Novel Method for the Enantioselective Synthesis of β-Lactams

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CHEM. RES. CHINESE UNIVERSITIES 2008, 24(1), 58-64

ScienceDirect

Article ID 1005-9040(2008)-01-058-04

Novel Method for the Enantioselective Synthesis of /?-Lactams YUAN Qing, JIAN Shan-zhong and WANG Yan-guang* Department of Chemistry, Zhejiang Universiv, Hangzhou 310027, P R. China

A novel method for the enantioselective synthesis of p-lactams is described in this study. 2,3-Dihydrobenzooxazin-4-onederived from salicylamide and L-menthone was used as the chiral auxiliary, which

Abstract

reacted with a-bromo-acyl bromides in the presence of pyridine to give carboximides 2. The stereo-controlled Reformatsky-type reactions of carboximides with imines yielded the corresponding trans p-lactams with high enantioselectivities(e.e. 75%-86%) and high chemical yields(63?46-85%), meanwhile, the chiral auxiliary dihydrobenzooxazin-4-onewas released and recovered. Keywords P-Lactams: Enantioselective: Chiral auxiliary: Reformatsky reaction

1 Introduction p-Lactams are one of the best known and extensively investigated heterocyclic ring systems because of their biological activity as antibiotics"-91 and their utility as synthetic The ketene-imine cycloaddition( Staudinger reaction) is the most common method for t h e s y n t h e s i s o f ,B-lactam~"~~'". The Refomatsky reagents participating ester enolate-imine condensation(Gi1man-Speeter reaction) is another classical method for the synthesis of plactam However, Gilman-Speeter

reaction generally yields a mixture of cis and trans p-lactams with cis isomer as the predominant"8-2'1. The economic importance of optically pure compounds has stimulated considerable research efforts to investigate the enantioselective synthesis of p-lactams[223231. Previously, we reported the diastereoselective synthesis of trans p-lactams via the Refomatsky addition reaction of imines with carboximides 1 bearing an auxiliary1243251. In connection with that study, we developed an enantioselective approach to synthesize trans p-lactams with carboximides 2 as the chiral auxiliary( Scheme We herein disclose the

l a R'=Me, l b R'=Et, 2a R'=Me. 2b R'=Et

Scheme 1 Enantioselective synthesis of /3-lactams 6 using chiral auxiliary 4

* Corresponding author. E-mail: [email protected] Received June 18,2007;accepted September 13,2007. Supported by the National Natural Science Foundation of China(No. 2027205 1) and the Natural Science Foundation of Zhejiang Province, China(No. R404109). Copyright 02008,Jilin University. Published by Elsevier Limited. All rights reserved

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full details of this method and its extension to other substrates.

2 Experimental 2.1 General All the solvents were distilled from appropriate drying reagents. All the reactions were performed under anhydrous conditions unless otherwise specially indicated and monitored by thin-layer chromatography(TLC) on silica gel GF254 plates. Silica gel(H, 300-400 mesh) was used for column chromatography. 'H NMR and I3C NMR spectra were obtained using Bruker ADVANCE DMX 500 instrument. LRMS data were recorded using Bruker Esquir 3000 plus instrument(ES1). HRMS data were obtained on a Bruker FT-ICR-MS Apex 111 apparatus(ES1). IR spectra were recorded using Perkin-Elmer 983 FTIR spectrometer. Elemental analyses were carried out using Flash EA-I 110 instrument. 2.2 Procedure for the Synthesis of(l'S, 2'S, 5'R)-5'-methyl-2'-isopropylspiro[2H-1,3- benzoxazi ne-2, l'-cyclo-hexan]-4(3H)-one(4) A mixture of salicylamide(l6.5 g, 120 mmol), L-menthone( 15.4 g, 100 mmol), and p-toluenesulfonic acid monohydrate(l.9 g, 10 mmol) in toluene(200 mL) was refluxed under conditions of the removal of water with a Dean-Stark apparatus overnight. After gradually cooling down to room temperature, the mixture was washed with lO%(mass fraction) NaOH solution(100 mL) and water(l00 mL) and dried over Na2S04. After the removal of the solvent in IIUCUO, the residue was dissolved in NMP(70 mL). To the resulting solution, DBU(l.O mL, 1.2 mmol) was added. The solution was stirred at room temperature for 24 h. After cooling down to -20 "C, the mixture was kept for 24 h at the same temperature and then diluted with ethyl acetate(300 mL). The organic phase was washed successively with brine (100 mLx3) and water(100 mLx3) and dried over Na2S04. After the removal of the solvent in vacuo, the residue was chromatographied through a silica gel column[ V(hexane)/V(CH,CI,)/V(EtOAc)= 5/5/1 ] to obtain 18.8 g(69%) of compound 4 as colorless crystals: m.p. 82-83 "C; 'H NMR(5OO MHz,

59

DMSO-d6), 6: 0.79(d, Jz6.7 Hz, 3H), 0.93(d, &6.8 H z , 3 H ) , 0 . 9 7 ( d , J = 7 . 1 Hz, 3 H ) , 1.021.09(m, lH), 1.26-1.33(m, lH), 1.60-1.82(m, 5H), 2.36-2.44(m, 2H), 6.91-7.91(m, 4H), 8.78 (brs, 1H); ESI-MS, m/z: 296 [M+Na]+. 2.3 General Procedure for the Acylation of Auxiliaries To a mixture of compound 4(10 mmol), pyridine( 12 mmol), and toluene(30 mL), 2-bromoalkanoyl bromide( 12 mmol) in toluene(5 mL) was added at 5-15 "C. This mixture was stirred at the same temperature for 30 min and then at room temperature overnight. The reaction mixture was poured into water(700 mL). The organic layer was washed successively with saturated aqueous NaHC03(10 mL) and brine(l0 mL), dried over anhydrous Na2S04,and evaporated in vucuo. The residue was dissolved in 2-propanol at 50-55 "C, gradually cooled to 10 "C, and stirred at the same temperature for 1 h. The resulting crystals were collected, washed with 2-propano1, and dried in vacuo at 40 "C overnight to yield pure compound 2. ( 1 'S,2'S,5'R)-3-(2-Bromopropionyl)-5'-methyl2'-isopropylspiro[2H-1,3-benzoxazine-2,1 '-cyclohexan]-4(3H)-one(2a): colorless crystals, yield 74%. m. p. 145-147 "C; 'H NMR(5OO MHz, CDC13),S: 0.78-1.10(m, 11H), 1.56(m, 3H), 1.60-1.82(m, 5H), 1.91-1.92(m, 3H), 2.23-2.27(m, lH), 2.552.59(m, lH), 5.15-5.25(m, lH), 6.95-7.98(m, 4H); ESI-MS, m/z: 430 [M + Na]'. ( 1'S,2'S,5'R)-3-(2-Bromobutanoyl)-5'-methyl-2'-

isopropyl-spiro[2H-1,3-benzoxazine-2,1'-cyclo hexan]-4(3H)-one(2b): colorless crystals, yield 69%. m.p. 126-129 "C; 'H NMR(5OO MHz, CDC13), S: 0.76-1.10(m, l l H ) , 1.60-1.83(m, 5H), 1.931.95(m, lH), 2.11-2.13(m, IH), 2.20-2.25(m, IH), 2.60-2.65(m, lH), 5.04-5.09(m, lH), 6.957.98(m, 1H); ESI-MS, m/z: 444 [M + Na]'. 2.4 General Procedure for the Synthesis of Compound 6 A mixture of carboximide 2(1.0 mmol), imine

S(1.2 mmol), and zinc dust(3 mmol) in THF(5 mL) was refluxed for 10-20 min, cooled to room temperature, poured into water(5 mL), and then extracted

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with CHzCIz(5 mLx3). The combined extracts were washed with brine, dried over anhydrous Na2S04, and evaporated in vucuo. The residue was chromatographied through a silica gel column with hexane-EtOAc to yield pure plactams 6 and chiral auxiliary 4. 3-Methyl- 1,4-diphenylazetidin-2-0ne(6a): color[a1D~~=+67.20(c 1.0, less crystals. m.p. 135-136 CHC13)[271;IR(film), Glcm-': 1748; 'H NMR(5OO MHz, CDCl3), 6: 1.51(d, J=7.4 Hz, 3H), 3.16(dq, J=2.4, 7.4 Hz, lH, H-3), 4.61(d, Jz2.4 Hz, lH, H-4), 7.06(m, IH), 7.26-7.43(m, 9H); I3C NMR(125 MHz, CDC13), S: 13.36, 55.57, 62.97, 117.20, 123.99, 126.08, 128.70, 129.29, 129.39, 138.108, 138.22, 168.65; ESI-MS, mlz: 238[M+H]+; elemental anal.(%) calcd. for C I ~ H I S N O C :80.98, H 6.37, N 5.90; found: C 80.92, H 6.35, N 5.88. 4-(4-Chlorophenyl)-3-methyl1-phenylazetidin2-one(6b): a colorless oil; [a]$5=+38.50(c 0.7, CHC13); IR(film), I7lcm-I: 1749; 'H NMR(5OO MHz, CDC13), 6: 1.50(d, Jz7.4 Hz, 3H), 3.11(dq, Jz2.3, 7.4 Hz, lH, H-3), 4.57(d, J=2.3 Hz, lH, H-4), 7.06(m, 8H); I3C NMR(125 MHz, 1H), 7.26-7.37(m, CDC13), 6: 13.35, 55.66, 62.25, 117.13, 124.19, 127.44, 129.36, 129.65, 134.48, 136.71, 137.83, 168.28; ESI-MS, mlz: 294[M+Na]'; elemental anal. calcd.(%) for ClbH14ClNO: C 70.72, H 5.19, N 5.15; found: C 70.78, H 5.10, N 5.15. 1-(4-Methoxyphenyl)-3-methyl-4-phenylazetidi n-2-one(6c): a colorless oil; [a]D2'=+50. lo(c 1.o, CHC13)[281;IR(film), 9lcm-I: 1749; 'H NMR(5OO MHz, CDC13), 6: 1.47(d, fi7.4 Hz, 3H), 3.11(dq, J=2.2, 7.4 Hz, lH, H-3), 3.81(~,3H), 4.53(d, J=2.2 Hz, lH, H-4), 6.89-7.29(m, 9H); 13C NMR(125 MHz, CDC13), 6: 13.51, 55.03, 55.09, 62.63, 114.01, 118.03, 125.58, 128.21, 128.92, 131.11, 137.67, 155.73, 167.60; ESI-MS: m/z 268 [M+H]+; elemental anal. calcd.(%) for C17H17N02: C 76.38, H 6.41, N 5.24; found: C 76.42, H 6.40,N 5.28. 1-(4-Chloropheny1)-3-methyl-4-[3,4-(methylene oxyl) phenyl]azetidin-2-one(6d): a colorless oil; [ a ] ~ ~ ~ = + 3 8 . 90.8, " ( c CHCI,); IR(film), I7lcm-I: 1745; 1 H NMR(5OO MHz, CDC13), 6: 1.47(d, J=7.4 Hz, 3H), 3.12(dq, Jz2.3, 7.4 Hz, lH, H-3), 4.48(d, J=2.3 Hz, IH, H-4), 5.96-5.98(m, 2H), 6.77-6.84(m, 3H), 7.20-7.25(m, 4H); 13C NMR(125 MHz, CDCI3), 6: OC;

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13.22, 55.48, 55.66, 101.32, 106.23, 107.86, 114.63, 118.57, 119.86, 131.58, 132.18, 148.04, 148.83, 156.24, 167.78; ESI-MS, m/z: 338[M+Na]', 653[2M+Na]+; elemental anal. calcd.(%) for C17H&1N03: C 64.67, H 4.47, N 4.44; found: C 64.73, H 4.45, N 4.42. 1,4-bis(4-methoxypheny1)-3methy lazetidin-2one(6e): a colorless oil; [a]G5=-3 1.3O(c 1.0, CHC13); IR(film), Wcm-': 1743; 'H NMR(5OO MHz, CDCI3), 6: 1.45(d, A7.4 Hz, 3H), 3.09(dq, J=2.2, 7.4 Hz,lH, H-3), 3.73(~,3H), 3.79(~,3H), 4.49(d, J=2.2 Hz, lH, H-4), 6.77(d, J=9.0 Hz, 2H), 6.89(d, J 4 . 7 Hz, 2H), 7.22(d, J=9.0 Hz, 2H), 7.27(d, J=8.7 Hz, 2H); I3C NMR(125 MHz, CDC13), S: 13.14, 55.49, 59.85, 62.23, 114.39, 114.65, 118.41, 127.31, 130.42, 131.60, 155.86, 159.69, 167.65; ESI-MS: mlz 320 [M+Na]+, 617[2M+Na]; elemental anal. calcd.(%) for C17Hj7N02:C 72.71, H 6.44, N 4.71; found: C 72.63, H 6.40, N 4.70. 4-(4-Chlorophenyl)- 1-(4-methoxyphenyl)-3-methylazetidin-2-one(6f): a colorless oil; [ ~ t ] ~ ~ ~ = + 5 4 . 6 ' (c 1.0, CHC13); IR(film), I7lcm-I: 1743; 'H NMR (500 MHz, CDC13), 6: 1.47(d, J=7.4 Hz, 3H), 3.07(dq, J=2.2, 7.4 Hz, lH, H-3), 3.73(~,3H), 3.79(~,3H), 4.52(d, J=2.2 Hz, lH, H-4), 6.77-7.34(m, 8H); I3C NMR(125 MHz, CDCI3), S: 13.30, 55.61, 55.65, 62.92, 114.57, 118.41, 127.46, 129.56, 131.38, 134.42, 136.80, 156.25, 167.64; HRMS(ESI), m/z: calcd.(%) for C17H17NNa02'([M+Na]+): 324.0762; found: 324.0754. 1-(4-Methoxyphenyl)-3-methyl-4-[3,4-(methyle neoxyl)phenyl] azetidin-2-one(6g): a colorless oil; IR(film), Vlcm-I: 1746; [ c ( ] D ~ ~ = + ~ O1..O, ~ " CHC13); (C 1 H NMR(5OO MHz, CDC13), 6: 1.47(d, J=7.4 Hz, 3H), 3.07(dq, J=2.3, 7.4 Hz, lH, H-3), 3.74(~,3H), 4.45(d, J=2.2 Hz, lH, H-4), 5.94-5.96(m, 2H), 6.77-7.34(m, 8 H); I3C NMR(125 MHz, CDC13), 6: 13.24, 55.55, 55.67, 62.94, 101.52, 106.10, 108.86, 114.53, 118.48, 119.91, 131.63, 132.10, 148.02, 148.72, 156.17, 167.98; HRMS(ESI), m/z: calcd.(%) for C 1gH17NNa04'( [M+Na]+): 334.1050; found: 334.1040. 1-(4-Methoxyphenyl)-3 -methyl-4-( trans-styry 1) azetidin-2-one(6h): a colorless oil; [ ~ t ] ~ ~ ~ = + 4 9 . 6 " (c 1.0, CHCI,); IR(film), Glcm-': 1748; 'H NMR (500 MHz, CDC13), 6: 1.43(d, h 7 . 4 Hz, 3H), 3.11(dq,

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61

Jz2.2, 7.4 Hz, lH, H-3), 3.74(~,3H), 4.20(dd, J=1.9, (c 1.0, CHCI3); IR(film), O/cm-': 1749; 'H NMR (500 MHz, CDC13), 6: 1.46(d, J=7.4 Hz, 3H), 3.16(dq, 8.4 Hz, lH, H-4), 6.27(dd, J 4 . 4 , 15.9 Hz, lH), 6.76-7.39(m, 10H); 13CNMR(125 MHz, CDCI3), 6: Jz2.3, 7.4 Hz, lH, H-3), 3.74(~,IH), 4.65(d, f i 2 . 2 12.99, 52.47, 55.65, 62,12, 114.51, 118.35, 126.79, Hz, lH, H-4), 6.78-7.33(m7 7H); 13C NMR(125 127.35, 128.51, 128.91, 132.15, 134.09, 135.95, MHz, CDC13), 6: 13.29, 54.68, 55.64, 58.85, 114.49, 118.42, 122.48, 125.28, 127.53, 131.67, 139.88, 156.95, 167.59; HRMS(ESI), m/z: calcd. for 156.16, 167.84; HRMS(ESI), m/z: calcd. for ClgHl9NNa0~([M+Na]+): 316.1308; found: 3 16.1298. C '5H IsNN~O~S'([M+N~]'): 296.071 6; found: 3-Methyl- 1-phenyl-4-(trans-styryl)azetidin-2-on 296.0707. 1-(4-Chlorophenyl)-3-ethyl-4-[3,4-(methyleneo e(6i): a yellow oil; [a]D25=+45.50(c1.0, CHC13); IR(film), Qlcm-': 1746; 'H NMR(5OO MHz, CDC13), xyl)phenyl] azetidin-2-one(6m): a colorless oil; 6: 1.47(d7'F7.4 Hz, 3H), 3.16(dq, J=1.7, 7.4 Hz, IH, [a]~~~=+43.6O(C 0.8, CHCl,); IR(film), Qlcm-': 1749; 1 H-3), 4.27(dd, J = l . l , 8.1 Hz, lH, H-4), 6.31(q, Jz8.4, H NMR(5OO MHz, CDClj), 6: 1.lO(t, J=7.4 Hz, 3H), 1.86(m, lH), 1.96(m, lH), 3.05(d), 4.57(d, J=2.2 Hz, 15.9 Hz, lH), 6.83(d, J=15.9 Hz, lH), 7.08(m, lH), lH), 5.96-6.00(m, 2H), 6.78-6.85(m, 3H), 7.207.27-7.48(m, 9H); I3C NMR(125 MHz, CDCI,), 6: 7.25(m, 4H); 13C NMR(125 MHz, CDC13), 6: 11.54, 13.09, 53.87, 55.56, 114.45, 118.12, 126.54, 127.44, 128.47, 128.88, 132.33, 134.18, 136.05, 156.78, 22.23, 55.35, 55.56, 101.43, 106.54, 107.78, 114.37, 167.66; ESI-MS, m/z: 264 [M + HI', 286 [M+Na]+, 118.63, 119.78, 131.61, 132.22, 148.11, 148.90, 156.19, 167.52; ESI-MS, m/z: 252 [M + Na]'; Ele549[2M+Na]+; Elemental anal. calcd.(%) for C18H1,NO:C 82.10, H 6.51, N 5.32; found: C 82.07, mental anal. calcd.(%) for C18H16N03: C 65.56, H 4.89, N 4.25; found: C 65.58, H 4.93, N 5.24. H 6.45, N 5.3 1. 1-(4-Chlorophenyl)-3 -ethyl-4-phenylazetidin-21-(4-Methoxyphenyl)-3-methyl-4-(2-naphthyl)a colorless oil; [ ~ ? ] ~ ~ ~ = + O ( c4 2 0.7, . 1 CHC1,); azetidin-2-one(6j): a colorless oil; [ ~ ( ] ~ ~ ~ = + 6 3 . 2one(6n): ~(c IR(film), Qlcm-I: 1744; 'H NMR(5OO MHz, CDCl3), 1.0, CHCI,); IR(film), 9lcm-': 1743; 'H NMR(5OO MHz, CDClj), 6: 1.50(d, Jz7.4 Hz, 3H), 3.18(dq7 J= b': 1.12(t, J=7.4 Hz, 3H), 1.88(m, lH), 1.98(m7 lH), 3.07-3.09(m, l H , H-3), 4.65(d, J=2.2 Hz, lH), 2.3, 7.4 Hz, lH, H-3), 3.68(~,3H), 4.69(d, &2.2 Hz, 7.19-7.24(m, 4H), 7.32-7.42(m, 5H); I3C NMR lH, H-4), 6.73-6.75(m, 2H), 7.25-7.27(m, 2H), (125 MHz, CDC13), 6: 13.24, 55.56, 61.94, 117.09, 7.41-7.49(m, 3H), 7.79-7.84(m, 4H); I3C NMR 124.23, 127.87, 129.22, 129.70, 134.63, 136.85, (125 MHz, CDCl,), 6: 13.32, 55.48, 55.55, 63.20, 137.90, 168.55; ESI-MS, m/z: 286 [M+H]+, 308 114.49, 118.41. 123.20, 125.58, 126.53, 126.80, [M+Na]'; Elemental anal. calcd.(%) for C I ~ H I ~ C ~ N O : 128.00, 129.44, 131.73, 133.50, 135.72, 156.11, 167.97; HRMS(ESI), m/z: calcd. for C21H19NNa02+ C 71.45, H 5.64, N 4.90; found: C 71.48, H 5.60, N 4.88. ([M+ Na]'): 340.1308; found: 340.1298. 3-Ethyl- 1-(4-methoxyphenyl)-4-phenylazetidin4-( Furan-2-y1)- 1-(4-methoxypheny1)-3-methylaz 2-one(60): a colorless oil; [a]$5=+72.30(c 0.9, etidin-2-one(6k): a colorless oil; [a]D2S=+44.60(c1.O, I1 CHC13); IR(film), 9/cm-': 1726; 'H NMR(5OO CHCI3); IR(tXm), Vlcm-': 1746; 'H NMR(5OO MHz, MHz, CDCI,), 6: l.lO(t, J=7.5 Hz, 3H), 1.87(m, lH), CDCI3), 6: 1.46(d, J=7.4 Hz, 3H), 3.27(dq, J=2.3, 7.4 1.96(m, IH). 3.05(m, lH), 3.76(s, 3H), 4.62(d, J=2.5 Hz, lH, H-3), 3.72(~,lH), 4.82(d7 J=2.2 Hz, lH, Hz, lH), 6.66-7.89(9H, m); ''C NMR(125 MHz, H-4), 6.78-7.27(m, 7H); 13C NMR( 125 MHz, CDCI,), 6: 11.53, 22.04, 55.38, 60.81, 61.89, 114.33, CDCl3), 8: 13.15, 55.54, 56.34, 58.70, 114.44, 118.51, 118.22, 125.76, 128.39, 128.30, 131.42, 138.30, 125.78, 125.82, 127.30, 131.32, 142.09, 156.21, 155.89, 167.25; ESI-MS, m/z: 304[M+Na]'; Elemen167.53; ESI-MS, mlz: 280 [M + Na]'; Elemental anal. tal anal. calcd. for C18Hl9NO2(%):C 76.84, H 6.81, calcd.(%) for CI5Hl5NO3:C 70.02, H 5.88, N 5.44; N 4.98; found: C 76.78, H 6.80, N 4.96. found: C 70.07, H 5.93, N 5.45. 4-(4-Chloropheny1)-3 -ethyl- 1-(4-methoxyphen1-(4-Methoxypheny1)-3 -methyl-4-(thiophen-3yl)azetidin-2-one(6p): a colorless oil; [o.]D25=+47.70 yl)-azetidin-2-one(61): a yellow oil; [a]$5=+57.80

62

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(c 1.0, CHCI3); lR(film), v"/cm-': 1747; 'H NMR (500 MHz, CDCl,), 6: 1.10(t, J=7.4 Hz, 3H), 1.96-1.87 (m, lH), 1.96-1.97(m, lH), 2.99-3.00 (m, lH, H-3), 3.74(s, 3H), 4.61(d, J=2.2 Hz, lH, H-4), 6.77-7.34(m, 9H); I3C NMR(125 MHz, CDC13), 6: 11.72, 22.20, 55.67, 60.37, 62.32, 114.59, 118.39, 127.47, 129.60, 131.36, 134.33, 137.13, 156.24, 167.11; HRMS(ESI), m/z: calcd. for CIBHIBC~"~~~'([M+N~]'): 338.09 18; found: 338.0905.

3-Ethyl-l,4-bis(4-methoxyphenyl)azetidin-2one(6q): a colorless oil; [ 0 r ] ~ ~ ~ = - 3 2 . 31".O,( ~CHCI3); IR(film), v"lcm-': 1743; 'H NMR(5OO MHz, CDC13), 6: 1.09(t, J=7.4 Hz, 3H), 1.83-1.85(m, lH), 1.92-1.96(m, lH), 2.99-3.02(m, lH, H-3), 3.71(s, 3H), 3.77(~, 3H), 4.58(d, J=2.2 Hz, lH, H-4), 6.75-7.27(m, 8H); 13C NMR(125 MHz, CDCI3), 6: 11.61, 22.08, 55.39, 60.60, 62.10, 114.37, 114.63, 118.36, 127.28, 130.31, 131.570, 155.96, 159.73, 167.49; HRMS(ESI), m/z: [M+Na]+: Elemental anal. calcd.(%) for C19H21NNa03': 334.1414; found: 334.1400. 3-Ethyl- 1-phenyl-4-(trans-styryl)azetidin-2-one (6r): a yellow oil; [a]D25=+53.20(~ 1.0, CHC13); IR(film), v"lcm-': 1751; 'H NMR(5OO MHz, CDC13), 6: l.ll(t, J=7.4 Hz, 3H), 1.84(m, lH), 1.94(m, lH), 3.06-3.08(m, H-3, lH), 4.33(dd, J=1.9, 8.4 Hz, lH, H-4), 6.31(dd, J=8.4, 15.9 Hz, lH), 6.79(d, fi15.9, lH), 7.06(m, lH), 7.25-7.35(m, 5H), 7.39(d, J=7.5 Hz, 2H), 7.45(d, J=8.4 Hz, 2H); 13C NMR (125 MHz, CDC13), 6: 11.63, 21.85, 59.21, 60.04, 117.03, 123.93, 126.83, 127.67, 128.53, 128.95, 129.28, 133.84, 136.02, 138.56, 167.61; ESI-MS, m/z: 278 [M+H]+, 300[M+Na]+; Elemental anal. calcd.(%) for CI9Hl9NO: C 82.28, H 6.90, N 5.05; found: C 82.26, H 6.88, N 5.04. 3-Ethyl- 1-(4-methoxyphenyl)-4-(2-naphthyl)aze tidin-2-one(6s): a colorless oil; [a]2'=-3 1.3"(c 1.O, CHCI,); IR(film), Wcrn-': 1743; 'H NMR(5OO MHz, CDCl,), 6: 1.12(t, J=7.4 Hz, 3H), 1.90-1.92(m, lH), 1.99-2.01(m, lH), 3.10-3.13(m, lH, H-3), 3.69(s, 3H), 4.78(d, J=2.2 Hz, lH, H-4), 6.73-7.85(m, 11H); 13C NMR(125 MHz, CDC13), 6: 11.74, 22.23, 55.58, 61.26, 62.19, 114.50, 118.40, 123.31, 125.51, 126.52, 126.79, 128.01, 129.46, 131.71, 133.48, 133.57, 136.07, 156.09, 167.44; HRMS(ESI), m/z:

calcd. for C22HzlNNa0g([M+Na]+):354.1465; found: 354.1456. 3-Ethyl-4-(furan-2-~1)-1-(4-methoxyphenyl)azet idin-2-one(6t): a colorless oil; [aID2'=+62.1"(c 1.O, CHC13); IR(film), v"lcm-': 1747; 'H NMR(5OO MHz, CDC13), 6: l.ll(t, h 7 . 4 Hz,3H), 1.85-1.87(m, lH), 1.95-11.97(m, lH), 3.18-3.21(m, lH, H-3), 3.74(s, 3H), 4.91(d, J=2.2 Hz, lH, H-4), 6.79-7.29(m, 7H); 13C NMR(125 MHz, CDCI3): 6: 11.60, 22.09, 55.38, 56.40, 58.78, 114.459, 118.50, 125.70, 125.78, 127.33, 131.35, 142.13, 156.22, 167.51; ESI-MS, m/z: 304[M+Na]+; Elemental anal. calcd.(%) for C 70.83, H 6.32, N 5.16; found: C 70.87, C15H15N03: H 6.39, N 5.11. 3-Methyl- 1-(4-methoxyphenyl)-4-(thiophen-3yl)-azetidin-2-one(6u): a yellow oil; [a]$S=+55.20(c 1.0, CHCI,); IR(film), Wcm-': 1749; 'H NMR(5OO MHz, CDC13), 6: 1.10(t, J=7.4 Hz, 3H), 1.841.86(m, lH), 1.94-1.96(m, lH), 3.07-3.09(m, lH, H-3), 3.74(~, 3H), 4.74(d, J=2.2 Hz, lH, H-4), 6.78-7.34(m, 7H); I3C NMR(125 MHz, CDC13), 8: 11.64, 22.11, 55.66, 56.91, 61.34, 114.51, 118.41, 122.26, 125.35, 127.52, 131.66, 140.20, 156.15, 167.30; HRMS(ESI), m/z: calcd. for Cl6HI7NNa02Sf ([M+Na]+): 310.0872; found: 310.0865.

3

Results and Discussion

We selected 2-substituted 2,3-dihydrobenzooxazin-4-one 4 as the chiral auxiliary, which was readily synthesized by the acid-catalyzed condensation of salicylamide 3 with L-menthone in toluene(Scheme 1). The acylation of chiral auxiliary 4 was completed by the use of pyridine as the base and toluene as the solvent. Thus, the reaction of chiral auxiliary 4 with 1.2 equiv of 2-bromo-alkanoyl bromide in the presence of 1.2 equiv of pyridine at 5-15 "C gave the corresponding carboximides 2 with high yields. The Reformatsky reactions of carboximides 2 with imines 5 in the presence of zinc dust was proceeded in THF under reflux conditions and was completed within 10-20 minutes to yield the corresponding p-lactams 6 and the chiral auxiliary 4. Pure chiral auxiliary 4 could be isolated by silica gel column chromatography and reused(recyc1e yield 78%-94%). The p-lactams 6 were exclusively trans isomers.

No.1

YUAN Qing et al.

The trans configurations of 6 were assigned from the 'H NMR spectra through the coupling constant JH--H of the two protons on C3 and C4 (J,rans=l.5-2.5 Hz, J,,=4.5-6.0 H z ) ' ~ ~ 'The . ex. value turned out to be in the range of 75%-86% determined by HPLC using a chiral column(Tab1e 1). Recrystallization from n-hexanelEtOAc gave optically pure compound 6b. X-Ray crystal structure analysis of compound 6b confirmed the 'H NMR assignment and showed that the absolute configurations of the novel chiral centers are 3s and 4R (Fig. 1). CCDC 273640 contains the supplementary crystalographic data(exc1uding structure factors) for compound 3b. These data can be obtained free via http://www.ccdc. cam.ac.uWcontslretrieving.htm1. As shown in Table 1, the imines were derived from anilines and aromatic or c@-unsaturated aldeTable 1

63

hydes with good yields(63%-85%). Unfortunately, N-benzylimine did not react. In all the cases, p-amino carbonyl compounds were not isolated, which are the typical by-products of Reformatsky-type reactions"8-211. This may be due to the good leaving ability of chiral auxiliary 4, which facilitates the cyclization of the intermediate(Scheme 2). 9

P l i

Fig.1 X-ray structure of compound 6b Enantioselective svnthesis of B-lactams with chiral auxiliarv

Entry

R'

1

Me

Ph

Ph

6a

85

65

2

Me

Ph

4-CIPh

6b

80

73 81

R'

R'

8-lactam"

Yield(%)'

3

Me

4-MeOPh

Ph

6c

I1

4

Me

4-CIPh

3,4-(OCH20)Ph

6d

83

75

5

Me

4-MeOPh

4-MeOPh

6e

82

66

6

Me

4-MeOPh

4-CIPh

6f

17

16

I

Me

4-MeOPh

3,4-(OCHzO)Ph

6g

79

18

8

Me

4-MeOPh

frans-Styryl

6h

80

82

9

Me

Ph

trans-Styryl

6i

I5

19

10

Me

4-MeOPh

2-Naphthalenyl

6j

86

80

11

Me

4-MeOPh

2-Furanyl

6k

83

61 11

12

Me

4-MeOPh

2-Thienyl

61

78

13

Et

4-CIPh

3,4-(OCH20)Ph

6m

85

12

14

Et

4-CIPh

Ph

6n

86

63

15

Et

4-MeOPh

Ph

60

83

69

16

Et

4-MeOPh

4-CIPh

6P

71

71

11

Et

4-MeOPh

4-MeOPh

6q

80

85

18

Et

Ph

trans-Styryl

6r

78

70

19

Et

4-MeOPh

2-Naphthalenyl

6s

85

81

20

Et

4-MeOPh

2-Furanyl

61

82

65

21

Et

4-MeOPh

2-Thienyl

6u

79

73

a. Determined by ' H NMR to be 100% trans; 6. determined by HPLC with chiral column(Chira1pak AD-H 0 . 4 6 ~ 1 5cm, Daicel Chemical Ind. Ltd); c.

isolated yields based on imines.

It is believed that the reaction proceeds via a Reformatsky-type reaction/cyclization cascade process as shown in Scheme 2. The first step of the Reformatsky reaction involves the reduction of the a-bromocarbonyl group of compound 2 to yield (2)-imide enolate, which nucleophilically attacks the

imine. The formation of the (2)-enolate in the transition state may be due to the steric repulsion of the methyl moiety. The stereochemistry of the reaction can be explained by the chair-like transition state involving imine and (2)-enolate. In the chelated transition state, zinc enolate disfavors a s-face attack on

CHEM. RES. CHINESE UNIVERSITIES

64

the imine because the isopropyl group is oriented in a sterically hindered environment. The zinc enolate

Vo1.24

then favors the less hindered R-face attack on the imine, preferably leading to major isomer.

Major

Favored reaction

Cyclization

Minor

Disfavored

Scheme 2

Proposed mechanism of Reformatsky-type reaction

4 Conclusions In conclusion, we developed an efficient and general enantioselective synthesis of trans /?-lactams via a chiral auxiliary induced Reformatsky reactions of carboximides 2 with imines. The procedure furnished trans plactams with good yields and high enantioselectivity. The chiral auxiliary could be recycled in the reaction. A Reformatsky-type reaction/cyclization cascade process involving a chair-like transition state is proposed for this reaction. References [ I ] Magriotis P A., Angew. Chem. Int. Ed., 2001, 40, 4377 [2] Ojima I , Delaloge F , Chem. SOC.Rev., 1997,26, 377386 [3] Ojirna I., Acc. Chem. Res., 1995, 28, 383 [4] Morin R. B , G o m a n M., Chemistry and Eiologv Ofp-Lactam Antibiotics, Vol. 1-3, Academic Press, New York, 1982 [5] Durckheirner W , Blumbach J., Latrell R , et a / . ,Angew. Chem. Int. Ed. Eng., 1985, 24, 180 [6] Nagahara T., Kametani T., Heterocycles. 1987,25, 729 [7] Page M. I., The Chemistry of 8-Lactams, Chapman and Hall, London, 1992 [8] Broccolo F., Cainelli G., Caltabiano G., e t a / . ,J Med. Chem.,2006, 49,2804 [9] Wright A. J., Mayo Clin. Proc., 1999, 74, 290

\ [lo] Alcaide B . , Almendros P , Curr. Med. Chem., 2004, 11, 1921 [ l l ] Deshmukh A. R. A. S., Bhawal B. M., Krishnaswamy D., ef a / . , Curr. Med. Chem , 2 0 0 4 , 1 1 , 1889 [12] Alcaide B., Almendros P., Synlett., 2002,381 [I31 Palomo C , Aizpurua J. M , Ganboa I., et al., Synlett, 2001, 1813 [I41 Alcaide B., Almendros P.,Chem. SOC.Rev., 2001, 30,226 [I51 van Brabandt W , Vanwalleghem M., D’hooghe M., e t a / . , J. Org. Chem., 2006, 71,7083 [16] Singh G . S , Tetrahedron, 2003,59, 7631 [I71 Palomo C., Aizpurua J M , Ganboa I., e t a / . , Euro. J. Ow. Chem , 1999,8,3223 [I81 Hart D J . , Ha D. C , Chem. Rev, 1989,89, 1447 [ 191 Chen L., Zhao G., Ding Y , Tetrahedron Lett., 2003,44,2611

[20] Gilman H., Speeter M., J. Am. Chem Soc., 1943,65,2255 [21] Juaristi E., Soloshonok V. A., Enanrioselecrive Synthesis of

8-Amino Acids, 2nd Ed., Wiley-VCH, Hoboken, 2005 [22] France S.,Weatherwax A., Taggi A. E., et ul., Acc. Chem. Res., 2004,37, 592 [23] Tomioka K., Fujieda H., Hayashi S , et at., Chem. Comm., 1999, 715 [24] Jian S . Z., Ma C., Wang Y G., Synthesis, 2005,725 [25] Jian S. Z., Yuan Q , Wang Y. G., Synthesis, 2006, 1829 [26] Yuan Q., Jian S. 2 ,Wang Y G.,Synlett, 2006, 11 13 [27] Gennari C., Venturini I., Gislon G., et a/., Tetrahedron Lett., 1987, 28,227 [28] Fujieda H., Kanai M., Karnbara T., era/., J. Am. Chem. Soc., 1997, 119, 2060 [29] Cainelli G.,Panunzio M., Bandini E., et af., 7etrahedroq 1996, 52, 1685