Asymmetric reduction of prochiral ketones with N-sulfonylated amino alcohols as catalysts

Article abstract of DOI:10.1080/00397910701818586

Novel N-sulfonylated amino alcohols were synthesized from L-amino acids and (+)-camphor, and their application to asymmetric reduction of prochiral ketones with NaBH4-BF3·Et2O is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701818586

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Asymmetric Reduction of Prochiral Ketones
with N‐Sulfonylated Amino Alcohols as
Catalysts
Zhongqiang Zhou a & Yajing Guo a
a Key Laboratory of Catalysis and Materials Science of Hubei Province ,
College of Chemistry and Materials Science, South‐Central University for
Nationalities , Wuhan, China
Published online: 15 Feb 2008.
To cite this article: Zhongqiang Zhou & Yajing Guo (2008) Asymmetric Reduction of Prochiral Ketones with
N‐Sulfonylated Amino Alcohols as Catalysts, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:5, 684-696, DOI: 10.1080/00397910701818586
To link to this article: http://dx.doi.org/10.1080/00397910701818586
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Synthetic Communicationsw, 38: 684–696, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701818586
Asymmetric Reduction of Prochiral Ketones
with N-Sulfonylated Amino Alcohols as
Catalysts
Zhongqiang Zhou and Yajing Guo
Key Laboratory of Catalysis and Materials Science of Hubei Province,
College of Chemistry and Materials Science, South-Central University
for Nationalities, Wuhan, China
Abstract: Novel N-sulfonylated amino alcohols were synthesized from L-amino acids
and (þ)-camphor, and their application to asymmetric reduction of prochiral ketones
.
with NaBH4–BF3 Et2O is described.
Keywords: asymmetric reduction, ketone, N-sulfonylated amino alcohol
INTRODUCTION
Enantioselective reduction of prochiral ketones to enantiomerically pure
secondary alcohols is an important reaction in asymmetric synthesis. The
chiral oxazaborolidine-catalyzed reduction (CBS reduction) of prochiral
ketones developed by Itsuno et al.[1] and then improved by Corey et al.[2]
is one of the most important methods for generation of chiral secondary
alcohols. However, the CBS reduction commonly requires borane, which
is toxic and rather expensive. Chiral sulfonamides prepared from
commercially available L-proline derivatives were also reported to be
efficient catalysts for the highly enantioselective reduction of ketones with
borane.[3,4] Jiang reported an enantioselective reduction of ketones
Received in Japan April 12, 2007
Address correspondence to Zhongqiang Zhou, College of Chemistry and Materials
Science, South-Central University for Nationalities, Wuhan 430074, China. E-mail:
zhou-zq@hotmail.com
684

Asymmetric Reduction of Prochiral Ketones
685
with the combined reagent of NaBH4/Me3SiCl and a catalytic amount of (S)-
a,a-diphenylpyrrolidinemethanol.[5] However, to the best of our knowledge,
.
there are no reports on the use of NaBH4-BF3 Et2O for the enantioselective
reduction of ketones. In this article, we report the synthesis of new N-sulfo-
nylated amino alcohols from L-amino acid and (þ)-camphor and their appli-
cation in the catalytic enantioselective reduction of alkyl aryl ketones with
.
the combined reagent of NaBH4-BF3 Et2O.
RESULTS AND DISCUSSION
The synthetic route for N-sulfonylated amino alcohols is summarized in
Scheme 1. After the typical methyl esteration of amino acid, the reaction of
the Grignard reagents with 2a–c afforded amino alcohols 3a–f. The
reaction of p-toluenesulfonyl chloride with amino alcohols 3a–f in the
presence of triethylamine produced compounds 4a–f. The reaction of (1S)-
(þ)-10-camphorsulfonyl chloride,[6] which was prepared from the commer-
cially available (þ)-camphor with amino alcohols 3a–f, catalyzed by
Scheme 1.

686
Z. Zhou and Y. Guo
triethylamine gave camphorsulfonamides 4g–l. Reduction of 4g and 4h with
sodium borohydride at 2158C afforded the expected hydroxyl camphorsulfo-
namides 5a and 5b respectively.
A borane–tetrahydrofuran complex was reportedly formed when NaBH4
[7]
was treated with BF3 Et2O in THF, and the asymmetric reduction of
.
aromatic ketones with borane was catalyzed by a class of recoverable and
highly stable chiral sulfonamides derived from (S)-proline to yield optically
active secondary alcohols in high yields and with enantiomeric excesses of
up to 91%.[3] This inspired us to investigate the possibility of carrying out
.
the asymmetric reductions of ketones by NaBH4–BF3 Et2O and N-sulfony-
lated amino alcohols (Scheme 2).
Acetophenone was tested as substrate in the enantioselective reduction
.
with NaBH4–BF3 Et2O using N-(p-toluenesulfonyl)amino alcohols 4a–f
as catalysts. As with previous reports,[3] when the reaction was carried out
in THF, the best result could be achieved if the reaction mixture was at
reflux. Hence, reactions were carried out in dry THF at reflux in the
presence of 10 mol% chiral catalyst. The results are listed in Table 1. These
catalysts afforded low enantioselectivities with the highest ee value of
16.9% when 4e was used as a catalyst. Catalysts 4a, 4c, and 4e derived
from amino acid methyl ester hydrochloride and phenylmagnesium bromide
show higher enantioselectivity than 4b, 4d, and 4f derived from benzylmagne-
sium chloride and amino acid methyl ester hydrochloride.
Hoping to improve the enantioselectivity, N-sulfonylated amino alcohols
4g–l and 5a–5b containing chiral camphorsulfonyl group were synthesized
and used as catalysts, the results are summarized in Table 2. To find
optimum reaction conditions, we examined the reduction of acetophenone
with chiral catalyst 4g under various temperatures. In this study, obvious
temperature effects were observed. When the reaction temperature was
raised from room temperature to refluxing temperature, the ee value
increased from 7.4 to 19.4% (entries 1 and 4). Hence, the best result could
be achieved if the reaction mixture was at reflux. Based on the optimum
reaction conditions, we chose acetophenone as substrate to examine the
effect of various catalysts. All sulfonamide catalysts gave good chemical
.
yields for acetophenone reduction by NaBH4–BF3 Et2O. Among the
catalysts examined, catalyst 4g gave the best enantioselectivity. N-sulfony-
lated amino alcohols 4g, 4i, and 4k, which derived from amino acid methyl
ester hydrochloride and phenylmagnesium bromide provided the product
Scheme 2.

Asymmetric Reduction of Prochiral Ketones
687
Table 1. Enantioselective reduction of acetophenone with catalysts 4a–4f
Entry
Catalyst
Yield (%)a
%e.e.b
Configurationc
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
92
99
95
93
94
99
12.2
5.1
R
R
R
R
R
R
11.3
6.5
16.9
12.0
aIsolated yields.
bDetermined by comparison of the optical rotation value with the literature[8] value.
cDetermined by comparison of the specific rotation with the literature.[8]
with 19.4% ee, 14.7% ee, and 15.0% ee, (entries 4, 6, 8), respectively. For
catalysts 4h, 4j, and 4l, which derived from benzylmagnesium chloride and
amino acid methyl ester hydrochloride, no enantioselectivity was observed
(entries 5, 7, 9). Catalysts 4g and 4h containing a carbonyl group on the
camphor moiety provided the product with 19.4% ee and 0 ee (entries 4 and
5), respectively. For catalysts 5a and 5b containing a hydroxy on the
camphor moiety, enantioselectivities were 13.2% ee and 8.1% ee (entries 10
and 11), respectively. This study indicates that the camphor moiety could
not improve enantioselectivity significantly.
We subsequently explored the scope of the asymmetric reduction of ketones
using thebestperformingcatalyst4g, and theresults areshowninTable3.For the
examined ketones, the catalyst 4g gave 0 to 33% ee and moderate to high
Table 2. Enantioselective reduction of acetophenone with catalysts 4g– l and 5a–5b
Entry
Catalyst
Temperature(8C)
Yield (%)a
%e.e.b
Configurationc
1
2
4g
4g
4g
4g
4h
4i
rt(25)
40
50
98.0
96.3
97.1
99.0
89.3
85.1
97.6
95.4
87.0
97.6
98.2
7.4
8.9
12.6
19.4
0
R
R
3
R
4
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
R
5
—
R
6
14.7
0
7
4j
—
R
8
4k
4l
15.0
0
9
—
R
10
11
5a
5b
13.2
8.1
R
aIsolated yields.
bDetermined by comparison of the optical rotation value with the literature[8] value.
cDetermined by comparison of the specific rotation with the literature.[8]

688
Z. Zhou and Y. Guo
Table 3. Enantioselective reduction of prochiral ketones with catalyst 4g
Entry
Catalyst
R1
R2
Yield (%)a
%e.e.b
Configurationc
1
2
3
4
5
6
7
4g
4g
4g
4g
4g
4g
4g
H
CH3
C2H5
CH3
99.0
65.7
78.6
72.8
81.0
73.5
67.1
19.4
8.6
R
R
R
S
H
Cl
16.2
32.2
33.0
18.9
0
H
CH2Br
CH2Cl
CH3
H
Br
S
R
—
CH3
CH3
aIsolated yields.
bDetermined by comparison of the optical rotation value with the literature[8] value.
cDetermined by comparison of the specific rotation with the literature.[8]
chemical yields. The results show that the reduction of a-haloketone could give a
higher enantioselectivity, which agrees with the results reported by other
authors.[8] Moreover, the results also show that a-haloketone was reduced to
the corresponding alcohol with (S)-configuration, whereas other ketones
provided alcohols with (R)-configuration.
In summary, 14 chiral N-sulfonylated amino alcohols have been synthesized
from readily available (þ)-camphor and L-amino acids and used as catalysts for
.
asymmetric reduction of prochiral ketones by NaBH4–BF3 Et2O. These results
reveal that N-sulfonylated amino alcohols containing one stereogenic center on
the amino alcohol moiety do not provide the product with high enantioselectiv-
ities. Synthesis of a series of N-sulfonylated amino alcohols containing two
stereogenic centers onthe amino alcohol moiety, hopingto improve the enantios-
electivity and to learn more about the structural features of the catalyst that influ-
ences the enantioselectivity and catalytic activity, is now in progress.
EXPERIMENTAL
Melting points are uncorrected. [a]D values were recorded in a WZZ-3 digital
polarimeter. FT-IR spectra were obtained on a Nexus 470 spectrophotometer.
1H NMR spectra were recorded on a Varian Mercury 300 using CDCl3 as
solvent and TMS as internal standard. All solvents were purified according
to standard procedures.
(S)-Phenylalanine Methyl Ester Hydrochloride (2a)
SOCl2 (11 mL) was added dropwise to methanol (100 mL) in a 250-mL, round-
bottomed flask cooled to 2108C. After stirring for 15 min, L-phenylalanine
(16.5 g, 100 mmol) was added. After warming up to room temperature and

Asymmetric Reduction of Prochiral Ketones
689
stirring for 3 h, the reaction mixture was refluxed for 2 h. Then reaction mixture
was condensed under reduced pressure; the residue was washed with ethanol
and gave 2a. Yield: 88.8%; mp 158–1608C; [a]2D5 ¼ þ39.0 (c ¼ 2, C2H5OH).
(S)-Leucine Methyl Ester Hydrochloride (2b)
This compound was prepared by procedures similar to those for 2a. Yield:
96.33%; mp 149–1518C; [a]2D5 ¼ þ13.65 (c ¼ 2.0, H2O).
(S)-Methionine Methyl Ester Hydrochloride (2c)
This compound was prepared by procedures similar to those for 2a. Yield:
65.35%; mp 151–1538C; [a]2D5 ¼ þ21.6 (c ¼ 1.005, H2O).
(S)-2-Amino-1,1,3-triphenyl-1-propanol (3a)
(S)-Phenylalanine methyl ester hydrochloride (2.16 g, 10 mmol) was added
portionwise to freshly prepared Grignard reagent PhMgBr (80 mmol) in the
usual way under 08C and an argon atmosphere in diethyl ether. Then the
mixture was stirred at ambient temperature overnight, and cold saturated
NH4Cl was dropped into it under vigorous stirring. The mixture was
extracted with ethyl acetate three times. The combined organic layer was
washed with brine and dried with anhydrous Na2SO4, then concentrated in
vacuum. This residue was recrystallized with petroleum ether and gave 3a
as a colorless crystal. Yield: 65.3%; mp 144–1458C; [a]2D5 ¼ 288.9
(c ¼ 1.53, CH2Cl2) [lit.[9]: mp 144–1458C; [a]2D5 ¼ 288.5 (c ¼ 0.604,
CHCl3)].
(S)-2-Amino-1,1-dibenzyl-3-phenyl-1-propanol (3b)
Compound 3b was prepared using a procedure similar to that of 3a (Grignard
reagent PhCH2MgCl). After the usual workup, the residue was recrystallized
with ethyl acetate and petroleum ether and gave 3b as a colorless crystal.
Yield: 63.4%; mp 134–1368C; [a]2D5 ¼ þ23.5 (c ¼ 2.0, CHCl3); IR (KBr),
n: 3377, 3315, 3060, 3025, 2932, 1597, 1493, 1448, 1386, 1328, 1236,
1179, 1079, 1032, 878, 841, 753, 697 cm21 1H NMR: d 7.39–6.99
;
(m, 15H, Ph), 3.83 (br, 1H), 3.26–3.28 (q, J ¼ 1.8 Hz, J ¼ 13.2 Hz, 1H),
2.97–3.01 (m, 2H), 2.69–2.84 (m, 3H), 2.42–2.47 (dd, 1H), 1.02 (s, 2H).

690
Z. Zhou and Y. Guo
(S)-2-Amino-4-methyl-1,l-diphenyl-1-pentanol (3c)
Compound 3c was prepared using a procedure similar to that of 3a (Grignard
reagent PhMgBr). After the usual workup, the residue was recrystallized with
ethanol and gave 3c as a colorless crystal. Yield: 52.45%; mp 136–1388C;
[a]2D5 ¼ 296.6 (c ¼ 1.00, CHCl3) [lit.[9]: mp 132–1348C; [a]D¼295.12
(c ¼ 1.01, CHCl3)].
(S)-2-Amino-4-methyl-1,l-dibenzyl-1-pentanol (3d)
Compound 3d was prepared using a procedure similar to that of 3a (Grignard
reagent PhCH2MgCl). After the usual workup, the residue was recrystallized
with ethanol and gave 3d as a colorless crystal. Yield: 42.1%; mp 89–908C;
[a]2D5 ¼ þ17.44 (c ¼ 1.08, CHCl3); IR (KBr), n: 3402, 3354, 3062, 3024,
2863, 1601, 1494, 1455, 1405, 1323, 1241, 1185, 1157, 1085, 1046, 900,
1
856, 810, 753, 700 cm21; H NMR: d 7.49–7.17 (m, 10H), 3.92 (br, 1H),
2.88–2.81 (dd, J ¼ 5.1 Hz, 13.8 Hz, 4H), 2.69–2.60 (m, 2H), 1.70–
1.49 (m, 3H), 1.38–1.21 (m, 1H), 0.99 (d, J ¼ 6.6 Hz, 3H), 0.71
(d, J ¼ 6.6 Hz, 3H).
(S)-2-Amino-4-methylthio-1,l-diphenyl-1-butanol (3e)
Compound 3e was prepared using a procedure similar to that of 3a (Grignard
reagent PhMgBr). After the usual workup, the residue was recrystallized
with petroleum ether and gave 3e as a colorless crystal. Yield: 64.5%;
mp 94–968C; [a]2D5 ¼ 2110.55 (c ¼ 0.986, CHCl3) [lit.[9]: mp 96–988C;
[a]D ¼ 2108.57 (c ¼ 0.986, CHCl3)].
(S)-2-Amino-4-methylthio-1,l-dibenzyl-1-butanol (3f)
Compound 3f was prepared using a procedure similar to that of 3a (Grignard
reagent PhCH2MgCl). After the usual workup, the residue was recrystallized
with petroleum ether and gave 3f as a colorless crystal. Yield: 63.5%; mp
130–1348C; [a]2D5 ¼ 230 (c ¼ 0.60, CHCl3); IR (KBr), n: 3372, 3308,
3064, 3029, 2944, 2914, 2857, 1600, 1494, 1447, 1399, 1343, 1240, 1185,
1
1142, 1078, 1043, 963, 874, 817, 757, 703 cm21; H NMR: d 7.32–7.19
(m, 10H), 3.65 (br, 1H), 2.86 (d, J ¼ 14.1 Hz, 2H), 2.71 (d, J ¼ 13.8 Hz,
2H), 2.66–2.57 (m, 2H), 2.50–2.35 (m, 2H), 2.11 (s, 3H), 1.64–
1.53(m, 1H), 1.08 (br, 2H).

Asymmetric Reduction of Prochiral Ketones
691
(S)-2-(p-Toluenesulfonylamino)-1,1,3-triphenyl-1-propanol (4a)
p-Toluenesulfonyl chloride (5 mmol) in CH2Cl2 (10 mL) was added to a
stirred solution of triethylamine (2.1 mL, 15 mmol) and (S)-2-amino-1,1,3-tri-
phenylpropanol (1.52 g, 5.0 mmol) in CH2Cl2 (20 mL) at 08C over a 1 h
period. The reaction mixture was allowed to warm to room temperature and
stirred for an additional 24 h. The reaction mixture was diluted with CH2Cl2
(10 mL) and washed with 2 N HCl (2 ꢀ 5 mL), saturated aqueous NaHCO3
(3 ꢀ 10 mL), and brine (3 ꢀ 10 mL). The organic layer was dried over
anhydrous MgSO4, concentrated under reduced pressure, and recrystallized
from ethanol to afford the sulfonylated amino alcohol. Yield: 72.9%; mp
129–1328C (lit.[10]: mp 120–1218C); [a]D25 ¼ þ120.5 (c ¼ 0.518, CH2Cl2);
IR (KBr), n: 3526, 3364, 3062, 3030, 2929, 1599, 1494, 1449, 1314, 1148,
1087, 1058, 1035, 957, 909, 811, 745, 699, 670 cm21
.
(S)-2-(p-Toluenesulfonylamino)-1,1-dibenzyl-3-phenyl-1-propanol (4b)
Compound 4b was prepared using a procedure similar to that of 4a. Yield: 75.6%;
mp 167–1698C; [a]2D5 ¼ 2113.6 (c ¼ 0.494, CH2Cl2); IR (KBr), n: 3503, 3341,
3029, 2926, 1599, 1493, 1450, 1411, 1343, 1318, 1156, 1086, 1049, 949, 912,
811, 754, 701, 665 cm21; 1H NMR: d 7.41–6.43 (m, 19H), 4.22( d, J ¼ 8.1 Hz,
1H), 3.79 (s, 1H), 3.31–3.24 (m, 1H), 3.12–2.99 (m, 3H), 2.85–2.73 (m, 2H),
2.46–2.37 (m, 1H), 2.31 (s, 3H). Anal. calcd. for C30H31NO3S: C, 74.20%; H,
6.43%; N, 2.88%. Found: C, 74.13%; H, 6.51%; N, 2.79%.
(S)-2-(p-Toluenesulfonylamino)-4-methyl-1,l-diphenyl-1-pentanol (4c)
Compound 4c was prepared using a procedure similar to that of 4a. Yield:
78.8%; mp 197–2008C; [a]D25 ¼ þ14.6(c ¼ 0.520, CH2Cl2); IR (KBr), n:
3520, 3261, 3027, 2958, 2869, 1600, 1495, 1448, 1304, 1150, 1094, 1063,
;
1019, 974, 948, 910, 879, 810, 743, 699 cm21 1H NMR: d 7.47–7.11
(m, 14H), 4.58–4.51 (m, 2H), 2.93 (d, J ¼ 18.3 Hz, 1H), 2.37 (s, 3H),
1.59–1.55 (m, 1H), 1.38–1.21 (m, 2H), 0.89 (d, J ¼ 6 Hz, 3H),
0.74(d, J ¼ 6.6 Hz, 3H). Anal. calcd. for C25H29NO3S: C, 70.89%; H,
6.90%; N, 3.31%. Found: C, 70.98%; H, 6.93%; N, 3.26%.
(S)-2-(p-Toluenesulfonylamino)-4-methyl-1,l-dibenzyl-1-pentanol (4d)
Compound 4d was prepared using a procedure similar to that of 4a. Yield:
73.9%; mp 153–1558C; [a]D25 ¼ 221.4 (c ¼ 0.495, CH2Cl2); IR (KBr),
n: 3424, 3229, 3027, 2954, 2870, 1598, 1494, 1456, 1391, 1313, 1197,
;
1153, 1086, 1037, 1010, 957, 925, 811, 749, 701, 663 cm21 1H NMR:

692
Z. Zhou and Y. Guo
d 7.45–7.15 (m, 14H), 4.13 (s, br, 1H), 3.22–3.15 (m, 1H), 2.88–2.58
(m, 5H), 2.38 (s, 3H), 1.43–1.20 (m, 3H), 0.81 (d, J ¼ 6.6 Hz, 3H), 0.22
(d, J ¼ 5.1 Hz, 3H). Anal. calcd. for C27H33NO3S: C, 71.81%; H, 7.37%;
N, 3.10%. Found: C, 71.89%; H, 7.41%; N, 3.02%.
(S)-2-(p-Toluenesulfonylamino)-4-methylthio-1,l-diphenyl-1-
butanol (4e)
Compound 4e was prepared using a procedure similar to that of 4a. Yield:
37.8%; mp 128–1328C; [a]D25 ¼ þ38.8(c ¼ 0.520, CH2Cl2); IR (KBr), n:
3465, 3279, 3058, 3028, 2974, 2918, 2857, 1597, 1495, 1434, 1292, 1151,
;
1077, 1027, 986, 868, 815, 746, 700 cm21 1H NMR: d 7.51–7.11
(m, 14H), 5.00 (s, br, 1H), 4.62–4.56 (m, 1H), 3.05 (s, br, 1H), 2.39
(s, 3H), 1.83 (s, 3H), 1.68–1.57 (m, 2H), 1.37–1.32(m, 2H). Anal. calcd.
for C24H27NO3S2: C, 65.28%; H, 6.16%; N, 3.17%. Found: C, 65.17%;
H,6.08%; N, 3.23%.
(S)-2-(p-Toluenesulfonylamino)-4-methylthio-1,l-dibenzyl-1-
butanol (4f)
Compound 4f was prepared using a procedure similar to that of 4a. Yield:
71.1%; mp 124–1268C; [a]D25 ¼ 220.2 (c ¼ 0.516, CH2Cl2); IR (KBr), n:
3433, 3208, 3028, 2923, 1599, 1493, 1436, 1391, 1315, 1155, 1074, 978,
813, 753, 703, 662 cm21
;
1H NMR: d 7.38–7.14 (m, 14H), 4.23
(d, J ¼ 9 Hz, 1H), 3.12–3.06 (t, J ¼ 9 Hz, 1H), 2.86–2.68 (m, 4H), 2.44
(s, 1H), 2.38 (s, 3H), 2.15–2.08 (m, 1H), 1.99 (s, 3H), 1.92–1.83 (m, 2H),
1.72–1.61 (m, 1H). Anal. calcd. for C26H31NO3S2: C, 66.49%; H, 6.65%;
N, 2.98%. Found: C, 66.57%; H, 6.73%; N, 2.91%.
N-(1S)-(1-Benzyl-2-hydroxy-2,2-diphenyl-ethyl)-C-[(1S)-7,7-
dimethyl-2-oxo-bicyclo[2.2.1]hept-1-yl]-methanesulfonamide (4g)
A solution of (1S)-(þ)-10-camphorsulfonyl chloride (1.25 g, 5.0 mmol) in
CH2Cl2 (10 mL) was added to a stirred solution of triethylamine (2.1 mL,
15 mmol) and (S)-2-amino-1,1,3-triphenylpropanol (1.52 g, 5.0 mmol) in
CH2Cl2 (20 mL) at 08C over a 1-h period. The reaction mixture was
allowed to warm to room temperature and stirred for an additional 24 h.
The reaction mixture was diluted with CH2Cl2 (10 mL) and washed with
2 N HCl (2 ꢀ 5 mL), saturated aqueous NaHCO3 (3 ꢀ 10 mL), and brine
(3 ꢀ 10 mL). The organic layer was dried over anhydrous MgSO4, concen-
trated under reduced pressure, and recrystallized from ethanol to afford the
sulfonamide. Yield: 58%; mp 173–1748C; [a]2D5 ¼ þ50 (c ¼ 2.0, CH2Cl2);

Asymmetric Reduction of Prochiral Ketones
693
IR (KBr), n: 3333, 3273, 2951, 1739, 1490, 1443, 1320, 1142, 1063, 969, 747,
1
697 cm21; H NMR: d 7.67–7.13 (m, 15H), 5.23 (d, J ¼ 9.3 Hz, 1H), 5.00
(m, 1H), 3.22 (br, 1H), 2.99 (d, J ¼ 14.1 Hz, 1H), 2.79 (dd, J ¼ 8.7,
14.1 Hz, 1 H), 2.28 –1.61 (m, 8H), 1.35–1.28 (m, 1H), 0.79 (s, 3H), 0.49
(s, 3H). Anal. calcd. for C31H35NO4S: C, 71.92%; H, 6.82%; N, 2.71%.
Found: C, 71.77%; H, 6.89%; N, 2.82%.
N-(1S)-(1,2,2-Tribenzyl-2-hydroxy-ethyl)-C-[(1S)-7,7-dimethyl-2-
oxo-bicyclo[2.2.1]hept-1-yl]-methanesulfonamide (4h)
Compound 4h was prepared using a procedure similar to that of 4g. Yield:
66.1%; mp 136–1388C; [a]2D5 ¼ þ16.2(c ¼ 1.1, CHCl3); IR (KBr), n: 3504,
3261, 3061, 3026, 2957, 1744, 1604, 1494, 1454, 1372, 1310, 1143, 1049,
1
964, 754, 703 cm21; H NMR: d 7.43–6.96 (m, 15H), 4.61 (d, J ¼ 9.6 Hz,
1H), 3.62 (m, 1H), 3.48 (dd, J ¼ 7.2, 14.4 Hz, 4H), 3.28 (d, 1H), 3.04
(d, J ¼ 13.8 Hz, 2H), 2.87 (dd, J ¼ 7.2, 14.4 Hz, 2H), 2.58 (dd, J ¼ 1.8,
11.4 Hz, 2H), 2.27(d, 1H), 2.06–1.79 (m, 2H), 1.46–1.40 (m, 1H), 1.22–
1.19 (m, 1H), 0.84 (s, 3H), 0.64 (s, 3H). Anal. calcd. for C33H39NO4S: C,
72.63%; H, 7.20%; N, 2.57%. Found: C, 72.54%; H, 7.15%; N, 2.61%.
N-(1S)-[1-(2-Methyl)propyl-2-hydroxy-2,2-diphenyl-ethyl]-C-[(1S)-
7,7-dimethyl-2-oxo-bicycle[2.2.1]hept-1-yl]-methanesulfonamide (4i)
Compound 4i was prepared using a procedure similar to that of 4g. Yield:
69.01%; mp 202–2048C; [a]2D5 ¼ þ9.30 (c ¼ 0.978, CHCl3); IR (KBr), n:
3447, 3373, 2957, 1723, 1449, 1326, 1143, 1071, 1020, 990, 804, 748,
1
701 cm21; H NMR: d 7.60 (d, J ¼ 8.1 Hz, 2H), 7.44 (d, J ¼ 7.5 Hz, 2H),
7.26–7.06 (m, 6H), 5.05 (d, J ¼ 9 Hz, 1H), 4.84–4.77 (m, 1H), 3.19
(s, 1H), 2.25–1.76 (m, 6H), 1.53 (s, 2H), 1.43–1.06 (m, 4H), 0.98
(d, J ¼ 5.7 Hz, 3H), 0.79 (d, J ¼ 6.6 Hz, 3H), 0.75 (s, 3H), 0.45 (s, 3H).
Anal. calcd. for C28H37NO4S: C, 69.52%; H, 7.72%; N, 2.90%. Found: C,
69.59%; H, 7.75%; N, 2.83%.
N-(1S)-[1-(2-Methyl)propyl-2-hydroxy-2,2-dibenzyl-ethyl]-C-[(1S)-
7,7-dimethyl-2-oxo-bicycle[2.2.1]hept-1-yl]-methanesulfonamide (4j)
Compound 4j was prepared using a procedure similar to that of as 4g. Yield:
52.18%; mp 149–1518C; [a]2D5 ¼ þ51.82 (c ¼ 0.961 CHCl3); IR (KBr), n:
3452, 3353, 3269, 2952, 1732, 1602, 1494, 1452, 1322, 1278, 1136, 1050,
;
1004, 964, 933, 820, 754, 702 cm21 1H NMR: d 7.34–7.21 (m, 10H),
5.24 (d, J ¼ 9 Hz, 1H), 3.77 (d, J ¼ 15.3 Hz, 1H), 3.63–3.56 (dd,
J ¼ 8.7 Hz, 14.1 Hz,1H), 3.01–2.94 (m, 2H), 2.84–2.68 (m, 3H), 2.57

694
Z. Zhou and Y. Guo
(s, 1H), 2.44–2.38 (m, 1H), 2.19–1.81 (m, 6H), 1.59 (s, 1H), 1.49–1.39
(m, 2H), 0.99 (s, 3H), 0.98 (d, J ¼ 6 Hz, 3H), 0.92 (s, 3H), 0.74
(d, J ¼ 6.3 Hz, 3H). Anal. calcd. for C30H41NO4S: C, 70.40%; H, 8.08%;
N, 2.75%. Found: C, 70.29%; H, 8.01%; N, 2.79%.
N-(1S)-[1-(2-Methylthio)ethyl-2-hydroxy-2,2-diphenyl-ethyl]-C-
[(1S)-7,7-dimethyl-2-oxo-bicycle[2.2.1]hept-1-yl]-
methanesulfonamide (4k)
Compound 4k was prepared using a procedure similar to that of 4g. Yield:
66.5%; mp 153–1558C; IR (KBr), n: 3477, 3272, 3060, 2961, 1789, 1493,
1447, 1317, 1145, 1058, 987, 860, 753, 702 cm21 1H NMR: d 7.66
;
(d, J ¼ 8.1 Hz, 2H), 7.55 (d, J ¼ 8.1 Hz, 2H), 7.34–7.14 (m, 6H), 5.48–
5.39 (m, 1H), 4.97–4.92 (m, 1H), 3.46–3.32 (m, 1H), 2.79–2.64 (m, 2H),
2.43–2.08 (m, 4H), 2.00 (s, 3H), 1.92–1.68 (m, 4H), 1.59 (s, 2H),1.40–
1.31 (m, 1H), 0.83 (s, 3H), 0.53 (s, 3H). Anal. calcd. for C27H35NO4S2: C,
64.64%; H, 7.03%; N, 2.79%. Found: C, 64.51%; H, 7.07%; N, 2.84%.
N-(1S)-[1-(2-Methylthio)ethyl-2-hydroxy-2,2-dibenzyl-ethyl]-C-
[(1S)-7,7-dimethyl-2-oxo-bicycle[2.2.1]hept-1-yl]-
methanesulfonamide (4l)
Compound 4l was prepared using procedure similar to that of 4g. After the usual
workup, the residue was recrystallized with ethyl acetate and petroleum ether
and gave 4l as a colorless crystal. Yield: 63.01%; mp 130–1318C;
[a]2D5 ¼ þ12.81 (c ¼ 0.960, CHCl3); IR (KBr), n: 3464, 3349, 3270, 3062,
3029, 2952, 1729, 1603, 1494, 1445, 1395, 1322, 1281, 1245, 1138, 1078,
1
1048, 971, 909, 851, 815, 758, 703 cm21; H NMR: d 7.35–7.17 (m, 10H),
5.48 (d, J ¼ 9.3 Hz, 1H), 3.73 (d, J ¼ 15.3 Hz, 1H), 3.46 (t, J ¼ 9.6 Hz, 1H),
2.99–2.87 (m, 2H), 2.80–2.73 (m, 3H), 2.52 (s, 1H), 2.47–2.39 (m, 2H),
2.15 (s, 3H), 2.12–1.91 (m, 5H), 1.76–1.70 (m, 1H), 1.59 (s, 2H), 1.47–1.40
(m, 1H), 0.95 (s, 3H), 0.90 (s, 3H). Anal. calcd. for C29H39NO4S2: C,
65.75%; H, 7.42%; N, 2.64%. Found: C, 65.66%; H, 7.34%; N, 2.73%.
N-(1S)-(1-Benzyl-2-hydroxy-2,2-diphenyl-ethyl)-C-[(1S,2R)-7,7-
dimethyl-2-hydroxyl-bicyclo[2.2.1]hept-1-yl]-methanesulfonamide (5a)
Compound 4g (3 mmol) was dissolved in a 1:1 mixture of ethanol and THF
(30 mL), and NaBH4 (0.78 g, 21 mmol) was added portionwise over 5 min
at 2158C. The reaction mixture was stirred for 10 h at 2158C, and then
quenched carefully with saturated NH4Cl (20 mL). After the organic solvent
was removed in vacuo, the residue was extracted with CHCl3 (3 ꢀ 20 mL).

Asymmetric Reduction of Prochiral Ketones
695
The organic layer was dried over anhydrous Na2SO4, concentrated under
reduced pressure, and recrystallized from ethyl acetate to afford the sulfona-
mide. Yield: 84.7%; mp 94–968C; [a]2D5 ¼ þ45 (c ¼ 1.0, CH2Cl2); IR
(KBr), n: 3471, 3399, 2930, 1494, 1448, 1295, 1135, 1061, 1030, 977, 743,
1
700 cm21; H NMR: d 7.61–7.14 (m, 15H), 4.76 (br, 1H), 4.62 (br, 1H),
3.88 (dd, J ¼ 4.2, 8.4 Hz, 1H), 3.72 (dd, J ¼ 7.2, 14.4 Hz, 1H), 3.15 (dd,
J ¼ 3, 14.4 Hz, 1H), 2.81 (dd, J ¼ 8.4, 14.4 Hz, 1H), 2.35 (d, J ¼ 14.4 Hz,
1H), 1.83–1.46 (m, 4H), 1.45–1.31 (m, 2H), 1.25–1.19 (m, 2H), 1.01–0.97
(m, 1H), 0.79 (s, 3H), 0.54 (s, 3H). Anal. calcd. for C31H37NO4S: C,
71.65%; H, 7.18%; N, 2.70%. Found: C, 71.77%; H, 7.23%; N, 2.65%.
N-(1S)-(1,2,2-Tribenzyl-2-hydroxy-ethyl)-C-[(1S,2R)-7,7-dimethyl-
2-hydroxyl-bicyclo[2.2.1]hept-1-yl]-methanesulfonamide (5b)
Compound 5b was prepared from 4h using a procedure similar to that of 5a.
After the usual workup, the residue was recrystallized with methanol and gave
5b as a colorless crystal. Yield: 69.2%; mp 214–2168C; [a]2D5 ¼ 2 32.5
(c ¼ 1.1, CHCl3); IR (KBr), n: 3497, 3263, 3063, 3025, 2947, 1493, 1452,
1
1360, 1305, 1132, 1073, 1048, 960, 753, 701 cm21; H NMR: d 7.49–6.94
(m, 15H), 3.88 (m, 1H), 3.72 (dd, J¼ 4.2, 7.8 Hz, 1H), 3.26 (dd, J ¼ 3,
7.8 Hz, 1H), 3.32 (br, 1H), 3.11(d, J ¼ 14.4 Hz, 1H), 2.97–2.89 (m, 3H),
2.62 (m, 1H), 1.92 (d, J ¼ 14.4 Hz, 2H), 1.60–1.53 (m, 6H), 1.38–1.32
(m, 1H), 1.21–1.17 (m, 1H), 0.99–0.93 (m, 1H), 0.64 (s, 3H), 0.43 (s, 3H).
Anal. calcd. for C33H41NO4S: C, 72.36%; H, 7.55%; N, 2.56%. Found: C,
72.45%; H, 7.61%; N, 2.48%.
General Procedure for the Catalytic Reduction of Prochiral
Ketones
The following procedure for the asymmetric reduction of acetophenone is
.
representative. Under a nitrogen atmosphere, freshly distilled BF3 Et2O
(0.4 mL, 3.2 mmol) in THF (5 mL) was added dropwise to a suspension of
NaBH4 (91 mg, 2.4 mmol) in dry THF (10 mL) at 08C. After the mixture
was stirred at 08C for 0.5 h and allowed to warm to refluxing temperature, a
solution of 4a (0.2 mmol) in THF (5 mL) was added dropwise. After
refluxing for 1.5 h, a solution of acetophenone (240 mg, 2 mmol) in THF
(4 mL) was added dropwise over 3 h at the same temperature. After
refluxing for another hour, the reaction mixture was cooled to 08C and
quenched with 5 mL of saturated ammonium chloride solution. Ethyl
acetate (3 ꢀ 10 mL) was added to extract the product, and the organic layer
was separated. The combined organic layers were washed with brine, and
dried with sodium sulfate. After removal of the solvent by distillation, chrom-
atography of the residue afforded the chiral alcohol.

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Z. Zhou and Y. Guo
ACKNOWLEDGMENT
Financial support of this work by the Natural Science Foundation of Hubei
Province (2007ABA291) is gratefully acknowledged.
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