Enzyme-catalyzed kinetic resolution of 1,3-anti-diol monoesters - Efficient preparation of enantiomerically highly enriched and unsymmetrically substituted 1,3-anti-diols

Article abstract of DOI:10.1002/ejoc.200700096

Candida antarctica Lipase B (CALB) catalyzed the highly enantioselective acetylation of 1,3-anti-diol monoesters which have been obtained through a zirconium-catalyzed aldol-Tishchenko reaction. The product 1,3-anti-diol diesters were formed in yields clo

Full text of DOI:10.1002/ejoc.200700096

FULL PAPER
DOI: 10.1002/ejoc.200700096
Enzyme-Catalyzed Kinetic Resolution of 1,3-anti-Diol Monoesters – Efficient
Preparation of Enantiomerically Highly Enriched and Unsymmetrically
Substituted 1,3-anti-Diols
[a]
[a]
Florian Jakob and Christoph Schneider*
Keywords: Aldol-Tishchenko reaction / Enzyme catalysis / Kinetic resolution / Lipase / 1,3-Diols
Candida antarctica Lipase B (CALB) catalyzed the highly
enantioselective acetylation of 1,3-anti-diol monoesters
which have been obtained through a zirconium-catalyzed al-
dol-Tishchenko reaction. The product 1,3-anti-diol diesters
were formed in yields close to 50% and Ͼ98% ee. Separa-
tion from the unreactive enantiomers and subsequent hydrol-
ysis furnished both enantiomers of unsymmetrically substi-
tuted 1,3-anti-diols in high optical purities. Alternatively, the
kinetic resolution process can be performed on the free 1,3-
anti-diols even more rapidly with equally good results. A
slow acyl migration during the reaction slightly deteriorated
the enantiomeric excess of the unreactive enantiomers.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
The 1,3-diol motif is a ubiquitous structural feature in
natural products of polyketide origin.[1] In the context of
natural product synthesis a great wealth of synthetic meth-
odology has been accumulated for their stereoselective
Scheme 1. Zirconium-catalyzed aldol-Tishchenko reaction of diace-
tone alcohol (1).
[
2]
preparation. Among the most valuable strategies is a se-
quence comprising a stereoselective aldol reaction followed
by a diastereoselective β-hydroxy ketone reduction giving
access to 1,3-syn- and 1,3-anti-diols, respectively, depending
upon the reductant employed. Alternatively, this sequence
may be executed in one step employing an aldol-Tishchenko
reaction of a ketone with 2 equiv. of an aldehyde one of
which is used as the coupling partner in the aldol reaction
while the second one is used as hydride donor for the Tish-
In a complementary study we have now investigated the
enzyme-catalyzed kinetic resolution of 1,3-anti-diol mono-
esters 3. Lipases are well established synthetic tools for the
enantiomer-differentiating acylation of racemic secondary
alcohols with activated acyl derivatives such as vinyl ace-
tate. Among the lipases most frequently employed Candida
antarctica Lipase B (CALB) occupies a prominent position
and has been immobilized on macroporous acrylic resin fa-
cilitating its use (Novozym 435 by Novozymes).[ The
three-dimensional structure of the enzyme’s active site has
been determined and the enzyme’s mode of action eluci-
[
3]
chenko reduction.
We have recently devised a conceptually novel strategy
for the aldol-Tishchenko process relying on the facile retro-
aldol tendency of ketone aldols. With zirconium alkoxides
as catalysts (10 mol-%) ketone aldols such as diacetone
alcohol (1) undergo rapid retro-aldol cleavage furnishing
ketone enolates in situ which react with the aldehydes 2
6]
[
7]
dated. Thus, a catalytic triad comprising the amino acid
(2 equiv.) in an aldol-Tishchenko reaction giving rise to 1,3-
residues Asp1 , His , and Ser reacts with the acyl do-
nor and forms a serine ester in the oxyanion hole of the
enzyme. The steric environment in the enzyme’s active site
now only allows R-alcohols to selectively add to this inter-
mediate furnishing the product esters with selectivity fac-
87
224
105
anti-diol monoesters 3 in typically high yields and complete
,3-anti diastereocontrol (Scheme 1).[ Subsequently, we
4]
1
have shown that chiral zirconium complexes with either
[
5a]
[5b]
TADDOL- or BINOL-ligands catalyzed enantioselec-
tive aldol-Tishchenko reactions and furnished products 3
with up to 60% ee.
[
8]
tors of greater than 200.
A large number of simple secondary alcohols have been
[
9]
shown to be readily resolved using CALB or other lipases.
[
a] Institut für Organische Chemie, Universität Leipzig,
Johannisallee 29, 04103 Leipzig, Germany
Fax: +341-9736599
[10]
[11]
[12]
In addition, Williams, Bäckvall, Kim and Park, and
more recently Berkessel et al. developed very interesting
dynamic kinetic resolutions of secondary alcohols in a pro-
[
13]
E-mail: schneider@chemie.uni-leipzig.de
2958
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2958–2963

Enzyme-Catalyzed Kinetic Resolution
FULL PAPER
cess comprising a fast metal-catalyzed racemization and en-
The enantiomeric excess of (R)-4a and (S)-3a was di-
zyme-catalyzed kinetic resolution. Examples of more highly rectly analyzed through GC on a chiral stationary phase
functionalized alcohols, however, are less frequent.
(FS-HydrodexR β-3P). The free 1,3-anti-diols (R)-5a and
A limited number of acyclic, but symmetrical 1,3-anti- (S)-5a were then obtained quantitatively through alkaline
diols have been kinetically resolved through an enzymatic methanolysis and their respective enantiomeric excesses
[
14]
[15]
acylation process by the groups of Sih,
Norin,
and were determined on the corresponding UV-active bis(p-bro-
[
16]
Rabiller et al. Bäckvall et al. employed their Ru-enzyme- mobenzoyl) derivatives with HPLC on a chiral OD-phase.
coupled process and converted a racemic and dia- Whereas no change in ee was observed for the R-carbinol
stereomeric mixture of 1,3-diols into enantiomerically pure enantiomer (98.5% ee for (R)-4a as well as (R)-5a), the ee
1
ity.
,3-syn-diol diacetates in good yields and diastereoselectiv- had dropped from 98% ee measured for (S)-3a to 92% ee
[17]
A single symmetrical 1,3-anti-diol diacetate was ob- for (S)-5a. At first sight surprising this decrease of enantio-
tained in high ee and excellent yield and diastereoselectivity meric excess was based upon a slow and apparently en-
by the same group using a similar procedure.[ More re- zyme-catalyzed acyl migration in both enantiomers.
18]
cently, Sung et al. reported the Candida rugosa Lipase-cata-
At the start of the kinetic resolution the ratio of rac-3a
lyzed kinetic resolution of 1-phenyl-1,3-butanediol which to its regioisomer was Ͼ98:2, i.e. the minor regioisomer
1
proceeded in good enantioselecitivity only for the unreac- could not be detected by 400-MHz H NMR spectroscopy.
tive diol enantiomer.[
19]
After the kinetic resolution this ratio had changed to (R)-
a/(S)-3a/regioisomers = 10:10:1. Upon chromatographic
4
separation of the desired product (R)-4a the remaining mix-
ture comprised 1,3-diol monoesters (S)-3a, regio-(S)-3a,
Results and Discussion
As a model we chose aldol-Tishchenko product rac-3a and regio-(R)-3a in a ratio of ca. 20:1:1 which was hy-
which was obtained in excellent yield and diastereoselectiv- drolyzed to eventually yield the product 1,3-anti-diol (S)-5a
ity through the zirconium alkoxide-catalyzed aldol-Tishch- in 92% ee. The proportion of regioisomers increased
[
4]
enko reaction previously developed in our laboratory.
When rac-3a was treated with CALB and vinyl acetate after ca. 40% conversion the amount of regioisomers rela-
4 equiv.) in hexane at 40 °C, complete conversion of the R- tive to the unreactive enantiomer (S)-3a was still just 3%,
carbinol was observed within 6 h and 1,3-anti-diol diester it increased to 10% after the resolution had been completed
R)-4a was isolated in 43% yield and 98.5% ee (Scheme 2). at 50% conversion.
The unreactive (S)-3a was recovered along with small Following the procedure described above various other
amounts of the enantiomeric regioisomers in a combined 1,3-anti-diol monoesters rac-3 obtained through the aldol-
yield of 41% and 98% ee. Tishchenko reaction were submitted to the CALB-catalyzed
sharply towards the end of the kinetic resolution. Whereas
(
(
Scheme 2. CALB-catalyzed kinetic resolution of 1,3-anti-diol monoester rac-3a with vinyl acetate.
Eur. J. Org. Chem. 2007, 2958–2963
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2959

F. Jakob, C. Schneider
FULL PAPER
Table 1. CALB-catalyzed kinetic resolution of 1,3-anti-diol monoesters rac-3 with vinyl acetate.
Entry
Substrate
R
Product
R)-4
Yield
[%][
ee
[%]
Product
(S)-3
Yield
[%]
ee [%][b]
a]
[b]
[a,c]
(
1
2
3
4
5
rac-3a
rac-3b
rac-3c
rac-3d
rac-3e
iPr
cPent
cHex
(R)-4a
(R)-4b
(R)-4c
(R)-4d
(R)-4e
43
44
45
44
49
98.5
99
98.5
Ͼ99
99
(S)-3a
(S)-3b
(S)-3c
(S)-3d
(S)-3e
41 (10:1)
50 (12:1)
45 (17:1)
47 (30:1)
48 (11:1)
92 (98)[d]
86
91
77
1-Et-C
2-Ph(CH
3 6
H
[
e]
2
)
2
92 (97)
[
a] Isolated yield after flash column chromatography over silica gel. [b] Determined by chiral HPLC analysis on the bis(p-bromobenzoyl)
derivative of diols 5 (see text). [c] Values in brackets refer to ratio of regioisomers (S)-3 relative to the sum of regio-(S)-3 and regio-(R)-
1
3
as determined by H NMR spectroscopy. [d] Value in brackets refers to ee of (S)-3a determined directly by chiral GC analysis. [e] Value
in brackets refers to ee of (S)-3e determined directly by chiral HPLC analysis.
esterification and yielded the corresponding 1,3-anti-diol di- straight-chain alkyl groups, α-branched alkyl groups, and
esters (R)-4 in 43–49% yield and 98.5 to Ͼ99% ee from cyclic alkyl groups. Thus, the enzymatic kinetic resolution
which the corresponding 1,3-anti-diols (R)-5 were obtained of aldol-Tishchenko products obtained in one step consti-
in essentially quantitative yields and identical enantiomeric tutes a valuable method to furnish highly enantiomerically
excesses (Table 1). The selectivity factors of this kinetic res- enriched and unsymmetrically substituted 1,3-anti-diols.
olution were calculated as E Ͼ 200 for all examples investi-
The enantiomeric 1,3-anti-diols (S)-5 were obtained in
[
20]
gated.
Whereas all compounds shared the methyl group 41–50% yield and 77–92% ee upon separation and hydroly-
at the C(2)-carbinol center to fit in the enzyme’s active site sis of the unreactive enantiomers (S)-3. The small amount
the C(4)-carbinol substituent was quite variable including of regio-(R)-3 formed again through acyl migration of (R)-
Table 2. CALB-catalyzed kinetic resolution of 1,3-anti-diols rac-5 with vinyl acetate.
Entry
Substrate
R
Product
R)-6
Yield
ee
(%)
Product
(S)-5
Yield
[%]
ee
(%)
(%)[
a,b]
[c]
[a]
[c]
(
1
2
3
rac-5a
rac-5c
rac-5f
rac-5g
iPr
cHex
Et
(R)-6a
(R)-6c
(R)-6f
(R)-6g
41 (11:1)
42 (30:1)
41 (30:1)
46 (20:1)
96
97.5
92.5
94
(S)-5a
(S)-5c
(S)-5f
(S)-5g
48
38
41
48
Ͼ99
96
99
[
d]
4
nHex
Ͼ99
[
(
5
a] Isolated yield after flash column chromatography over silica gel. [b] Values in brackets refer to ratio of regioisomers (R)-6 and regio-
1
R)-6 as determined by H NMR spectroscopy. [c] Determined by chiral HPLC analysis on the bis(p-bromobenzoyl) derivative of diols
(see text). [d] The selectivity factor E was calculated to be 140.
2960
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Eur. J. Org. Chem. 2007, 2958–2963

Enzyme-Catalyzed Kinetic Resolution
FULL PAPER
3
was not converted by the enzyme and hence was isolated Optical rotation values were measured with a Schmidt&Haensch
Polartronic-D digital polarimeter. The 1,3-anti-diol monoesters 3
were prepared according to the literature procedure[ and care-
fully purified by flash chromatography using diethyl ether/pentane
and hydrolyzed along with (S)-3 thereby deteriorating the
enantiomeric excess of (S)-5.
In an effort to overcome the difficulties associated with
the acyl migration of the 1,3-diol monoesters we attempted
the enzyme-catalyzed kinetic resolution of some 1,3-anti-
diols rac-5 which turned out to be a much more rapid pro-
cess and was completed within just 30–45 min at 40 °C with
4b]
(
1:3) i.e. minor amounts of the respective regioisomers could not
1
be detected by 400 MHz H NMR spectroscopy. The spectroscopic
and analytical data of the 1,3-anti-diols 5 were reported in a pre-
[4b]
vious publication.
The lipase Candida antarctica Lipase B (No-
vozym 435) was provided by Novozymes and used without further
4
equiv. of vinyl acetate. The regioisomeric 1,3-anti-diol purification. Enantiomeric excesses (ee) of 1,3-anti-diols 5 were
monoesters (R)-6 and regio-(R)-6 were obtained in 41–46% measured on the corresponding bis(p-bromobenzoyl) derivatives by
yield, 92.5–97.5% ee, and 11–30:1 ratio (Table 2). Since HPLC using a Chiralcel OD column with 2-propanol/n-hexane as
the eluent and for 3a and 4a by GC-FID using a FS-Hydrodex β-
CALB is known to readily accept as substrates only second-
ary alcohols with one substituent being as small as methyl
or ethyl it is unlikely that a direct esterification of the
3P column (25 mϫ0.25 mm; 0.25 µm film thickness).
General Procedure for the CALB-Catalyzed Acetylation of 1,3-anti-
wrong” carbinol had taken place. Apparently, again an Diol Monoesters 3 (GP 1): Immobilized Candida antarctica lipase
“
acyl migration accounts for the formation of regio-(R)-6 B (Novozym 435) (260 mg) and vinyl acetate (0.32 mL, 4.00 mmol)
which in contrast to the situation discussed above did not were added at 40 °C to a solution of 1,3-anti-diol monoester 3
(
1.00 mmol) in n-hexane (10 mL). After stirring the mixture for 6 h
deteriorate the enantiomeric excess of the product because
both regioisomers shared the same absolute configuration
and were subsequently hydrolyzed to the identical 1,3-anti-
diol (R)-5. The unreactive diols (S)-5 were recovered in 38–
at 40 °C, the enzyme was filtered off and washed with n-hexane
and diethyl ether. The solvents were removed in vacuo and the resi-
due was purified by flash chromatography over silica gel with mix-
tures of diethyl ether and pentane. For the purpose of ee-determi-
nation 3 was hydrolyzed with NaOH/MeOH and the resulting 1,3-
48% yield and 96 to Ͼ99% ee (Table 2).
anti-diols 5 were converted with p-bromobenzoyl chloride, NEt
2 equiv. each) and DMAP (5 mol-%) in CH Cl into the bis(p-
bromobenzoyl) derivatives.
3
(
2
2
Conclusions
A practical method for the synthesis of highly enantio- 1,3-Diol Diester (R)-4a: 1,3-anti-Diol monoester 3a (195 mg,
merically enriched and unsymmetrically substituted 1,3- 1.00 mmol) was kinetically resolved with CALB and vinyl acetate
according to the general procedure to furnish 105 mg of 1,3-diester
anti-diols has been developed based upon an enzymatic ki-
(
=
6
1
5
4
R)-4a (43%) as a colorless oil (98.5% ee by HPLC). R
f
(E/PE, 1:1)
netic resolution of 1,3-anti-diol monoesters 3. The sub-
strates 3 were easily available in one step and complete dia-
stereocontrol through the zirconium-catalyzed aldol-Tish-
chenko reaction of diacetone alcohol and aldehydes. Can-
dida antarctica Lipase B effectively catalyzed the acetylation
of the R-carbinol enantiomer with vinyl acetate and fur-
1
0.68. H NMR (300 MHz, CDCl
.9 Hz, 6 H, 6-H , 7-H ), 1.14, 1.16 (2ϫd, J = 7.0 Hz, 3 H, 10-H
1-H ), 1.21 (d, J = 6.3 Hz, 3 H, 1-H ), 1.62–1.85 (m, 3 H, 3-H
-H), 2.04 (s, 3 H, 13-H
.91 (m, 2 H, 2-H, 4-H) ppm. C NMR (100 MHz, CDCl
3
, 25 °C): δ = 0.88 (d, J =
3
3
3
,
,
3
3
2
3
), 2.60 (sept, J = 7.0 Hz,1 H, 9-H), 4.78–
13
3
, 25 °C):
δ = 17.7, 18.3, 19.1, 19.3, 20.7, 21.4 (C-1, C-6, C-7, C-10, C-11, C-
nished the 1,3-anti-diol diesters 4 in yields close to 50% and 13), 32.0, 34.4 (C-5, C-9), 37.4 (C-3), 67.3 (C-2), 73.6 (C-4), 170.7
8 to Ͼ99% ee from which the free 1,3-anti-diols 5 were (C-12), 178.7 (C-8) ppm. MS (ESIpos, MeOH): m/z = 267 [M +
9
+
obtained through alkaline hydrolysis in identical ee. The un- Na] . IR (film): ν˜ = 2972, 2936, 2878, 1738, 1470, 1372, 1240, 1192,
–
1
1
158, 1119 cm . C13
C 63.97, H 9.83. GC-FID [FS-Hydrodex β-3P, 60 °C (4 min),
0 °Cmin , 100 °C (0 min), 5 °Cmin
[(1S,3S)-4a] = 24.7 min; t [(1R,3R)-4a] = 25.0 min. HPLC [Chir-
acel OD, n-hexane/2-propanol (97:3), 20 °C, 1.0 mLmin ]:
23 4
H O (244.5) calcd. C 64.18, H 9.52; found
reactive (S)-1,3-anti-diol enantiomers 5 were obtained in
slightly lower enantiomeric excess due to a slow acyl mi-
gration in the substrates. Alternatively, the free 1,3-anti-di-
ols 5 were resolved with CALB and vinyl acetate even more
rapidly and furnished both enantiomers in high enantio-
meric excesses.
–
1
–1
1
115 °C (20 min)]:
t
R
R
–
1
25
t
R
[(1S,3S)] = 5.6 min; t
CHCl ).
R D
[(1R,3R)] = 6.9 min. [α] = –33.4 (c = 0.72,
3
1,3-Diol Diester (R)-4b: 1,3-anti-Diol monoester 3b (254 mg,
1
.00 mmol) was kinetically resolved with CALB and vinyl acetate
Experimental Section
according to the general procedure to furnish 112 mg of 1,3-diester
(R)-4b (44%) as a colorless oil (99% ee by HPLC). R (E/PE, 1:1)
, 25 °C): δ = 1.22 (d, J =
), 1.47–2.1 (m,19 H, 3-H , cyclopentyl-CH , cy-
clopentyl-CH, 5-H ), 2.03 (s, 3 H, 8-H), 2.65–2.75 (m, 1 H, 6-H),
4.84 (ddq, J = 9.9, 6.2, 3.5 Hz, 1 H, 2-H), 5.00 (ddd, J = 10.2, 7.2,
General: All reactions were carried out in flame-dried glassware
with magnetic stirring under nitrogen. The solvents were dried by
standard procedures, distilled, and stored under nitrogen. Flash
chromatography was carried out with Merck silica gel 60 (40–
f
1
= 0.73. H NMR (300 MHz, CDCl
6.2 Hz, 3 H, 1-H
3
3
2
2
2
1
13
6
3 µm). All H and C NMR spectra were recorded in CDCl
ambient temperature with Varian Gemini 200, 300, and Mercury
00 spectrometers. Chemical shifts are reported relative to tet-
3
at
1
3
3.0 Hz, 1 H, 4-H) ppm. C NMR (75 MHz, CDCl
20.7 (C-8), 21.4 (C-1), 25.4, 25.7, 25.8, 25.8, 28.5, 29.0, 30.0, 30.3
(cyclopentyl-CH ), 40.0 (C-3), 44.3, 44.6 (cyclopentyl-CH), 67.2
(C-2), 72.7 (C-4), 170.7 (C-7), 176.4 (C-5) ppm. MS (ESIpos
3
, 25 °C): δ =
4
ramethylsilane as internal standard or residual solvent signals. IR
spectra were obtained with a Mattson/Unicam FT-IR spectrome-
2
,
+
+
+
ter. Mass spectra were measured with a Bruker APEX II FT-ICR MeOH): m/z = 615 [2M + Na] , 319 [M + Na] , 297 [M + H] .
ESI). Elemental analyses were obtained from the microanalytical IR (film): ν˜ = 3445, 2956, 2870, 1738, 1451, 1372, 1243, 1183, 1149,
28 4
laboratory of the Dept. of Chemistry at the University of Leipzig. 1111, 1031, 973, 804, 607 cm . C17H O (296.3) calcd. C 68.90,
(
–
1
Eur. J. Org. Chem. 2007, 2958–2963
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2961

F. Jakob, C. Schneider
FULL PAPER
H 9.51; found C 68.67, H 9.81. HPLC [Chiracel OD, n-hexane/2-
(10 mL). The mixture was stirred at 40 °C for 30–45 min where-
upon the product 1,3-anti-diol monoesters 6 were isolated and their
enantiomeric excesses determined as described above in GP 1.
–1
propanol (97:3), 20 °C, 1.0 mLmin ]:
t
R
[(1S,3S)
= 5.6 min;
25
t
R
[(1R,3R)] = 6.5 min. [α]
D
= –28.7 (c = 0.56, CHCl ).
3
1
,3-Diol Diester (R)-4c: 1,3-anti-Diol monoester 3c (282 mg,
f
1,3-Diol Monoester (R)-6a: Yield: 41% (96% ee by HPLC). R =
1
1.00 mmol) was kinetically resolved with CALB and vinyl acetate
0.42 (E/PE, 1:1). H NMR (300 MHz, CDCl
J = 6.7 Hz, 3 H, 6-H ), 0.92 (d, J = 6.7 Hz, 3 H, 7-H
(d, J = 6.3 Hz, 3 H, 1-H ), 1.50–1.67 (m, 3 H, 3-H , 5-H), 2.06 (s,
, 25 °C): δ = 0.88–2.04 (m, 3 H, 9-H), 3.28 (ddd, J = 7.8, 5.4, 2.3 Hz, 1 H, 4-H), 5.18 (ddq, J
3
3
, 25 °C): δ = 0.91 (d,
according to the general procedure to furnish 146 mg of 1,3-diester
3
3
, 7-H ) 1.27
3
(
(
R)-4c (45%) as a colorless oil (98.5% ee by HPLC). R
E/PE, 1:1). H NMR (400 MHz, CDCl
f
= 0.72
3
2
1
1
3
2
3
4
=
2
6
3 H, 3-H
H, 1-H ), 2.08 (s, 3 H, 8-H
.79–4.91 (m, 2 H, 2-H, 4-H) ppm. C NMR (75 MHz, CDCl
20.7, 21.4 (C-1, C-8), 25.6, 25.7, 25.9, 26.2, 26.3, 26.5, 28.1, 29.0,
9.1, 29.4 (cyclohehyl-CH
7.2 (C-2), 73.0 (C-4), 170.7 (C-8), 175.7 (C-5) ppm. MS (ESIpos
2
, cyclohexyl-CH
2
, cyclohexyl-CH), 1.21 (d, J = 6.2 Hz,
3
= 9.6, 6.3, 2.8 Hz,1 H, 2-H) ppm. C NMR (100 MHz, CDCl ,
) 2.34 (tt, J = 7.1, 3.6 Hz, 1 H, 6-H), 25 °C): δ = 17.8, 18.8 (C-6, C-7), 20.9 (C-9), 21.3 (C-1), 33.7 (C-5),
3
3
13
): δ 41.1 (C-3), 68.7 (C-2), 72.2 (C-4), 171.8 (C-8) ppm. MS (ESIpos,
+
3
MeOH): m/z = 197 [M + Na] . IR (Film): ν˜ = 3453, 2961, 2876,
), 37.7 (C-3), 42.1, 43.7 (cyclohexyl-CH), 1737, 1716, 1669, 1463, 1374, 1248, 1147, 1129, 1045, 1023, 988,
2
–1 +
,
954, 915, 865, 821, 802, 635, 611 cm . HRMS for [M + Na] calcd.
197.11482; found 197.11497. HPLC [Chiralcel OD, n-hexane/2-pro-
+
+
MeOH): m/z = 671 [2M + Na] , 347 [M + Na] . IR (film): ν˜ =
3
1
calcd. C 70.39, H 9.93; found C 70.09, H 9.97. HPLC [Chiralcel
OD, n-hexane/2-propanol (97:3), 20 °C, 1.0 mLmin ]: t
–
1
444, 2930, 2854, 1736, 1450, 1372, 1312, 1247, 1169, 1145, 1132,
panol (97:3), 20 °C, 1.0 mLmin ]:
t
R
[(1S,3S)]
= –22.0 (c = 0.55, CHCl
f
,3-Diol Monoester (R)-6c: Yield: 42% (97.5% ee by HPLC). R =
=
3
).
5.6 min;
–1
25
028, 972, 958, 894, 844, 788, 762, 607 cm . C19
H
32
O
4
(324.4)
t
R
[(1R,3R)] = 6.9 min. [α]
D
1
0
1
6
–1
[(1S,3S)]
1
R
.44 (E/PE, 1:1). H NMR (200 MHz, CDCl
.93 (m, 13 H, cyclohexyl-CH , cyclohexyl-CH, 3-H
.3 Hz, 3 H, 1-H ) 2.04 (s, 3 H, 7-H ), 2.57 (d, J = 4.0 Hz, 1 H,
, 1 H, 4-H), 5.16 (ddq, J = 9.6, 6.3, 3.4 Hz,1 H, 2-H)
ppm. C NMR (50 MHz, CDCl , 25 °C): δ = 21.0 (C-7), 21.4 (C-
), 26.3, 26.4, 26.7, 28.3, 29.5 (cyclohexyl-CH ), 41.3 (C-3), 43.7
(cyclohexyl-CH), 68.7 (C-2), 71.6 (C-4) 171.8 (C-6) ppm. MS (ES-
, 25 °C): δ = 0.90–
3
[(1R,3R)] = 11.3 min. [α]2
5
= –26.2 (c = 0.30, CHCl ).
=
10.3 min; t
R
D
3
2
2
), 1.21 (d, J =
1,3-Diol Diester (R)-4d: 1,3-anti-Diol monoester 3d (258 mg,
3
3
OH), 3.27 (m
c
1.00 mmol) was kinetically resolved with CALB and vinyl acetate
1
3
according to the general procedure to furnish 105 mg of 1,3-diester
3
1
2
(R)-4d (44%) as a colorless oil (Ͼ99% ee by HPLC). R
f
= 0.75
, 25 °C): δ = 0.89–0.94 (m,
), 1.19 (d, J = 6.2 Hz, 3 H, 1-H ),
, 5-H, 6-H , 8-H , 12-H , 14-H ), 2.02 (s,
H, H-17), 2.23 (tt, J = 8.3, 5.7 Hz, 1 H, 11-H), 4.82 (m , 1 H, 2-
, 25 °C):
1
(E/PE, 1:1). H NMR (300 MHz, CDCl
3
+
+
I
pos, MeOH): m/z = 441 [2M + Na]
,
419 [2M + M] , 237 [M +
1
2 H, 7-H
3
, 9-H
3
, 13-H
3
, 15-H
3
3
+
Na] . IR (film): ν˜ = 3439, 2926, 2853, 1736, 1449, 1374, 1248, 1181,
1.28–1.72 (m, 11 H, 3-H
2
2
2
2
2
–
1
+
1
123, 1065, 1042, 956, 892, 788 cm . HRMS for [M + Na] calcd.
3
c
, 1 H, 4-H) ppm. 1 C NMR (75 MHz, CDCl
3
237.14612; found 237.14635. HPLC [Chiralcel OD, n-hexane/2-pro-
H), 5.11 (m
c
3
–
1
panol (97:3), 20 °C, 1.0 mLmin ]:
t
R
[(1S,3S)]
= –10.0 (c = 0.60, CHCl
), 49.3 (C-11), 67.7 (C-2), 71.4 (C-4), 170.6 (C-16), 177.9 (C-10) 1,3-Diol Monoester (R)-6f: Yield: 41% (92.5% ee by HPLC). R =
= 10.3 min;
3
).
δ = 11.9, 12.0, 12.2 (C-7, C-9, C-13, C-15), 20.7 (C-17), 21.3 (C-1),
2
5
t
R
[(1R,3R)] = 11.3 min. [α]
D
2
5
2.2, 22.6 (C-6, C-8), 24.8, 25.0 (C-12, C-14), 36.6 (C-3), 45.0 (C-
f
+
1
ppm. MS (ESIpos, MeOH): m/z = 623 [2M + Na] , 323 [M +
Na] , 301 [M + H] . IR (film): ν˜ = 3444, 2964, 2935, 2877, 1732, 7.4 Hz 3 H, 7-H ), 1.24 (d, J = 6.3 Hz, 3 H, 1-H ), 1.39–1.68 (m,
3
0.45 (E/PE, 1:1). H NMR (300 MHz, CDCl ): δ = 0.92 (t, J =
+
+
3
3
1
461, 1372, 1325, 1242, 1179, 1145, 1115, 1078, 1023, 985, 958,
2 2 3
4 H, 3-H , 5-H ), 2.05 (s, 3 H, 8-H ), 2.73 (br. s, 1 H, OH), 3.37–
–1
912, 801, 608 cm . C17
H
32
O
4
(300.3) calcd. C 67.98, H 10.73;
3.47 (m, 1 H, 4-H), 5.16 (ddq, J = 9.6, 6.3, 3.1 Hz, 1 H, 2-H) ppm.
1
3
found C 68.55, H 10.23. HPLC [Chiralcel OD, n-hexane/2-propa-
nol (97:3), 20 °C, 1.0 mLmin ]: t
=
3
C NMR (75 MHz, CDCl ): δ = 10.7 (C-7), 20.9 (C-8), 21.4 (C-
–1
R
[(1S,3S)] = 5.1 min; t
R
[(1R,3R)]
1), 30.1 (C-5), 44.1 (C-3), 68.5, 68.9 (C-2, C-4), 171.9 (C-7) ppm.
5.9 min. [α]2
5
= –37.4 (c = 0.59, CHCl ).
+
+
D
3
MS (ESIpos, MeOH): m/z = 183 [M + Na] , 161 [M + H] . IR
(
1
Film): ν˜ = 3435, 2970, 2879, 1737, 1716, 1461, 1374, 1247, 1150,
1
,3-Diol Diester (R)-4e: 1,3-anti-Diol monoester 3e (326 mg,
–
1
118, 1034, 965, 891, 807, 611, 451 cm . HPLC [Chiralcel OD, n-
1.00 mmol) was kinetically resolved with CALB and vinyl acetate
–
1
R
hexane/2-propanol (99:1), 20 °C, 1.0 mLmin ]: t [(1S,3S)] =
9
according to the general procedure to furnish 160 mg of 1,3-diester
2
5
.2 min; t
R
[(1R,3R)] = 12.6 min. [α]
D
= –28.6 (c = 0.28, CHCl
3
).
f
(R)-4e (49%) as a colorless oil (99% ee by HPLC). R = 0.70
1
(E/PE, 1:1). H NMR (200 MHz, CDCl
3
, 25 °C): δ = 1.21 (d, J = 1,3-Diol Monoester (R)-6g: Yield: 46% (94% ee by HPLC). R
f
=
1
6
1
.2 Hz, 3 H, 1-H
1-H ), 2.50–2.64 (m, 4 H, 6-H
), 4.90 (m , 1 H, 2-H), 5.07 (m
0 H, phenyl-H
) ppm. 13C NMR (75 MHz, CDCl
0.6 (C-11), 21.4 (C-1), 31.0 (C-6), 31.6 (C-9), 36.0 (C-8), 36.5 (C- ppm. C NMR (100 MHz, CDCl
), 40.6 (C-3), 67.1 (C-2), 70.2 (C-4), 126.1, 126.4 (p-phenyl-CH),
(C-12), 21.4 (C-1), 22.7 (C-9), 25.8 (C-6), 29.4 (C-7), 31.9 (C-8),
28.4, 128.4, 128.5, 128.6 (m-, o-phenyl-CH), 140.7, 141.5 (phenyl- 37.4 (C-5), 44.5 (C-3), 67.6 (C-2), 68.5 (C-4), 171.9 (C-11) ppm.
3
), 1.72–1.90 (m, 4 H, 3-H
, 8-H ), 2.90–2.98 (t, J = 7.5 Hz, 2
, 1 H, 4-H), 7.10–7.32 (m, 8-H
, 25 °C): δ = 3.46–3.54 (m, 1 H, 4-H), 4.18 (ddq, J = 9.6, 6.3, 3.1 Hz, 1 H, 2-H)
2
, 5-H
2
), 2.00 (s, 3 H, 0.45 (E/PE, 1:1). H NMR (300 MHz, CDCl
0.90 (m, 3 H, 10-H ), 1.20–1.69 (m, 10 H, 3-H
, 9-H ), 1.23 (d, J = 6.3 Hz, 3 H, 1-H ), 2.07 (s, 3 H, 12-H
3
, 25 °C): δ = 0.86–
, 5-H , 6-H , 7-H ,
2
2
2
3
2
2
3
2
H, 9-H
2
c
c
2
2
3
3
),
1
2
5
1
5
3
1
3
3
, 25 °C): δ = 14.2 (C-10), 20.9
+
C), 170.7, 174.3 (C-7) ppm. MS (ESIpos, MeOH): m/z = 391 [M +
MS (ESIpos, MeOH): m/z = 239 [M + Na] . IR (film): ν˜ = 3444,
Na] , 369 [M + H] . IR (film): ν˜ = 3443, 3062, 3027, 2977, 2932, 2930, 2857, 1738, 1716, 1459, 1374, 1246, 1147, 1043, 954, 809,
+
+
–
1
+
2
9
863, 1736, 1603, 1496, 1454, 1373, 1244, 1148, 1121, 1078, 1029,
611 cm . HRMS for [M
239.16199. HPLC [Chiralcel OD, n-hexane/2-propanol (97:3),
20 °C, 1.0 mLmin ]: t
[α]
+ Na] calcd. 239.16177; found
–
1
28 4
54, 788, 751, 699 cm . C23H O (368.3) calcd. C 74.98, H 7.65;
–
1
found C 74.63, H 7.72. HPLC [Chiralcel OD, n-hexane/2-propanol
R
[(1S,3S)] = 5.2 min; t
R
[(1R,3R)] = 5.8 min.
–1
25
(99.5:0.5), 20 °C, 1.0 mLmin ]: t
R
[(1S,3S)] = 53.0 min; t
R
[(1R,3R)]
D
= –11.6 (c = 0.34, CHCl ).
3
56.2 min. [α]2
5
= –14.1 (c = 0.71, CHCl ).
=
D
3
General Procedure for the CALB-Catalyzed Acetylation of 1,3-anti- Acknowledgments
Diols 5 (GP 2): Immobilized Candida antarctica lipase B (Novozym
435) (260 mg) and vinyl acetate (0.32 mL, 4.00 mmol) were added
Support of this work through the Deutsche Forschungsgemein-
at 40 °C to a solution of 1,3-anti-diol 5 (1.00 mmol) in n-hexane schaft is gratefully acknowledged. We would like to thank Novo-
2962
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2958–2963

Enzyme-Catalyzed Kinetic Resolution
FULL PAPER
zymes for the generous donation of Novozym 435 and Prof. J.-E.
Bäckvall (University of Stockholm) for valuable suggestions.
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Received: February 5, 2007
Published Online: April 23, 2007
Eur. J. Org. Chem. 2007, 2958–2963
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2963