671Full PaperReceived: 24 July 2008 Revised: 12 August 2008 Accepted: 12 August 2008 Published online in Wiley Interscience: 15 September 2008(www.interscience.com) DOI 10.1002/aoc.1457Efficient asymmetric addition of diethylzinc toaldehydes using 3-hydroxyazetidinederivatives as chiral ligandsRuochen Liu, Xuemei Bai, Zhanbin Zhang and Guofu Zi∗A new series of chiral 3-hydroxyazetidines has been prepared from (S)-1-(4-methoxyphenyl)ethylamine. These ligands haveshown excellent catalytic activities and enantiomeric selectivities in asymmetric addition of diethylzinc to aromatic aldehydes.Copyrightc 2008 John Wiley & Sons, Ltd.Keywords: azetidines; chiral ligands; asymmetric addition; diethylzinc; aldehydeIntroductionThe stereoselective addition of organometallics to one of thetwo heterotopic faces of a carbonyl group has been extensivelystudied.[1 –5]The enantioselective addition of organozinc tocarbonyl compounds is of particular importance in organicsynthesis, because the products, chiral alcohols, are ubiquitousin the structure of natural products and drug compounds, andare also important precursors for many other functional organicmolecules.[6 –10]Therefore, it is not surprising that the efforts havefocused on the development of chiral ligands which work forcatalytic asymmetric addition of diethylzinc to aldehydes overthe last two decades.[1 –10]Although a variety of ligands, suchas chiral amino alcohols, amino thiols, amino disulfides, aminodiselenides, diamines and diols, for the asymmetric diethylzincaddition reactions have been reported,[1 –10]only a small numberof effective ligands are obtained by simple synthetic methods.Thus, the development of easily accessible, stable, operationallysimple and effective ligands is still a desirable goal. In recent years,chiral azetidine has been extensively used as a chiral auxiliary,[11]but only a few studies have focused on the applications of itsderivatives as chiral catalysts.[12 –24]Chiral azetidines that caneffectively catalyze the diethylzinc addition with high levels ofenantioselectivity havebeen reported;[19 –24]however, noexampleof chiral hydroxyazetidine (hydroxyl group seated on the azetidinering) for enantioselective catalysis has been described. Thus,research on asymmetric addition of diethylzinc to aldehydescatalyzed by chiral hydroxyazetidines remains an interesting topicin asymmetric synthesis. Taking the advantage of the chiralityof (R)-1-phenylethylamine or (S)-1-phenylethylamine, we havedesigned and prepared a series of chiral 3-hydroxyazetidinesand 3-aminoazetidines, and they have been successfully appliedto the asymmetric addition of diethylzinc to aldehydes.[25 –26]In our attempt to further explore the chemistry of small-ringfunctionalized heterocycles, we recently have expanded ourresearch to a new series of chiral 3-hydroxyazetidines derivedfrom (S)-1-(4-methoxyphenyl)ethylamine. Herein we report thesynthesis of these new chiral 3-hydroxyazetidines and their use inthe asymmetric addition of diethylzinc to aldehydes.ExperimentalGeneral methodsAll chemicals were purchased from Aldrich Chemical Co. andBeijing Chemical Co. and used as received unless otherwise noted.Infrared spectra were obtained on an Avatar 360 Fourier transformspectrometer.1Hand13C NMR spectra were recorded on aBruker AV-500 spectrometer. All chemical shifts were reportedin δ units with reference to the residual protons of the deuteratedsolvents for proton and carbon chemical shifts. Melting pointswere measured on an X-6 melting point apparatus and wereuncorrected. Optical rotations were measured on a Perkin–Elmer343 polarimeter, and mass spectra were obtained with a TRACEMS spectrometer. Elemental analyses were performed on a VarioEL elemental analyzer. Enantiomeric excesses were determined bygas chromatography with an FID detector using chiral column SGEβ-CYCLODEX, 25 m×0.25 mm i.d. on a Varian CP-3800 instrument.General procedure for the preparation of chiral azetidinesfrom (S)-1-(4-methoxyphenyl)ethylamineThe synthesis of 1-[1-(4-methoxyphenyl)ethyl]-2-phenyl-3-hydroxylazetidine (L1) is representative. Anhydrous MgSO4(4.8 g,40 mmol) was added to a CH2Cl2(60 ml) solution of benzalde-hyde (2.14 g, 20 mmol) and (S)-1-(4-methoxyphenyl)ethylamine(3.02 g, 20 mmol) at room temperature. After this solution hadbeen stirred at room temperature for 12 h, MgSO4was fil-tered off. Triethylamine (4.04 g, 40 mmol) was added to thesolution at −10◦C with stirring. This solution was stirred for1 h at this temperature, then acetoxyacetyl chloride (5.46 g,40 mmol) was added. The resulting solution was slowly warmedup to room temperature and stirred for 24 h. Triethylamine hy-drochloride was filtered off, and the filtrate was washed withsaturated NaHCO3(50 ml). After drying over MgSO4,solvent∗Correspondence to: Guofu Zi, Department of Chemistry, Beijing NormalUniversity, Beijing 100875, People’s Republic of China. E-mail: [email protected] of Chemistry, Beijing Normal University, Beijing 100875, People’sRepublic of ChinaAppl. Organometal. Chem. 2008, 22, 671–675 Copyrightc 2008 John Wiley & Sons, Ltd.672R. Liu et al.was removed to give a crude mixture (2). The mixture wasdissolved in 40 ml of dry THF, then the solution was addedto a suspension of aluminum chloride (3.10 g, 23 mmol) andlithium aluminum hydride (0.88 g, 23 mmol) in 50 ml of dryTHF with stirring at reflux. After this mixture had been re-fluxed for 2 h, then cooled to 0◦C, 20 ml of water was carefullyadded. The water phase was extracted with dichloromethaneand dried over MgSO4. Removal of the solvent gave acrude mixture, 1-(1-phenylethyl)-2-phenyl-3-hydroxylazetidine(L1), which was further purified by chromatography (hexane/ethylacetate = 6/1) to give pure compounds (2R,3R)-1-[(1S)-1-(4-methoxyphenyl)ethyl]-2-phenylazetidin-3-ol (L1a)and(2S,3S)-1-[(1S)-1-(4-methoxyphenyl)ethyl]-2-phenylazetidin-3-ol (L1b).(2R,3R)-1-[(1S)-1-(4-methoxyphenyl)ethyl]-2-phenylazetidin-3-ol (L1a). Yield: 1.47 g, 26%. Colorless crystals, m.p.: 128–129◦C;[α]D20=−106.2(c 0.15, CH3OH).1HNMR(CDCl3): δ 1.03 (d,J = 6.0Hz,3H,Me),1.62(br,s,1H,OH), 3.02 (m, 1H, CH), 3.13 (m,1H, CH), 3.47 (m, 1H, CH), 3.84 (s, 3H, OMe), 4.40 (m, 2H, CH), 6.91(d, J = 8.0 Hz, 2H, aryl H), 7.34 (m, 3H, aryl H), 7.44 (m, 2H, aryl H),7.61 (d, J = 8.0 Hz, 2H, aryl H).13CNMR(CDCl3): δ 22.8 (CH3), 55.2(OCH3), 58.8 (CH2), 65.8 (CH), 67.2 (CH), 72.3 (CH), 113.7, 127.6,127.9, 128.2, 128.4, 135.8,