Kinetic resolution and chemoenzymatic dynamic kinetic resolution of functionalized γ-hydroxy amides

Article abstract of DOI:10.1021/jo0478252

(Chemical Equation Presented) An efficient kinetic resolution of racemic γ-hydroxy amides 1 was performed via Pseudomas cepacia lipase (PS-C)-catalyzed transesterification. The enzyme PS-C tolerates both variation in the chain length and different functionalities giving good to high enantioselectivity (E values of up to >250). The combination of enzymatic kinetic resolution with a ruthenium-catalyzed racemization led to a dynamic kinetic resolution. The use of 2,4-dimethyl-3-pentanol as a hydrogen source to suppress ketone formation in the dynamic kinetic resolution yields the corresponding acetates in good yield and good to high enantioselectivity (ee's up to 98%). The synthetic utility of this procedure was illustrated by the practical synthesis of the versatile intermediate γ-lactone (R)-5-methyltetrahydrofuran-2-one.

Full text of DOI:10.1021/jo0478252

Kinetic Resolution and Chemoenzymatic Dynamic Kinetic
Resolution of Functionalized γ-Hydroxy Amides
Ann-Britt L. Fransson, Linne´a Bore´n, Oscar Pa`mies, and Jan-E. Ba¨ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-10691 Stockholm, Sweden
jeb@organ.su.se
Received December 11, 2004
An efficient kinetic resolution of racemic γ-hydroxy amides 1 was performed via Pseudomas cepacia
lipase (PS-C)-catalyzed transesterification. The enzyme PS-C tolerates both variation in the chain
length and different functionalities giving good to high enantioselectivity (E values of up to >250).
The combination of enzymatic kinetic resolution with a ruthenium-catalyzed racemization led to a
dynamic kinetic resolution. The use of 2,4-dimethyl-3-pentanol as a hydrogen source to suppress
ketone formation in the dynamic kinetic resolution yields the corresponding acetates in good yield
and good to high enantioselectivity (ee’s up to 98%). The synthetic utility of this procedure was
illustrated by the practical synthesis of the versatile intermediate γ-lactone (R)-5-methyltetrahy-
drofuran-2-one.
Introduction
Lipase-catalyzed kinetic resolutions can be useful alter-
natives, especially because coenzyme regeneration, an
inherent problem of enzymatic redox reactions, is not
required.3
In the past few years, only a few studies dealing with
lipase-catalyzed kinetic resolution (KR) of γ-hydroxy acid
derivatives via either esterification or transesterification
have been reported.1e,4 However, the efficiency of the KR
is limited to a maximum yield of 50%. By applying
dynamic kinetic resolution (DKR) this limitation can be
The importance of enantiomerically enriched γ-hydroxy
acid derivatives as precursor of versatile building blocks
in asymmetric synthesis is well established. Perhaps the
most important products that can be synthesized from
γ-hydroxy acid derivatives are the corresponding γ-lac-
tones. Chiral γ-lactones are present in a large variety of
natural products (e.g., fragrances, attractants, and phero-
mones). In addition, they are important structural ele-
ments for the synthesis of natural products and biologi-
cally active compounds.1 Several approaches for the
preparation of enantiomerically pure γ-hydroxy acid
derivatives have been developed.2 Among them, microbial
or enzymatic reductions have played a dominant role.2c,d
(2) For example, see: (a) Corey, E. J.; Bakshi, R. K.; Shibata, S.;
Chen, C. P.; Shing, V. K. J. Am. Chem. Soc. 1987, 109, 7925. (b)
Ohkuma, T.; Kitamura, M.; Noyori, R. Tetrahedron Lett. 1990, 31,
5509. (c) Jacobs, H.; Berryman, K.; Jones, J.; Gopalan, A. Synth.
Commun. 1990, 20, 999. (d) Fantin, G.; Fogagnolo, M.; Medici, A.;
Pedrini, P.; Poli, S.; Gardini, F.; Guerzoni, M. E. Tetrahedron:
Asymmetry 1991, 2, 243. (e) Taylor, S. K.; Fried, J. A.; Grassl, Y. N.;
Marolewski, A. E.; Pelton, E. A.; Poel, T. J.; Rezanka, D. S.; Whittaker,
M. R. J. Org. Chem. 1993, 58, 7304. (f) Armstrong, J. D.; Dimichele,
L.; Douglas, A. W.; Keller, J. L.; King, S. A.; Thompson, A. S.;
Verhoeven, T. R. WO 9518784. (g) Nair, V.; Prabhakaran, J.; George,
T. G. Tetrahedron 1997, 53, 15061.
(1) (a) Mosandl, A.; Gu¨nter, C. J. Agric. Food Chem. 1989, 37, 413.
(b) Umano, K.; Hagi, Y.; Nakahara, K.; Shoji, A.; Shibamoto, T. J. Agric.
Food Chem. 1992, 40, 599. (c) Brown, H. C.; Kulkarni, S. V.; Racherla,
U. S. J. Org. Chem. 1994, 59, 365. (d) Xiaojun, H.; Corey, E. J. Org.
Lett. 2000, 2, 2543. (e) Matsumura, Y.; Fukawa, H.; Chiba, M.; Endo,
T. JP 2000139493, 2000. (f) Garc´ıa, C.; Mart´ın, T.; Mart´ın, V. S. J.
Org. Chem. 2001, 66, 1420. (g) Xu, M.-H.; Wang, W.; Xia, L.-J.; Lin,
G.-Q. J. Org. Chem. 2001, 66, 3953.
(3) Engel, K. H.; Boh Nen, M.; Dobe, M. Enzyme Microb. Technol.
1991, 13, 655.
10.1021/jo0478252 CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/02/2005
2582
J. Org. Chem. 2005, 70, 2582-2587

Kinetic Resolution of Functionalized γ-Hydroxy Amides
SCHEME 1. Principle of Dynamic Kinetic
Resolution
γ-hydroxy amides. The viability of this strategy is il-
lustrated by the practical synthesis of (R)-5-methyltet-
rahydrofuran-2-one.
Result and Discussion
Synthesis of Starting Materials. The requisite ra-
cemic γ-hydroxy amides were prepared according to two
different methods. In the first method, reaction of a
monosubstituted epoxide with the lithium enolate of N,N-
diisopropylacetamide (2) afforded the γ-hydroxy amides
in moderate to good yields (eq 1).9 In the second method
1h was transformed into 1e (eq 2).10
overcome.5 With DKR, the unreactive enantiomer is
continuously racemized and the desired enantiomer can
be theoretically obtained in 100% yield and 100% ee. In
a good DKR process the rate of racemization should be
higher than the rate of product formation, rR, rS, and the
reaction rate of one of the enantiomers should be con-
siderably faster than that of the other (rR . rS) (Scheme
1).
However if the enantiomeric ratio (E) is very high, the
racemization may be slower than rR, although, in all cases
the racemization has to be faster than rS.
We and others have recently developed an easy ap-
proach to perform DKR on secondary alcohols in which
the traditional enzymatic kinetic resolution is combined
with an in situ racemization of the substrate using a
metal catalyst.6 Following our ongoing project dealing
with the DKR of different functionalized alcohols,7 we
decided to study the DKR of γ-hydroxy carboxylic acid
derivatives, which would lead to interesting building
blocks for the synthesis of high-value compounds. We
easily envisaged the DKR of γ-hydroxy esters, but the
efficiency of the DKR of γ-hydroxy esters was low, due
to their high tendency to undergo enzymatic and nonen-
zymatic lactonization. However, we could perform an
efficient KR and DKR on the sterically hindered N,N-
diisopropyl-4-hydroxypentanamide (1a).8 We now report
on the scope of the KR and DKR of sterically hindered
Kinetic Resolution. To achieve an efficient DKR, the
basic requirement is that the KR conditions should be
compatible with the in situ racemization process. There-
fore, 4-chlorophenyl acetate (3) was chosen as the pri-
mary acyl donor, since it is known to be compatible with
the ruthenium-catalyzed racemization of alcohols.6e The
use of vinyl acetate or isopropenyl acetate, commonly
used as an acyl donor, results in the formation of
acetaldehyde and acetone, respectively, after the acyl
transfer process, which can interfere with the Ru catalyst
411 usually employed in the DKR. The use of these
acyldonors in DKR requires very dry conditions and a
hydrogen donor.12 In a first set of experiments, the
efficiency of several commercially available lipases to
catalyze the transesterification of γ-hydroxy amides 1
was investigated. For this purpose, racemic N,N-diiso-
propyl-4-hydroxypentanamide (1a) was chosen as model
substrate.
From the enzymes tested Candida antarctica lipase B
(Novozyme 435, N-435), Pseudomonas species lipase (PS-
C) and Pseudomonas fluorescens (PF) showed good activ-
ity. Although the enzyme N-435 showed high activity,
the transesterification proceeded with low enantiomeric
ratio (E ) 3). However, the enzyme PS-C showed reason-
able activity and excellent enantioselectivity (Table 1,
entry 2). The corresponding reaction with PF was very
slow although the enantioselectivity was excellent. To
obtain a reasonable rate of the acylation of 1a, the
amount of enzyme had to be increased (Table 1, entry
3). In an attempt to further enhance the acylation
(4) See, for example: (a) Gutman, A. L.; Zuobi, K.; Boltansky, A.
Tetrahedron Lett. 1987, 28, 3861. (b) Gutman, A. L.; Zuobi, K.; Bravdo,
T. J. Org. Chem. 1990, 55, 3546. (c) Huffer, M.; Schreier, P. Tetrahe-
dron: Asymmetry 1991, 2, 1157. (d) Fukusaki, E.; Senda, S.; Nakazono,
Y.; Omata, T. Tetrahedron 1991, 47, 6223. (e) Taylor, S. K.; Atkinson,
R. F.; Almli, E. P.; Carr, M. D.; Van Huis, T. J.; Whittaker, M. R.
Tetrahedron: Asymmetry 1995, 6, 157. (f) Komatsu, Y.; Sasaki, F.;
Takei, S.; Kitazume, T. J. Org. Chem. 1998, 63, 8058. (g) Adam, W.;
Groer, P.; Saha-Mo¨ller, C. R. Tetrahedron: Asymmetry 2000, 11, 2239.
(5) For reviews on DKR, see: (a) Ward, R. S. Tetrahedron: Asym-
metry 1995, 6, 1475. (b) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull.
Chem. Soc. Jpn. 1995, 68, 36. (c) Caddick, S.; Jenkins, K. Chem. Soc.
Rev. 1996, 25, 447. (d) Stecher, H.; Faber, K. Synthesis 1997, 1. (e)
Stu¨rmer, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 1173. (f) El Gihani,
M. T.; Williams, J. M. J. Curr. Opin. Chem. Biol. 1999, 3, 11. (g)
Strauss, U. T.; Felfer, U.; Faber, K. Tetrahedron: Asymmetry. 1999,
10, 107. (h) Azerad, R.; Buisson, D. Curr. Opin. Biotechnol. 2000, 11,
565. (i) Huerta, F. F.; Minidis, A. B. E.; Ba¨ckvall, J.-E. Chem. Soc.
Rev. 2001, 30, 321. (j) Pa`mies, O.; Ba¨ckvall, J.-E. Chem Rev. 2003,
103, 3247. (k) Kim, M.-J.; Ahn, Y.; Park, J. Curr. Opin. Biotechnol.
2002, 13, 578.
(6) (a) Allen, J. V.; Williams, J. M. J. Tetrahedron Lett. 1996, 37,
1859. (b) Dinh, P. M.; Howarth, J. A.; Hudnott, A. R.; Williams, J. M.
J.; Harris, W. Tetrahedron Lett. 1996, 37, 7623. (c) Reetz, M. T.;
Schimossek, K. Chimia 1996, 50, 668. (d) Larsson, A. L. E.; Persson,
B. A.; Ba¨ckvall, J.-E. Angew. Chem. Int. Ed. Engl. 1997, 36, 1211. (e)
Persson, B. A.; Larsson, A. L. E.; LeRay, M.; Ba¨ckvall, J.-E. J. Am.
Chem. Soc. 1999, 121, 1645.
(9) (a) Woodbury, R. P.; Rathke, M. W. J. Org. Chem. 1977, 42, 1688.
(b) Sauriol-Lord, F., Grindly, T. B. J. Org. Chem. 1981, 46, 2831. (c)
Talyor, S. K. Tetrahedron 2000, 56, 1149.
(7) (a) Persson, B. A.; Huerta, F. F.; Ba¨ckvall, J.-E. J. Org. Chem.
1999, 64, 5237. (b) Huerta, F. F.; Laxmi, Y. R. S.; Ba¨ckvall, J.-E. Org.
Lett. 2000, 2, 1037. (c) Huerta, F. F.; Ba¨ckvall, J.-E. Org. Lett. 2001,
3, 1209. (d) Pa`mies, O.; Ba¨ckvall, J.-E. J. Org. Chem. 2001, 66, 4022.
(e) Pa`mies, O.; Ba¨ckvall, J.-E. Adv. Synth. Catal. 2001, 343, 726. (f)
Pa`mies, O.; Ba¨ckvall, J.-E. J. Org. Chem. 2002, 67, 1261.
(10) Shuto, S.; Ono, S.; Hase, Y.; Kamiyama, N.; Takada, H.;
Yamasihita, K.; Matsuda, A. J. Org. Chem. 1996, 61, 915.
(11) (a) Blum, Y.; Czarkie, D.; Rahamin, Y.; Shvo, Y. Organometal-
lics 1985, 4, 1459. (b) Shvo, Y.; Czarkie, D.; Rahamin, Y. J. Am. Chem.
Soc. 1986, 108, 7400. (c) Menasche, N.; Shvo, Y. Organometallics 1991,
10, 3885.
(8) Runmo, A.-B. L.; Pa`mies, O.; Faber, K.; Ba¨ckvall, J.-E. Tetra-
hedron Lett. 2002, 43, 2983.
(12) Steinreiber, J. Diploma thesis, Stockholm University, 2002.
J. Org. Chem, Vol. 70, No. 7, 2005 2583

Fransson et al.
TABLE 1. Kinetic Resolution of γ-Hydroxy Amide 1aa
TABLE 2. Kinetic Resolution of γ-Hydroxy Amides 1a
time % of % ee
entry
enzymeb
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
(h)
5c of 5d
Ee
1
CAL B
PS-C
PF
0.25 43
36
3
2
6
24
8
41
47
40
40
nr
nr
nr
48
49
45
99 >25013
3f
99 >35013
time % of % ee
entry substrate
R
(h)
5b of 5c
Ed
4f,g PF
98
195 ( 40
5f,h PF
24
24
24
24
8
99 >25013
1
1a
1a
1b
1b
1c
1c
1d
1e
1f
Me-
Me-
Et-
6
41
99 >25013
2e
3
24 47
24 48
144 35
36 41
144 35
144 44
24 40
36 42
22 43
22 41
99 >35013
6
PPL
C. rugosa
Aspergillus toluene
PS-C
PS-C
PS-C
7
96
98
93
95
ndf
95
95
96
95
146 ( 25
4e
5
Et-
168 ( 30
54 ( 5
8
9i
TBMEj
95
93
94
113 ( 15
83 ( 8
75 ( 5
n-Pr-
n-Pr-
n-Bu-
6e
7
65 ( 5
10
11
DIPEk
5
cyclohexane
4
8
9
10
11
NCCH2-
74 ( 5
80 ( 5
a Unless otherwise noted, all reactions were performed on a 0.1
mmol scale with 5 mg of enzyme and 3 equiv of 3 in 1 mL of solvent
at 70 °C. b CAL B ) Candida antarctica lipase B, PS-C )
Pseudomonas cepacia lipase, PF ) Pseudomonas fluorescens lipase,
PPL ) porcine pancreas lipase, C. rugosa ) Candida rugosa,
Aspergillus ) Aspergillus sp. c Determined by 1H NMR. d Deter-
mined by GC using a CP-Chirasil-Dex CB column using racemic
1a as reference. e Enantiomeric ratio14 with estimated errors. f 50
mg of enzyme used. g Vinyl acetate was used as acyl donor.
h Isopropenyl acetate was used as acyl donor. nr ) no reaction.
i The reaction was performed at 60 °C. j TBME ) tert-butyl methyl
ether. k DIPE ) diisopropyl ether.
CH2dCHCH2-
MeOCH2-
ClCH2-
1g
1h
106 ( 10g
78 ( 5
a Unless otherwise noted, all reactions were performed on a 0.1
mmol scale with 5 mg of Pseudomonas cepacia lipase and 3 equiv
of 3 in 1 mL of toluene at 70 °C. b Determined by 1H NMR.
c Determined by GC using a CP-Chirasil-Dex CB column using
racemic compounds as references. d Enantiomeric ratio14 with
estimated errors. e 50 mg of Pseudomonas fluorescens lipase was
used. f nd ) not determined. g Determined by HPLC using an OJ
column.
process, the more reactive acyl donors, vinyl acetate and
isopropenyl acetate were used (Table 1, entries 4 and 5).
In fact, using vinyl acetate enhanced the enzymatic
acylation, however, a decrease in enantioselectivity was
observed. The conclusion is that these acyl donors are
not better than p-chlorophenyl acetate considering their
drawbacks in the DKR process (vide supra). Other lipases
examined (lipase from porcine pancreas, Candida rugosa
and Aspergillus sp.) showed no reaction after 24 h (Table
1, entries 6-8). The choice of solvent is important, since
the results show that the enantioselectivity of the enzyme
in the acylation of 1a is greatly dependent on the solvent.
Ethers and cyclohexane gave a lower enantioselectivity
compared to toluene (Table 1, entry 2 versus entries
9-11).
On the basis of the preliminary results of KR of 1a,
we applied this new procedure to a series of γ-hydroxy
amides 1 with different R groups (Table 2), using toluene
as solvent at 70 °C.
Our study indicates that the enantioselectivity and the
activity decrease with increasing chain length (Table 2,
entries 1-6). Thus, in the cases when PS-C is used as
the enzyme, for methyl the E value was >250, whereas
for ethyl and propyl it was 146 and 54, respectively. It is
interesting to note that, even propyl as the small group
gave a reasonable selectivity and acylation rate.15 When
the carbon chain was extended further, to the butyl
group, we found that we had reached the limitation for
achieving an efficient enzymatic acylation. The reaction
was running for 6 days in order to achieve a reasonable
yield (Table 2, entry 7). Using PF as the enzyme, the E
value was slightly higher than for the corresponding
substrates using PS-C although the acylation rate was
very slow and this rules out the use of PF as an efficient
enzyme in the DKR due to its lower reactivity. The KR
of the functionalized substrates 1e-h proceeds with high
enantiomeric excess (Table 2, entries 8-11).
Dynamic Kinetic Resolution. On the basis of our
preliminary results on KR, we combined the KR of
γ-hydroxy amides 1 using PS-C and the acyl donor 3 with
a ruthenium-catalyzed racemization process via hydrogen
transfer employing the dimeric Ru-precatalyst 4 in
toluene.11c These results are summarized in Table 3.
Under “standard” DKR conditions (i.e., 70 °C, 5 mg of
PS-C and 4 mol % of 4), formation of large amounts of
the corresponding ketone 6a was observed; the latter is
formed during the hydrogen transfer process (Table 3,
entry 1). Several attempts to increase the efficiency of
the process by reducing the amount of ketone have been
carried out. Thus, 2,4-dimethyl-3-pentanol (7), 2,6-di-
methyl-4-heptanol (8), hydrogen gas (9), HCOOH (10),
and HCOOH‚NEt3 (1:1) (11) were tested as hydrogen
sources with the aim to push the equilibrium back to the
alcohol 1a. The equilibrium between the alcohol 1a and
the ketone 6a was successfully shifted toward the alcohol
(13) Table 1, entry 2, and Table 2, entry 1: The calculated E value
was 410 and the error was estimated to (150. Table 1, entry 3, and
Table 2, entry 2: The calculated E value was 580 and the error was
estimated to (200. Table 1, entry 5: The calculated E value was 390
and the error was estimated to (135.
(14) Faber, K. Biotransformations in Organic Chemistry, 4th ed.;
Springer-Verlag: Berlin, 2000.
(15) (a) For other lipases such as Candida antartica lipase B propyl
is not accepted as a small group.15b For a general discussion of the
stereochemical outcome with regard to the empirical rules, see ref 15c.
(b) Rotticci, D.; Haeffner, F.; Orrenius C.; Norin, T.; Hult, K. J. Mol.
Catal. B: Enzymol. 1998, 5, 267. (c) Kazlauskas, R. J.; Weissfloch, A.
N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org. Chem. 1991, 56, 2656.
2584 J. Org. Chem., Vol. 70, No. 7, 2005

Kinetic Resolution of Functionalized γ-Hydroxy Amides
TABLE 3. Dynamic Kinetic Resolution of γ-Hydroxy
TABLE 4. Dynamic Kinetic Resolution of γ-hydroxy
Amide 1aa
Amides 1a
mg of
entry
substrate (R)
enzymeb % of 5c % of 6c % eed
1e
2
1a (Me-)
5
5
20
10
10
5
93
65
59
90
85
70
2
10
9
98
98
92
80
91g
95
1b (Et-)
3
1c (Pr-)
4f
5
1e (NCCH2-)
1g (CH3OCH2-)
1h (CH2Cl-)
9
6
1
6h
a Unless otherwise noted, all reactions were performed on a 0.1
mmol scale for 72 h using 5 mg of PS-C lipase, 4 mol % of 4, and
3 equiv of 3 in 1 mL of toluene at 70 °C. 2,4-Dimethyl-3-pentanol
(7) (0.5 equiv) was added after 24 h. b mg enzyme/0.1 mmol
substrate. c Determined by 1H NMR. d Determined by GC using
a CP-Chirasil-Dex CB column. e The reaction was performed on a
0.8 mmol scale using 3.9 equiv of 3 and 6 mol % of 4. f 4 mol % of
4 was added after 14 h, and at the same time the temperature
was raised to 80 °C, 7 was added after 38 h. g Determined by
HPLC using an OJ column. h 4 mol % of 4 was added after 22 h,
and 7 was added after 46 h.
hydrogen
entry
source
time (h)
% of 5ab
% of 6ab
% eec
1
48
48
48
48
48
48
48
48
57
76
79
89
nr
48
77
78
43
11
1
99
97
96
96
2
7
8
9
3
4
3
5
10
11
7
6
28
10
11
95
98
97
SCHEME 2. Synthesis of Lactone 12
7d
8e
7
a Unless otherwise noted, all reactions were performed on a 0.1
mmol scale for 48 h using 5 mg of Pseudomonas cepacia lipase,
0.5 equiv of hydrogen source, 3 equiv of 3, and 4 mol % of 4 in 1
mL of toluene at 70 °C. b Determined by 1H NMR. c Determined
by GC using a CP-Chirasil-Dex CB column using racemic com-
pounds as references. d 2,4-Dimethyl-3-pentanol (7) was added
after 24 h. e 6 mol % of 4 was used. nr ) no reaction.
catalyst 4, forming both the corresponding saturated
ketone and the corresponding conjugated ketone in high
yields.
Synthetic Applications. A wide range of synthetic
applications of this dynamic kinetic resolution procedure
can be envisaged. One example is the practical synthesis
of the versatile intermediate (R)-5-methyltetrahydrofu-
ran-2-one 12.17 Thus, the enantiomerically enriched
acetate 5a was isolated in 86% yield from 1a on a 0.8
mmol scale with an enantioselectivity of 98%. Acetate 5a
was transformed to the (R)-lactone 12 via a one-pot two-
step procedure involving hydrolysis with LiOH in metha-
nol followed by acid-catalyzed lactone formation (Scheme
2). The ee of 12 was determined by chiral GC and the
absolute configuration was established by comparison
with literature data.18
1a with hydrogen sources 7, 8 and 9 (Table 3, entry 1
versus entries 2-4). When 10 and 11 were used as
hydrogen sources, no activity or slower reaction rate was
observed and the selectivity was decreased slightly (Table
3, entries 2-4 versus entries 5-6).
Although the DKR is faster with hydrogen gas (9) than
with 7 as a hydrogen donor (Table 3, entry 2 vs 4), the
latter was chosen as a hydrogen source to perform DKR
since it provided better enantioselectivity and it is a
milder hydrogen donor compared to hydrogen gas.
For 1a and 1b the same conditions were used, yielding
an excellent enantioselectivity. Due to the longer carbon
chain in 1b a slower acylation (65% conversion) was
observed compared to 1a (93% conversion) after a reac-
tion time of 72h (Table 4, entries 2 and 1, respectively).
To achieve a reasonable acylation rate of 1c, the amount
of enzyme was increased, however this resulted in a
decrease in enantioselectivity (Table 4, entry 3). For 1e
the DKR was unsuccessful at 70 °C and this agrees with
the results of DKR of nitriles previously reported by
Pa`mies et al.7e Therefore, the reaction temperature was
increased to 80 °C affording the corresponding acetate
in high yield. The lower enantioselectivity in this case
might be due to that the optimum temperature of the
enzyme was exceeded (Table 4, entry 4).16 In the DKR
both 1g and 1h gave good yields and high enantioselec-
tivities (Table 4, entries 5 and 6). Substrate 1f was under
the DKR conditions, incompatible with the racemization
Conclusions
Enantioselective transformations of important sub-
strate class, γ-hydroxyamides, were carried out under KR
and DKR conditions. PS-C allowed variations in the
carbon chain attached to the γ-carbon. For a variety of
substrates PS-C showed high enantioselectivity, in all
cases over 93% ee. Together with a racemization catalyst
4 and a hydrogen source, an efficient DKR was achieved.
The DKR gives access to enantiomerically enriched
functionalized γ-acetoxyamides with yields up 90% and
ee up to 95%. In conclusion, comparing the dynamic
(16) The optimum performance of the PS-C is set to 55-60 °C. PS-C
product sheet from Amano Pharmaceutical Co. Ltd., Japan.
(17) For example, see: (a) Mori, K. Tetrahedron 1975, 31, 3011. (b)
Imagi, S.; Wada, S.; Ito, N.; Hasebe, A. JP 11189783, 1999.
(18) Compound 12 is the R-(+) enantiomer. The S-(-) enantiomer
was prepared by an independent method according to ref 4e for the
assignment of the absolute configuration.
J. Org. Chem, Vol. 70, No. 7, 2005 2585

Fransson et al.
(2 C), 20.5, 20.4. HRMS (m/z) calcd for C12H23N2O2 (M + H)+
227.1760, found 227.1763.
kinetic resolution results with those obtained from the
kinetic resolution, the efficiency of the former method is
striking: the yields are higher in the dynamic process
and the enantioselectivity ranges from good to excellent.
N,N-Diisopropyl-4-hydroxyhept-6-enamide (1f). From
the general method using 4,5-epoxy-1-pentene.19 Flash chro-
matography (pentane/EtOAc 2:3) gave 1f (0.453 g, 20%) as a
pale yellow oil: 1H NMR (CDCl3) δ 5.91-5.79 (m, 1H), 5.14-
5.06 (m, 2H), 3.99 (sept, J ) 6.7 1H), 3.71-3.62 (m, 1H), 3.55-
3.40 (m, 2H), 2.56-2.40 (m, 2H), 2.25 (t, J ) 7.2, 2H), 1.89-
1.70 (m, 2H), 1.36 (d, J ) 6.7, 6H), 1.20 (d, J ) 6.7, 6H); 13C
NMR (CDCl3) δ 172.5, 135.1, 117.4, 70.9, 48.5, 45.8, 42.4, 32.0,
31.4, 20.9 (2 C) 20.7, 20.6.
N,N-Diisopropyl-4-hydroxy-5-methoxypentanamide
(1g). Flash chromatography (pentane/EtOAc 4:1 to 1:3) gave
1h (0.97 g, 42%) as a pale yellow oil: 1H NMR (CDCl3) δ 3.99
(sept, J ) 6.7, 1H), 3.81-3.72 (m, 1H), 3.63 (d, J ) 3.3, 1H),
3.54-3.42 (m, 1H), 3.39-3.28 (m, 5H), 2.48 (t, J ) 6.7, 2H),
1.90-1.64 (m, 2H), 1.35 (d, J ) 6.7, 6H), 1.18 (d, J ) 6.9, 6H);
13C NMR (CDCl3) δ 172.4, 77.0, 70.1, 59.1, 48.4, 45.7, 31.5,
28.4, 20.9 (2 C), 20.6, 20.5.
5-Chloro-N,N-diisopropyl-4-hydroxypentanamide (1h).
Flash chromatography (pentane/EtOAc 1:2) gave 1i (0.81 g,
35%) as a colorless oil: 1H NMR (CDCl3) δ 4.51 (d, J ) 4.1,
1H), 3.98 (sept, J ) 6.9, 1H), 3.86-3.74 (m, 1H), 3.61-3.41
(m, 3H), 2.66-2.52 (m, 1H), 2.52-2.39 (m, 1H), 2.03-1.79 (m,
2H), 1.35 (d, J ) 6.7, 6H), 1.20 (d, J ) 6.7, 6H); 13C NMR
(CDCl3) δ 172.4, 71.6, 49.3, 48.6, 46.0, 31.6, 28.9, 20.8 (2 C),
20.6, 20.5; HRMS (m/z) calcd for C11H23ClNO2 (M + H)+
236.1417, found 236.1417.
General Procedure for Synthesis of Racemic γ-
Acetoxy Amides (5). To a solution of the appropriate hy-
droxyamide 1 (0.5 mmol) in dichloromethane (2.5 mL) were
added triethylamine (0.5 mL) and acetic anhydride (0.5 mL)
at 0 °C. The reaction was stirred at room temperature
overnight. The solution was evaporated and purified by flash
chromatography. The yields of acetoxyamides 5 were >95%.
4-Acetoxy-N,N-diisopropylpentanamide (5a): 1H NMR
(CDCl3) δ 4.98-4.89 (m, 1H), 3.93 (sept, J ) 6.9, 1H), 3.60-
3.41 (m, 1H), 2.38-2.23 (m, 2H), 2.03 (s, 3H), 1.95-1.82 (m,
2H), 1.36 (d, J ) 6.7, 6H), 1.24 (d, J ) 6.2, 3H), 1.19 (d, J )
6.7, 6H); 13C NMR (CDCl3) δ 170.8, 170.7, 70.7, 48.1, 45.6, 31.4,
31.0, 21.3, 20.9 (2 C), 20.6 (2 C), 20.1.
Experimental Section
Synthesis of γ-Hydroxy Amides. N,N-Diisopropyl-4-
hydroxypentanamide (1a). General Method. To a solution
of diisopropylamine (1.44 mL, 10.0 mmol) in dry THF (10.0
mL) under argon atmosphere at 0 °C was added n-BuLi (6.25
mL, 10.0 mmol) in n-hexane dropwise. The reaction was stirred
at 0 °C for 5 min and for an additional 5 min at room
temperature. The solvent was evaporated, and THF (15 mL)
was added followed by dropwise addition of N,N-diisopropyl-
acetamide (1.6 mL, 10.0 mmol) at 0 °C. The solution was
stirred for 10 min at 0 °C, and Et2AlCl 1M in n-hexane (6.0
mL, 6.00 mmol) was added. The epoxide (0.75 mL, 11.0 mmol)
was added, and the mixture was stirred at 0 °C for 30 min
and then at reflux for 2 h. The reaction was cooled to room
temperature and quenched with 1 M acetic acid in ether (10
mL). The salts were filtered off, and the γ-hydroxy amide was
purified by flash chromatography.
5-Cyano-N,N-diisopropyl-4-hydroxypentanamide (1e).
NaCN (2.00 mmol) was added at room temperature to a
solution of 1h (231 mg, 0.98 mmol) in DMF (15 mL), and the
resulting mixture was heated with stirring at 105 °C for 4 h.
After the reaction was cooled, the DMF was evaporated and
the residue was dissolved with water (15 mL) and extracted
with EtOAc (3 × 20 mL). The combined organic phase was
washed with brine, dried over anhydrous Na2SO4, evaporated,
and purified by flash chromatography (pentane/EtOAc 1:1) to
give 1e (155 mg, 70%) as a colorless oil.
Hydroxyamides 1a-d and 1f-h were prepared according
to the general method.
N,N-Diisopropyl-4-hydroxypentanamide (1a). Flash
chromatography (pentane/EtOAc 1:3) gave 1a (1.42 g, 71%)
as a colorless oil: 1H NMR (CDCl3) δ 3.99 (sept, J ) 6.9, 1H),
3.90-3.75 (m, 1H), 3.59-3.40 (m, 2H), 2.57-2.36 (m, 2H),
1.84-1.67 (m, 2H), 1.37 (d, J ) 6.9, 6H), 1.29-1.13 (m, d, J )
6.9, 9H); 13C NMR (CDCl3) δ 172.6, 68.6, 48.5, 45.7, 33.8, 31.9,
23.7, 20.9 (2 C), 20.6, 20.5.
N,N-Diisopropyl-4-hydroxyhexanamide (1b). Flash chro-
matography (pentane/EtOAc 1:3) gave 1b (1.52 g, 70%) as a
pale yellow oil: 1H NMR (CDCl3) δ 3.96 (sept, J ) 6.9, 1H),
3.53-3.31 (m, 3H), 2.48-2.38 (m, 2H), 1.83-1.59 (m, 2H),
1.50-1.39 (m, 2H), 1.32 (d, J ) 6.9, 6H), 1.15 (d, J ) 6.9, 6H),
0.89 (dt, J ) 7.5, 2.3, 3H); 13C NMR (CDCl3) δ 172.7, 73.0,
48.4, 45.7, 32.0, 31.4, 30.6, 20.8 (2 C), 20.6, 20.5, 9.9.
N,N-Diisopropyl-4-hydroxyheptanamide (1c). Flash
chromatography (pentane/EtOAc 1:1) gave 1c (0.68 g, 30%)
as a pale yellow oil: 1H NMR (CDCl3) δ 3.99 (sept, J ) 6.9,
1H), 3.64-3.54 (m, 1H), 3.54-3.43 (m, 1H), 3.40 (d, J ) 3.9,
1H), 2.55-2.38 (m, 2H), 1.85-1.64 (m, 2H), 1.51-1.29 (m, d,
J ) 6.9, 10H), 1.19 (d, J ) 6.9, 6H), 0.91 (t, J ) 6.9, 3H); 13C
NMR (CDCl3) δ 172.9, 71.6, 48.7, 46.0, 40.3, 32.3, 32.2, 21.1
(2 C) 20.8, 20.7, 19.1, 14.3. HRMS (m/z) calcd for C13H28NO2
(M + H)+ 230.2120, found 230.2128.
N,N-Diisopropyl-4-hydroxyoctanamide (1d). Flash chro-
matography (pentane/EtOAc 1:1) gave 1d (1.05 g, 43%) as a
pale yellow oil: 1H NMR (CDCl3) δ 4.00 (sept, J ) 6.6, 1H),
3.63-3.54 (m, 1H), 3.54-3.40 (m, 1H), 3.36 (d, J ) 4.5, 1H),
2.56-2.40 (m, 2H), 1.85-1.66 (m, 2H), 1.51-1.26 (m, d, J )
6.7, 12H), 1.20 (d, J ) 6.7, 6H), 0.89 (t, J ) 6.7, 3H); 13C NMR
(CDCl3) δ 172.7, 71.7, 48.5, 45.8, 37.6, 32.1, 32.0, 27.9, 22.8,
20.9 (2 C) 20.6, 20.5, 14.1.
5-Cyano-N,N-diisopropyl-4-hydroxypentanamide (1e).
Flash chromatography (pentane/EtOAc 1:1) gave 1e (0.155 g,
70%) as a colorless oil: 1H NMR (CDCl3) δ 4.03-3.90 (m, 2H),
3.60-3.43 (m, 1H), 2.73-2.43 (m, 4H), 2.00-1.93 (m, 2H), 1.37
(dd, J ) 6.7, 2.1, 6H), 1.22 (dd, J ) 6.7, 2.1, 6H); 13C NMR
(CDCl3) δ 172.5, 117.8, 68.1, 48.7, 46.2, 32.0, 30.8, 26.3, 20.7
4-Acetoxy-N,N-diisopropylhexanamide (5b): 1H NMR
(CDCl3) δ 4.87-4.78 (m, 1H), 3.91 (sept, J ) 6.9, 1H), 3.58-
3.34 (m, 1H), 2.31-2.24 (m, 2H), 2.04 (s, 3H), 1.98-1.74 (m,
2H), 1.57 (dq, J ) 7.4, 1.1, 2H), 1.35 (d, J ) 6.7, 6H), 1.17 (d,
J ) 6.7, 6H), 0.89 (t, J ) 7.4, 3H); 13C NMR (CDCl3) δ 171.2
(2 C), 75.2, 48.2, 45.7, 31.2, 29.3, 27.3, 21.2, 20.8 (2 C), 20.6 (2
C), 9.6.
4-Acetoxy-N,N-diisopropylheptanamide (5c): 1H NMR
(CDCl3) δ 4.98-4.85 (m, 1H), 3.91 (sept, J ) 6.9, 1H), 3.60-
3.33 (m, 1H), 2.32-2.22 (m, 2H), 2.04 (s, 3H), 1.99-1.74 (m,
2H), 1.61-1.44 (m, 2H), 1.41-1.24 (m, d, J ) 6.7, 8H), 1.17
(d, J ) 6.7, 6H) 0.89 (t, J ) 7.2, 3H); 13C NMR (CDCl3) δ 171.0,
170.8, 73.8, 48.1, 45.6, 36.5, 31.0, 29.7, 21.2, 20.9 (2 C), 20.7,
20.6, 18.5, 13.9.
4-Acetoxy-N.N-diisopropyl-octanamide (5d): 1H NMR
(CDCl3) δ 4.93-4.85 (m, 1H), 3.92 (sept, J ) 6.4, 1H), 3.58-
3.37 (m, 1H), 2.31-2.24 (m, 2H), 2.04 (s, 3H), 1.98-1.75 (m,
2H), 1.63-1.47 (m, 2H), 1.35 (d, J ) 6.7, 6H), 1.33-1.23 (m,
4H), 1.18 (d, J ) 6.7, 6H), 0.87 (t, J ) 6.7, 3H); 13C NMR
(CDCl3) δ 171.0 (2C), 74.1, 48.1, 45.6, 34.1, 31.1, 29.7, 27.4,
22.5, 21.2, 20.9 (2 C,), 20.6 (2 C), 13.9.
4-Acetoxy-5-cyano-N,N-diisopropylpentanamide
(5e): 1H NMR (CDCl3) δ 5.11-5.02 (m, 1H), 3.90 (sept, J )
6.7, 1H), 3.54-3.38 (m, 1H), 2.77 (dd, J ) 17, 5.1, 1H), 2.65
(dd, J ) 17, 5.1, 1H), 2.34 (t, J ) 7.1, 2H), 2.09 (s, 3H), 2.08-
1.95 (m, 2H), 1.35 (d, J ) 6.7, 6H), 1.18 (dd, J ) 6.7, 2.9, 6H);
13C NMR (CDCl3) δ 170.2, 169.6, 116.3, 68.4, 48.2, 45.7, 30.2,
28.9, 23.2, 20.9, 20.8 (2 C), 20.6, 20.5.
(19) Schuda, A. D.; Mazzocchi, P. H.; Fritz, G.; Morgan, T. Synthesis
1986, 309.
2586 J. Org. Chem., Vol. 70, No. 7, 2005

Kinetic Resolution of Functionalized γ-Hydroxy Amides
4-Acetoxy-N,N-diisopropylhept-6-enamide (5f): 1H NMR
(CDCl3) δ 5.82-5.65 (m, 1H), 5.12-4.99 (m, 2H), 4.99-4.86
(m, 1H), 3.90 (sept, J ) 6.7, 1H), 3.56-3.37 (m, 1H), 2.36-
2.22 (m, 4H), 2.02 (s, 3H), 1.99-1.74 (m, 2H), 1.35 (d, J ) 6.7,
6H), 1.17 (d, J ) 6.7, 6H); 13C NMR (CDCl3) δ 170.8, 170.7,
133.4, 117.8, 73.0, 48.1, 45.6, 38.9, 31.0, 29.3, 21.2, 20.9 (2 C)
20.7, 20.6; HRMS (m/z) calcd for C15H28NO3 (M + H)+
270.2069, found 270.2059.
4-Acetoxy-N,N-diisopropyl-5-methoxypentanamide
(5g): 1H NMR (CDCl3) δ 5.11-5.01 (m, 1H), 3.92 (sept, J )
6.9, 1H), 3.55-3.40 (m, 3H), 3.34 (s, 3H), 2.30 (t, J ) 7.7, 2H),
2.07 (s, 3H), 2.04-1.80 (m, 2H), 1.35 (d, J ) 6.7, 6H), 1.17 (d,
J ) 6.7, 6H); 13C NMR (CDCl3) δ 170.8, 170.5, 73.9, 72.2, 59.1,
48.1, 45.6, 30.8, 26.6, 21.2, 20.9 (2 C), 20.7, 20.6; HRMS (m/z)
calcd for C14H28NO4 (M + H)+ 274.2018, found 274.2012.
4-Acetoxy-5-chloro-N,N-diisopropylpentanamide
(5h): 1H NMR (CDCl3) δ 5.16-5.04 (m, 1H), 3.92 (sept, J )
6.9, 1H), 3.67 (dd, J ) 11.8, 4.5, 1H), 3.59 (dd, J ) 11.8, 5.7,
1H), 3.55-3.38 (m, 1H), 2.37-2.28 (m, 2H), 2.09 (s, 3H), 2.07-
1.86 (m, 2H), 1.36 (d, J ) 6.7, 6H), 1.19 (d, J ) 6.7, 6H); 13C
NMR (CDCl3) δ 170.5, 170.1, 72.6, 48.2, 45.9, 45.7, 30.5, 27.4,
21.0, 20.9 (2 C) 20.7, 20.6.
General Procedure for the Kinetic Resolution of
γ-Hydroxy Amides. In a typical experiment, 1a (20.1 mg, 0.1
mmol) and p-ClC6H4OAc 3 (51 mg, 0.3 mmol) in toluene (1
mL) were degassed with argon for 1 min and added to a
Schlenk tube containing enzyme (5 mg). The mixture was
stirred under argon atmosphere at 70 °C. The mixture was
filtered through a silica pad to remove the enzyme, the solid
was washed with Et2O (3 × 3 mL), the combined solvent was
evaporated, and the residue was analyzed by GC and 1H NMR.
General Procedure for the Dynamic Kinetic Resolu-
tion of γ-Hydroxy Amides. In a typical experiment, 1a (20.1
mg, 0.1 mmol) and p-ClC6H4OAc 3 (51 mg, 0.30 mmol) in
toluene (1 mL) were degassed with argon for 1 min and added
to an Schlenk tube containing PS-C (5 mg) and the ruthenium
catalyst 4 (5.4 mg, 4 mol %). The mixture was stirred at 70 °C
for 24 h, and 2,4-dimethyl-3-pentanol as a hydrogen source
(0.5 equiv) was added. The mixture was stirred for another
48 h and worked up by filtering through a silica pad to remove
the enzyme. The solid was washed with Et2O (3 × 3 mL), the
combined solvent was evaporated, and the residue was ana-
1
lyzed by GC and H NMR.
Synthesis of (R)-5-Methyltetrahydrofyran-2-one (12).
The enantiomerically enriched γ-acetoxy amide 5a (125 mg,
0.51 mmol) was stirred in methanol (5 mL) together with LiOH
(15.4 mg, 0.64 mmol) at room temperature. After 12 h, 2 M
HCl (1.25 mL) was added. The mixture was stirred at 70 °C
for 3 days, during which time additional 2 M HCl (1.45 mL)
was added. The reaction mixture was cooled to room temper-
ature and purified by bulb-to-bulb distillation, affording enan-
tiomerically enriched 12 (44.0 mg, 86%) in 92% ee as a pale
yellow oil. The spectroscopic data were in accordance with
those in the literature.4e
Acknowledgment. Financial support from the Swed-
ish Foundation for Strategic Research is gratefully
acknowledged. We thank Amano Pharmaceutical Co.
Ltd., Japan, for the donation of PS-C and Novo Nordisk
A/S, Denmark, for the sample of N-435. We thank Prof.
Kurt Faber for useful comments and suggestions.
1
Supporting Information Available: Copies of H NMR
and 13C NMR spectra of compounds 1a-h and 5a-h. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO0478252
J. Org. Chem, Vol. 70, No. 7, 2005 2587