Asymmetric transfer hydrogenation of α-aminoalkyl α′-chloromethyl ketones with chiral Rh complexes

Article abstract of DOI:10.1021/jo0491455

Asymmetric transfer hydrogenation of N-substituted (3S)-3-amino-1-chloro-4- phenyl-2-butanones in the presence of Cp*RhCl[(R,R)-Tsdpen] (S/C = 1000) with a mixture of formic acid/triethylamine gave N-substituted (2R,3S)-3-amino-1-chloro-2-hydroxy-4-phenylbutanes with up to 93% de in a quantitative yield, and reduction with the enantiomeric catalyst Cp*RhCl[(S,S)-Tsdpen] gave (2S.3S)-diastereomeric alcohol with up to 96% de.

Full text of DOI:10.1021/jo0491455

Asym m etr ic Tr a n sfer Hyd r ogen a tion of
r-Am in oa lk yl r′-Ch lor om eth yl Keton es
w ith Ch ir a l Rh Com p lexes
Takayuki Hamada,† Takayoshi Torii,† Tomoyuki Onishi,†
Kunisuke Izawa,*,† and Takao Ikariya*,‡
Aminoscience Laboratories, Ajinomoto Co., Inc.,
1-1, Suzuki-cho, Kawasaki-ku, Kawasaki, 210-8681 J apan,
and Graduate School of Science and Engineering and
Frontier Collaborative Research Center, Tokyo
Institute of Technology, 2-12-1 O-okayama,
F IGURE 1. Chiral Rh, Ir, and Ru catalysts for asymmetric
transfer hydrogenation.
Meguro-ku, Tokyo 152-8552 J apan
2-butanone (3a ) afforded (2S,3S)-2a in <98% de.5 The
reduction of 3a with NaBH4 at -10 °C gave a mixture of
(2S,3S)-2a and (2R,3S)-2a in a ratio of 80:20, and a single
crystallization increased the ratio to >98:2.6 When LiAlH-
(O-t-Bu)3 was used as a metal hydride agent, 3a prefer-
entially gave (2R,3S)-2a as a 87:13 mixture of (2R,3S)-
and (2S,3S)-2a .7 In these reductions, the carbonyl dia-
stereofaces were differentiated by a proper combination
of metal hydride species and the chirality of the adjacent
nitrogen-substituted stereogenic center of 3. To obtain
the desired diastereomer, a matched combination of
substrate and reducing reagent is crucial.
kunisuke_izawa@ajinomoto.com; tikariya@apc.titech.ac.jp
Received May 20, 2004
Abstr a ct: Asymmetric transfer hydrogenation of N-substi-
tuted (3S)-3-amino-1-chloro-4-phenyl-2-butanones in the
presence of Cp*RhCl[(R,R)-Tsdpen] (S/C ) 1000) with a
mixture of formic acid/triethylamine gave N-substituted
(2R,3S)-3-amino-1-chloro-2-hydroxy-4-phenylbutanes with
up to 93% de in a quantitative yield, and reduction with the
enantiomeric catalyst Cp*RhCl[(S,S)-Tsdpen] gave (2S,3S)-
diastereomeric alcohol with up to 96% de.
Recently, we reported an industrial preparation of
N-(tert-butyloxycarbonyl)-(3S)-3-amino-1-chloro-4-phenyl-
2-butanone.9 We have also developed a practical method
for the asymmetric syntheses of optically active styrene
oxides via 2-chloro-1-phenylethanols generated by the
reductive transformation of ring-substituted 2-chloroac-
etophenones.10 Optically active alcohols with up to 97%
ee were obtainable from the asymmetric transfer hydro-
genation of 2-chloroacetophenones with a substrate/
catalyst (S/C) ratio of 1000-5000 in a formic acid/
triethylamine mixture containing a chiral Rh complex,
Cp*RhCl[(R,R)-Tsdpen] (4a ), where Cp* ) pentameth-
ylcyclopentadienyl and TsDPEN ) (1R,2R)-N-p-toluene-
sulfonyl-1,2-diphenylethylenediamine (Figure 1).11 In this
paper, we describe an effective means for preparing the
desired diastereomers 2 with excellent to good selectivity
by the asymmetric transfer hydrogenation of aliphatic
ketones 3 with the catalyst 4a (Scheme 2).
Reduction of N-(tert-butyloxycarbonyl)-(3S)-3-amino-
1-chloro-4-phenyl-2-butanone, 3a , with the use of the
chiral Rh complex (4a ) in a 5:2 formic acid/triethylamine
azeotropic mixture (S/C ) 1000, S/HCOOH ) 1/1) in 0.8
M ethyl acetate at 25 °C afforded (2R,3S)-2a with 80%
de in a quantitative yield. When the reduction was
conducted with the enantiomeric catalyst (S,S-4a ), the
corresponding diastereomer (2S,3S)-1a with 80% de was
obtained quantitatively. Thus, the diastereoselectivity of
the reduction was controlled by the chirality of the ligand,
while the chirality of the adjacent stereogenic center did
Optically active N-(tert-butyloxycarbonyl)-(3S)-3-amino-
1,2-epoxy-4-phenylbutanes (1a ) are useful intermediates
for the syntheses of pharmaceuticals such as inhibitors
of HIV protease1-3 and â-secretase in Alzheimer’s dis-
ease.4 As shown in Scheme 1, (2S,3S)-1a is used to
produce saquinavir and amprenavir, while diastereomer-
ic alcohol (2R,3S)-1a is similarly employed in the syn-
thesis of atazanavir.3 These diastereomers of 1a are
readily accessible using conventional procedures from
N-(tert-butyloxycarbonyl)-(3S)-3-amino-1-chloro-2-hydroxy-
4-phenylbutanes (2) obtained by means of chemical5-7 or
microbial reduction of the corresponding ketones (3a ).8
For example, the Meerwin-Pondorf-Verlay reduction of
N-(tert-butyloxycarbonyl)-(3S)-3-amino-1-chloro-4-phenyl-
† Ajinomoto Co., Inc.
‡ Tokyo Institute of Technology.
(1) Roberts, N. A.; Martin, J . A.; Kinchington, D.; Broadhurst, A.
V.; Craig, J . C.; Duncan, I. B.; Galphin, S. A.; Handa, B. K.; Krohn,
A.; Lambert, R. W.; Merrett, J . H.; Mills, J . S.; Parkes, K. E. B.;
Redshaw, S.; Ritchie, A. J .; Taylor, D. L.; Thomas, G. J .; Machin, P. J .
Science 1990, 248, 358-361.
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G.; Tung, R. D.; Navia, M. A. J . Am. Chem. Soc. 1995, 117, 1181-
1182.
(3) Xu, Z.; Singh, J .; Schwinden, M. D.; Zheng, B.; Kissick, T. P.;
Patel, B.; Humora, M. J .; Quiroz, F.; Dong, L.; Hsieh, D.-M.; Heikes,
J . E.; Pudipeddi, M.; Lindrud, M. D.; Srivastava, S. K.; Kronenthal,
D. R.; Mueller, R. H. Org. Proc. Res. Dev. 2002, 6 (3), 323-328.
(4) Bi, X.; Haque, T. S.; Zhou, J .; Skillman, A. G.; Lin, B.; Lee, C.
E.; Kuntz, I. D.; Ellman, J . A.; Lynch, G. J . Neurochem. 2000, 74,
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1997. (b) Matsuo, K.; Matsumoto, S. WO 9855452, 1998.
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Thottathil, J .; Polniaszek, R. P. Tetrahedron Lett. 1997, 38, 3175-
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Hirose, N.; Nakazawa, M.; Izawa, K. Tetrahedron Lett. 2001, 42, 5887-
5890.
(10) (a) Hamada, T.; Torii, T.; Izawa, K.; Noyori, R.; Ikariya, T. Org.
Lett. 2002, 4, 4373-4376. (b) Hamada, T.; Torii, T.; Izawa, K.; Ikariya,
T. Tetrahedron 2004, 60, 7411-7417
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2186-2187.
(7) (a) Raddatz, P.; J onczyk, A.; Minck, K.-O.; Schmitges, C. J .;
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10.1021/jo0491455 CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/17/2004
J . Org. Chem. 2004, 69, 7391-7394
7391

SCHEME 1
TABLE 2. Asym m etr ic Tr a n sfer Hyd r ogen a tion of
Am in oa lk yl Ch lor om eth yl Keton es, 3, Ca ta lyzed by
Ch ir a l Ca ta lysts 4a w ith a HCOOH/N(C2H5)3 Mixtu r ea
SCHEME 2
Rh(R,R)-Tsdpen Rh(S,S)-Tsdpen
ketone
R
R′
(R,S)-2/(S,S)-2
(R,S)-2/(S,S)-2
3a
3b
3c
3d
3e
3f
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
(CH3)2CHCH2 Cbz
p-F-C6H4CH2 Cbz
2-NaphCH2
Boc
Cbz
Bz
90:10
90:10
97:3
10:90
9:91
4:96
2:98
11:89
5:95
8:92
Ts
91:9
83:17
87:13
91:9
3g
Cbz
a
Reaction of 3 in a 1.0 M solution containing the catalyst (4a )
was conducted with a mixture of HCOOH and N(C2H5)3 at 25 °C.
The product ratio was determined by HPLC analysis using an
Inertsil ODS-2 column.
TABLE 1. Asym m etr ic Tr a n sfer Hyd r ogen a tion of
N-(ter t-Bu tyloxyca r bon yl)-(3S)-3-a m in o-1-ch lor o-4-
p h en yl-2-bu ta n on e (3a ) Ca ta lyzed by Ch ir a l Ca ta lysts 4a
w ith a HCOOH/N(C2H5)3 Mixtu r e in Va r iou s Solven tsa
Rh(R,R)-Tsdpen
(R,S)-2a /(S,S)-2a
Rh(S,S)-Tsdpen
(R,S)-2a /(S,S)-2a
a benzoyl protecting group. The reduction of 3d bearing
a tosyl protecting group with (S,S)-4a gave the product
(2S,3S)-2d with the highest de value (up to 96%). It
should be noted that the reduction of the nonaromatic
substrates 3e derived from L-leucine with the chiral Rh
complex gave the product with a moderate de. While aryl
and R,â-unsaturated groups at the R-position in carbonyl
compounds were the crucial structural factors leading to
excellent enantioselectivity for asymmetric transfer hy-
drogenation using RuCl[(R,R)-Tsdpen](p-cymene)12,13 or
a Rh-diamine complex.11 However, this reaction provides
one of the successful examples of asymmetric transfer
hydrogenation of acyclic dialkyl ketones.14
solvent
ethyl acetate
toluene
dichloromethane
2-propanol
90:10
89:11
87:13
90:10
10:90
11:89
10:90
11:89
a
Reaction of 3 in a 1.0 M solution containing the catalyst (4a )
was conducted with a mixture of HCOOH and N(C2H5)3 at 25 °C.
The product ratio was determined by HPLC analysis using an
Inertsil ODS-2 column.
not play significant role. The effect of the solvent was
also examined. Table 1 shows that ethyl acetate gave the
highest turnover number in the asymmetric reduction
of 3a , as observed in the asymmetric transfer hydrogena-
tion of 2-chloroacetophenones with the same catalyst.10
The diastereoselectivity of 2a was solvent-dependent; for
instance, the most suitable solvent for the preparation
of (2R,3S)-2a was 2-propanol, while for (2S,3S)-2a it was
ethyl acetate.
Various chloro ketones can be reduced with chiral Rh
catalysts 4a , leading to chiral alcohols in excellent yields.
Table 2 shows the results of the reduction of a series of
chloromethyl ketones (3a -g) derived from L-amino acids.
The outcome of the reaction in terms of product yield and
diastereoselectivity is influenced by the catalyst used and
the structures of the substrates, including N-protecting
groups. The de values of the reduction products obtained
with the (S,S)-TsDPEN catalyst are somewhat higher
than those obtained with the (R,R) enantiomeric catalyst,
regardless of the structures of the R substituents and
N-protecting groups, except for the reaction of 3c bearing
The asymmetric transfer hydrogenation of 3a with the
chiral Ru complex, RuCl[(R,R)-Tsdpen]](p-cymene) (4b),
resulted in a low conversion, while that with an Ir
complex, Cp*IrCl[(R,R)-Tsdpen] (4c), provided the de-
(12) (a) Hashiguchi, S.; Fujii, A.; Takehara, J .; Ikariya, T.; Noyori,
R. J . Am. Chem. Soc. 1995, 117, 7562-7563. (b) Fujii, A.; Hashiguchi,
S.; Uematsu, N.; Ikariya, T.; Noyori, R. J . Am. Chem. Soc. 1996, 118,
2521-2522. (c) Haack, K.-J .; Hashiguchi, S.; Fujii, A.; Ikariya, T.;
Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285-288. (d)
Hashiguchi, S.; Fujii, A.; Haack, K.-J .; Matsumura, K.; Ikariya, T.;
Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 288-290. (e)
Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J . Am. Chem.
Soc. 1997, 119, 8738-8739. (f) Noyori, R.; Hashiguchi, S. Acc. Chem.
Res. 1997, 30, 97-102. (g) Murata, K.; Okano, K.; Miyagi, M.; Iwane,
H.; Noyori, R.; Ikariya, T. Org. Lett. 1999, 1, 1119-1121. (h) Okano,
K.; Murata, K.; Ikariya, T. Tetrahedron Lett. 2000, 41, 9277-9280. (i)
Koike, T.; Murata, K.; Ikariya, T. Org. Lett. 2000, 2, 3833-3836. (j)
Watanabe, M.; Murata, K.; Ikariya, T. J . Org. Chem. 2002, 67, 1712-
1715.
(13) (a) Palmer, M. J .; Wills, M. Tetrahedron: Asymmetry 1999, 10,
2045-2061 and references therein. (b) Hannedouche, J .; Kenny, J . A.;
Walsgrove, T.; Wills, M. Synlett 2002, 263-266.
7392 J . Org. Chem., Vol. 69, No. 21, 2004

SCHEME 3
simple 1:1 mixture of 98% formic acid and triethylamine
can also be used instead of its azeotrope. Commercially
available reagents and solvents could be used in this
reaction without special purification. One-pot synthesis
of chiral epoxide 1 from the corresponding chloro ketones
3 can be readily performed at room temperature.
Exp er im en ta l Section
sired product in quantitative yield, albeit with low de.
Formic acid was the best hydrogen source. The simple
mixture of formic acid and triethylamine could be used
instead of a 5:2 formic acid/triethylamine azeotropic
mixture. Attempted reactions using a 2-propanol solution
of 3a containing (S,S)-4a and KO-t-Bu hardly proceeded
(S/C ) 100, <1% yield, after 24 h at 25 °C).
The NMR spectra (400 MHz) were recorded in CDCl3 with
TMS (δ 0.00) as internal standard. Infrared (IR) spectra were
obtained by placing neat samples directly in situ IR instrument.
Diastereomer excess of samples were determined by HPLC.
Yields are for isolated product, and no impurities were detectable
by NMR and HPLC.
Typ ica l Exp er im en ta l P r oced u r e for P r ep a r a tion of
1-Ch lor o-2-h yd r oxy-3-(N-su bstitu ted a m in o)-4-p h en ylbu -
ta n e (2). Formic acid (46 µL, 1.05 mmol) was added to an ethyl
acetate solution (1.25 mL) of 1-chloro-3-(N-substituted)-4-phenyl-
butanone 3 (1.0 mmol), catalyst (1.0 µmol), and triethylamine
(0.14 mL, 1.05 mmol). The mixture was stirred at 25 °C for 2 h
and diluted with methanol to dissolve completely in order to
determine the yield and de value by HPLC analysis. Crystal-
lization of crude product gave 1-chloro-2-hydroxy-3-(N-substi-
tuted)amino-4-phenylbutane 2.
The purification of the product (2S,3S)-2a having 93%
de after reduction was performed by crystallization from
a mixture of toluene-EtOH-water to give the product
in >98% de in 80% yield. The reaction of 3a with
Cp*RhCl[(R,R)-Tsdpen] (4a ) was followed by the precipi-
tation of minor product (2S,3S)-2a to give (2R,3S)-2a
with >96% de in 80% yield after crystallization from
2-propanol-water.15 These diastereomers 2 can be con-
verted to epoxides 1 in good yields without a decrease in
de value under basic conditions. This reductive trans-
formation of 2a to the optically active epoxides 1a is more
appealing as a one-pot synthetic procedure as shown in
Scheme 3. A sequential asymmetric reduction of 3a with
a mixture of formic acid and triethylamine in 2-propanol
containing the catalyst Cp*RhCl[(S,S)-Tsdpen] or Cp*-
RhCl[(R,R)-Tsdpen] and treatment of its reaction mixture
with 1 M NaOH aqueous solution at 0 °C gave (2S,3S)-
1a in 86% yield with 90% de or (2R,3S)-1a in 83% yield
with 80% de as crystals after the addition of water. These
diastereomers (2S,3S)- and (2R,3S)-1a were separable as
reported in the literature.16
In summary, we have demonstrated that the asym-
metric transfer hydrogenation of aliphatic ketones 3 with
catalyst 4a gives the desired corresponding diastereomers
2 in excellent yields with high de with a simple change
in the ligand chirality. The diastereoselectivity of the
reaction is markedly influenced by both the N-protecting
group of 3 and the solvent used. This reductive trans-
formation of chloro ketones to optically active alcohols is
characterized by high reactivity and practicality. A
Sp ectr a l Da ta . These compounds 2a ,17 2b,18 and 2e17 were
identified by the spectral data described in the literature.
(2R,3S)-1-Ch lor o-2-h yd r oxy-3-(N-ben zyla m in o)-4-p h en -
ylbu ta n e (2c): mp 161 °C; 1H NMR (400 MHz, CDCl3) δ 3.01-
3.17 (m, 2H), 3.54 (d, 2H, J ) 12.2 Hz), 3.87 (dd, 1H, J ) 8.6,
3.6 Hz), 4.38 (dd, 1H, J ) 8.6, 3.6 Hz), 7.23- -7.70 (m, 10H); 13
C
NMR(100 MHz, CDCl3) δ 168.46, 138.07, 134.33, 132.26, 129.71,
129.12, 129.07, 127.38, 127.20, 71.89, 54.08, 48.06, 38.36; IR
(neat, cm-1) 3327, 1627, 1538, 1181, 1046, 700.4; [R]25 -75.2
Na
(c 1.0, CHCl3); MS(FAB) m/z 304 [M+ + H]. Anal. Calcd for
C
17H18ClNO2: C, 67.21; H, 5.97; N, 4.61. Found; C, 66.96; H,
5.89; N, 4.53.
(2S,3S)-1-Ch lor o-2-h yd r oxy-3-(N-ben zyla m in o)-4-p h en -
ylbu ta n e (2c): mp 200 °C; 1H NMR (400 MHz, CDCl3) δ 3.01-
3.17 (m, 2H), 3.54 (d, 2H, J ) 10.3 Hz), 3.87 (m, 1H, J ) 8.4, 4.6
Hz), 4.38 (dd, 1H, J ) 8.4, 10.3 Hz), 7.23-7.70 (m, 10H); 13C
NMR(100 MHz, CDCl3) δ 168.45, 138.06, 132.26, 129.70, 129.12,
129.07, 127.37, 127.21, 71.91, 54.08, 48.08, 38.37; IR (neat, cm-1
)
3392, 1640, 1532, 1333, 1054, 696.6; [R]25 -38.3 (c 1.0, CHCl3);
Na
MS(FAB) m/z 304 [M+ + H]. Anal. Calcd for C17H18ClNO2: C,
67.21; H, 5.97; N, 4.61. Found; C, 67.22; H, 5.84; N, 4.50.
(2R,3S)-1-Ch lor o-2-h yd r oxy-3-(N-tosyla m in o)-4-p h en yl-
bu ta n e (2d ): mp 91 °C; 1H NMR (400 MHz, CDCl3) δ 2,40 (s,
3H), 2.56-2.61 (m, 1H), 2.83-2.90 (m, 2H), 3.43-3.67 (m, 2H),
6.95-7.70 (m, 9H); 13C NMR(100 MHz, CDCl3) δ 143.93, 138.09,
137.26, 130.21, 130.13, 129.89, 129.59, 129.10, 127.45, 127.31,
127.15, 71.20, 57.16, 47.85, 39.11, 21.94, 14.59; IR (neat, cm-1
)
3496, 3274, 1455, 1322, 1152, 1092, 1059, 700.4; [R]25 -72.7
Na
(c 1.0, CHCl3); MS(FAB) m/z 352[M+ + H]. Anal. Calcd for
(14) (a) J iang, Y.; J iang, Q.; Zhu, G.; Zhang, X. Tetrahedron Lett.
1997, 38, 215-218. (b) Bianchini, C.; Glendenning, L.; Zanobini, F.;
Farnetti, E.; Graziani, M.; Nagy, E. J . Mol. Catal. A: Chem. 1998,
132, 13-19. (c) Everaere, K.; Carpentier, J .-F.; Mortreux, A.; Bulliard,
M. Tetrahedron: Asymmetry 1998, 9, 2971-2974. (d) Nishibayashi,
Y. Takei, I.; Uemura, S.; Hidai, M. Organometallics 1999, 18, 2291-
2293. (e) Everaere, K.; Carpentier, J .-F.; Mortreux, A.; Bulliard, M.
Tetrahedron: Asymmetry 1999, 10, 4083-4086. (f) Kawamoto, A.;
Wills, M. Tetrahedron: Asymmetry 2000, 11, 3257-3261. (g) Everaere,
K.; Mortreux, A.; Bulliard, M.; Brussee, J .; Gen, A.; Nowogrocki, G.;
Carpentier, J .-F. Eur. J . Org. Chem. 2001, 275-291. (h) Eustache, F.;
Dalko, P. I.; Cossy, J . Org. Lett. 2002, 4, 1263-1265. (i) Everaere, K.;
Franceschini, N.; Mortreux. A.; Carpentier, J .-F. Tetrahedron Lett.
2002, 43, 2569-2571.
(15) Onishi, T.; Hirose, N.; Otake, Y.; Nakano, T.; Honda, Y.;
Nakazawa, M.; Izawa, K. EP 1081133, 2000. After completion of the
reaction of 3a with Cp*RhCl[(R,R)-Tsdpen] (R,R-4a ), the mixture was
warmed to 40 °C and water was added. After being stirred at 40 °C
for 2 h, the mixture was cooled to 20 °C. (2S,3S)-2a was precipitated
and filtered. The filtrate was cooled to 0 °C, and water was added to
give (2R,3S)-2a in 96% de in 80% yield.
C
17H20ClNO3S: C, 57.70; H, 5.70; N, 3.96. Found; C, 57.54; H,
5.57; N, 3.72.
(2S,3S)-1-Ch lor o-2-h yd r oxy-3-(N-tosyla m in o)-4-p h en yl-
1
bu ta n e (2d ): syrup; H NMR (400 MHz, CDCl3) δ 2,40 (s, 3H),
2.66-2.79 (m, 2H), 3.18 (d, 1H, J ) 3.5 Hz), 3.56-3.69 (m, 2H),
3.88-3.91 (m, 1H), 6.92-7.80 (m, 9H); 13C NMR(100 MHz,
CDCl3) δ 143.80, 137.04, 136.46, 130.09, 129.87, 129.65, 129.04,
127.43, 127.32, 127.07, 73.03, 57.33, 46.96, 35.46, 21.92, 14.59;
IR (neat, cm-1) 3471, 3255, 1428, 1318, 1150, 1086, 700.4; [R]25
Na
-35.0 (c 1.0, CHCl3); MS(FAB), m/z 352 [M+ + H]. Anal. Calcd
for C17H20ClNO3S: C, 57.70; H, 5.70; N, 3.96. Found; C, 57.68;
H, 5.58; N, 3.83.
(2R,3S)-1-Ch lor o-2-h ydr oxy-3-(N-ben zyloxycar bon ylam i-
n o)-4-(p-flu or op h en yl)bu ta n e (2f): mp 114 °C; 1H NMR (400
(17) Barrish, J . C.; Gordon, E.; Alam, M.; Lin, P.-F.; Bisacchi, G. S.;
Chen, P.; Cheng, P. T. W.; Fritz, A. W.; Greytok, J . A. J . Med. Chem.
1994, 37, 1758-1768.
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J . Org. Chem, Vol. 69, No. 21, 2004 7393

MHz, CDCl3) δ 2.87-2.98 (m, 2H), 3.52 (d, 2H, J ) 10.0 Hz),
3.87 (m, 1H), 3.92 (dd, 1H, J ) 10.0 Hz, 5.0 Hz), 5.11 (s, 2H),
6.94-7.38 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 160.55, 156.60,
136.20, 133.16, 130.77, 130.69, 128.28, 128.05, 115.57, 115.36,
71.28, 67.04, 54.36, 47.77, 37.77; IR (neat, cm-1) 3330, 1694,
(m, 1H), 4.04 (dd, 1H, J ) 8.6 Hz, 3.6 Hz), 5.06(s, 1H), 7.19-
7.81 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 156.97, 136.61,
135.42, 133.93, 132.74, 128.77, 128.66, 128.39, 128.30, 128.08,
127.96, 127.83, 126.56, 71.61, 67.41, 54.73, 48.20, 39.11; IR (neat,
cm-1) 3330, 1690, 1536, 1268, 1237, 1042, 752.5, 696.6; [R]25
Na
1677, 1542, 1509, 1262, 1219, 1027, 750.6, 698.5; [R]25 -36.8
-39.5 (c 1.0, MeOH); MS(FAB) m/z 384 [M+ + H]. Anal. Calcd
for C22H22ClNO3: C, 68.84; H, 5.78; N, 3.65. Found: C, 68.68;
H, 5.65; N, 3.55.
Na
(c 1.0, CHCl3); MS(FAB) m/z 350 [M+ + H]. Anal. Calcd for
C
18H19ClFNO3: C, 61.45; H, 5.44; N, 3.98. Found; C, 61.52; H,
5.22; N, 3.90.
(2S,3S)-1-Ch lor o-2-h yd r oxy-3-(N-ben zyloxyca r bon yla m i-
n o)-4-(2-n a p h th yl)bu ta n e (2g): mp 171 °C; 1H NMR (400 MHz,
CDCl3) δ 2.99-3.19 (m, 2H), 3.64 (m, 2H), 3.90 (m, 1H, J ) 8.6
Hz), 4.09 (m, 1H), 5.00 (s, 2H), 7.20-7.82 (m, 12H), 13C NMR
(100 MHz, CDCl3) δ 156.31, 145.83, 136.15, 134.63, 133.50,
132.36, 128.51, 128.36, 128.17, 128.05, 127.93, 127.68, 127.58,
(2S,3S)-1-Ch lor o-2-h ydr oxy-3-(N-ben zyloxyca r bon yla m i-
n o)-4-(p-flu or op h en yl)bu ta n e (2f): mp 176 °C; 1H NMR (400
MHz, CDCl3) δ 2.88-2.97 (m, 2H), 3.62 (dd, 2H, J ) 4.6, 18.8
Hz), 3.84 (m, 1H), 3.95 (m, 1H), 5.03 (s, 2H), 6.93-7.35 (m, 9H);
13C NMR (100 MHz, CDCl3) δ 163.02, 156.20, 136.83, 135.48,
132.73, 130.83, 128.57, 128.30, 128.05, 115.57, 115.36, 73.23,
67.00, 54.70, 46.70, 34.88; IR (neat, cm-1) 3311, 1692, 1546, 1509,
126.18, 125.68, 73.35, 66.95, 54.74, 47.62, 35.88; IR (neat, cm-1
3313, 1688, 1540, 1268, 1032, 742.9, 698.5; [R]25 -2.7 (c 1.0,
)
1264, 1219, 1027, 748.7, 698.5; [R]25 -5.6 (c 1.0, CHCl3); MS-
Na
Na
(FAB) m/z 350 [M+ + H]. Anal. Calcd for C18H19ClFNO3: C,
61.45; H, 5.44; N, 3.98. Found: C, 61.65; H, 5.29; N, 3.88.
(2R,3S)-1-Ch lor o-2-h ydr oxy-3-(N-ben zyloxycar bon ylam i-
n o)-4-(2-n a p h th yl)bu ta n e (2g): mp 118 °C; 1H NMR (400
MHz, CDCl3) δ 3.05-3.17 (m, 2H), 3.52 (d, 2H, J ) 4.1 Hz), 3.87
MeOH); MS(FAB) m/z 384 [M+ + H]. Anal. Calcd for C22H22
-
ClNO3: C, 68.84; H, 5.78; N, 3.65. Found: C, 68.86; H, 5.65; N,
3.56.
J O0491455
7394 J . Org. Chem., Vol. 69, No. 21, 2004