Enzymatic kinetic resolution and chemoenzymatic dynamic kinetic resolution of δ-hydroxy esters. An efficient route to chiral δ-lactones

Article abstract of DOI:10.1021/jo016096c

A successful kinetic resolution of a racemic mixture of δ-hydroxy esters 1 was obtained via lipase-catalyzed transesterification (E value up to 360). The combination of the enzymatic kinetic resolution with a ruthenium-catalyzed alcohol racemization led t

Full text of DOI:10.1021/jo016096c

J . Org. Chem. 2002, 67, 1261-1265
1261
En zym a tic Kin etic Resolu tion a n d Ch em oen zym a tic Dyn a m ic
Kin etic Resolu tion of δ-Hyd r oxy Ester s. An Efficien t Rou te to
Ch ir a l δ-La cton es
Oscar Pa`mies and J an-E. Ba¨ckvall*
Arrhenius Laboratory, Department of Organic Chemistry, Stockholm University,
SE-106 91 Stockholm, Sweden
jeb@organ.su.se
Received September 7, 2001
A successful kinetic resolution of a racemic mixture of δ-hydroxy esters 1 was obtained via lipase-
catalyzed transesterification (E value up to 360). The combination of the enzymatic kinetic resolution
with a ruthenium-catalyzed alcohol racemization led to an efficient dynamic kinetic resolution (ee
up to 99% and conversion up to 92%). The synthetic utility of this procedure was illustrated by the
practical syntheses of δ-lactones (R)-6-methyl- and (R)-6-ethyl-tetrahydropyran-2-one and (S)-5-
(tert-butyldimethylsiloxy)heptanal. The former are important building blocks in the synthesis of
natural products and biologically active compounds, and the latter is a key intermediate in the
synthesis of widely used commercial insecticide Spinosyn A.
In tr od u ction
via microbial or enzymatic reduction followed by chemical
lactonization has had a dominant role.5 Lipase-catalyzed
kinetic resolutions of racemic substrates can be useful
alternatives, especially because coenzyme regeneration,
an inherent problem of processes based on enzymatic
reductions, is not required.6
The importance of enantiopure δ-hydroxy esters as
precursors of versatile building blocks in asymmetric
synthesis is well established. Perhaps the most important
building blocks that can be easily synthesized from
δ-hydroxy esters are the δ-lactones. The interest in chiral
δ-lactones is due to the fact that they are present in a
variety of natural products isolated from insects, plants,
fungi, and marine organisms, especially in attractants
and pheromones.1 In addition, lactones are important
building blocks for the synthesis of natural products, such
as alkaloids and terpenoids,2 and biologically active
compounds (e.g., antitumor and antiviral agents).3
In the last few years, only a few studies dealing with
the lipase-catalyzed kinetic resolution (KR) of δ-hydroxy
esters by either intramolecular esterification or transes-
terification have been reported.6,7 The efficiency of the
KR for this type of substrate is usually rather low due to
the competition with the enzyme-catalyzed esterification
and transesterification.6 Moreover, a major drawback
with KR is that the yield is limited to a maximum of 50%.
By applying dynamic kinetic resolution (DKR), this
limitation can be overcome. With DKR the unreactive
enantiomer, is continuously racemized and the product
can be obtained optically pure in 100% yield (Scheme 1).
To the best of our knowledge the only example of the use
of DKR for obtaining δ-hydroxy esters was carried out
using a special class of substrates, the γ-alkylated â-δ-
keto esters, and alcohol dehydrogenase from Lactobacil-
lusa brevis (refLBADH).8
Many approaches for the preparation of enantiomeri-
cally pure δ-lactones have been developed.4 Among these
methods, the reduction of the corresponding keto esters
* To whom correspondence should be addressed.
(1) For example, see: (a) Fandeur, T.; Moretti, C.; Polonski, J . Planta
Med. 1985, 5, 20. (b) Arisawa, M.; Fujita, A.; Norita, N.; Kinghorn, A.
D.; Cordell, G. A.; Farnsworth, N. R. Planta Med. 1985, 5, 348. (c)
Genusekera, S. P.; Genusekera, M.; Longley, R. E.; Shulte, G. K. J .
Org. Chem. 1990, 55, 4912. (d) Sun, H. D.; Qiu, S. X.; Lin, L. Z.; Zhang,
R. P.; Zhon, Y.; Zheng, Q. T.; J ohnson, M. E.; Fong, H. H. S.;
Farnsworth, N. R.; Cordell, G. A. J . Nat. Prod. 1997, 60, 203.
(2) See for instance: (a) Davies-Coleman, M. T.; Rivett, D. E. A. Prog.
Chem. Nat. Prod. 1989, 55, 1. (b) J efford, C. W.; J aggi, D.; Sledeski,
A. W.; Boukouvalas, J . In Studies in Natural Products Chemistry;
Rahman, A., Ed.; Elsevier: Amsterdam, 1989; Vol 3, pp 157-171. (c)
Paquette, L. A.; Wang, T. Z.; Pinard, E. J . Am. Chem. Soc. 1995, 117,
1455. (d) Nemoto, H.; Tanabe, T.; Fukumoto, K. J . Org. Chem. 1995,
60, 6785.
Following our investigations dealing with bioconver-
sions,9 we now report on the efficient kinetic resolution
(5) For instance, see: (a) Utaka, M.; Watabu, H.; Takeda, A. J . Org.
Chem. 1987, 52, 4363. (b) Cotterill, I. C.; Dorman, G.; Faber, K.;
J aouhari, R.; Roberts, S. M.; Scheinmann, F.; Spreitz, J .; Sutherland,
A. G.; Winders, J . A.; Wakefield, B. J . J . Chem. Soc., Chem. Commun.
1990, 1661. (c) Keinan, E.; Sinha, S. C.; Sinha-Bagchi, A. J . Chem.
Soc., Perkin Trans. 1 1990, 3333. (d) Fantin, G.; Fogagnolo, M.; Medici,
A.; Pedrini, P.; Poli, S.; Gardini, F.; Guerzoni, E. Tetrahedron:
Asymmetry 1992, 2, 107. (e) Cohen, T.; Tong, S. Tetrahedron 1997,
53, 9487. (f) Forzato, C.; Nitti, P.; Pitacco, G.; Valentin, E. Tetrahe-
dron: Asymmetry 1999, 10, 1243. (g) Fogal, E.; Forzato, C.; Nitti, P.;
Pitaco, G.; Valentin, E. Tetrahedron: Asymmetry 2000, 11, 2599. (h)
Wu, Y.; Esser, L.; De Brabander, J . K. Angew. Chem., Int. Ed. 2000,
39, 4308.
(6) Engel, K. H.; Bohnen, M.; Dobe, M. Enzyme Microb. Technol.
1991, 13, 655.
(7) (a) Huffer, M.; Schereier, P. Tetrahedron: Asymmetry 1991, 2,
1157. (b) Sugai, T.; Hamada, K.; Akeboshi, T.; Ikeda, H.; Ohta, H.
Synlett 1997, 983.
(8) (a) J i, A.; Wolberg, M.; Hummel, W.; Wandrey, C.; Mu¨ller, M.
Chem. Commun. 2001, 57. (b) Woldberg, M.; J i, A.; Hummel, W.;
Mu¨ller, M. Synthesis 2001, 937.
(3) For some recent applications, see: (a) Fukui, H.; Tsuchiya, Y.;
Fujita, K.; Nakagawa, T.; Koshino, H.; Nakata, T. Bioorg. Med. Chem.
Lett. 1997, 7, 2081. (b) Uchida, T.; Fukui, H.; Tsuchiya, Y.; Fujita, K.
J P Patent 10072468.
(4) For some representative examples, see: (a) Ley, S. V.; Cox, L.
R.; Meek, G. Chem. Rev. 1995, 96, 423. (b) Mulzer, J . In Comprehensive
Organic Functional Group Transformations; Katrizky, A. R., Meth-
Cotn, O., Rees, C. W., Eds.; Elsevier: Oxford, 1995; Vol. 5, pp 121-
179. (c) Downham, R.; Edwards, P. J .; Entwistle, D. A.; Hughes, A. B.;
Kim, K. S.; Ley, S. V. Tretahedron: Asymmetry 1995, 6, 2403. (d)
Sa´nchez-Sancho, F.; Valverde, S.; Herrado´n, F. Tetrahedron: Asym-
metry 1996, 6, 3209. (e) Ager, D. J .; Laneman, S. A. Tetrahedron:
Asymmetry 1997, 8, 3327. (f) Nair, V.; Prabhakaran, George, T. G.
Tetrahedron 1997, 8, 15061. (g) Ramachandran, P. V.; Krzeminski,
M. P.; Ram Reddy, M. V.; Brown, H. C. Tetrahedron: Asymmetry 1999,
10, 11. (h) Hsu, J . L.; Chen, C. T.; Fang, J . M. Org. Lett. 1999, 1, 1989.
10.1021/jo016096c CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/24/2002

1262 J . Org. Chem., Vol. 67, No. 4, 2002
Pa`mies and Ba¨ckvall
Ta ble 1. Kin etic Resolu tion of 1a
Sch em e 1. Dyn a m ic Kin etic Resolu tion
sub-
% convn
entry strate enzymeb
solvent
toluene
ratec (t/h)d % eee Ef
of tert-butyl δ-hydroxy esters 1 via lipase-catalyzed
esterification. We also report on the combination of the
enzymatic kinetic resolution with ruthenium-catalyzed
alcohol isomerization that results in an efficient dynamic
kinetic resolution. The viability of this strategy is il-
lustrated by the practical syntheses of (R)-6-methyltet-
rahydropyran-2-one, widely used as a building block (e.g.,
in the preparation of antiviral and antitumoral agent
mycalamide A),3 the naturally occurring fragrance (R)-
6-ethyltetrahydropyran-2-one,10 and (S)-5-(tert-butyldi-
methylsiloxy)heptanal, a building block used in the
synthesis of widely used commercial insecticide Spinosyn
A.11
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1b
AK
7
38 (8)
56 47 (1)
21
98
98
182
282
N-435 toluene
PS-C toluene
37 (2.5) >99g >360
PS-C cyclohexane 45 36 (1)
99
99
99
98
98
349
360
315
282
202
PS-C t-BuOMe
PS-C (i-Pr)2O
PS-C (n-Bu)2O
PS-C toluene
46 37 (1)
32 32 (1)
28
27
47 (2.5)
41 (2.5)
a
Reactions were performed on a 0.1 mmol scale with 5 mg of
b
enzyme and 3 equiv of 3 in 1 mL of solvent at 60 °C. AK ) P.
fluorescens lipase, N-435 ) C. antarctica lipase B, PS-C ) P.
cepacia lipase. c Initial rate (µmol × h-1). Determined by NMR.
d
e % ee of 2 determined by GC. f Enantiomeric ratio. The other
g
enantiomer was not observed.
influenced by variation of solvent.12 We therefore screened
the acetylation of rac-1a with 3 at 60 °C in the presence
of lipase PS-C in various nonpolar solvents (entries 4-8).
The results showed that the reaction rates are very
dependent on the solvent. However, the variation of
solvent did not considerably affect the enantioselectivity.
On the basis of our preliminary results on KR, we
combined the KR of δ-hydroxy esters 1 using PS-C and
the acyl donor 3 with a ruthenium-catalyzed racemization
process via hydrogen transfer with the so-called Shvo
catalyst 4 in toluene.13 Despite the fact that the KR was
Resu lts a n d Discu ssion
In the first set of experiments, the efficiency of different
commercially available lipases to catalyze the transes-
terification of chiral δ-hydroxy esters was investigated.
For this purpose, racemic δ-hydroxy tert-butyl esters 1
were chosen as models to avoid the competition with the
enzyme-catalyzed intramolecular esterification.6 A neces-
sary condition for a successful DKR is that the KR
conditions should be compatible with the racemization
process.9 Therefore, we screened different lipases in the
kinetic resolution of 1 under different reaction conditions,
using p-chlorophenyl acetate (3) as acyl donor. The latter
is known to be compatible with Ru-catalyzed racemiza-
tion of alcohols.9 The results are summarized in Table 1.
In a control experiment, it was shown that the reaction
did not proceed in the absence of enzyme. Moreover, the
formation of six-membered lactones via either thermal
lactonization or enzyme-catalyzed esterification was not
observed.
Although the enzyme Candida antarctica lipase B
(Novozyme 435, N-435) showed the highest activity (entry
2), the enantiomeric ratio was better using Pseudomonas
cepacia lipase (PS-C) (E > 360, entry 3). Lipase Pseudomo-
nas fluorescens (AK) showed low activity (entry 1). The
other examined lipases (lipase from porcine pancreas,
Candida rugosa, and Aspergillus sp.) showed either very
low conversion or no reaction after 24 h. Thus, from all
the lipases tested, the optimum result with respect to
both enantioselectivity and reaction rate was achieved
using lipase PS-C.
faster in ether solvents, i.e., tert-butyl methyl ether, than
in toluene (Table 1), the latter was chosen as a solvent
to perform DKR due to the higher solubility of the Ru
catalyst 4 in toluene than in ethers, and this results in
higher racemization rates.9f The results are summarized
in Table 2.
Under “standard” conditions (i.e., 60 °C, 5 mg of PS-
C, and 4 mol % 4), the formation of large amounts of the
corresponding ketone 5, formed during the hydrogen-
transfer process, was observed (entry 1). Moreover, the
racemization proceeded slowly, resulting in a slightly
lower enantioselectivity than the maximum observed in
the KR (99%). In previous studies we have shown that
increasing the temperature leads to a significantly higher
racemization rate.9f,g Therefore, we performed the DKR
at 70 °C.14 At 70 °C, the activity and enantioselectivity
were better; however, high amounts of ketone 5a were
also formed.
It is well-known that enantioselectivity and reaction
rates in the kinetic resolutions by lipases can be greatly
(9) (a) Larsson, A. L. E.; Persson, B. A.; Ba¨ckvall, J . E. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1211. (b) Persson, B. A.; Larsson, A.
L. E.; LeRay, M.; Ba¨ckvall, J . E. J . Am. Chem. Soc. 1999, 121, 1645.
(c) Persson, B. A.; Huerta, F. F.; Ba¨ckvall, J . E. J . Org. Chem. 1999,
64, 5237. (d) Huerta, F. F.; Laxmi, Y. R. S.; Ba¨ckvall, J . E. Org. Lett.
2000, 2, 1037. (e) Huerta, F. F.; Ba¨ckvall, J . E. Org. Lett. 2001, 3, 1209.
(f) Pa`mies, O.; Ba¨ckvall, J . E. J . Org. Chem. 2001, 66, 4022. (g) Pa`mies,
O.; Ba¨ckvall, J . E. Adv. Synth. Catal., in press.
Several attempts to increase the efficiency of the
process by reducing the amount of ketone have been
(12) a) Faber, K. Biotransformations in Organic Media, 4th ed.;
Springer: Graz, Austria, 2000. (b) Ema, T.; Maeno, S.; Takaya, Y.;
Sakai, T.; Utaka, M. Tetrahedron: Asymmetry 1996, 7, 625.
(13) Menasche, N.; Shvo, Y. Organometallics 1991, 10, 3885.
(14) PS-C lipase is thermostable up to 70-80 °C.
(10) Imagi, S.; Wada, S.; Ito, N.; Hasebe, A. J P Patent 11189783.
(11) Paquette, L. A.; Collado, I.; Purdie, M. J . Am. Chem. Soc. 1998,
120, 2553.

Kinetic Resolution of δ-Hydroxy Esters
J . Org. Chem., Vol. 67, No. 4, 2002 1263
Ta ble 2. Dyn a m ic Kin etic Resolu tion a
Sch em e 2. Syn th esis of (R)-La cton es 10a
entry substrate H-donor T/°C t/h
% 2b
% 5b % eec
a
Reagents and conditions: (i) LiOH, toluene/MeOH; (ii) HCl
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
60
70
70
70
70
70
70
70
70
70
70
70
70
70
70
48 59
37
38
34
25
13
7
97
99
99
98
98
98
99
99
96
89
99
99
98
95
98
(pH 1).
2
24 52
Sch em e 3. Syn th esis of Com p ou n d (S)-12a
3
48 66
48 65
48 86
72 92
4
6d
6d
6d
6f
7f
8f
9
5e
6e
7e
48 63
25
2
4
8e
48 50g
48 54
9e
10
11h
12h,i
13h,i
14e
15k
48 78
48 65
9
9
48 71
9
92 89 (80)j
72 91
6d
9
8
92 87 (81)j
a
Reactions were performed on a 0.1 mmol scale with 5 mg of
PS-C, 4 mol % 4, and 3 equiv of acyl donor in 1 mL of toluene.
b
d
Determined by 1H NMR. c % ee of 2a determined by HPLC. 0.5
equiv of H-donor used. e H-donor added after 24 h. f 1 equiv of
H-donor used. 27% lactone formed. 1 mg of PS-C used. 6 mol
% 4. Reaction performed on a 0.6 mmol scale. Isolated yield in
parentheses. 0.75 mg of PS-C and 6 mol % 4 used.
g
h
i
j
a
k
Reagents and conditions: (i) PS-C, 3, toluene (8 h, 41%); (ii)
TBSOTf, 2,6-lutidine, CH2Cl2 (91%); (iii) DIBALH, CH2Cl2 (88%).
carried out. Thus, several hydrogen sources, 6-9, were
tested with the aim to push the equilibrium back to the
alcohol 1.
(89% ee, entry 10) than in the kinetic resolution experi-
ments (see Table 1). This is mainly due to a decrease of
the racemization rate under 1 bar of hydrogen gas. To
obtain better enantioselectivity, one has to take full
advantage of the DKR by increasing the ratio of the rate
of racemization and rate of enzymatic acetylation. Thus,
by reducing the enzyme/ruthenium catalyst ratio, the
relative rate of enzymatic acylation toward racemization
decreased and the enantioselectivity was substantially
improved (entries 11-13). Comparing these results with
those using 6, we can conclude that, although longer
reaction times were needed, the use of molecular hydro-
gen is advantageous since no byproducts are formed.16
The addition of 0.5 equiv of 2,4-dimethyl-3-pentanol
(6) to the reaction mixture reduced the amount of ketone
5a considerably (25%), but did not show an improvement
in the formation of acetate 2a (entry 4). This can be
attributed to the competition between alcohols 6 and 1
in the transfer hydrogenation process. To minimize this
competitive reaction, we decided to add 6 (0.5 equiv) after
24 h, when almost no alcohol 1 is present in the reaction
mixture (entries 5 and 6). This significantly increases the
efficiency of the process, and the desired acetate 2a was
formed in 92% yield after 72 h of reaction in almost
enantiomerically pure form (98% ee, entry 6). The addi-
tion of larger amounts of 6 had a negative effect on the
activity (entry 7).
The use of formic acid (7) inhibited the formation of
undesired ketone 5a , but catalyzed the lactone formation
via acid-catalyzed reaction (27% lactone after 48 h, entry
8).
The use of a mixture of formic acid/triethylamine,
which has been successfully used in DKR involving
hydrogen-transfer racemization,15 inhibited both ketone
and lactone formation, however, the activity and enan-
tioselectivity was low (entry 9).
The DKR of δ-hydroxy ester 1b followed the same
trend as observed for substrate 1a . Thus, both good yields
and excellent enantioselectivity (98% ee) were obtained
using molecular hydrogen (entry 15).
A wide range of synthetic applications of this dynamic
kinetic resolution procedure can be envisaged. One
example is the practical synthesis of the versatile inter-
mediates (R)-6-methyl- and (R)-6-ethyltetrahydropyran-
2-one ((R)-10a and (R)-10b) (Scheme 2). Dynamic kinetic
resolution of the racemic δ-hydroxy esters 1a and 1b
afforded the corresponding acetates (R)-2a and (R)-2b in
98% ee (entries 13 and 15, Table 2). The transformation
of the latter to (R)-lactones (R)-10a and (R)-10b, respec-
tively, was performed in a one-pot two-step procedure
involving hydrolysis with LiOH in toluene/methanol (1/
1) followed by acid-catalyzed lactone formation.
The lipase-catalyzed transesterification was applied to
the practical synthesis of (S)-5-(tert-butyldimethylsiloxy)-
heptanal ((S)-12), which is a key intermediate in the
The use of hydrogen gas (1 bar) inhibited the formation
of ketone completely. However, the DKR under these
conditions gave the acetate in lower enantioselectivity
(15) J ung, H. M.; Koh, J . H.; Kim, M. J .; Park, J . Org. Lett. 2000, 2,
2487.
(16) The separation of 2,4-dimethylpentan-3-one was difficult in the
purification of acetates 2.

1264 J . Org. Chem., Vol. 67, No. 4, 2002
Pa`mies and Ba¨ckvall
3
3J H-H ) 7.2 Hz), 2.45 (t, 1H, CH2, J H-H ) 7.6 Hz). 13C NMR:
δ 8.0 (CH3), 19.4 (CH2), 28.3 (CH3, t-Bu), 34.8 (CH2), 36.1 (CH2-
Me), 41.4 (CH2), 80.5 (C, t-Bu), 172.8 (CO), 211.1 (CO).
Gen er a l P r oced u r e for th e P r ep a r a tion of δ-Hyd r oxy
Ester s. ter t-Bu tyl 5-Hyd r oxyh exa n oa te (1a ). To a solution
of 5a (0.93 g, 5 mmol) in methanol (25 mL) was added NaBH4
(94.6 mg, 2.5 mmol) at 0 °C. The reaction mixture was stirred
for 2 h. The mixture was then quenched with saturated NH4-
Cl (25 mL), and the methanol was evaporated. The mixture
was extracted with CH2Cl2 (3 × 25 mL), and the combined
ether phases were dried over Na2SO4 and evaporated. The
residue was purified by flash chromatography to give 0.86 g
synthesis of Spinosyn A, a commercially important
insecticidal macrocyclic lactone (Scheme 3).11 The kinetic
resolution of rac-1b afforded (S)-1b in 41% yield and in
essentially enantiomerically pure form (99% ee). The
protection of secondary carbinol (S)-1b as the silyl ether
(S)-11 followed by reduction of the ester group by
DIBALH in THF at -78 °C afforded (S)-12 in good yield.
The enantiomer (R)-12 can be obtained more efficiently
by using the new DKR procedure disclosed here since the
in situ hydrolysis of acetate (R)-2b with LiOH gave
quantitatively tert-butyl (R)-5-hydroxyheptanoate in es-
sentially enantiomerically pure form (98% ee).
1
(92%) of alcohol 1a as a colorless oil. H NMR: δ 1.19 (d, 3H,
3
CH3, J H-H ) 6.4 Hz), 1.43 (s, 9H, CH3, t-Bu), 1.46 (m, 2H,
3
CH2), 1.65 (m, 2H, CH2), 2.24 (dt, 2H, CH2, J H-H ) 7.2 Hz,
3J H-H ) 1.2 Hz), 3.80 (m, 1H, CH). 13C NMR: δ 21.3 (CH2),
23.7 (CH2), 28.3 (CH3, t-Bu), 35.5 (CH3), 38.5 (CH2), 67.8 (CH),
80.4 (C, t-Bu), 173.4 (CO). GC retention times: 20.9 (S), 20.9
(R).
Con clu sion
We have described a highly selective kinetic resolution
of racemic δ-hydroxy esters 1 via inexpensive lipase PS-C
catalyzed transesterification (E values >360). This en-
zymatic kinetic resolution combined with ruthenium-
catalyzed alcohol isomerization led to an efficient dy-
namic kinetic resolution. The efficiency of the process
together with the easy transformation of these δ-acetoxy
esters to δ-lactones makes the present method an attrac-
tive alternative to existing methods for obtaining δ-lac-
tones in enantiomerically pure form.
ter t-Bu tyl 5-Hyd r oxyh ep ta n oa te (1b). Yield: 0.92 g
1
3
(91%). H NMR: δ 0.93 (t, 3H, CH3, J H-H) 7.6 Hz), 1.45 (s,
9H, CH3, t-Bu), 1.48 (m, 4H, CH2, CH2Me), 1.68 (m, 2H, CH2),
2.24 (t, 2H, CH2, 3J H-H ) 6.8 Hz), 3.51 (m, 1H, CH). 13C NMR:
δ 10.1 (CH3), 21.3 (CH2), 28.3 (CH3, t-Bu), 30.5 (CH2Me), 35.6
(CH2), 36.5 (CH2), 72.9 (CH), 80.4 (C, t-Bu), 173.4 (CO). GC
retention times: 33.8 (S), 34.0 (R).
Gen er a l P r oced u r e for th e P r ep a r a tion of δ-Acetoxy
Ester s. ter t-Bu tyl 5-Acetoxyh exa n oa te (2a ). To a solution
of 1a (0.19 g, 1 mmol) in dichloromethane (5 mL) were added
triethylamine (1 mL) and acetic anhydride (5 mmol) at 0 °C.
The reaction was then stirred at room temperature overnight.
The mixture was then evaporated and the residue purified by
chromatography to give 207 mg (90%) of acetate 2a as a
Exp er im en ta l P r oced u r es
Gen er a l Exp er im en ta l P r oced u r es. All reactions were
carried out under a dry argon atmosphere in oven-dried
glassware. Solvents were purified by standard procedures. All
other reagents are commercially available and were used
without further purification. Acyl donor 3 was prepared
according to a literature procedure.9b Ruthenium catalyst 4
was synthesized according to a literature procedure9d and
recrystallized from CH2Cl2/pentane prior to use. Novozym-435
was a generous gift from Novo Nordisk A/S, Denmark. Lipases
PS-C and AK were a generous gift from Amano Pharmaceuti-
cal Co. Ltd., J apan. 1H and 13C NMR spectra were recorded in
CDCl3 at 400 and 100 MHz, respectively. Solvents for extrac-
tion and chromatography were technical grade and distilled
before use. Column chromatography was performed with
Merck 60 silica gel. The enantiomeric excess of 2 was deter-
mined by analytical GLC employing a CP-Chirasil-Dex CB
column using racemic compounds as references. The oven
temperature was 110 °C for 30 min and then was increased 5
°C/min to 200 °C.
colorless oil. 1H NMR: δ 1.20 (d, 3H, CH3, J H-H ) 6.4 Hz),
3
1.43 (s, 9H, CH3, t-Bu), 1.57 (m, 4H, CH2), 2.01 (s, 3H, CH3-
CO), 2.21 (t, 2H, CH2, J H-H ) 7.2 Hz), 4.89 (m, 1H, CH). 13C
3
NMR: δ 20.1 (CH3), 21.1 (CH2), 21.6 (CH3CO), 28.3 (CH3, t-Bu),
35.4 (2C, CH2), 70.7 (CH), 80.4 (C, t-Bu), 170.9 (CO), 172.9
(CO). GC retention times: 39.2 (S), 39.5 (R).
ter t-Bu tyl 5-Acetoxyh ep ta n oa te (2b). Yield: 232 mg
1
3
(95%). H NMR: δ 0.86 (t, 3H, CH3, J H-H ) 7.6 Hz), 1.42 (s,
9H, CH3, t-Bu), 1.56 (m, 6H, 2 × CH2, CH2Me), 2.03 (s, 3H,
3
CH3CO), 2.20 (t, 2H, CH2, J H-H ) 7.2 Hz), 4.78 (m, 1H, CH).
13C NMR: δ 9.74 (CH3), 21.0 (CH2), 21.4 (CH3CO), 27.0 (CH2-
Me), 28.3 (CH3, t-Bu), 33.0 (CH2), 35.4 (CH2), 75.2 (CH), 80.3
(C, t-Bu), 171.1 (CO), 172.9 (CO). GC retention times: 23.8
(S), 30.5 (R).
Gen er a l P r oced u r e for th e Kin etic Resolu tion of
δ-H yd r oxy E st er s. ter t-Bu t yl (R)-5-Acet oxyh exa n oa t e
((R)-2a ). To a solution of rac-1a (18.8 mg, 0.1 mmol) and 3
(66 mg, 0.3 mmol) in dry toluene (1 mL) under argon (5 min
of argon bubbling) was added the lipase PS-C (5 mg). The
resulting reaction mixture was stirred at 60 °C for 2.5 h. The
enzyme was then filtered off and washed with toluene (3 × 5
mL). The combined toluene phases were evaporated, and the
residue was analyzed. The product (R)-2a was obtained in 37%
conversion and in >99% ee.
Gen er a l P r oced u r e for th e DKR of δ-Hyd r oxy Ester s.
ter t-Bu tyl (R)-5-Acetoxyh exa n oa te ((R)-2a ). To a solution
of rac-1a (112.8 mg, 0.6 mmol) and 3 (336 mg, 1.8 mmol) in
dry toluene (6 mL) under argon were added ruthenium catalyst
4 (48.7 mg, 6 mol %) and lipase PS-C (6 mg). The resulting
reaction mixture was bubbled with H2 for 5 min, and the
reaction mixture was stirred at 70 °C for 72 h under a
hydrogen atmosphere. The enzyme was then filtered off and
washed with toluene (3 × 5 mL). The combined toluene phases
were evaporated, and the product was purified by flash
chromatography (pentane/ethyl acetate, 15/1) to yield 110.4
mg (80%) of (R)-2a in 98% ee.
Gen er a l P r oced u r e for th e Syn th esis of δ-Keto Ester s.
ter t-Bu tyl 5-Ketoh exa n oa te (5a ). To a solution of 5-keto-
hexanoic acid (1.30 g, 10 mmol) in CH2Cl2 (100 mL) under an
argon atmosphere were added DCC (2.64 g, 10 mmol), tert-
butyl alcohol (5 mL), and 4-DMAP (12.2 mg, 0.1 mmol). After
40 h, the reaction was quenched with saturated NaHCO3 (100
mL). The mixture was extracted with CH2Cl2 (3 × 50 mL),
and the combined ether phases were dried over Na2SO4 and
evaporated. The residue was purified by flash chromatography
(pentane/ethyl acetate, 4/1) to give 1.07 g (58%) of ketone 5a
1
as a colorless oil. H NMR: δ 1.43 (s, 9H, CH3, t-Bu), 1.84 (q,
3
3
2H, CH2, J H-H ) 7.2 Hz), 2.23 (t, 2H, CH2, J H-H ) 7.2 Hz),
2.47 (t, 2H, CH2, J H-H ) 7.2 Hz). 13C NMR: δ 19.3 (CH2),
28.3 (CH3, t-Bu), 30.1 (CH3), 34.7 (CH2), 42.8 (CH2), 80.5 (C,
t-Bu), 172.7 (CO), 208.4 (CO).
3
ter t-Bu tyl 5-Ketoh ep ta n oa te (5b). Treatment of 5-keto-
heptanoic acid17 (1.44 g, 10 mmol) as described for compound
5a afforded δ-keto ester 5b, which was purified by flash
chromatography (pentane/ethyl acetate, 4/1) to give 0.98 g
Gen er a l P r oced u r e for th e Syn th esis of (R)-La cton es
10. (R)-6-Meth yltetr a h yd r op yr a n -2-on e ((R)-10a ). To a
solution of δ-acetoxy ester (R)-2a (92.1 mg, 0.4 mmol) in
toluene/methanol (4 mL) was added LiOH (12 mg, 0.5 mmol).
The solution was allowed to stir at room temperature for 12
h. Then the solution was acidified (pH 1) with HCl. The
1
3
(49%) as a colorless oil. H NMR: δ 1.04 (t, 3H, CH3, J H-H
)
3
7.2 Hz), 1.42 (s, 9H, CH3, t-Bu), 1.84 (q, 2H, CH2, J H-H ) 7.6
Hz), 2.22 (t, 2H, CH2, J H-H ) 7.6 Hz), 2.39 (t, 1H, CH2Me,
3
(17) Prepared by hydrolysis of methyl 5-ketoheptanoate.

Kinetic Resolution of δ-Hydroxy Esters
J . Org. Chem., Vol. 67, No. 4, 2002 1265
3
reaction was allowed to stir for 2 h at 60 °C. The mixture was
then evaporated, the residue was extracted with CH2Cl2 (3 ×
25 mL), and the combined organic phases were dried over Na2-
SO4 and evaporated to afford lactone 10a as a colorless oil (44
mg, 96%). The characterization data are in agreement with
t-Bu), 1.60 (m, 2H, CH2), 2.19 (t, 1H, CH2, J H-H) 7.6 Hz),
3.57 (m, 1H, CH). 13C NMR: δ -4.3 (CH3Si), -4.2 (CH3Si),
9.68 (CH3), 18.3 (CSi), 21.3 (CH2), 26.1 (CH3, t-BuSi), 28.3
(CH3, t-Bu), 29.8 (CH2Me), 36.0 (2C, CH2), 73.3 (CH), 80.1 (C,
t-Bu), 173.3 (CO).
those previously reported for (R)-10a 18 ([R]D +36.9 (c 1.82,
Syn th esis of (S)-5-(ter t-Bu tyld im eth ylsiloxy)h ep ta n a l
((S)-12). To a solution of (S)-11 (100 mg, 0.32 mmol) in CH2-
Cl2 (2 mL) was added dropwise DIBALH (0.33 mL of a 1 M
solution in hexanes, 0.33 mmol) at -78 °C. The solution was
then stirred for 1 h and quenched with MeOH (0.25 mL) and
saturated Rochelle’s salt solution (5 mL). The mixture was
extracted with ethyl acetate (5 × 10 mL), and the combined
organic phases were dried over Na2SO4 and evaporated. The
residue was purified by flash chromatography (pentane/ethyl
acetate, 15/1) to give 69 mg (88%) of 12 as a colorless oil. The
characterization data are in agreement with those previously
reported for (S)-12.11
20
EtOH) [lit.19 [R]D20 +37.2 (c 1.82, EtOH)]) and (R)-10b5a ([R]D
20
20
+54.1 (c 1.13, THF) [lit.5a [R]D +55.0 (c 1.13, THF]).
Syn th esis of ter t-Bu tyl (S)-5-(ter t-Bu tyld im eth ylsil-
oxy)h ep ta n oa te ((S)-11). tert-Butyldimethylsilyl triflate (114
µL, 0.5 mmol) was added to a solution of (S)-1b (94 mg, 0.46
mmol) and 2,6-lutidine (235 µL, 2 mmol) in CH2Cl2 (5 mL) at
0 °C. The solution was then stirred at room temperature for
90 min and quenched with a 10% aqueous citric acid solution
(5 mL). The mixture was extracted with CH2Cl2 (3 × 10 mL),
and the combined organic phases were dried over Na2SO4 and
evaporated. The residue was purified by flash chromatography
(pentane/ethyl acetate, 10/1) to give 132 mg (91%) of 11 as a
colorless oil. 1H NMR: δ 0.03 (s, 6H, CH3Si), 0.84 (m, 3H, CH3),
0.88 (s, 9H, CH3, t-BuSi), 1.42 (m, 13H, CH2, CH2Me, CH3,
Ackn owledgm en t. Financial support from the Swed-
ish Foundation for Strategic Research and the Swedish
Science Research Council is gratefully acknowledged.
We thank Prof. Kurt Faber and Dr. Fernando F. Huerta
for useful comments and suggestions.
(18) White, J . D.; Somers, T. C.; Reddy, G. N. J . Org. Chem. 1992,
57, 4991.
(19) Chen, J .; Fletcher, M. T.; Kitching, W. Tetrahedron: Asymmetry
1995, 6, 967.
J O016096C