Synthesis of new chiral cis-3-hydroxyazetidines and their application in diethylzinc addition to aldehydes

Article abstract of DOI:10.1002/chir.20470

A new series of chiral cis-3-hydroxyazetidines have been prepared from (R)-1-phenylethylamine. They have excellent catalytic activities and enantiomeric selectivities in asymmetric addition of diethylzinc to aromatic aldehydes.

Full text of DOI:10.1002/chir.20470

CHIRALITY 19:802–808 (2007)
Synthesis of New Chiral cis-3-Hydroxyazetidines and Their
Application in Diethylzinc Addition to Aldehydes
*
ZHANBIN ZHANG, MIN LI, AND GUOFU ZI
Department of Chemistry, Beijing Normal University, Beijing, China
ABSTRACT
A new series of chiral cis-3-hydroxyazetidines have been prepared from
(R)-1-phenylethylamine. They have excellent catalytic activities and enantiomeric selec-
tivities in asymmetric addition of diethylzinc to aromatic aldehydes. Chirality 19:802–
C
VV
808, 2007.
2007 Wiley-Liss, Inc.
KEY WORDS: cis-3-hydroxyazetidines; chiral auxiliary; synthesis; application;
asymmetric diethylzinc addition reaction
INTRODUCTION
solvents for proton and carbon chemical shifts. Melting
points were measured on an X-6 melting point apparatus
and were uncorrected. Optical rotations were measured on
a PerkinElmer 343 polarimeter. Elemental analyses were
performed on a Vario EL elemental analyzer. Gas chroma-
tography was conducted on Varian CP-3800 series with
FID detector using chiral column SGE b-CYCLODEX,
25 m 3 0.25 mm I.D. Retention time was given in minutes.
The stereoselective addition of organometallics to one
of the two heterotopic faces of a carbonyl group has been
extensively studied.1–4 Among them, the enantioselective
addition of organozinc to carbonyl compounds is of partic-
ular importance in organic synthesis, because the prod-
ucts, chiral alcohols, represent valuable structural units
found in many natural products and they are readily func-
tionalized.5 Since the pioneering work of Oguni in 1984,6
there has been extensive research into the diethylzinc
addition to benzaldehyde, and it is now regarded as one of
the benchmark reactions for understanding the catalytic
potential of new ligands.
Although a variety of ligands, such as chiral amino alco-
hols, amino thiols, amino disulfides, amino diselenides,
diamines, or diols have been studied,7–11 the development
of new ligands for asymmetric addition of diethylzinc to
aldehydes is a desirable goal. Chiral azetidines have been
extensively used as a chiral auxiliary in recent years,12 but
only few studies have focused on the applications of its
derivatives as chiral catalysts.13–24 Chiral azetidines that
can effectively catalyze the diethylzinc addition with high
levels of enantioselectivity are scarcely reported,20–24 and
to our knowledge, no example of chiral hydroxyazetidine
(hydroxyl group seated on the azetidine ring) for enantio-
selective catalysis has been described. We report herein
the synthesis of a new series of chiral cis-3-hydroxyazeti-
dines and their application in asymmetric addition of dieth-
ylzinc to aldehydes.
General Procedure for the Preparation of
cis-3-Hydroxyazetidines from ( R)-1-Phenylethylamine
The synthesis of 1-(10-phenylethyl)-2-phenyl-3-hydroxy-
azetidine (L1) is representative. Anhydrous MgSO4 (4.8 g,
40 mmol) was added to a CH2Cl2 (60 ml) solution of benz-
aldehyde (2.14 g, 20 mmol) and (R)-1-phenylethylamine
(2.42 g, 20 mmol) at room temperature. After this solution
was stirred at room temperature for 12 h, MgSO4 was fil-
tered off. To the resulting solution, triethylamine (4.04 g,
40 mmol) and acetoxyacetyl chloride (5.46 g, 40 mmol)
were slowly added with stirring at 2108C. After the solu-
tion was stirred for 24 h at room temperature, triethyl-
amine hydrochloride was filtered off, and the filtrate was
washed with saturated NaHCO3 (25 ml 3 2). Drying over
anhydrous MgSO4, solvent was removed to give a crude
mixture (2a and 2b). The mixture was dissolved in 40 ml
of dry THF, then the solution was added to a suspension
of aluminum chloride (10.68 g, 80 mmol) and lithium alu-
minum hydride (3.04 g, 80 mmol) in 150 ml of dry THF
with stirring at reflux. After this mixture was refluxed for 3
h, then cooled to 08C, and 40 ml of water was carefully
added. The water phase was extracted with dichloromethane
(50 ml 3 3). The organic layer was dried over anhydrous
EXPERIMENTAL SECTION
All chemicals were purchased from Aldrich Chemical
Co. and Beijing Chemical Co. used as received unless oth-
erwise noted. Infrared spectra were obtained on an Avatar
360 Fourier transform spectrometer. Single-crystal X-ray
diffraction measurements were carried out on a Bruker
CCD diffractometer. 1H and 13C NMR spectra were
recorded on Bruker AV-300, AVQ-400, and AV-500 spec-
trometers. All chemical shifts were reported in d units
Contract grant sponsor: National Natural Science Foundation of China
(NSFC); Contract grant number: 20602003
Contract grant sponsor: SRF for ROCS, SEM; Contract grant number:
102213018
*Correspondence to: Guofu Zi, Department of Chemistry, Beijing Normal
University, Beijing 100875, China. E-mail: gzi@bnu.edu.cn
Received for publication 30 June 2007; Accepted 31 July 2007
DOI: 10.1002/chir.20470
Published online 22 August 2007 in Wiley InterScience
with reference to the residual protons of the deuterated (www.interscience.wiley.com).
C
VV
2007 Wiley-Liss, Inc.

SYNTHESIS OF CHIRAL CIS-3-HYDROXYAZETIDINES
803
MgSO4, then solvent was removed to give a crude Calcd for C17H18ClNO: C, 71.0; H, 6.30; N, 4.87. Found: C,
mixture, 1-(10-phenylethyl)-2-phenyl-3-hydroxyazetidine (L1a 70.9; H, 6.39; N, 4.64.
and L1b), which was further purified by chromatography
(hexane/ethyl acetate 5 5/1) to afford pure compounds
(10R,2R,3R)-1-(10-phenylethyl)-2-(3-chlorophenyl)-3-
(10R,2R,3R)-1-(10-phenylethyl)-2-phenyl-3-hydroxyazetidine
hydroxyazetidine (L3a)
(L1a; 2.18 g, 43%) and (10R,2S,3S)-1-(10-phenylethyl)-2-
phenyl-3-hydroxyazetidine (L1b; 1.06 g, 21%), total yield:
3.24 g, 64%.
Colorless crystals, mp 89–918C; [a]2D0 5 2200.2 (c 0.44,
1
CH2Cl2); H NMR (500 MHz, CDCl3): d 1.35 (d, J 5 6.5
Hz, 3H), 1.65 (br, s, 1H), 3.32 (m, 1H), 3.46 (q, J 5 6.2 Hz,
1H), 3.50 (d, J 5 8.2 Hz, 1H), 4.20 (d, J 5 5.2 Hz, 1H), 4.43
(q, J 5 5.6 Hz, 1H), 7.03–7.10 (m, 6H), 7.18–7.21 (m, 3H)
ppm; 13C NMR (125 MHz, CDCl3): d 19.5, 58.8, 66.1, 67.1,
71.7, 126.0, 127.1, 127.3, 127.8, 128.1, 128.3, 128.9, 133.7,
139.3, 141.9 ppm; IR (KBr): 3437, 2975 1601 cm21; MS
(EI): m/z 287 (M1); Anal. Calcd for C17H18ClNO: C, 71.0;
H, 6.30; N, 4.87. Found: C, 70.9; H, 6.45; N, 4.83.
(10R,2R,3R)-1-(10-phenylethyl)-2-phenyl-3-
hydroxyazetidine (L1a)
Colorless crystals, mp 136–1388C; [a]2D0 5 2188.0 (c
1
0.67, CH2Cl2); H NMR (300 MHz, CDCl3): d 1.30 (d, J 5
6.6 Hz, 3H), 1.71 (d, J 5 5.7 Hz, 1H), 3.29 (m, 1H), 3.47
(m, 2H), 4.23 (d, J 5 6.0 Hz, 1H), 4.38 (q, J 5 5.7 Hz, 1H),
6.99–7.07 (m, 3H), 7.09–7.26 (m, 7H) ppm; 13C NMR (75
MHz, CDCl3): d 19.5, 58.6, 66.0, 66.7, 72.0, 127.0, 127.1,
127.6, 127.7, 128.0, 136.9, 142.1 ppm; IR (KBr): 3464, 2963,
1602 cm21; MS (EI): m/z 253 (M1); Anal. Calcd for
C17H19NO: C, 80.6; H, 7.56; N, 5.53. Found: C, 80.3; H,
7.50; N, 5.43.
(10R,2S,3S)-1-(10-phenylethyl)-2-(3-chlorophenyl)-3-
hydroxyazetidine (L3b)
Colorless crystals, mp 64–668C; [a]2D0 5 193.2 (c 0.31,
1
CH2Cl2); H NMR (500 MHz, CDCl3): d 1.05 (d, J 5 6.5
(10R,2S,3S)-1-(10-phenylethyl)-2-phenyl-3-
hydroxyazetidine (L1b)
Hz, 3H), 1.61 (d, J 5 6.5 Hz, 1H), 3.05 (m, 1H), 3.15 (d, J
5 9.0 Hz, 1H), 3.52 (q, J 5 6.5 Hz, 1H), 4.36 (d, J 5 6.0
Hz, 1H), 4.43 (q, J 5 6.0 Hz, 1H), 7.28–7.50 (m, 8H), 7.64
(s, 1H) ppm; 13C NMR (125 MHz, CDCl3): d 22.7, 59.0,
65.9, 67.8, 71.8, 126.0, 127.1, 127.2, 127.8, 128.1, 128.4,
129.6, 134.5, 140.9, 143.4 ppm; IR (KBr): 3423, 2966 1600
cm21; MS (EI): m/z 286 (M1 2 1); Anal. Calcd for
C17H18ClNO: C, 71.0; H, 6.30; N, 4.87. Found: C, 70.9; H,
6.64; N, 4.81.
Colorless crystals, mp 108–1108C; [a]2D0 5 1116.3 (c
1
0.32, CH2Cl2); H NMR (400 MHz, CDCl3): d 1.06 (d, J 5
6.4 Hz, 3H), 1.68 (s, 1H), 3.04 (m, 1H), 3.16 (d, J 5 8.8 Hz,
1H), 3.53 (q, J 5 6.4 Hz, 1H), 4.42 (s, 2H), 7.27–7.47 (m,
8H), 7.63 (d, J 5 7.6 Hz, 2H) ppm; 13C NMR (100 MHz,
CDCl3): d 22.9, 59.0, 65.8, 67.9, 72.2, 127.0, 127.2, 127.6,
127.8, 128.3, 128.4, 138.4, 143.7 ppm; IR (KBr): 3412, 2973,
1605 cm21; MS (EI): m/z 253 (M1); Anal. Calcd for
C17H19NO: C, 80.6; H, 7.56; N, 5.53. Found: C, 80.5; H,
7.53; N, 5.53.
(10R,2R,3R)-1-(10-phenylethyl)-2-(4-chlorophenyl)-3-
hydroxyazetidine (L4a)
Colorless crystals, mp 105–1078C; [a]2D0 5 2204.2 (c
0.43, CH2Cl2); H NMR (500 MHz, CDCl3): d 1.34 (d, J 5
(10R,2R,3R)-1-(10-phenylethyl)-2-(2-chlorophenyl)-3-
hydroxyazetidine (L2a)
1
6.5 Hz, 3H), 1.63 (br, S, 1H), 3.33 (m, 1H), 3.46 (d, J 5 6.0
Hz, 1H), 3.51 (d, J 5 8.5 Hz, 1H), 4.20 (d, J 5 5.5 Hz, 1H),
4.42 (d, J 5 5.5 Hz, 1H), 7.04–7.08 (m, 3H), 7.12–7.17 (m,
6H) ppm; 13C NMR (125 MHz, CDCl3): d 19.7, 58.9, 66.0,
67.1, 71.6, 127.2, 127.8, 127.9, 128.0, 129.5, 132.7, 135.7,
142.0. IR (KBr): 3461, 2943, 1598 cm21; MS (EI): m/z 286
(M1 2 1); Anal. Calcd for C17H18ClNO: C, 71.0; H, 6.30;
N, 4.87; Found: C, 70.9; H, 6.66; N, 4.79.
Colorless crystals, mp 50–528C; [a]2D0 5 2112.8 (c 0.19,
CH2Cl2); H NMR (500 MHz, CDCl3): d 1.40 (d, J 5 5.5
1
Hz, 3H), 1.52 (d, J 5 5.0 Hz, 1H), 3.41 (m, 1H), 3.51 (m,
2H), 4.63 (q, J 5 5.5 Hz, 1H), 4.69 (br, s, 1H), 7.05–7.16
(m, 5H), 7.28 (m, 3H), 7.49 (br, s, 1H) ppm; 13C NMR
(125 MHz, CDCl3): d 18.6, 58.6, 65.3, 66.4, 69.2, 125.9,
127.2, 127.9, 128.0, 128.4, 130.7, 131.7, 134.6, 142.0 ppm;
IR (KBr): 3438, 2970, 1630 cm21; MS (EI): m/z 286 (M1
–
1); Anal. Calcd for C17H18ClNO: C, 71.0; H, 6.30; N, 4.87.
Found: C, 70.9; H, 6.60; N, 4.79.
(10R,2S,3S)-1-(10-phenylethyl)-2-(4-chlorophenyl)-3-
hydroxyazetidine (L4b)
(10R,2S,3S)-1-(10-phenylethyl)-2-(2-chlorophenyl)-3-
hydroxyazetidine (L2b)
Colorless crystals, mp 110–1128C; [a]2D0 5 199.7 (c
1
0.30, CH2Cl2); H NMR (500 MHz, CDCl3): d 1.03 (d, J 5
Colorless crystals, mp 92–948C; [a]2D0 5 1140.4 (c 0.29, 6.5 Hz, 3H), 1.56 (d, J 5 6.5 Hz, 1H), 3.04 (m, 1H), 3.14
1
CH2Cl2); H NMR (500 MHz, CDCl3): d 1.10 (d, J 5 6.5 (d, J 5 9.0 Hz, 1H), 3.51(q, J 5 6.5 Hz, 1H), 4.36 (d, J 5
Hz, 3H), 1.54 (d, J 5 6.5 Hz, 1H), 3.12 (dd, J 5 9.5, 6.5 Hz, 6.0 Hz, 1H), 4.42 (q, J 5 6.0 Hz, 1H), 7.27–7.42 (m, 7H),
1H), 3.19 (d, J 5 9.5 Hz, 1H), 3.58 (q, J 5 6.5 Hz, 1H), 4.65 7.57 (d, J 5 8.0 Hz, 2H) ppm; 13C NMR (125 MHz,
(q, J 5 5.5 Hz, 1H), 4.73 (d, J 5 6.0 Hz, 1H), 7.27–7.46 (m, CDCl3): d 22.9, 59.0, 65.9, 67.9, 71.7, 127.1, 127.2, 128.4,
8H), 8.13 (d, J 5 7.0 Hz, 1H) ppm; 13C NMR (125 MHz, 128.6, 129.3, 133.4, 137.1, 143.5 ppm; IR (KBr): 3432, 2966
;
CDCl3): d 22.9, 59.3, 65.0, 68.1, 69.7, 126.6, 127.2, 127.3, cm21 MS (EI): m/z 287 (M1); Anal. Calcd for
128.4, 128.6, 129.0, 130.8, 132.0, 136.3, 143.7 ppm; IR C17H18ClNO: C, 71.0; H, 6.30; N, 4.87. Found: C, 70.9; H,
(KBr): 3442, 2965 cm21; MS (EI): m/z 286 (M1 – 1); Anal. 6.21; N, 4.75.
Chirality DOI 10.1002/chir

804
ZHANG ET AL.
(10R,2R,3R)-1-(10-phenylethyl)-2-(2-methoxyphenyl)-3-
hydroxyazetidine (L5a)
1
Colorless oil, [a]D20 5 2100.0 (c 0.17, CH2Cl2); H NMR
(500 MHz, CDCl3): d 1.43 (d, J 5 5.4 Hz, 3H), 1.68 (br, s,
1H), 3.42 (br, s, 1H), 3.51 (br, s, 1H), 3.57 (br, s, 1H), 3.79
(s, 3H), 4.55 (q, J 5 5.9 Hz, 1H), 4.73 (br, s, 1H), 6.73 (d, J
5 8.1 Hz, 1H), 6.82 (t, J 5 7.4 Hz, 1H), 7.10–7.19 (m, 4H),
7.32 (m, 3H); 13C NMR (125 MHz, CDCl3): d 18.7, 55.4,
58.8, 65.7, 66.2, 66.9, 109.6, 120.0, 125.2, 127.1, 127.8,
127.9, 128.0, 129.8, 142.6, 156.1 ppm; IR (neat): 3415, 2965,
1601 cm21; MS (EI): m/z 283 (M1); Anal. Calcd for
C18H21NO2: C, 76.3; H, 7.47; N, 4.94. Found: C, 76.3; H,
7.47; N, 4.78.
(10 R,2S,3S)-1-(10-phenylethyl)-2-(2-methoxyphenyl)-3-
hydroxyazetidine (L5b)
1
Colorless oil, [a]D20 5 185.5 (c 0.11, CH2Cl2); H NMR
(500 MHz, CDCl3): d 1.14 (d, J 56.4 Hz, 3H), 1.65 (d, J 5
6.3 Hz, 1H), 3.10 (m, 1H), 3.21 (d, J 5 9.2 Hz, 1H), 3.57
(q, J 5 6.4 Hz, 1H), 3.92 (s, 3H), 4.55 (q, J 5 6.2 Hz, 1H),
4.77 (d, J 5 5.8 Hz, 1H), 6.95 (d, J 5 8.1 Hz, 1H), 7.14 (t, J
5 7.2 Hz, 1H), 7.03–7.50 (m, 6H), 8.04 (d, J 5 7.2 Hz, 1H)
ppm; 13C NMR (125 MHz, CDCl3): d 23.1, 55.4, 59.8, 65.3,
67.5, 68.4, 109.8, 120.5, 126.7, 127.0, 127.2, 127.3, 128.4,
Scheme 1. Synthesis of chiral cis-3-hydroxyazetidines.
129.8, 144.1, 156.3 ppm; IR (neat): 3421, 2965, 1600 cm21
;
MS (EI): m/z 283 (M1); Anal. Calcd for C18H21NO2: C,
3.76 (s, 3H), 4.21 (d, J 5 6.0 Hz, 1H), 4.37 (br, s , 1H),
6.72 (d, J 5 8.8 Hz, 2H), 7.01–7.20 (m, 7H) ppm; 13C NMR
(100 MHz, CDCl3): d 19.6, 55.2, 58.5, 66.0, 66.6, 71.4,
113.2, 127.0, 127.6, 128.0, 129.0, 129.2, 142.2, 158.6 ppm;
76.3; H, 7.47; N, 4.94. Found: C, 76.4; H, 7.81; N, 4.67.
(10 R,2R,3R)-1-(10-phenylethyl)-2-(3-methoxyphenyl)-3-
hydroxyazetidine (L6a)
Colorless crystals, mp 75–778C; [a]2D0 5 2199.3 (c 0.43, IR (KBr): 3473, 2938, 1586 cm21; MS (EI): m/z 283 (M1);
1
CH2Cl2); H NMR (500 MHz, CDCl3): d 1.35 (d, J 5 6.4 Anal. Calcd for C18H21NO2: C, 76.3; H, 7.47; N, 4.94.
Hz, 3H), 1.71 (br, s, 1H), 3.31 (m, 1H), 3.49 (m, 2H), 3.77 Found: C, 76.1; H, 7.37; N, 4.74.
(s, 3H), 4.28 (d, J 5 5.2 Hz, 1H), 4.40 (d, J 5 4.9 Hz, 1H),
(10 R,2S,3S)-1-(10-phenylethyl)-2-(4-methoxyphenyl)-3-
hydroxyazetidine (L7b)
6.67 (m, 1H), 6.77 (m, 2H), 7.05–7.11 (m, 4H), 7.22 (d, J 5
7.0 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3): d 19.4,
55.2, 58.6, 66.0, 66.4, 72.0, 113.1, 113.2, 120.1, 127.1, 127.7,
128.1, 128.8, 138.7, 142.2, 159.3 ppm; IR (KBr): 3442, 2996,
1583 cm21; MS (EI): m/z 283 (M1); Anal. Calcd for
C18H21NO2: C, 76.3; H, 7.47; N, 4.94. Found: C, 76.3; H,
7.77; N, 4.90.
Colorless crystals, mp 81–838C; [a]2D0 5 197.1 (c 0.31,
1
CH2Cl2); H NMR (500 MHz, CDCl3): d 1.04 (d, J 5 5.9
Hz, 3H), 1.63 (br, s, 1H), 3.00 (br, s, 1H), 3.13 (d, J 5 8.7
Hz, 1H), 3.51 (d, J 5 5.8 Hz, 1H), 3.86 (s, 3H), 4.37 (s,
2H), 6.99 (d, J 5 8.4 Hz, 2H), 7.35–7.43 (m, 5H), 7.56 (d, J
5 7.8 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3, d): 22.9,
55.3, 58.9, 65.9, 68.0, 71.9, 113.9, 127.1, 127.3, 128.4, 129.1,
(10 R,2S,3S)-1-(10-phenylethyl)-2-(3-methoxyphenyl)-3-
hydroxyazetidine (L6b)
130.3, 143.8, 159.2 ppm; IR (KBr): 3511, 3020, 1608 cm21
;
1
Colorless oil, [a]D20 5 191.7 (c 0.22, CH2Cl2); H NMR
MS (EI): m/z 283 (M1); Anal. Calcd for C18H21NO2: C,
(500 MHz, CDCl3): d 1.08 (d, J 5 6.2 Hz, 3H), 1.70 (br, s,
1H), 3.02 (m, 1H), 3.15 (d, J 5 8.9 Hz, 1H), 3.52 (d, J 5 6.2
Hz, 1H), 3.90 (s, 3H), 4.40 (s, 2H), 6.98 (dd, J 5 8.0, 1.6
Hz, 1H), 7.17–7.44 (m, 8H) ppm; 13C NMR (125 MHz,
CDCl3): d 22.9, 55.3, 59.1, 65.9, 67.9, 72.2, 113.0, 113.6,
120.0, 127.1, 127.3, 128.4, 129.5, 140.2, 143.7, 159.9 ppm;
IR (neat): 3426, 2966, 1600 cm21; MS (EI): m/z 283 (M1);
Anal. Calcd for C18H21NO2: C, 76.3; H, 7.47; N, 4.94.
Found: C, 76.4; H, 7.78; N, 4.90.
76.3; H, 7.47; N, 4.94. Found: C, 76.3; H, 7.44; N, 4.91.
(10 R,2R,3R)-1-(10-phenylethyl)-2-(10-naphthyl)-3-
hydroxyazetidine (L8a)
Colorless crystals, mp 107–1098C; [a]2D0 5 2100.6 (c
1
0.53, CH2Cl2); H NMR (500 MHz, CDCl3): d 1.46 (d, J 5
6.4 Hz, 3H), 1.54 (d, J 5 6.6 Hz, 1H), 3.53 (m, 2H), 3.65
(d, J 5 6.4 Hz, 1H), 4.72 (d, J 5 6.0 Hz, 1H), 5.12 (d, J 5
5.4 Hz, 1H), 7.04 (d, J 5 7.2 Hz, 1H), 7.10 (m, 2H), 7.30
(m, 3H), 7.47 (m, 2H), 7.64 (d, J 5 8.2 Hz, 1H), 7.69 (d, J
5 6.8 Hz, 1H), 7.82–7.87 (m, 2H) ppm; 13C NMR (100
(10 R,2R,3R)-1-(10-phenylethyl)-2-(4-methoxyphenyl)-3-
hydroxyazetidine (L7a)
Colorless crystals, mp 98–1008C; [a]2D0 5 2206.3 (c MHz, CDCl3): d 18.4, 58.7, 65.9, 66.1, 69.1, 122.2, 125.1,
1
0.35, CH2Cl2); H NMR (400 MHz, CDCl3): d 1.32 (d, J 5 125.4, 126.0, 126.7, 127.2, 127.4, 127.9, 128.0, 128.8, 130.4,
6.8 Hz, 3H), 1.72 (br, s, 1H), 3.28 (m, 1H), 3.49 (m, 2H), 131.9, 133.3, 142.3 ppm; IR (KBr): 3565, 2935, 1595 cm21
;
Chirality DOI 10.1002/chir

SYNTHESIS OF CHIRAL CIS-3-HYDROXYAZETIDINES
805
TABLE 1. Synthesis and yields of (10R,2R,3R)-2-Aryl-3-hydroxyazetidines (La)
and (10R,2S,3S)-2-Aryl-3-hydroxyazetidines (Lb) from (R)-1-phenylethylamine
Compound
Ar
Yield of La (%)
Yield of Lb (%)
Total yield (%)
L1a; 1b
L2a; 2b
L3a; 3b
L4a; 4b
L5a; 5b
L6a; 6b
L7a; 7b
L8a; 8b
Ph
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
1-naphthyl
43
48
39
38
45
36
40
45
21
22
22
24
28
18
19
33
64
70
61
62
73
54
59
78
MS (EI): m/z 303 (M1); Anal. Calcd for C21H21NO: C, were dried over anhydrous Na2SO4 and concentrated in
83.1; H, 6.98; N, 4.62. Found: C, 82.9; H, 7.33; N, 4.64.
vacuo. The crude products were purified by flash column
chromatography (hexane/EtOAc 5 4/1). The ee values of
the alcohol products were determined by GC analysis on a
chiral cyclodextrin capillary column. Conditions of GC
analyses: N2 as carrier gas (1.5 ml/min). For 1-phenylpro-
panol: DET 5 2808C, INJ 5 2408C, OVEN 5 1208C, tR 5
20.0 min for (R) and tR 5 20.3 min for (S). For 1-(2-chloro-
phenyl)propanol: DET 5 3008C, INJ 5 3008C, OVEN 5
1508C, tR 5 16.0 min for (R) and tR 5 16.2 min for (S). For
1-(3-chlorophenyl)propanol: DET 5 2808C, INJ 5 2808C,
OVEN 5 1308C, tR 5 48.0 min for (R) and tR 5 48.6 min
for (S). For 1-(4-chlorophenyl)propanol: DET 5 3008C, INJ
5 3008C, OVEN 5 1508C, tR 5 19.8 min for (R) and tR 5
20.2 min for (S). For 1-(2-methoxyphenyl)propanol: DET
5 3008C, INJ 5 3008C, OVEN 5 1508C, tR 5 17.8 min for
(R) and tR 5 17.2 min for (S). For 1-(3-methoxyphenyl)pro-
panol: DET 5 2808C, INJ 5 2808C, OVEN 5 1208C, tR 5
88.5 min for (R) and tR 5 89.2 min for (S). For 1-(4-
methoxyphenyl)propanol: DET 5 2808C, INJ 5 2808C,
OVEN 5 1308C, tR 5 56.3 min for (R) and tR 5 57.2 min
for (S). For 1-(4-fluorophenyl)propanol: DET 5 2808C, INJ
5 2408C, OVEN 5 1208C, tR 5 23.6 min for (R) and tR 5
24.4 min for (S). For 1-(1-naphthyl)propanol: DET 5
(10 R,2S,3S)-1-(10-phenylethyl)-2-(10-naphthyl)-3-
hydroxyazetidine (L8b)
1
Colorless oil, [a]D20 5 1116.0 (c 0.28, CH2Cl2); H NMR
(500 MHz, CDCl3): d 1.15 (d, J 5 6.2 Hz, 3H), 1.57 (br, s,
1H), 3.21 (m, 1H), 3.27 (d, J 5 9.0 Hz, 1H), 3.65 (d, J 5 6.3
Hz, 1H), 4.74 (d, J 5 5.8 Hz, 1H), 5.13 (d, J 5 5.4 Hz, 1H),
7.31 (m, 1H), 7.40 (t, J 5 7.5 Hz, 2H), 7.50–7.65 (m, 5H),
7.86 (d, J 5 8.1 Hz, 1H), 7.97 (m, 2H), 8.31 (d, J 5 6.5 Hz,
1H) ppm; 13C NMR (125 MHz, CDCl3): d 23.0, 59.8, 65.7,
68.4, 69.6, 122.3, 125.6, 125.8, 126.3, 126.9, 127.2, 127.4,
127.9, 128.5, 129.0, 130.6, 133.6, 143.7 ppm; IR (neat):
3409, 3059, 1596 cm21; MS (EI): m/z 303 (M1); Anal.
Calcd for C21H21NO: C, 83.1; H, 6.98; N, 4.62. Found: C,
82.8; H, 7.23; N, 4.54.
X-ray Crystal Structure Data for L6a and L7b
Compound L6a: C18H21NO2, Mr 5 283.36, monoclinic,
˚
˚
P1211, a 5 9.1306(12) A, b 5 7.0797(9) A, c 5 12.5002(14)
3
˚
˚
A; b 5 95.645(8)8; V 5 804.12(17) A ; 3.288 < 2y < 55.688;
qcalc 5 1.170 g cm23, Z 5 2, F(000) 5 304; Final R1 5
0.0499, wR2 5 0.1144, all data, R1 5 0.0625, wR2 5 0.1217.
Compound L7b: C18H21NO2, Mr 5 283.36, monoclinic,
˚
˚
˚
P21, a 5 12.226(3) A, b 5 5.8444(16) A, c 5 12.296(3) A; b
3
˚
5 114.222(4)8; V 5 801.2(4) A ; 3.648 < 2y < 52.868; qcalc
5 1.175 g cm23, Z 5 2, F(000) 5 304; Final R1 5 0.0396,
wR2 5 0.0827, all data, R1 5 0.0737, wR2 5 0.0973.*
General Procedure for Diethylzinc Addition to Aldehydes
The chiral ligand (0.1 mmol) was dissolved in toluene (3
ml) at room temperature, and diethylzinc (2.0 ml of 1.5 M
of toluene solution, 3.0 mmol) was injected. After the mix-
ture was stirred for 20 min, benzaldehyde (0.1 g, 1 mmol)
was added dropwise via a syringe, and the mixture stirred
for the corresponding reaction time under N2. The reac-
tion was quenched by the addition of a saturated aqueous
solution of NH4Cl (10 ml). The mixture was then extracted
with Et2O (15 ml 3 3). The combined organic phases
* Crystallographic data (CCDC 645974 and 645975) for the structures of L6a
and L7b have been deposited with the Cambridge Crystallographic Data
Centre. Copies of the data can be obtained, free of charge, on application to the
Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, United Kingdom (Fax:
44-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
Fig. 1. Molecular structure of (10R,2R,3R)-L6a.
Chirality DOI 10.1002/chir

806
ZHANG ET AL.
The configurations of aryl and hydroxyl groups in L6a
and L7b are assigned as cis by their crystal structure
(Figs. 1 and 2). The hydroxyl group and electron lone pair
on N atom are situated on the same side of the azetidine
backbone, indicating that a metal ion can easily chelate to
both of them.
In order to obtain excellent enantioselectivity under
mild conditions, the addition of diethylzinc to benzalde-
hyde using L1a has been studied at room temperature.
Increasing the ratio of ligand L1a to benzaldehyde,
increases the yield and enantioselectivity of (S)-1-phenyl-1-
propanol (Table 2, entries 1–3), and the best enantioselec-
tivity (94% ee) is obtained, when 20 mol% of L1a is used
(Table 2, entry 3). A further increase in the ratio of ligand
L1a to benzaldehyde does not increase the enantioselec-
tivity (Table 2, entries 4 and 5). After having optimized the
reaction conditions, various aromatic aldehydes have been
studied for the ethylation using diethylzinc catalyzed by
L1a. The additions to aromatic aldehydes provided the
corresponding S-configuration alcohols as the major iso-
mer with excellent enantioselectivities (79–97% ee) and in
moderate to high yields (Table 2, entries 6–13) similar to
the result obtained for benzaldehyde. Electron-deficient and
electron-rich aromatic aldehydes are tolerated and exhibit
similar enantioselectivities, and 1-naphthaldehyde gives the
best enantioselectivity of 97% ee (Table 2, entry 13).
Fig. 2. Molecular structure of (10R,2S,3S)-L7b.
2808C, INJ 5 2808C, OVEN 5 1608C, tR 5 66.3 min for
(R) and tR 5 64.7 min for (S). The absolute configuration
of the major enantiomer was assigned by the comparison
of optical rotation with literature data.25,26
RESULTS AND DISCUSSION
Toward the development of a chiral 3-hydroxyazetidine,
we adopt (R)-1-phenylethylamine as the origin of chirality,
which has been well employed to create a promising chiral
reaction sphere.27,28 The chiral 3-hydroxyazetidines L1a-
L8b are easily prepared by a three-step procedure
(Scheme 1). Condensation of (R)-1-phenylethylamine with
the appropriate aldehyde in dichloromethane in the pres-
ence of anhydrous MgSO4 affords the corresponding aldi-
mines 1. Subsequently, performing the Staudinger reac-
tion of imines 1 with acetoxyketene, derived from acet-
oxyacetyl chloride and Et3N,29 gives a crude mixture of cis-
b-lactams 2a and 2b. Finally, reduction of cis-b-lactams 2
(2a and 2b) by AlH2Cl, prepared from LiAlH4 and AlCl3 in
ratio of 1:1 in dry THF,30 gives a series of cis-3-hydroxyaze-
tidines L1a-8a and L1b-8b in moderate to good overall
yields after purification by flash chromatography (Table 1).
Ligands L1a-8b are roughly divided into two types,
namely the cis-(10R,2R,3R)-2-aryl-3-hydroxyazetidine lig-
ands (La; L1-8a) and cis-(10R,2S,3S)-2-aryl-3-hydroxyazeti-
dine ligands (Lb; L1-8b). In exploring the addition of
diethylzinc to aldehydes, ligands L1a–8b have been
screened under the optimized conditions (20 mol % of
ligand in toluene and 3 equiv of Et2Zn at room tempera-
ture). Initial experiments showed that the addition reac-
TABLE 2. Diethylzinc addition to aromatic aldehydes using ligand L1aa
Entry
Ar0
Amount of ligand (mol%)
Yieldb (%)
eec (%) (config.)
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
Ph
Ph
Ph
Ph
5
10
20
30
50
20
20
20
20
20
20
20
20
36
53
76
85
96
98
43
29
97
98
98
80
74
87 (S)
91 (S)
94 (S)
94 (S)
94 (S)
79 (S)
93 (S)
88 (S)
94 (S)
94 (S)
95 (S)
91 (S)
97 (S)
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-FC6H4
1-naphthyl
aReaction conditions: Et2Zn (300 mol %), toluene as a solvent, at room temperature, 29 h.
bIsolated yield after flash chromatography.
cDetermined by GC analysis on a chiral cyclodextrin capillary column. Absolute configuration was determined by the comparison of specific rotation
with literature data.25,26
Chirality DOI 10.1002/chir

SYNTHESIS OF CHIRAL CIS-3-HYDROXYAZETIDINES
807
TABLE 3. Screening of ligands L1a–8b in asymmetric
addition of diethylzinc to benzaldehydea
entry 13). Replacement of the hydrogen atom at para posi-
tion (L1b) with an electron-withdrawing group (chloro,
L4b) results in decreased yield and enantiomeric excess
(Table 3, entry 12), while electron-rich ligands L7b with
an electron-donating group (MeO) at para position and
L8b with a 1-naphthyl group exhibit similar activity and
selectivity as ligand L1b does (Table 3, entries 9, 15
and 16).
The stereochemical outcome of these diethylzinc addi-
tions to aldehydes is in agreement with the anti-transition
state structures proposed by Noyori and coworkers,31–35
which may well explain our experimental observations
that the substituted aryl groups on the azetidine backbone
have considerable influence on the enantioselectivity of
the ligands L1a-8b and the configuration of the resulting
adducts (Fig. 3). The reasons for the different stereoelec-
tronic sensitivity between ligands, La and Lb, are not clear
at this time, however, the sterically encumbered environ-
ment around the metal center seems to be a major reason
for these differences. Further computational investigation
of the ligand architecture for this transformation is cur-
rently underway.
Entry
Ar (ligand)
Ph (L1a)
Yieldb (%)
eec (%) (config.)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
76
78
54
48
95
82
87
98
88
98
81
66
98
91
88
98
94 (S)
83 (S)
86 (S)
73 (S)
79 (S)
89 (S)
81 (S)
93 (S)
92 (R)
95 (R)
89 (R)
83 (R)
57 (R)
82 (R)
90 (R)
90 (R)
2-ClC6H4 (L2a)
3-ClC6H4 (L3a)
4-ClC6H4 (L4a)
2-MeOC6H4 (L5a)
3-MeOC6H4 (L6a)
4-MeOC6H4 (L7a)
1-naphthyl (L8a)
Ph (L1b)
2-ClC6H4 (L2b)
3-ClC6H4 (L3b)
4-ClC6H4 (L4b)
2-MeOC6H4 (L5b)
3-MeOC6H4 (L6b)
4-MeOC6H4 (L7b)
1-naphthyl (L8b)
CONCLUSIONS
In conclusion, a new series of chiral cis-3-hydroxyazeti-
dines have been synthesized from (R)-1-phenylethylamine.
These ligands promote the addition of diethylzinc reagent
to aromatic aldehydes under mild conditions to afford the
corresponding secondary alcohols in high yield with good
to excellent enantioselectivity. These results demonstrate
that the chiral azetidine-based ligand is promising in asym-
metric catalysis and deserves certainly more attention.
Further efforts will focus on the applications of these
ligands toward other types of asymmetric reactions and
the exploration of new ligands based on chiral azetidine.
aReaction conditions: Et2Zn (300 mol %), ligand (20 mol %), toluene as a
solvent, at room temperature, 29 h.
bIsolated yield after flash chromatography.
cDetermined by GC analysis on a chiral cyclodextrin capillary column.
Absolute configuration was determined by the comparison of specific rota-
tion with literature data.25,26
tion catalyzed by ligand L1a proceeded smoothly to afford
(S)-1-phenyl-1-propanol in 76% yield and 94% ee (Table 3,
entry 1). Similar to the results of L1a, all the other cis-
(10R,2R,3R)-2-aryl-3-hydroxyazetidine ligands (La) induce
enantiomeric excess in (S)-configuration alcohol, (S)-1-
phenyl-1-propanol, as the major isomer with good to excel-
lent enantioselectivities (73–93% ee) (Table 3, entries 2–8),
while under the same condition, cis-(10R,2S,3S)-2-aryl-3-
hydroxyazetidine ligands (Lb) induce the enantiomeric
excess in (R)-configuration alcohol in good yields and
enantioselectivities (Table 3, entries 9–16). The results of
the reactions with ligands cis-(10R,2R,3R)-2-aryl-3-hydroxy-
azetidine ligands La can not be easy ruled out (Table 3,
entries 1–8), while the results of the reactions with ligands
Lb (L1-8b demonstrate the noticeable steric and elec-
tronic effects of a variety of comparable substituents at the
ortho, meta, and para positions of the phenyl group. For
example, moving chlorine atom from para to meta to ortho
position results in increased enantiomeric excess (Table 3,
entries 10–12) due to steric effects, and the best enantiose-
lectivity (95% ee) is obtained by using L2b as catalyst (Ta-
ble 3, entry 10). In contrast, moving MeO group from para
to meta to ortho position results in decreased enantiomeric
excess (Table 3, entries 13–15) due to the coordination
effects of MeO group, and the lowest enantioselectivity
(57% ee) is obtained by using L5b as catalyst (Table 3,
Fig. 3. Proposed transition states.
Chirality DOI 10.1002/chir

808
ZHANG ET AL.
21. Wilken J, Erny S, Wassmann S, Martens J. New C2-symmetric 2,4-
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Chirality DOI 10.1002/chir