Efficient Lipase-Catalyzed Kinetic Resolution and Dynamic Kinetic Resolution of β-Hydroxy Nitriles. Correction of Absolute Configuration and Transformation to Chiral β-Hydroxy Acids and γ-Amino Alcohols

Article abstract of DOI:10.1002/1615-4169(200210)344:9<947::AID-ADSC947>3.0.CO;2-Z

Chemoenzymatic dynamic kinetic resolution of β-hydroxy nitriles 1 has been carried out using Candida antarctica lipase B and a ruthenium catalyst. The use of a hydrogen source to depress ketone formation in the dynamic kinetic resolution yields the corresponding acetates 2 in good yield and high enantioselectivity. It is shown that the ruthenium catalyst and the enzyme can be recycled when used in separate reactions. We also report on the preparation of various enantiomerically pure β-hydroxy acid derivatives and γ-amino alcohols from 1 and 2. The latter compounds were also used to establish the correct absolute configuration of 1 and 2.

Full text of DOI:10.1002/1615-4169(200210)344:9<947::AID-ADSC947>3.0.CO;2-Z

UPDATES
Efficient Lipase-Catalyzed Kinetic Resolution and Dynamic
Kinetic Resolution of b-Hydroxy Nitriles. Correction of Absolute
Configuration and Transformation to Chiral b-Hydroxy Acids
and g-Amino Alcohols
¡
Oscar Pamies, Jan-E. B‰ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
Fax: ( ‡ 46)-8-154908, e-mail: jeb@organ.su.se
Received: May 21, 2002; Accepted: July 4, 2002
Dedicated to Roger A. Sheldon on the occasion of his 60th birthday.
OH
Abstract: Chemoenzymatic dynamic kinetic resolu-
X
tion of b-hydroxy nitriles 1 has been carried out
R
using Candida antarctica lipase B and a ruthenium
catalyst. The use of a hydrogen source to depress
ketone formation in the dynamic kinetic resolution
yields the corresponding acetates 2 in good yield and
HO
OH
O
high enantioselectivity. It is shown that the ruthe-
O
nium catalyst and the enzyme can be recycled when
used in separate reactions. We also report on the
preparation of various enantiomerically pure b-
hydroxy acid derivatives and g-amino alcohols
from 1 and 2. The latter compounds were also used
to establish the correct absolute configuration of 1
and 2.
R
R
OR'
OR'
n
n
n = 0,1
OH
OH
n = 2,3
N3
CN
R
R
Scheme 1. Dynamic kinetic resolution of functionalized
alcohols with efficient use of all racemate.
In a recent publication[5d] we reported on the kinetic
resolution (KR) of b-hydroxy nitriles (Scheme 1, X ˆ
CN) and gave a few examples of dynamic kinetic
resolution (DKR). These compounds are potentially
valuable for the synthesis of natural products and
biologically active compounds. During the course of
our studies on further functionalization of these enantio-
merically pure nitriles we found that the absolute
Keywords: g-amino alcohols; dynamic kinetic reso-
lution; b-hydroxy acids; kinetic resolution; ruthenium
Introduction
During the last decade dynamic kinetic resolution configuration of the b-hydroxy nitriles 1 and b-acetoxy
(DKR) has become an active and important area of nitriles 2 obtained via the lipase-catalyzed esterification
research in organic synthesis.[1] DKR is a powerful tool were erroneously assigned.[6] We now report on the
to prepare enantiomerically enriched compounds in determination of the correct stereochemistry for 1 and 2
high yields that overcomes the limitation of the and provide a complete study of the DKR reaction with
maximum 50% yield in the traditional kinetic resolu- additionalexamplesandnewprotocols. Wealsoreporton
tion (KR).[2] We have recently developed a simple the preparation of various enantiomerically pure b-
approach to perform DKR of alcohols in which the hydroxy acid derivatives 8 and g-amino alcohols 9 from
traditional enzymatic kinetic resolution is combined the corresponding b-hydroxy nitriles.
with an in situ racemization of the substrate using a
ruthenium-based hydrogen transfer catalyst.[3]
The importance of optically active amino alcohols and
Results and Discussion
hydroxy acid derivatives as versatile building blocks in
both asymmetric synthesis and medicinal chemistry is
Kinetic Resolution and Dynamic Kinetic Resolution
well established.[4] Recently, we have applied our DKR
approach to the preparation of these valuable com- The kinetic resolutions of various b-hydroxy nitriles 1
pounds (Scheme 1).[5]
using the acyl donor p-chlorophenyl acetate 3 and
Adv. Synth. Catal. 2002, 344, No. 9
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1615-4150/02/34409-947 952 $ 17.50+.50/0
947

¡
Oscar Pamies, Jan-E. B‰ckvall
UPDATES
Table 1. Lipase-catalyzed kinetic resolution of rac-1.[a]
OH
OAc
OH
CN
3 / N-435
R
CN
CN
R
R
+
Toluene
(rac)-1a-k
2a-k
1a-k
Entry
Substrate
R
Time [h]
% Conv. of 1[b]
% ee of 2[c]
% ee of 1[c]
E[d]
1
2
3
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
24
16
12
36
60
20
6
6
3
36
6
50
50
50
50
43
51
49
52
49
49
51
>99 (R)
>99 (R)
>99 (R)
99 (R)
89 (R)
97 (R)
91 (S)
95 (R)
96 (R)
>99 (R)
94 (S)
>99 (S)
>99 (S)
>99 (S)
>99 (S)
77 (S)
>1000
>1000
>1000
>1000
40 Æ 1
220 Æ 10
61 Æ 2
197 Æ 7
225 Æ 15
840 Æ 40
148 Æ 6
p-MeO-C6H4
p-NO2-C6H4
2-Naphthyl
2-Furyl
3-Pyridyl
Benzyl
4
5[e]
6
> 99 (S)
88 (R)
7
8[e]
9[e]
10
11
PhOCH2
99 (S)[f]
98 (S)
1-Naphthyl-OCH2
Cyclohexyl
CH3-(CH2)7-
1j
1k
97 (S)
98 (R)
[a]
Conditions: 0.2 mmol of rac-1, 0.6 mmol of 3, 20 mg of Candida antarctica lipase B (N-435) and 2 mL toluene at 60 8C.
% conversion measured by NMR.
Enantiomeric excess determined by GC or HPLC. Absolute configuration shown in parenthesis.
Enantiomeric ratio.
[b]
[c]
[d]
[e]
Tˆ 30 8C.
Novozym 435 (Candida antarctica lipase B) are given in 1. The addition of 0.5 equivalents of 2,4-dimethyl-3-
Table 1. The experimental details for this procedure is pentanol 6 to the reaction mixture reduced the amount
given in ref. [5d]. The correct absolute configurations, of ketone 5a considerably (11%), moreover it improved
established via derivatization (vide infra) are given in the yield of acetate 2a (entry 8). The use of hydrogen gas
Table 1.
(1 bar) inhibited the formation of ketone almost
The dynamic kinetic resolutions were carried out at completely (4%), but the DKR under these conditions
100 8C using ruthenium catalyst 4 as racemization gave the acetate in low enantioselectivity (87% ee,
chemocatalyst, Novozym 435 (N-435) as transesterifi- entry 9). This is mainly due to a decrease of the
cation biocatalyst, and p-chlorophenyl acetate 3 as acyl racemization rate under 1 bar of hydrogen gas.
donor.[7] The DKR of various b-cyano-a-phenethyl
In previous studies we have shown that by reducing
alcohols 1a c gave the corresponding acetates 2 in the enzyme/ruthenium catalyst ratio the enzymatic
good yields and enantioselectivities (Table 2, entries 1 acylation becomes the rate-determining step and the
3). The DKR of 3-hydroxy-3-(2-naphthyl)-propaneni- enantioselectivity can therefore substantially im-
trile 1d under these conditions also gave enantiopure proved.[5c] Therefore, the DKR of 3-hydroxy-4-(phe-
acetoxy nitrile 2d in high enantioselectivity (entry 4). nyloxy)-butanenitrile 1h using 5 mg N-435/mmol prod-
However, the formation of large amounts of the uct and 4 mol % 4 at 100 8C improved the enantiose-
corresponding ketone 5, formed during the hydrogen lectivity (entry 13).[8]
À
transfer process, was observed for substrates 1a d. For
We then turned our attention to investigate the
the 3-hydroxyundecanenitrile 1k, the DKR under the possibility of recycling both the catalyst 4 and the
conditions used for 1a d (i.e., 100 mg N-435/mmol enzyme. To study the reuse of enzyme, the recovered
product, 100 8C, 4 mol % 4) gave the acetates in good enzyme from the DKR of 1a (Table 2, entry 7) was
yields and enantioselectivity (Table 2, entry 7). How- employed in a KR of 1a under the conditions described
ever, for the 3-hydroxy-4-(aryloxy)-butanenitriles 1h in Table 1. Only traces of acetate 2a were observed on
and 1g low enantioselectivity was achieved (Table 2, the GC after 24 h. However, the recovered enzyme from
entries 5 and 6). This is attributed to the lower the KR (Table 1, entry 1) could be reused in the KR of
enantiopreference of the enzyme for these substrates 1a more than three times.[9] To study the reuse of catalyst
at this temperature.
4, we applied the catalyst 4 in the repetitive racemization
Several attempts to increase the efficiency of the process of (S)-1a. On completion of the racemization of
process by reducing the amount of ketone for substrates (S)-1a, the reaction was cooled, additional aliquots of
À
1a d have been carried out. Thus, hydrogen gas and 2,4- (S)-1a and proton source 6 were added, and racemiza-
dimethyl-3-pentanol 6 were tested as hydrogen sources tion was repeated. Up to 3 cycles were carried out
with the aim to push the equilibrium back to the alcohol without addition of more catalyst. From these results, it
948
Adv. Synth. Catal. 2002, 344, 947 952

Lipase-Catalyzed Kinetic and Dynamic Kinetic Resolution of b-Hydroxy Nitriles
Table 2. Dynamic kinetic resolution (DKR) of rac-1.[a]
UPDATES
Entry
Substrate
R
Time [h]
% of 2[b]
% ee of 2[c]
% of 5[b]
1
2
3
4
5
6
7
1a
1b
1c
1d
1h
1g
1k
1a
1a
1b
1c
1d
1h
Ph
36
36
36
36
36
36
36
36
36
36
36
36
36
74
81
72
78
98
95
93
85
72
86
80
82
73
97 (R)
99 (R)
96 (R)
94 (R)
36 (R)
44 (R)
92 (S)
97 (R)
87 (R)
97 (R)
94 (R)
91 (R)
74 (R)
23
19
26
21
2
3
4
11
4
8
p-MeO-C6H4
p-NO2-C6H4
2-Naphthyl
PhOCH2
1-Naphthyl-OCH2
CH3-(CH2)7-
Ph
8[d]
9[e]
10[d]
11[d]
12[d]
13[f]
Ph
p-MeO-C6H4
p-NO2-C6H4
2-Naphthyl
PhOCH2
13
14
1
[a]
Conditions: 0.2 mmol of rac-1a, 0.6 mmol of 3, 20 mg of Candida antarctica lipase B (N-435), 4 mol % of 4 and 2 mL
toluene at 100 8C.
% yield measured by NMR.
Optical purity measured by GC or HPLC. Absolute configuration shown in parenthesis.
0.1 mmol of 6 added.
Reaction performed under 1 bar of hydrogen gas.
5 mg of enzyme used.
[b]
[c]
[d]
[e]
[f]
is easy to envisage the synthesis of a wide range of b-
The hydrolysis of enantiomerically pure acetate 2a
acetoxy nitriles 2 from the corresponding b-hydroxy could be achieved by using NaHCO3/MeOH and KCN/
nitriles 1 in a two-step manner by combining the MeOH. However, in both cases small amounts of
racemization of 1 at 100 8C with the enzymatic KR at elimination product (5 10%) were obtained. Surpris-
lower temperature without sacrificing the enzyme.[10]
ingly, the enantiopurity dropped considerably. We then
decided to use the lipase-catalyzed hydrolysis of acetate
2a using different lipases (PS-C, N-435, AK) under the
conditions described by Itoh et al. (pH ˆ 7, 35 8C).[6] To
our surprise, the enantiopurity of the alcohol obtained
Hydrolysis of b-Acetoxy Nitriles
In a first set of experiments we studied the hydrolysis of dropped considerably, i.e., 1a was obtained in quantita-
compounds 2a, 2d, 2h and 2i using LiOH in methanol. tive yield and 86% ee by using lipase-AK.
As expected the reaction with substrates 1a and 1d led
predominantly to the elimination of the acetate group to
form exclusively 3-phenyl- and 3-naphthyl-2-propene- Synthesis of b-Hydroxy Acids and b-Amino Alcohols
nitriles 7, respectively. However, the reaction proceeds
smoothly for substrates 2h and 2i and with total In a first set of experiments, the basic hydrolysis of the b-
retention of configuration (Scheme 2).
hydroxy nitriles 1 was carried out using NaOH in H2O/
EtOH. Under these conditions, the reaction proceeded
fast, but several by-products were observed by NMR.
The addition of H2O2 inhibited the formation of the
byproducts, yielding the corresponding b-hydroxy acids
8 in good yields (Scheme 3). Compounds 8h and 8i can
also be obtained from the corresponding b-acetoxy
nitriles 2h and 2i, since under these conditions the
acetate is also hydrolyzed.
OAc
LiOH
CN
7a, 7d
CN
R
O
MeOH
R
2a R= Phenyl
2d R= 2-Naphthyl
LiOH
OAc
OH
O
CN
CN
Aseries of b-amino alcohols 9 were prepared by
borane reduction of the corresponding nitriles 1
(Scheme 4).
MeOH
R
R
2h R= Phenoxymethyl
2i R= 1-Naphthoxymethyl
1c, 1d
Scheme 2.
Adv. Synth. Catal. 2002, 344, 947 952
949

¡
Oscar Pamies, Jan-E. B‰ckvall
UPDATES
enantiomerically pure (R)-2-cyano-1-phenylethyl ace-
tate (R)-2a, [a]D23: ‡ 69.9 (c 1.1, CHCl3)[13] and unreacted
OH
O
OH
NaOH (3 M)
H2O2 (30%)
CN
R
OH
R
23
[14]
20
À
À
À
the S-( )-1a, [a]D : 57.9 (c 2.6, EtOH), lit. [a]D : 57.7
(c 2.6, EtOH, 96% ee).
8a 93%
8d 95%
8h 90%
8i 95%
1a R= Phenyl
1d R= 2-Naphthyl
1h R= Phenoxymethyl
1i R= 1-Naphthoxymethyl
Scheme 3.
Conclusion
OH
OH
.
1) BH3
SMe2 / THF
Acomplete study of the chemoenzymatic DKR of b-
hydroxy nitriles using Candida antarctica lipase B
(CALB) as transesterification biocatalyst and rutheni-
um catalyst 4 as racemization chemocatalyst has been
carried out. The study indicates that the efficiency of the
process can be increased by: (i) using 2,4-dimethyl-3-
pentanol 6 as a mild hydrogen source to depress ketone
formation during the DKR of aryl-substituted b-
hydroxy nitriles, and (ii) reducing the enzyme/rutheni-
um catalyst ratio to improve the enantioselectivity for
substrates for which the enzyme shows low enantio-
meric ratio. The absolute configuration of the b-hydroxy
and b-acetoxy nitriles, established by transformation to
enantiomerically pure b-hydroxy acid derivatives 8 and
g-amino alcohols 9, shows that the enzymatic reactions
follow Kazlauskas× rule[2] with CH2CN being accepted as
the small group by CALB.
CN
R
NH2
R
2) HCl in MeOH
9a 98%
9d 95%
9h 88%
9i 91%
1a R= Phenyl
1d R= 2-Naphthyl
1h R= Phenoxymethyl
1i R= 1-Naphthoxymethyl
Scheme 4.
Determination of the Absolute Configuration
The absolute configuration of the optically active
products 1a and 2a was determined, on the basis of the
recovered unreacted alcohol from the kinetic resolution
of (rac)-1a, by two independent methods (Scheme 5).
OH
Ph
NH2
OH
(−)-9a
CN
Ph
(−)-1a
OH O
Experimental Section
Ph
OH
Scheme 5.
(−)-8a
General Remarks
*
Method 1: The unreacted enantiomerically pure
Solvents were purified by standard procedures. All other
reagents are commercially available and were used without
further purification. 1H and 13C NMR spectra were recorded in
CDCl3 at 400 and 100 MHz, respectively. Solvents for
extraction were technical grade and distilled before use.
Kinetic resolution and dynamic kinetic resolution of com-
pounds 1 were carried out as described in ref. [5d].
À
( )-1a was reduced using borane ¥ methyl sulfide com-
À
plex to the corresponding ( )-3-phenyl-3-hydroxypro-
À
pylamine [( )-9a] (vide supra). The product obtained
was compared with a sample of enantiomerically pure
(S)-( )-9a obtained from (R)-styrene oxide by regiose-
À
lective epoxide ring opening with cyanide followed by
borane reduction.[11]
*
Method 2: The unreacted enantiomerically pure
À
Racemization of (S)-1a
( )-1a was converted into the corresponding hydroxy
À
À
acid ( )-3-hydroxy-3-phenylpropanoic acid [( )-8a] by
To a solution of (S)-1a (29.4 mg, 0.2 mmol), 6 (14 mL,
0.1 mmol) in toluene (2 mL) ruthenium catalyst 4 (10.85 mg,
4 mol %) was added. The resulting reaction mixture was stirred
at 100 8C for 30 h under argon.
treatment with NaOH (3 M) and H2O2 (30%) (vide
supra). The optical rotation was compared with com-
[12]
À
mercially available (S)-( )-8a.
Thus, in accordance with the Kazlauskas rule[2] the R-
enantiomer of the alcohol reacts faster than the S-
enantiomer (Scheme 6) yielding, for hydroxy nitrile 1a,
General Procedure for the Hydrolysis of 2c and 2d
In a typical experiment, LiOH (19 mg, 0.8 mmol) was added to
a solution of 2-cyano-1-(phenoxymethyl)ethyl acetate 2c
(75 mg, 0.4 mmol) in methanol (2 mL). The mixture was
stirred for 1 h, and then saturated ammonium chloride solution
(10 mL) was added. The mixture was evaporated, and then
extracted with diethyl ether (3 Â 25 mL). The combined ether
phases were dried over Na2SO4 and evaporated to give alcohol
1c as a colorless oil; yield: 58 mg (99%).
OH
OAc
OH
Candida antarctica
CN
CN
CN
+
Ph
Ph
Ph
p-Cl-C6H4-OAc
(rac)-1a
(R)-2a
(S)-1a
50% (99% ee)
50% (99% ee)
Scheme 6. Lipase-catalyzed transesterification of b-hydroxy
nitrile 1a.
950
Adv. Synth. Catal. 2002, 344, 947 952

Lipase-Catalyzed Kinetic and Dynamic Kinetic Resolution of b-Hydroxy Nitriles
UPDATES
3.09 (m, 1H, CH2-N), 5.34 (dd, 1H, CH, 3JH-H ˆ 8.7 Hz, 3JH-H
ˆ
General Procedure for the Preparation of b-Hydroxy
Acids
3.3 Hz), 7.45 (m, 3H, CH ), 7.83 (m, 4H, CH ); 13C NMR: d ˆ
ˆ
ˆ
ˆ
ˆ
39.8 (CH2), 40.8 (CH2), 75.8 (CH), 124.3 (CH ), 124.4 (CH ),
(S)-3-Hydroxy-3-phenylpropanoic acid [(S)-8a]: In a two-
necked round-bottomed flask equipped with a condenser
were placed (S)-3-hydroxy-3-phenyl-propanenitrile 1a (74 mg,
0.5 mmol), 3.7 mL of NaOH (3 M), and 1.3 mL of H2O2 (30%).
The reaction mixture was heated at 70 8C for 1 h and 1 h at
90 8C and cooled to room temperature. The solution was
washed once with ether (3 mL). The aqueous solution was
acidified with 2 M HCl (10 mL), and then extracted with
dichloromethane (3 Â 20 mL) The combined ether phases
were dried over Na2SO4 and evaporated to give hydroxy acid
(S)-8a as a pale yellow solid; yield: 77 mg (93%). The NMR
data are in agreement with those previously reported.[15] [a]D23:
ˆ
ˆ
ˆ
ˆ
125.7 (CH ), 126.1 (CH ), 127.8 (CH ), 128.1 (CH ), 128.2
ˆ
(CH ), 132.9 (C), 133.6 (C), 142.8 (C).
1
(S)-4-Amino-1-phenoxy-2-butanol [(S)-9h]: H NMR: d ˆ
1.68 (m, 1H, CH2), 1.81 (m, 1H, CH2), 2.79 (bs, 3H, NH2, OH),
2.94 (m, 1H, CH2-N), 3.16 (m, 1H, CH2-N), 3.89 (dd, 1H, CH2-
O, 3JH-H ˆ 9.2 Hz, 3JH-H ˆ 3.6 Hz), 3.94 (dd, 1H, CH2-O, 3JH-H
ˆ
9.2 Hz, 3JH-H ˆ 5.6 Hz), 4.20 (m, 1H, CH), 6.92 (m, 3H, CH ),
ˆ
7.27 (m, 2H, CH ); 13C NMR: d ˆ 34.3 (CH2), 40.5 (CH2), 71.3
ˆ
ˆ
(CH2-O or CH-O), 72.0 (CH2-O or CH-O), 114.8 (CH ), 121.1
ˆ
ˆ
(CH ), 129.7 (CH ), 159.0 (C).
(S)-4-Amino-1-(2-naphthyloxy)-2-butanol
[(S)-9i]:
1H NMR: d ˆ 1.76 (m, 1H, CH2), 1.89 (m, 1H, CH2), 2.90 (b,
4H, NH2, OH, CH2-N), 3.20 (m, 1H, CH2-N), 4.05 (dd, 1H,
CH2-O, 3JH-H ˆ 9.3 Hz, 3JH-H ˆ 6.0 Hz), 4.15 (dd, 1H, CH2, 3JH-
[10]
20
À
À
21.9 (c 4, MeOH) [lit. [a]D : 22.5 (c 4, MeOH)].
(S)-3-Hydroxy-3-(1-naphthyl)propanoic acid [(S)-8d]:
1H NMR: d ˆ 2.87 (d, 1H, CH2, JH-H ˆ 16.4 Hz, JH-H
ˆ
3
3
ˆ 9.3 Hz, 3JH-H ˆ 5.1 Hz), 4.37 (m, 1H, CH), 6.82 (d, 1H, CH ,
ˆ
H
3
3
3
4.0 Hz), 2.94 (dd, 1H, CH2, JH-H ˆ 16.4 Hz, JH-H ˆ 9.2 Hz),
5.34 (dd, 1H, CH, 3JH-H ˆ 9.2 Hz, 3JH-H ˆ 4.0 Hz), 7.52 (m, 3H,
ˆ
ˆ
JH-H ˆ 7.5 Hz), 7.46 (m, 4H, CH ), 7.78 (m, 1H, CH ), 8.26 (m,
1H, CH ); 13C NMR: d ˆ 34.8 (CH2), 40.5 (CH2), 71.4 (CH2-O
ˆ
CH ), 7.85 (m, 4H, CH ); 13C NMR: d ˆ 43.0 (CH2), 70.5
ˆ
ˆ
ˆ
ˆ
or CH-O), 72.23 (CH2-O or CH-O), 105.1 (CH ), 120.6 (CH ),
ˆ
ˆ
ˆ
ˆ
(CH), 123.8 (CH ), 124.8 (CH ), 126.4 (CH ), 126.6 (CH ),
ˆ
ˆ
ˆ
ˆ
122.1 (CH ), 125.4 (CH ), 126.1 (CH ), 126.6 (CH ), 127.7
ˆ
ˆ
ˆ
128.0 (CH ), 128.3 (CH ), 128.8 (CH ), 133.3 (C), 133.5 (C),
139.7 (C), 175.9 (CO).
ˆ
(CH ), 134.7 (C), 155.0 (C).
(S)-3-Hydroxy-4-(phenoxy)butanoic
acid
[(S)-8h]:
3
3
1H NMR: d ˆ 2.68 (dd, 1H, CH2, JH-H ˆ 16.8 Hz, JH-H
ˆ
3
3
Acknowledgements
7.5 Hz), 2.76 (dd, 1H, CH2, JH-H ˆ 16.8 Hz, JH-H ˆ 5.1 Hz),
ˆ
3.99 (m, 2H, CH2-O), 4.43 (m, 1H, CH), 6.89 (m, 2H, CH ),
6.95 (m, 1H, CH ), 7.27 (m, 2H, CH ); 13C NMR: d ˆ 38.1
ˆ
ˆ
Financial support from the Swedish Foundation for Strategic
Research is gratefully acknowledged.
ˆ
ˆ
(CH2), 66.9 (CH2-O), 70.1 (CH), 114.7 (CH ), 121.5 (CH ),
ˆ
129.7 (CH ), 159.3 (C), 176.9 (CO).
(S)-3-Hydroxy-4-(2-naphthyloxy)butanoic acid [(S)-8i]:
3
3
1H NMR: d ˆ 2.85 (d, 1H, CH2, JH-H ˆ 16.4 Hz, JH-H
ˆ
References and Notes
3
3
7.6 Hz), 2.89 (dd, 1H, CH2, JH-H ˆ 16.4 Hz, JH-H ˆ 4.4 Hz),
ˆ
4.20 (m, 2H, CH2-O), 4.61(m, 1H, CH-O), 6.81 (d, 1H, CH ,
[1] For recent reviews on DKR, see: a) M. T. El Gihani,
J. M. J. Williams, Curr. Opin. Chem. Biol. 1999, 3, 11;
b) U. T. Strauss, U. Felfer, K. Faber, Tetrahedron:
Asymmetry 1999, 10, 107; c) R. Azerad, D. Buisson,
Curr. Opin. Biotechnol. 2000, 11, 565; d) F. F. Huerta,
A. B. E. Minidis, J.-E. B‰ckvall, Chem. Soc. Rev. 2001,
30, 321.
3
3
ˆ
JH-H ˆ 7.6 Hz), 7.36 (t, 1H, CH , JH-H ˆ 8.0 Hz), 7.47 (m, 3H,
CH ), 7.80 (m, 1H, CH ), 8.22 (m, 1H, CH ); 13C NMR: d ˆ
ˆ
ˆ
ˆ
ˆ
38.3 (CH2), 67.0 (CH2-O), 70.9 (CH), 105.2 (CH ), 121.3
ˆ
ˆ
ˆ
ˆ
ˆ
(CH ), 121.9 (CH ), 125.6 (CH ), 125.9 (CH ), 126.7 (CH ),
ˆ
127.8 (CH ), 134.7 (C), 154.1 (C), 177.1 (CO).
[2] K. Faber, Biotransformations in Organic Media, 3rd ed.,
Springer, Graz, Austria, 1996.
[3] a) A. L. E. Larsson, B. A. Persson, J. E. B‰ckvall, Angew.
Chem. Int. Ed. Engl. 1997, 36, 1211; b) B. A. Persson,
A. L. E. Larsson, M. LeRay, J. E. B‰ckvall, J. Am. Chem.
Soc. 1999, 121, 1645.
[4] See for instance: a) D. J. Ager, I. Prakash, D. R. Schaad,
Chem. Rev. 1996, 96, 835; b) C. P. Kordik, A. B. Reitz, J.
Med. Chem. 1999, 42, 181; c) L. A. Paquette, T. Z. Wang,
E. Pinard, J. Am. Chem. Soc. 1995, 117, 1455; d) H.
Xiaojun, E. J. Corey, Org. Lett. 2000, 2, 2543.
General Procedure for the Preparation of b-Amino
Alcohols
(S)-3-Amino-1-phenyl-1-propanol [(S)-9a]: Borane ¥ methyl
sulfide complex (0.35 mL of 2 M solution in THF, 0.70 mmol)
was added to a THF (2 mL) solution of (S)-3-hydroxy-3-
phenylpropanenitrile 1a (74 mg, 0.5 mmol). The methyl sulfide
was then distilled off. The resulting THF solution was refluxed
for 2 h. The reaction was cooled down, and quenched with
methanolic hydrogen chloride. The mixture was then evapo-
rated to dryness. The residue was dissolved in 2 M HCl (10 mL)
and extracted with dichloromethane (2 Â 5 mL). The aqueous
solution was made alkaline with 3 M NaOH (15 mL), and then
extracted with ethyl acetate (3 Â 20 mL). The combined ether
phases were dried over Na2SO4 and evaporated to give amino
[5] a) F. F. Huerta, Y. R. S. Laxmi, J. E. B‰ckvall, Org. Lett.
2000, 2, 1037; b) F. F. Huerta, J. E. B‰ckvall, Org. Lett.
¡
2001, 3, 1209; c) O. Pamies, J.-E. B‰ckvall, J. Org. Chem.
¡
2001, 66, 4022; d) O. Pamies, J.-E. B‰ckvall, Adv. Synth.
¡
Catal. 2001, 343, 726; e) O. Pamies, J.-E. B‰ckvall, J. Org.
alcohol 3a as a colorless liquid; yield: 73 mg (98%). The NMR
23
data are in agreement with those previously reported.[9] [a]D
:
¡
Chem. 2002, 67, 1261; f) A.-B. L. Runmo, O. Pamies, K.
[9]
25
À
À
Faber, J.-E. B‰ckvall, Tetrahedron Lett. 2002, 43, 2983.
[6] Our assignment was based on the reported sign of the
(R)-2-cyano-1-phenylethyl acetate: T. Itoh, K. Mitsu-
43.0 (c 1, MeOH) [lit. [a]D : 43.6 (c 1, MeOH)].
(S)-3-Amino-1-(1-naphthyl)-1-propanol [(S)-9d]: 1H NMR:
d ˆ 1.82 (m, 1H, CH2), 1.93 (m, 1H, CH2), 2.97 (m, 1H, CH2-N),
Adv. Synth. Catal. 2002, 344, 947 952
951

¡
Oscar Pamies, Jan-E. B‰ckvall
UPDATES
kura, W. Kanphai, Y. Takagi, H. Kihara, H. Tsukube, J.
Org.Chem. 1997, 62, 9165. Unfortunately, this turned out
to be in error.
[11] D. Mitchell, T. M. Koenig, Synth. Commun. 1995, 25,
1231.
[12] (S)-3-Hydroxy-3-phenylpropanoic acid product sheet
from Fluka Chemie AG, Switzerland.
[13] The (‡)-2-cyano-1-phenylethyl acetate is erroneously
assigned as the S-enantiomer in ref.[6]
[14] J. R. Dehli, V. Gotor, Tetrahedron: Asymmetry 2000, 11,
3693.
[7] The experimental details for the DKR are given in ref.[5d]
[8] Further decrease of the amount of enzyme gives slightly
better enantioselectivity, but with lower conversions.
[9] This indicates that the enzyme is denatured under the
DKR conditions.
[10] Asimilar procedure has been used in the practical
synthesis of different enantiomerically pure acetamides,
[15] I. Fleming, S. B. D. Winter, J. Chem. Soc. Perkin Trans. 1
1998, 2687.
¬
¡
see: O. Pamies, A. H. Ell, J. S. M. Samec, N. Hermanns,
J.-E. B‰ckvall, Tetrahedron Lett. 2002, 43, 4699.
952
Adv. Synth. Catal. 2002, 344, 947 952