scheme 1). α-Bromoenals with a range of substitu-

NHC

Base

Solvent

Reaction conditions as in Table 1, entry 11; yields (after SiO2 chromatography purification) were based on α-amino ketones 2.


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ents (such as Me, OMe, F, Cl, Br, NO 2 and COOEt) with diverse electronic and steric properties on the β-aryl were well tolerated, delivering the corresponding γ-lactam 3b-3j in 7498% yields, 6.5:1->20:1 drs and 96-99% ee. α-Bromoenals bearing β-2-naphtyl or 2-furyl also worked efficiently to generate the corresponding γ-lactams (3k&3l). We then investigated the generality of α-amino ketones 2 under the optimized conditions. Variation of the R2 group also showed a broad scope and led to similar results as for the α-bromoenals. Notably, when R2, besides aryl or heteroaryl groups, is an alkyl group, the reaction proceeded smoothly to generate 3w & 3x in acceptable yield with excellent enantioselectivity, albeit with a lower diastereoselectivity. Delightingly, replacement of Ts with Ns did not influence the outcome. Notably, compared to the group of Ye pioneered work for the synthesis of γlactams, our present strategy shows better outcomes in term of yield, dr and ee. Resulting structurally diverse γ-lactams with excellent diastereoselectivities and enantioselectivities by our present strategy should substantially increase potential uses. After establishment of this efficient strategy, we then addressed one-pot synthesis of important 6-hydroxyl butyrolactams 4 directly starting from a formal [3+2] annulation of αbromoenals 1 with α-amino ketones 2, followed by the reduction of a keto carbonyl to a hydroxyl group under mild conditions (Scheme 2). A variety of 6-hydroxyl butyrolactams 4 containing three consecutive stereocenters were obtained in 65-85% yields with 14:1->20:1 drs and 93-99 ee. Notably, a new generated stereocenter was formed with excellent outcomes in this transformation. These results indicated the important 6-hydroxyl butyrolactams could be directly prepared starting from α-bromoenals 1 with α-amino ketones 2.

of 3a with SmI2 underwent C-N bond breakage to efficiently generate ring-opening product 5 in 92% yield without any loss in dr or ee. Surprisingly, reductive ring-opening of γ-lactam 3a could be readily realized by the use of LiAlH 4 as a reluctant and led to the formation of 6 containing three consecutive stereocenters in 78% yield with >20:1 dr and 97% ee. Treatment of γ-lactam 3a with methanol or benzyl amine underwent ring-opening to deliver the products 7 & 8 without any loss in dr and ee, respectively. γ-lactam 3y underwent deprotection of an Ns group followed by methylation to furnish compound 10 in 47% overall yield with >20:1 dr and 97% ee, which could be converted to enantioenriched epi-neoclausenamide via known processes.13 Scheme 4. Synthetic transformations of γ-lactams 3

Scheme 2. Scope of One-pot reaction a

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a

Reaction conditions: i. Reaction conditions as in Table 1, entry 11; ii. LiAlH(t-BuO)3 (2.0 equiv), THF (0.1 M), 0℃ to rt, 12 h.

To show the practicality of our strategy, a gram-scale reaction was carried out (Scheme 3). The scaled-up reaction worked very well under standard conditions, affording γlactams 3a in 80% yield with 18.6 dr and 97% ee. Scheme 3. A gram-scale reaction

In summary, an efficient route to 6-hydroxyl butyrolactams has been successfully developed starting from an NHCcatalyzed formal [3+2] annulation of α-bromoenals with αamino ketone, followed by a reduction under mild conditions. A structurally diverse set of butyrolactams was efficiently obtained in acceptable to good yields with good to excellent diastereoselectivities and excellent enantioselectivities. Synthetic transformations show the potential application of the products. Notably, epi-neoclausenamide, an important natural product, was efficient synthesized from the resulting butyrolactam. Further investigations and exploration of this process are underway in our laboratory.

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Subsequently, further synthetic transformations of obtained γ-lactams 3 were conducted as shown in Scheme 4. Treatment

CONCLUSIONS

EXPERIMENTAL SECTION

General Information. Commercially available materials purchased from Adamas-beta® were used as received. Dioxane was dried over Pure Solv solvent purification system. Other solvents were dried over 4Å molecular sieve prior use. Pro-



ton nuclear magnetic resonance (1H NMR) spectra were recorded on a Bruker (400 MHz & 500 MHz) spectrometer. Chemical shifts were recorded in parts per million (ppm, δ) relative to tetramethylsilane (δ 0.00) or chloroform (d = 7.26, singlet). 1H NMR splitting patterns are designated as singlet (s), doublet (d), triplet (t), quartet (q), dd (doublet of doublets); m (multiplets), and etc. All first-order splitting patterns were assigned on the basis of the appearance of the multiplet. Splitting patterns that could not be easily interpreted are designated as multiplet (m) or broad (br). Carbon nuclear magnetic resonance (13C NMR) spectra were recorded on a Bruker 100 MHz & 125 MHz spectrometer. High resolution mass spectral analysis (HRMS) was performed on a Waters Q–TOF Premier Spectrometer. The determination of enantiomeric excess was performed via chiral HPLC analysis using Shimadzu LC20AD HPLC workstation. X-ray crystallography analysis was performed on Bruker X8 APEX X-ray diffractionmeter. Optical rotations were measured using a 1 mL cell with a 1 dm path length on a Jasco P-1030 polarimeter and are reported as follows: [α]rtD (c is in g per 100 mL solvent). Analytical thinlayer chromatography (TLC) was carried out on Merck 60 F254 pre-coated silica gel plate (0.2 mm thickness). Visualization was performed using a UV lamp or potassium permanganate stain. Bromoenals 1 were synthesized according to the method reported in the literature.14 Various α-amino ketones were synthesized according to the literature.15-18 General procedure for the synthesis of products 3 (3a as an example): To a flame-dried screw-capped test tube equipped with a magnetic stir bar, compound 2a (57.9 mg, 0.2 mmol), bromocinnamaldehyde 1a (76.0 mg, 0.36 mmol), Et3N (83 μl, 0.6 mmol), NHC B (7.3 mg, 10 mol%) and dry 1,4-dioxane (2 mL) was added. The reaction mixture was kept stirring at room temperature for 12 h. When the reaction was completed, the crude residue was purified by flash column chromatography on silica gel using Petroleum ether/EtOAc (3:1) as eluent to afford the product 3a as a white solid in 82% yield, >20:1 dr and 99% ee.

Procedure for the scale-up synthesis of product 3a: αbromocinnamaldehyde 1a (1.52 g, 7.2 mmol), α-amino ketone 2a (1.16 g, 4 mmol) and NHC B (147.0 mg, 10 mol%) were added as a solid to an oven-dried 50mL round-bottomed flask before the dry 1,4-dioxane (15 mL) was added. Et3N (1.7 ml, 3.5 equiv) was then slowly added to the system. The resultant reaction mixture was kept stirring at room temperature for 12 h. Upon completion of the reaction, the mixture was concentrated under vacuum and purified by column chromatography using Petroleum ether/EtOAc (3:1) as eluent to afford the product 3a as a white solid (1.37g, 80% yield,18.6:1 dr and 97% ee ). General procedure for the product 4: To a flame-dried screw-capped test tube equipped with a magnetic stir bar compound 2a (57.9 mg, 0.2 mmol), bromocinnamaldehyde 1a (76.0 mg, 0.36 mmol), Et3N (83.0 μl, 0.6 mmol), NHC B (7.3 mg, 10 mol%) and dry 1,4-dioxane (2 mL) was added. The reaction mixture was kept stirring at room temperature for 12 h. After extracting with CH2Cl2 (3 x 15 mL) and washing with brine (10 mL), the organic phase was dried (Na2SO4) filtered and the solvent was removed under reduced pressure. Then to the crude residue in the THF (2 mL) at 0 ℃ was added LiAlH(t-BuO)3 (101.7 mg, 0.4 mmol), and stirred at room temperature for 12 h. The reaction was quenched with H 2O and extracted with EtOAc (3 × 10 mL). The organic layer

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was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc and n-hexane as eluent) to afford 4a with 85% yield, 20:1 dr and 99% ee. General procedure for the product 5:19 To a dry round bottom flask containing product 3a (83.4 mg, 0.2 mmol) cooled at 0℃ was added dropwise a solution of SmI2 (0.1 M, 10.0 mL, 5 equiv) and the resulting mixture was stirred for 30 min at 0℃ and then, 1 M HCl (5 mL) was added and the stirring was continued for 5 min. After extracting with EtOAc (3 x 15 mL) and washing with brine (10 mL), the organic phase was dried (Na2SO4) filtered and the solvent was removed under reduced pressure, and the crude residue was purified by flash chromatography to afford product 5 with 92% yield and 99% ee. General procedure for the product 6: To the product 3a (41.9 mg, 0.1 mmol) in THF (1 mL) at 0 ℃ was added LiAlH4(11.4 mg, 0.3 mmol) slowly. After 10 min the cooling bath was removed, and stirring was continued for 12 h. The reaction was quenched with NH4Cl and extracted with CH2Cl2 (3 × 10 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc and nhexane as eluent) to afford 6 with 78% yield, >20:1 dr and 99% ee. General procedure for the product 7:To a flame-dried screw-capped test tube equipped with a magnetic stir bar, product 3a (83.4 mg, 0.2 mmol), NaOMe (10.8 mg, 0.2 mmol), and dry CH3OH (2 mL) was added. The reaction mixture was kept stirring at room temperature for 2 h. When the reaction was completed, the crude residue was purified by flash column chromatography on silica gel using Petroleum ether/EtOAc (3:1) as eluent to afford the product 7 as a white solid in 98% yield, >20:1 dr and 99% ee. General procedure for the product 8:To a dry test tube containing product 3a (83.4 mg, 0.2 mmol) in DCM(2 mL)was added DBU (45 μl, 1.5 equiv) and BnNH2 (132 μl, 6 equiv). The reaction mixture was kept stirring at room temperature for 36 h. When the reaction was completed, the crude residue was purified by flash column chromatography on silica gel using Petroleum ether/EtOAc (1:1) as eluent to afford the product 8 as a white solid in 57% yield, >20:1 dr and 99% ee. General procedure for the product 9,20 10:21 Under N2 atmosphere, one drop DMSO was added to PhSNa (106 mg, 0.8 mmol), product 3y (90 mg, 0.2 mmol) and K2CO3 (138 mg, 1 mmol) in CH3CN (2 mL) at room temperature. The reaction was stirred for 12 h. And was diluted with saturated aqueous NH4Cl solution and extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were washed with brine, dried (MgSO4), concentrated, and was purified by flash chromatography to the product 9 with 78% yield, >20:1 dr and 97% ee. To the product 7 (25 mg, 0.1 mmol) in DMF (1 mL) at 0℃ was added NaH (7.2 mg, 0.18 mmol) slowly. After 30 min, to the reaction was added CH3I (7.5 μl, 0.12 mmol) and stirred at room temperature for 12 h. The reaction was quenched with H2O and extracted with EtOAc (3 × 10 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash


Page 5 of 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


chromatography to afford 10 with 60% yield, >20:1 dr and 97% ee. Structures of known compounds, 1a,22 1b,22 1c, 22 1d, 23 1e, 22 1f, 14 1g, 22 1h, 22 1i, 221k, 24 1l, 25 2a, 27 2b, 26 2c, 27 2d, 27 2e,28 2f, 15 2g,27 2h, 27 2j, 28 2k,29 2l,18 2m,30 3a,11 3b, 11 3c, 11 3d, 11 3e, 11 3f, 11 3h,31 3i,31 3l,31were confirmed by NMR spectral comparison with literature data. (Z)-methyl-4-(2-bromo-3-oxoprop-1-en-1-yl)benzoate (1j): 70% yield (937.7 mg), yellow solid; 1H NMR(400 MHz, CDCl3) δ = 9.38 (s, 1H), 8.13 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.95 (s, 1H), 3.95 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 186.8, 166.2, 147.4, 137.0, 132.2, 130.6, 129.8, 126.3, 52.5; HRMS(ESI) calcd for C 11H9BrO3Na (M+Na)+: 290.9627, Found: 290.9622. 4-methyl-N-(2-(naphthalen-2-yl)-2oxoethyl)benzenesulfonamide (2i): 80% yield (1356 mg), white solid; 1H NMR (400 MHz, CDCl3) δ = 8.37 (s, 1 H), 7.95 (d, J = 8.4 Hz, 1H), 7.86-7.89 (m, 3H), 7.81 (d, J = 8.4 Hz, 2H), 7.56-7.66 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 5.73 (t, J = 4.4 Hz, 1H), 4.61 (d, J = 4.4 Hz, 2H), 2.39 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 192.5, 143.8, 136.1, 136.0, 132.3, 131.1, 129.9, 129.8, 129.7, 129.3, 128.9, 127.9, 127.3, 127.2, 123.1, 48.8, 21.5; HRMS(ESI) calcd for C19H17NO3SNa (M+Na)+: 362.0821，Found: 362.0828. 4-nitro-N-(2-oxo-2-phenylethyl)benzenesulfonamide (2n): 75% yield (1200 mg), white solid; 1H NMR (400 MHz, DMSO) δ = 8.51 (t, J = 5.6 Hz, 1H), 8.40 (d, J = 8.8 Hz, 2H), 8.11 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 7.2 Hz, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 4.61 (d, J = 5.6 Hz, 2H); 13C{H} NMR (100 MHz, DMSO) δ = 194.4, 149.9, 147.0, 134.8, 134.3, 129.2, 128.6, 128.4, 124.8, 49.6; HRMS(ESI) calcd for C14H12N2O5SNa (M+Na)+: 343.0359, Found: 343.0353. (4R,5S)-5-benzoyl-4-phenyl-1-tosylpyrrolidin-2-one (3a):11 82% yield (67.1 mg), white solid; [α]D 23 +103.6 (c 0.48, CHCl3); 99% ee as determined by HPLC (Chiralcel AD, 90:10 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 55.4 min, tr (minor) = 33.2 min (4R,5S)-5-benzoyl-4-(2-chlorophenyl)-1-tosylpyrrolidin-2one (3b)11: 88% yield (79.7 mg), white solid; [α]D 23 +8.5 (c 0.59, CHCl3); 97% ee as determined by HPLC (Chiralcel AD, 92:8 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 61.1 min, tr (minor) = 27.6 min (4R,5S)-5-benzoyl-4-(2-methoxyphenyl)-1-tosylpyrrolidin-2one (3c):11 80% yield (71.9 mg), white solid; [α]D 23 +81.5 (c 0.37, CHCl3); 98% ee as determined by HPLC (Chiralcel ADH, 93:7 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 83.8 min, tr (minor) = 51.9 min (4R,5S)-5-benzoyl-4-(3-chlorophenyl)-1-tosylpyrrolidin-2one (3d):11 97% yield (87.9 mg), white solid; [α]D 23 +18.5 (c 0.54, CHCl3); 97% ee as determined by HPLC (Chiralcel AD, 90:10 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 51.4 min, tr (minor) = 36.9 min (4R,5S)-5-benzoyl-4-(4-chlorophenyl)-1-tosylpyrrolidin-2one (3e):11 98% yield (88.8 mg), white solid; [α]D 23 +100.9 (c 0.69, CHCl3); 97% ee as determined by HPLC (Chiralcel ODH, 90:10 hexanes/i-PrOH, 0.7 mL/min), tr (major) = 53.2 min, tr (minor) = 41.5 min

(4R,5S)-5-benzoyl-4-(4-bromophenyl)-1-tosylpyrrolidin-2one (3f):11 74% yield (73.6 mg), white solid; [α]D 23 +92.4 (c 0.43, CHCl3); 99% ee as determined by HPLC (Chiralcel AD, 80:20 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 73.2 min, tr (minor) = 22.5 min (4R,5S)-5-benzoyl-4-(4-fluorophenyl)-1-tosylpyrrolidin-2one (3g): 95% yield (83.1 mg), white solid; [α]D 23 +77.5 (c 0.39, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.90-7.96 (m, 4H), 7.64-7.68 (m, 1H), 7.51(t, J = 7.6 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.13-7.17 (m, 2H), 7.04 (t, J = 8.4 Hz, 2H), 5.82 (d, J = 2.0 Hz, 1H), 3.39 (dt, J = 9.2, 2.0 Hz, 1H), 2.98 (dd, J = 17.6, 9.2 Hz, 1H), 2.46-2.51 (m, 4H); 13C{H} NMR (100 MHz, CDCl3) δ = 194.5, 172.1, 162.4 (d, JC-F =246 Hz ), 145.6, 137.5, 137.4, 134.6, 134.5, 133.5, 129.4, 129.3, 129.2, 128.7, 128.0, 127.9, 116.5 (d, JC-F =21 Hz ) 68.9, 40.1, 38.6, 21.8; HRMS(ESI) calcd for C24H20FNO4SNa (M+Na)+: 460.0989, Found: 460.0984; 97% ee as determined by HPLC (Chiralcel AD, 90:10 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 75.2 min, tr (minor) = 35.3 min. (4R,5S)-5-benzoyl-4-(4-nitrophenyl)-1-tosylpyrrolidin-2one (3h): 31 89% yield (82.6 mg), white solid; [α]D 23 +162.0 (c 0.22, CHCl3); 96% ee as determined by HPLC (Chiralcel IB, 82:18 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 60.1 min, tr (minor) = 41.5 min (4R,5S)-5-benzoyl-4-(4-methoxyphenyl)-1-tosylpyrrolidin-2one (3i): 31 98% yield (88.0 mg), white solid; [α]D 23 +40.3 (c 0.50, CHCl3); 96% ee as determined by HPLC (Chiralcel AD, 90:10 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 65.7 min, tr (minor) = 37.1 min methyl 4-((2S,3R)-2-benzoyl-5-oxo-1-tosylpyrrolidin-3yl)benzoate (3j): 98% yield (93.5 mg), white solid; [α]D 23 +83.3 (c 0.48, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 8.01 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.4 Hz, 2H), 7.90 (dd, J = 8.0, 1.2 Hz, 2H), 7.66-7.70 (m, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 5.84 (d, J = 2.0 Hz, 1H), 3.93 (s, 3H), 3.44 (dt, J = 9.2, 2.0 Hz, 1H), 3.02 (dd, J = 18.0, 9.2 Hz, 1H), 2.52 (dd, J = 17.6, 2.0 Hz, 1H), 2.47 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 194.3, 171.9, 166.4, 146.4, 145.6, 134.6, 134.5, 133.4, 130.9, 130.1, 129.4, 129.3, 129.2, 128.7, 126.4, 68.3, 52.3, 40.6, 38.2, 21.8; HRMS (ESI) calcd for C26H23NO6SNa (M+Na)+: 500.1138, Found: 500.1154; 96% ee as determined by HPLC (Chiralcel AD, 80:20 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 59.3 min, tr (minor) = 30.4 min (4R,5S)-5-benzoyl-4-(naphthalen-2-yl)-1-tosylpyrrolidin-2one (3k): 80% yield (75.1 mg), white solid; [α]D 23 +44.1 (c 0.34, CHCl3); 1H NMR(400 MHz, CDCl3) δ = 7.95-7.99 (m, 4H), 7.85-7.88 (m, 2H), 7.71 (dd, J = 6.0, 3.6 Hz, 1H), 7.637.67 (m, 1H), 7.48-7.55 (m, 5H), 7.35 (d, J = 8.0 Hz, 2H), 7.29 (dd, J = 8.4, 1.6 Hz, 1H), 5.95 (d, J = 1.6 Hz, 1H), 3.56-3.58 (m, 1H), 3.09 (dd, J = 18.0, 9.2 Hz, 1H), 2.61 (dd, J = 18.0, 2.4 Hz, 1H), 2.47 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 194.6, 172.3, 145.5, 139.0, 134.7, 134.5, 133.6, 133.4, 132.9, 129.9, 129.4, 129.2, 129.1, 128.8, 127.9, 127.8, 126.8, 126.5, 125.1, 123.9, 68.8, 40.8, 38.5, 21.8; HRMS (ESI) calcd for C28H23NO4SNa (M+Na)+: 492.1240, Found: 492.1243; 95% ee as determined by HPLC (Chiralcel AD, 85:15 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 69.6 min, tr (minor) = 23.9 min.



(4S,5S)-5-benzoyl-4-(furan-2-yl)-1-tosylpyrrolidin-2-one (3l): 31 92% yield (75.3 mg), white solid; [α]D 23 +52.3 (c 0.48, CHCl3); 92% ee as determined by HPLC (Chiralcel AZH, 85:15 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 112.0 min, tr (minor) = 85.8 min (4R,5S)-5-(2-methylbenzoyl)-4-phenyl-1-tosylpyrrolidin-2one (3m): 86% yield (72.3 mg), white solid; [α]D 23 +65.4 (c 0.31, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.96 (d, J = 8.4 Hz, 2H), 7.67 (dd, J = 8.0, 1.2 Hz, 1H), 7.46 (td, J = 7.6, 1.6 Hz, 1H), 7.28-7.36 (m, 7H), 7.07-7.10 (m, 2H), 5.74 (d, J = 2.0 Hz, 1H), 3.34 (dt, J = 9.2, 2.0 Hz, 1H), 3.00 (dd, J = 17.6, 8.8 Hz, 1H), 2.52-2.56 (m, 4H), 2.47 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 197.5, 172.3, 145.5, 141.6, 140.0, 134.7, 133.8, 132.8, 132.5, 129.5, 129.3, 129.3, 129.2, 128.1, 126.2, 126.1, 70.6, 40.4, 38.3, 21.8, 21.5; HRMS(ESI) calcd for C25H23NO4SNa (M+Na)+: 456.1240, Found: 456.1238; 95% ee as determined by HPLC (Chiralcel ADH, 90:10 hexanes/iPrOH, 1.0 mL/min), tr (major) = 37.0 min, tr (minor) = 27.2 min. (4R,5S)-5-(3-chlorophenyl)-4-phenyl-1-tosylpyrrolidin-2one (3n): 93% yield (84.3 mg), white solid; [α]D 23 +24.3 (c 0.41, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.95 (d, J = 8.4 Hz, 2H), 7.90 (t, J = 2.0 Hz, 1H), 7.74 (dt, J = 8.0, 1.2 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.33-7.38 (m, 6H), 7.14-7.17 (m, 2H), 5.78 (d, J = 2.4 Hz, 1H), 3.37 (dt, J = 9.2, 2.4 Hz, 1H), 2.98 (dd, J = 18.0, 9.2 Hz, 1H), 2.56 (dd, J = 17.6, 2.8 Hz, 1H), 2.47 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 193.8, 172.1, 145.6, 141.2, 135.6, 135.2, 134.6, 134.4, 130.5, 129.7, 129.4, 129.3, 128.9, 128.4, 126.8, 126.2, 69.0, 40.8, 38.5, 21.8; HRMS(ESI) calcd for C24H20ClNO4SNa (M+Na)+: 476.0694, Found: 476.0690; 94% ee as determined by HPLC (Chiralcel IB, 93:7 hexanes/i-PrOH, 0.5 mL/min), tr (major) = 80.9 min, tr (minor) = 49.9 min. (4R,5S)-5-(4-chlorophenyl)-4-phenyl-1-tosylpyrrolidin-2one(3o): 92% yield (83.4 mg), white solid; [α]D 23 +118.2 (c 0.30, CHCl3); 1H NMR (400 MHz,CDCl3 ) δ = 7.94 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.34-7.38 (m, 5H), 7.14-7.16 (m, 2H), 5.79 (d, J = 2.4 Hz, 1H), 3.36 (dt, J = 9.2, 2.4 Hz, 1H), 2.99 (dd, J = 18.0, 9.6 Hz, 1H), 2.55 (dd, J = 17.6, 2.4 Hz, 1H), 2.47 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 193.7, 172.2, 145.6, 141.4, 141.1, 134.6, 132.0, 130.2, 129.7, 129.5, 129.4, 129.3, 128.4, 126.2, 68.7, 40.8, 38.6, 21.8; HRMS(ESI) calcd for C24H20ClNO4SNa (M+Na)+: 476.0694, Found: 476.0698; 97% ee as determined by HPLC (Chiralcel ADH, 90:10 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 58.9 min, tr (minor) = 36.2 min. (4R,5S)-5-(4-fluorophenyl)-4-phenyl-1-tosylpyrrolidin-2one (3p): 93% yield (81.3 mg), white solid; [α]D 23 +89.5 (c 0.39, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.72-7.76 (m, 4H), 7.14-7.17 (m, 5H), 6.94-6.99 (m, 4H), 5.61 (d, J = 2.4 Hz, 1H), 3.16 (dt, J = 9.2, 2.4 Hz, 1H), 2.79 (dd, J = 17.6, 9.2 Hz, 1H), 2.34 (dd, J = 17.6, 2.8 Hz, 1H), 2.27 (s, 3H)；13C{H} NMR (100 MHz, CDCl3) δ = 193.3, 172.2, 166.5 (d, JC-F =256 Hz ), 145.5, 141.4, 134.7, 131.6, 131.5, 130.1, 130.0, 129.7, 129.4, 129.3, 128.3, 126.2, 116.4 (d, JC-F =22 Hz ), 68.7, 40.9, 38.6, 21.8; HRMS(ESI) calcd for C24H20FNO4SNa (M+Na)+: 460.0989, Found: 460.0996; 97% ee as determined by HPLC (Chiralcel AD, 90:10 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 62.7 min, tr (minor) = 34.1 min.

Page 6 of 10

(4R,5S)-5-(4-bromobenzyl)-4-phenyl-1-tosylpyrrolidin-2one (3q): 92% yield (91.5 mg), white solid; [α]D 23 +108.0 (c 0.42, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.94 (d, J = 8.4Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.33-7.38 (m, 5H), 7.15 (dd, J = 7.6, 4.0 Hz, 2H), 5.79 (d, J = 2.4 Hz, 1H), 3.35 (dt, J = 9.2, 2.8 Hz, 1H), 2.99 (dd, J = 17.9, 9.2 Hz, 1H), 2.55 (dd, J = 17.6, 2.4 Hz, 1H), 2.47 (s, 3H); 13 C{H} NMR (100 MHz, CDCl3) δ = 194.0, 172.2, 145.6, 141.3, 134.6, 132.5, 130.2, 129.9, 129.7, 129.4, 129.3, 128.4, 128.1, 126.2, 68.7, 40.8, 38.6, 21.8; HRMS(ESI) calcd for C24H20BrNO4SNa (M+Na)+: 520.0189, Found: 520.0190; 97% ee as determined by HPLC (Chiralcel ADH, 90:10 hexanes/iPrOH, 1.0 mL/min), tr (major) = 60.3 min, tr (minor) = 39.0 min. (4R,5S)-5-(4-methylbenzoyl)-4-phenyl-1-tosylpyrrolidin-2one (3r): 94% yield (81.2 mg), white solid; [α]D 23 +152.7 (c 0.49, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.95 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H), 7.34-7.36 (m, 5H), 7.30 (d, J = 8.0 Hz, 2H), 7.16-7.18 (m, 2H), 5.84 (d, J = 2.0 Hz, 1H), 3.38 (dt, J = 9.2, 2.0 Hz, 1H), 2.99 (dd, J = 17.6, 9.2 Hz, 1H), 2.51 (dd, J = 17.6, 2.4 Hz, 1H), 2.46 (s, 3H), 2.43 (s, 3H); 13 C{H} NMR (100 MHz, CDCl3) δ = 194.2, 172.4, 145.6, 145.4, 141.8, 134.8, 131.1, 129.9, 129.6, 129.3, 129.2, 128.9, 128.2, 126.2, 68.9, 40.8, 38.5, 21.8, 21.8; HRMS(ESI) calcd for C25H23NO4SNa (M+Na)+: 456.1240, Found: 456.1238; 99% ee as determined by HPLC (Chiralcel AD, 90:10 hexanes/iPrOH, 1.0 mL/min), tr (major) = 58.9 min, tr (minor) = 34.7 min. (4R,5S)-5-(4-methoxybenzoyl)-4-phenyl-1-tosylpyrrolidin-2one (3s): 98% yield (88.0 mg), white solid; [α]D 23 +59.5 (c 0.67, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.95 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H), 7.34-7.36 (m, 5H), 7.177.19 (m, 2H), 6.96 (d, J = 8.8 Hz, 2H), 5.81 (d, J = 2.0 Hz, 1H), 3.89 (s, 3H), 3.38 (dt, J = 9.2, 2.0 Hz, 1H), 3.00 (dd, J = 17.6, 9.2 Hz, 1H), 2.51 (dd, J = 17.6, 2.0 Hz, 1H), 2.46 (s, 3H); 13 C{H} NMR (100 MHz, CDCl3) δ = 193.0, 172.5, 164.6, 145.4, 141.9, 134.8, 131.2, 129.6, 129.3, 128.2, 126.4, 126.2, 114.4, 68.7, 55.7, 41.0, 38.6, 21.8; HRMS(ESI) calcd for C25H23NO5SNa (M+Na)+: 472.1189, Found: 472.1187; 99% ee as determined by HPLC (Chiralcel AD, 90:10 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 77.5 min, tr (minor) = 53.3 min. (4R,5S)-5-(2-naphthoyl)-4-phenyl-1-tosylpyrrolidin-2-one (3t): 95% yield (89.1 mg), white solid; [α]D 23 +86.6 (c 0.29, CHCl3);1H NMR (400 MHz, CDCl3) δ = 8.37 (d, J = 2.0 Hz, 1H), 7.94-8.03 (m, 4H), 7.89 (dd, J = 14.8, 8.0 Hz, 2H), 7.647.68 (m, 1H), 7.57-7.60 (m, 1H), 7.37-7.40 (m, 5H), 7.20-7.23 (m, 2H), 6.02 (d, J = 2.4 Hz, 1H), 3.45 (dt, J = 9.2, 2.4 Hz, 1H), 3.04 (dd, J = 18.0, 9.6 Hz, 1H), 2.59 (dd, J = 17.6, 2.4 Hz, 1H), 2.48 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 194.6, 172.4, 145.5, 141.8, 136.1, 134.8, 132.4, 131.0, 130.9, 129.8, 129.6, 129.4, 129.3, 129.2, 128.3, 127.9, 127.3, 126.4, 123.9, 69.1, 41.0, 38.6, 21.8; HRMS(ESI) calcd for C28H23NO4SNa (M+Na)+: 492.1240, Found: 492.1243; 96% ee as determined by HPLC (Chiralcel ADH, 90:10 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 75.9 min, tr (minor) = 46.4 min. (4R,5S)-5-(furan-2-carbonyl)-4-phenyl-1-tosylpyrrolidin-2one (3u): 97% yield (79.4 mg), white solid; [α]D 23 +152.4 (c 0.49, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.93 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 1.6 Hz, 1H), 7.32-7.36 (m, 5H), 7.28 (d,


Page 7 of 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


J = 3.6 Hz, 1H), 7.17-7.19 (m, 2H), 6.61 (dd, J = 3.6, 1.6 Hz, 1H), 5.61 (d, J = 2.4 Hz, 1H), 3.47 (dt, J = 8.8, 2.8 Hz, 1H), 2.99 (dd, J = 17.6, 8.8 Hz, 1H), 2.57 (dd, J = 17.6, 2.8 Hz, 1H), 2.45 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 183.5, 172.3, 150.2, 148.0, 145.5, 141.4, 134.6, 129.4, 129.3, 129.2, 128.1, 126.3, 119.9, 113.1, 69.2, 41.1, 38.1, 21.8; HRMS(ESI) calcd for C22H19NO5SNa (M+Na)+ 432.0876, Found: 432.0870; 97% ee as determined by HPLC (Chiralcel ADH, 90:10 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 108.9 min, tr (minor) = 64.2 min. (4R,5S)-4-phenyl-5-(thiophene-2-carbonyl)-1tosylpyrrolidin-2-one (3v): 93% yield (79.1 mg), white solid; [α]D 23 +157.0 (c 0.32, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ = 7.94 (d, J = 8.4 Hz, 2H), 7.78 (dd, J = 5.2, 1.2 Hz, 1H), 7.64 (dd, J = 3.6, 0.8 Hz, 1H), 7.33-7.38 (m, 5H), 7.14-7.19 (m, 3H), 5.64 (d, J = 2.4 Hz, 1H), 3.46 (dt, J = 9.2, 2.8 Hz, 1H), 3.04 (dd, J = 17.6, 9.2 Hz, 1H), 2.57 (dd, J = 17.6, 2.8 Hz, 1H), 2.46 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 187.7, 172.3, 145.5, 141.5, 140.4, 135.9, 134.6, 133.5, 129.6, 129.4, 129.3, 128.9, 128.3, 126.3, 69.6, 41.5, 38.5, 21.8; HRMS(ESI) calcd for C22H19NO4S2Na (M+Na)+: 448.0648, Found: 448.0645; 96% ee as determined by HPLC (Chiralcel AD, 92:8 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 112.7 min, tr (minor) = 61.4 min. (4R,5S)-5-acetyl-4-phenyl-1-tosylpyrrolidin-2-one (3w): 50% (35.7 mg) yield, colorless oil; [α]D 23 +219.3 (c 0.09, CHCl3); 1 H NMR (400 MHz, CDCl3) δ = 7.62 (d, J = 8.4 Hz, 2H), 7.29-7.37 (m, 4H), 7.22-7.25 (m, 3H), 5.49 (s, 1H), 4.09 (d, J = 13.2 Hz, 1H), 3.72 (d, J = 0.8 Hz, 1H), 3.51 (d, J = 13.2 Hz, 1H), 2.42 (s, 3H), 1.69 (s, 3H)； 13C{H} NMR (100 MHz, CDCl3) δ = 203.6, 171.8, 145.5, 140.7, 134.6, 129.5, 129.4, 129.1, 128.2, 126.3, 72.2, 40.5, 38.6, 27.9, 21.8; HRMS(ESI) calcd for C19H19NO4SNa (M+Na)+: 380.0927, Found: 380.0935; 99% ee as determined by HPLC (Chiralcel AD, 95:5 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 66.8 min, tr (minor) = 52.0 min.

130.6, 129.6, 129.5, 129.2, 128.9, 128.7, 128.5, 128.3, 127.2, 124.8, 68.8, 41.5, 38.8; HRMS(ESI) calcd for C23H18N2O6SNa (M+Na)+: 473.0778, Found: 473.0780; 98% ee as determined by HPLC (Chiralcel AD, 80:20 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 38.4min, tr (minor) = 24.7 min. (4R,5S)-5-((S)-hydroxy(phenyl)methyl)-4-phenyl-1tosylpyrrolidin-2-one (4a): 85% yield (71.6 mg), white solid; [α]D 23 +66.7 (c 0.15, CHCl3); 1H NMR (500 MHz, CDCl3) δ = 7.80 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 7.0 Hz, 2H), 7.41-7.44 (m, 2H), 7.36-7.39 (m, 1H), 7.26 (d, J = 8.5 Hz, 2H), 7.157.19 (m, 1H), 7.09 (t, J = 7.5 Hz, 2H), 6.70 (d, J = 7.5 Hz, 2H), 5.33 (t, J = 4.5 Hz, 1H), 4.39 (d, J = 5.0 Hz, 1H), 3.46 (d, J = 9.0 Hz, 1H), 2.61 (d, J = 4.0 Hz, 1H), 2.46 (s, 3H), 1.99 (d, J = 18.0 Hz, 1H), 1.68 (t, J = 9.0 Hz, 1H); 13C{H} NMR (125 MHz, CDCl3) δ = 173.6, 145.3, 143.5, 138.5, 134.8, 129.4, 128.9, 128.8, 128.6, 128.5, 127.1, 126.6, 126.0, 74.2, 72.5, 37.1, 37.0, 21.7; HRMS(ESI) calcd for C24H23NO4SNa (M+Na)+: 444.1240, Found: 444.1245; 96% ee as determined by HPLC (Chiralcel ADH, 96:4 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 154.6 min, tr (minor) = 66.3 min. (4R,5S)-4-(4-chlorophenyl)-5-((S)-hydroxy(phenyl)methyl)1-tosylpyrrolidin-2-one (4b): 81% yield (73.7 mg), white solid; [α]D 23 -177.7 (c 0.51, CHCl3); 1H NMR (500 MHz, CDCl3) δ = 7.77 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 7.0 Hz, 2H), 7.37-7.43 (m, 3H), 7.26 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 8.5 Hz, 2H), 5.32 (t, J = 4.5 Hz, 1H), 4.30 (d, J = 5.0 Hz, 1H), 3.44 (d, J = 9.0 Hz, 1H), 2.73 (d, J = 4.0 Hz, 1H), 2.47 (s, 3H), 1.93 (d, J = 18.0 Hz, 1H), 1.61-1.66 (m, 1H); 13 C{H} NMR (125 MHz, CDCl3) δ = 173.4, 145.6, 141.9, 138.4, 134.6, 132.9, 129.5, 129.0, 128.9, 128.7, 128.4, 127.4, 126.6, 74.0, 72.4, 36.8, 36.5, 21.7; HRMS(ESI) calcd for C24H22ClNO4SNa (M+Na)+: 478.0850, Found: 478.0851; 94% ee as determined by HPLC (Chiralcel ODH, 96:4 hexanes/iPrOH, 0.8 mL/min), tr (major) = 106.4min, tr (minor) = 49.5 min.

141.7, 134.7, 129.6, 129.4, 129.2, 128.3, 126.2, 77.4, 77.1, 76.8, 70.5, 48.9, 40.2, 38.7, 28.9, 27.8, 25.7, 25.4, 21.9; HRMS(ESI) calcd for C24H27NO4SNa (M+Na)+: 448.1553, Found: 448.1555; 92% ee as determined by HPLC (Chiralcel AD, 90:10 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 32.6 min, tr (minor) = 17.6 min.

(4R,5S)-5-((R)-furan-2-yl(hydroxy)methyl)-4-phenyl-1tosylpyrrolidin-2-one (4c): 65% yield (53.4 mg), white solid; [α]D 23 -270.5(c 0.35, CHCl3); 1H NMR (500 MHz, CDCl3) δ = 7.83 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 1.5 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.20 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 2H), 6.80 (d, J = 7.0 Hz, 2H), 6.39-6.42 (m, 2H), 5.25 (t, J = 5.5 Hz, 1H), 4.45 (d, J = 5.5 Hz, 1H), 3.58 (d, J = 8.5 Hz, 1H), 2.94 (d, J = 5.5 Hz, 1H), 2.45 (s, 3H), 2.22 (dd, J = 18.0, 1.5 Hz, 1H), 2.14 (dd, J = 18.0, 8.5 Hz, 1H); 13C{H} NMR (125 MHz, CDCl3) δ = 173.45, 151.3, 145.3, 143.3, 142.9, 134.9, 129.4, 129.0, 128.6, 127.2, 126.0, 111.1, 109.2, 71.3, 69.1, 37.7, 36.9, 21.7; HRMS(ESI) calcd for C22H21NO5SNa (M+Na)+: 434.1033, Found: 434.1030; 96% ee as determined by HPLC (Chiralcel ADH, 90:10 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 77.0 min, tr (minor) = 25.9 min.

(4R,5S)-5-benzoyl-1-((4-nitrophenyl)sulfonyl)-4phenylpyrrolidin-2-one (3y): 84% yield (75.6 mg), white solid; [α]D 23 +79.4 (c 0.44, CH3CN); 1H NMR (400 MHz, DMSO) δ = 8.53 (d, J = 8.4 Hz, 2H), 8.35 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 7.6 Hz, 2H), 7.72-7.76 (m, 1H), 7.58 (t, J = 7.6 Hz, 2H), 7.33 (d, J = 5.2 Hz, 3H), 7.18-7.20 (m, 2H), 6.18 (d, J = 4.0 Hz, 1H), 3.66 (t, J = 4.4 Hz, 1H), 3.07 (q, J = 8.8 Hz, 1H), 2.66 (dd, J = 17.6, 4.4 Hz, 1H); 13C{H} NMR (100 MHz, DMSO) δ = 195.5, 173.2, 151.3, 143.2, 140.8, 135.0, 134.0,

(R)-5-oxo-3,5-diphenyl-N-tosylpentanamide (5): 92% yield (77.5 mg), white solid; [α]D 23 +164.5 (c 0.18, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 9.05 (br, 1H), 7.73-7.75 (m,4H), 7.45 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.05-7.10 (m, 3H), 7.01 (d, J = 7.2 Hz, 2H), 3.683.61 (m, 1H), 3.19 (d, J = 6.8 Hz, 2H), 2.65 (dd, J = 14.8, 6.4 Hz, 1H), 2.49 (dd, J = 14.8, 8.0 Hz, 1H), 2.31 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ = 198.6, 169.4, 144.9, 142.3, 136.6, 135.5, 133.4, 129.5, 128.8, 128.6, 128.3, 128.2, 127.2,

(4R,5S)-5-(cyclohexanecarbonyl)-4-phenyl-1tosylpyrrolidin-2-one (3x): 48% yield (40.8 mg), white solid; [α]D 23 +225.2 (c 0.09, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.89 (d, J = 8.4 Hz, 2H), 7.33-7.36 (m, 5H), 7.16-7.18 (m, 2H), 5.10 (d, J = 2.8 Hz, 1H), 3.23 (dt, J = 9.2, 2.8 Hz, 1H), 2.92 (dd, J = 17.6, 9.2 Hz, 1H), 2.50-2.51 (m, 1H), 2.46 (s), 2.03-2.07 (m, 1H), 1.70-1.82 (m, 4H), 1.21-1.52 (m, 6H); 13 C{H} NMR (100 MHz, CDCl3) δ =208.4, 172.2, 145.5,



127.0, 44.0, 42.7, 37.6, 21.7 ； HRMS(ESI) calcd for C24H23NO4SNa (M+Na)+: 444.1240, Found: 444.1232; 99% ee as determined by HPLC (Chiralcel ADH, 80:20 hexanes/iPrOH, 1.0 mL/min), tr (major) = 39.1 min, tr (minor) = 20.3 min. N-((1R,2R,3S)-1,5-dihydroxy-1,3-diphenylpentan-2-yl)-4methylbenzenesulfonamide (6): 78% yield (33.2 mg), white solid; [α]D 23 +37.0 (c 0.68, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.34-7.37 (m, 4H), 7.24-7.28 (m, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.02 (t, J = 7.2 Hz, 1H), 6.88-6.95 (m, 6H), 5.88 (t, J = 7.6 Hz, 1H), 4.54 (s, 1H), 3.90 (t, J = 9.6 Hz, 1H), 3.583.63 (m, 1H), 3.31-3.38 (m, 2H), 2.63 (br, 2H), 2.41-2.46 (m,1H), 2.32 (s, 3H), 1.88-1.97 (m, 1H); 13C{H} NMR (100 MHz, CDCl3) δ = 142.2, 142.0, 141.7, 138.7, 129.3, 129.1, 128.4, 128.0, 127.1, 126.7, 126.2, 125.3, 71.7, 65.5, 60.6, 45.7, 35.8, 21.4; HRMS(ESI) calcd for C24H27NO4SNa (M+Na)+: 448.1553, Found: 448.1548; 97% ee as determined by HPLC (Chiralcel IB, 95:5 hexanes/i-PrOH, 0.5 mL/min), tr (major) = 112.8 min, tr (minor) = 86.4 min. methyl (3R,4S)-4-((4-methylphenyl)sulfonamido)-5-oxo-3,5diphenylpentanoate (7)：98% yield (88.4 mg), white solid; [α]D 23 +99.0 (c 1.01, CHCl3); 1H NMR (400 MHz, CDCl3 ) δ 7.48-7.51 (m, 2H), 7.38-7.42 (m, 1H), 7.31-7.33 (m, 2H), 7.18 (t, J = 7.6 Hz, 2H), 7.12-7.14 (m, 3H), 7.08-7.10 (m, 1H), 7.02-7.06 (m, 1H), 6.93 (d, 8.4 Hz 2H), 5.75 (t, J = 10.0 Hz, 1H), 4.90-4.94 (m, 1H), 3.56 (s, 3H), 3.49 (td, J = 8.4, 6.0 Hz, 1H), 3.07 (dd, J = 16.4, 6.0 Hz, 1H), 2.74-2.80 (m, 1H), 2.16 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ =199.2, 172.3, 143.7, 138.6, 136.3, 134.9, 133.6, 129.5, 128.7, 128.3, 128.2, 128.2, 127.7, 127.3, 77.5, 77.1, 76.8, 60.7, 51.9, 45.4, 36.4, 21.4. HRMS(ESI) calcd for C25H25NO5SNa (M+Na)+: 474.1346, Found: 474.1350; 99% ee as determined by HPLC (Chiralcel ADH, 90:10 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 79.8 min, tr (minor) = 57.4 min. (3R,4S)-N-benzyl-4-((4-methylphenyl)sulfonamido)-5-oxo3,5-diphenylpentanamide (8): 57% yield (60.0 mg), white solid; [α]D 23 +297.6 (c 0.22, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.51 (d, J = 8.0 Hz, 2H), 7.36-7.41 (m, 1H), 7.327.35 (m, 2H), 7.15-7.22 (m, 7H), 7.07-7.13 (m, 3H), 6.97-6.70 (m, 2H), 6.93 (d, J = 8.4 Hz, 2H), 6.07 (d, J = 10.0 Hz, 1H), 5.93-5.96 (m, 1H), 4.95-4.99 (dd, 1H), 4.42 (dd, J = 14.8, 6.4 Hz, 1H), 4.16-4.21 (m, 1H), 3.60-3.66 (m, 1H), 2.95-3.00 (m, 1H), 2.64 (dd, J = 14.8, 8.4 Hz, 1H), 2.16 (s, 3H); 13C{H} NMR (100 MHz, CDCl3) δ=199.0, 170.7, 143.6, 139.1, 138.1, 136.4, 135.0, 133.5, 129.5, 128.8, 128.6, 128.5, 128.3, 128.2, 127.7, 127.6, 127.3, 127.2, 79.8, 77.5, 77.1, 76.8, 60.9, 45.5, 43.6, 39.1, 21.4. HRMS(ESI) calcd for C31H30N2O4SNa (M+Na)+: 549.1818, Found: 549.1820; 99% ee as determined by HPLC (Chiralcel IC, 80:20 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 88.7 min, tr (minor) = 83.2 min. (4R,5S)-5-benzoyl-4-phenylpyrrolidin-2-one (9): 78% yield (41.4 mg), white solid; [α]D 23 +103.0 (c 0.15, CHCl3); 1H NMR (400 MHz, CDCl3) δ = 7.73 (dd, J = 8.0, 1.2 Hz, 2H), 7.55-7.59 (m, 1H), 7.32-7.41 (m, 5H), 7.27 (dd, J = 6.0, 1.6 Hz, 2H), 6.65 (s, 1H), 5.14 (d, J = 4.0 Hz, 1H), 3.53-3.58 (m, 1H), 2.85 (dd, J = 17.2, 9.6 Hz, 1H), 2.48 (dd, J = 17.6, 4.8 Hz, 1H); 13C{H} NMR (100 MHz, CDCl3) δ = 196.8, 177.5, 142.8, 134.0, 133.9, 129.3, 128.8, 128.7, 127.7, 126.9, 65.7, 43.8, 38.0; HRMS(ESI) calcd for C17H15NO2Na (M+Na)+: 288.0995,

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Found: 288.0992; 97% ee as determined by HPLC (Chiralcel AZH, 80:20 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 81.0 min, tr (minor) = 54.1 min. (4R,5S)-5-benzoyl-1-methyl-4-phenylpyrrolidin-2-one (10): 60% yield (16.0 mg), colorless oil; [α]D 23 +124.4 (c 0.16, CHCl3); 1H NMR (400 MHz, CHCl3) δ = 7.87 (d, J = 8.0 Hz, 2H), 7.64-7.68 (m, 1H), 7.48-7.52 (m, 2H), 7.36-7.44 (m, 3H), 7.25-7.27 (m, 2H), 5.10 (d, J = 3.2 Hz, 1H), 3.39-3.43 (m, 1H), 2.95-3.01 (m, 4H), 2.51-2.56 (m, 1H). 13C NMR (100 MHz, CDCl3) δ = 195.7, 174.7, 143.4, 134.3, 134.1, 129.5, 129.1, 128.9, 128.7, 126.6, 77.4, 77.1, 76.8, 71.9, 41.3, 38.2, 29.2; HRMS(ESI) calcd for C18H17NO2Na (M+Na)+: 302.1151, Found: 302.1155; 97% ee as determined by HPLC (Chiralcel AZH, 85:15 hexanes/i-PrOH, 1.0 mL/min), tr (major) = 112.6 min, tr (minor) = 29.4



ASSOCIATED CONTENT

Supporting Information Experimental procedures and spectral data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.



AUTHOR INFORMATION

Corresponding Author [email protected]; [email protected].

Notes The authors declare no competing financial interests.



ACKNOWLEDGMENT

We acknowledge financial support by National Key R&D Program of China (2017YFA0204704), National Natural Science Foundation of China (21602105), and Natural Science Foundation of Jiangsu Province (BK20171460). We thank M. Gong in this group for reproducing the reactions of 3a, 3f and 3o.

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REFERENCES

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