Dynamic kinetic resolution of γ-hydroxy acid derivatives

Article abstract of DOI:10.1016/S0040-4039(02)00418-5

Enzymatic resolution and dynamic kinetic resolution of γ-hydroxy acid derivatives 1 have been investigated. Efficient kinetic resolution was obtained using Pseudomonas cepacia lipase in toluene (E value ～400). The combination of enzymatic kinetic resoluti

Full text of DOI:10.1016/S0040-4039(02)00418-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2983–2986
Dynamic kinetic resolution of g-hydroxy acid derivatives
Ann-Britt L. Runmo,a Oscar Pa`mies,a Kurt Faberb and Jan-E. Ba¨ckvalla,*
aDepartment of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-10691 Stockholm, Sweden
bDepartment of Organic & Bioorganic Chemistry, University of Graz, A-8010 Graz, Austria
Received 11 December 2001; revised 11 February 2002; accepted 28 February 2002
Abstract—Enzymatic resolution and dynamic kinetic resolution of g-hydroxy acid derivatives 1 have been investigated. Efficient
kinetic resolution was obtained using Pseudomonas cepacia lipase in toluene (E value ꢀ400). The combination of enzymatic
kinetic resolution with a ruthenium-catalyzed racemization resulted in an efficient dynamic kinetic resolution. The use of a
hydrogen source to depress ketone formation in the dynamic kinetic resolution yields the corresponding acetates in good yield (up
to 93%) and enantioselectivity (up to 99%). © 2002 Elsevier Science Ltd. All rights reserved.
alcohol derivatives2d–f,j,k,m,n we now report our novel
results on kinetic and dynamic kinetic resolution of
g-hydroxy acid derivatives.
During the last decade dynamic kinetic resolution
(DKR) has become an active and important area of
research in organic synthesis.1 DKR is a powerful tool
to prepare enantiomerically enriched compounds in
high yields1 that overcome the limitation of the maxi-
mum 50% yield in the traditional kinetic resolution
(KR).
g-Hydroxy acid esters constitute a more challenging
class of substrates than for example a- and b-hydroxy
acid esters due to their high tendency to undergo
lactonization. Preliminary experiments using ethyl 4-
hydroxypentanoate showed that both enzymatic and
non-enzymatic lactonization occurred under standard
dynamic kinetic resolution conditions (vide infra).7 In
order to avoid the enzymatic lactonization, the ethyl
group in the latter substrate was changed to a larger,
more sterically hindered tert-butyl ester 1a. This signifi-
cantly improved the outcome of the reaction but the
non-enzymatic lactonization leading to racemic lactone
was still a competing reaction.8 For this purpose, we
also investigated the use of the sterically hindered N,N-
diisopropyl-4-hydroxypentanamide (1b), since amides
are known to be less reactive than their corresponding
esters.
One of the easiest approaches to perform DKR is the
combination of the traditional enzymatic kinetic resolu-
tion with an in situ racemization of the substrate using
a transition metal catalyst.2 Recently, we and others
have applied this strategy in the DKR of secondary
alcohols by combining a lipase-catalyzed transesterifica-
tion with a ruthenium-catalyzed racemization.2d–n
The importance of optically active g-hydroxy acid
derivatives as chiral building blocks in the synthesis of
natural products and enantiomerically enriched lac-
tones is well established.3 Several approaches for the
preparation of enantiomerically pure g-hydroxy acid
derivatives have been developed.4 Among them, micro-
bial or enzymatic reductions have played a dominant
role.4c,d Lipase-catalyzed kinetic resolutions can be use-
ful alternatives, especially because coenzyme regenera-
tion, an inherent problem of enzymatic redox-reactions,
is not required.5 To the best of our knowledge, only a
few examples of lipase-catalyzed kinetic resolution of
g-hydroxy acid derivatives via either esterification or
transesterification have been reported.3d,6 In connection
with previous work on dynamic kinetic resolution of
The main requirement for an efficient DKR is that the
KR conditions should be compatible with the in situ
racemization process. Therefore, we screened different
OH
Lipase
p-Cl-C6H4-OAc (2)
OAc
R
R
O
O
Solvent
70 oC
1a R = OtBu
1b R = N(iPr)2
3a-b
* Corresponding author. Tel.: +46-(8)-674 71 78; fax: +46-(8)-15 49
08; e-mail: jeb@organ.su.se
Figure 1. Kinetic resolution of g-hydroxy acid derivatives.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00418-5

2984
A.-B. L. Runmo et al. / Tetrahedron Letters 43 (2002) 2983–2986
necessary to increase the relative rate of the racemiza-
tion compared to acylation. This was accomplished by
reducing the enzyme/ruthenium catalyst ratio, which
increased the enantiomeric excess of 3a to 89% (Table
2, entry 3). Further improvement of the enantioselectiv-
ity was obtained when the reaction was carried out at
60°C (Table 2, entry 4).13
lipases in the KR of 1 under various reaction condi-
tions, using p-chlorophenyl acetate (2) as the acyl
donor (Fig. 1).9 The latter is known to be compatible
with ruthenium-catalyzed racemization of alcohols.2d,e
The results are summarized in Table 1.
In a first set of experiments, we screened different
lipases for the KR of 1a in toluene. Even though
Candida antarctica lipase B (N-435) showed the highest
activity (entry 2), the best enantiomeric ratio (E) was
obtained using Pseudomonas cepacia lipase (PS-C, entry
3). Pseudomonas fluorescens lipase (PF) showed good
activity but the enantiomeric ratio was very low (entry
1). It is known that lipase-catalyzed kinetic resolutions
can be greatly influenced by solvent variation.10 There-
fore, we studied the solvent effect in the PS-C catalyzed
transesterification of 1a (entries 3–6). Although reaction
rates were similar in all the solvents, the best enan-
tiomeric ratio was observed in toluene (entry 3). Simi-
larly, for substrate 1b the combination of Pseudomonas
species lipase (PS-C) and toluene as solvent showed the
best enantiomeric ratio.
The DKR of N,N-diisopropyl-4-hydroxypentanamide
(1b) followed the same general trend as observed for
substrate 1a, but the efficiency of the process was
improved and no lactonization was observed with this
substrate (Table 2, entries 5–8). Thus, acetate 3b was
obtained in good yield (up to 93%) and high enan-
tiomeric excess (up to 99%) when molecular hydrogen
or 2,4-dimethyl-3-pentanol (6) was used as hydrogen
donor.
Comparing the dynamic kinetic resolution results with
those obtained by kinetic resolution, the efficiency of
the former method is striking: the yields are higher in
the dynamic process and the enantioselectivity is good
to excellent.
On the basis of our preliminary results on KR, we
combined the KR of g-hydroxy acid derivatives 1 using
lipase PS-C and the acyl donor 2 with a ruthenium-cat-
alyzed racemization process via hydrogen transfer with
the dimeric Ru-precatalyst 511 (Fig. 2). The results are
summarized in Table 2. Under ‘standard’ DKR condi-
tions,12 the formation of large amounts of the corre-
sponding ketone 4 was observed (Table 2, entries 1 and
5). The latter is formed in the racemization process.
Therefore, the use of a hydrogen source was needed to
shift the equilibrium back to alcohol 1. Several hydro-
gen donors including molecular hydrogen itself were
tried.
The equilibrium between 4a and 1a was successfully
shifted towards the alcohol 1a by the use of hydrogen
gas (1 bar). However, the racemization became slower
resulting in a drop of enantioselectivity (Table 2, entry
2). In order to improve the enantioselectivity it was
Figure 2. Dynamic kinetic resolution of g-hydroxy acid
derivatives 1a and 1b.
Table 1. Kinetic resolution of compound 1a and 1ba
Entry
Enzymeb
Solvent
Substrate
% 3c
% eed
Ee
1
PF
PhCH3
PhCH3
PhCH3
tBuOMe
C6H12
EtOAc
PhCH3
PhCH3
1a
1a
1a
1a
1a
1a
1b
1b
55
51
52
56
54
44
58
41
9
67
89
77
80
93
30
99
1.3
10
68
34
31
60
2f
3
N-435
PS-C
PS-C
PS-C
PS-C
N-435
PS-C
4
5
6
7
3
8g
400h
a Unless otherwise noted, all reactions were performed on a 0.2 mmol scale for 4 h using 20 mg of enzyme (for a typical experiment see Ref. 9).
b PF=Pseudomonas fluorescens lipase, N-435=Candida antarctica lipase B, PS-C=Pseudomonas cepacia lipase.
c Determined by 1H NMR.
d Determined by GC using a CP-Chirasil-Dex CB column using racemic compounds as references.
e Enantiomeric ratio.10
f After 20 min.
g After 24 h, 1 mg of enzyme.
h Estimated error 30.

A.-B. L. Runmo et al. / Tetrahedron Letters 43 (2002) 2983–2986
Table 2. Dynamic kinetic resolution of compounds 1a
2985
Entry
Substrate
H-sourceb
T (°C)
% 3c
% 4c
% eed
1
2
1a
1a
1a
1a
1b
1b
1b
1b
1b
–
70
70
70
60
70
70
70
70
70
43
80
65
70
57
89
70
77
93
50
3
4
3
43
3
10
10
2
93
71
89
94
99
96
98
98
98
H2
H2
H2
–
H2
H2
6
3e
4f
5
6
7g
8h
9h,i
6
a Unless otherwise noted, all reactions were performed on a 0.1 mmol scale for 48 h using 5 mg of enzyme as described for the typical experiment
in Ref. 12.
b H2 (1 bar) was added in the beginning and 6 was added after 24 h.
c Determined by 1H NMR.
d Determined by GC using a CP-Chirasil-Dex CB column.
e 1 mg of enzyme and 6 mol% of 5.
f 3 mg of enzyme and 6 mol% of 5.
g 4 mg of enzyme and 6 mol% of 5, yield determined after 96 h.
h After 24 h reaction time 0.5 equiv. of 2,4-dimethyl-3-pentanol (6) was added.
i The reaction was performed on a 0.8 mmol scale using 6 mol% of 5; yield determined after 72 h.
2 (3.9 eq.)
5 (6 mol %)
6 (0.5 eq)
(i) LiOH
OAc
PS-C lipase
Toluene 70 oC
(86%)
N(iPr)2
MeOH, rt
1b
O
(ii) 0.4 M HCl in
MeOH:H2O (80:20)
70 oC
O
O
3b
7
98% ee
92% ee
Figure 3. Synthesis of lactone 7 from racemic alcohol 1b.
This new DKR procedure was applied to the practical
synthesis of the versatile intermediate (R)-5-methyltetra-
hydrofuran-2-one (7).14 The hydrogen source used in this
reaction was 2,4-dimethyl-3-pentanol (6). In our group
we have recently discovered that 6 is compatible with the
enzymatic DKR as a mild and efficient hydrogen source.
Thus, the enantiomerically enriched acetate 3b was
isolated in 86% yield from 1b on a 0.8 mmol scale with
an enantioselectivity of 98% following the general proce-
dure of Ref. 12. Acetate 3b was transformed to the
(R)-lactone 7 via a one-pot two-step procedure involving
hydrolysis with LiOH in methanol followed by acid-cat-
alyzed lactone formation (Fig. 3). The ee of 7 was
determined by chiral GC and the absolute configuration
was established by comparison with literature data.15
Acknowledgements
Financial support from the Swedish 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 Dr. Fernando F. Huerta for his
useful comments and suggestions.
References
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In summary, we have demonstrated that ruthenium- and
enzyme-catalyzed dynamic kinetic resolution of sub-
strates 1a and 1b is a valuable tool for preparing
enantiomerically enriched g-hydroxy acid derivatives in
good yields in a single step. This provides an easy and
straightforward method to synthesize the corresponding
enantiomerically enriched lactones. We also reported the
potential use of alcohol 6 as a mild hydrogen source in
the DKR process. Further studies to investigate the scope
and limitations of this procedure are on the way.

2986
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1
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a typical experiment 1 (0.1 mmol) and p-
ClC6H4OAc 2 (66 mg, 0.39 mmol) in toluene (1 ml) was
degassed with argon for 1 min and added to a Schlenk
tube containing PS-C (5 mg) and the ruthenium catalyst
5 (5.4 mg, 4 mol%). The mixture was stirred at 70°C for
48 h. The mixture was filtered through a silica pad to
remove the enzyme and washed with Et2O (3×3 ml), the
solvent was evaporated and the residue was analyzed
1
with GC and H NMR; (b) In the 0.8 mmol experiment
(Fig. 3) 1b (161 mg, 0.8 mmol), 2 (528 mg, 3.1 mmol), 5
(65 mg, 6 mol%), and PS-C (40 mg) in toluene (8 mL)
were used. After 24 h 6 (56 ml, 0.4 mmol) was added and
the reaction was stirred for another 48 h.
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