Chemoenzymatic synthesis of both enantiomers of 3-hydroxy-2,2- dimethylcyclohexanone

Article abstract of DOI:10.1021/jo801954v

(Chemical Equation Presented) The stereoselective acetylation of meso-2,2-dimethyl-1,3-cyclohexanediol by vinyl acetate in the presence of three lipases gave the (1R,3S)-monoester in high enantiomeric excess (ee ≥ 98%). The hydrolysis of the corresponding meso-diacetate in the presence of Candida antarctica lipase in phosphate buffer provided the opposite enantiomer. Optically active monoacetates were converted to both enantiomers of 3-hydroxy-2,2-dimethylcyclohexanone, a versatile chiral building block.

Full text of DOI:10.1021/jo801954v

SCHEME 1
Chemoenzymatic Synthesis of Both Enantiomers
of 3-Hydroxy-2,2-dimethylcyclohexanone
Robert Cheˆnevert,* Carine Le´vesque, and Pierre Morin
De´partement de Chimie, CREFSIP, Faculte´ des Sciences et
de Ge´nie, UniVersite´ LaVal, Que´bec (QC), Canada G1K 7P4
TABLE 1. Enzymatic Desymmetrization (Acylation) of Diol 3
robert.cheneVert@chm.ulaVal.ca
ReceiVed September 3, 2008
entry
enzymea
time (h)
yieldb (%)
eec (%)
abs conf
1
2
3
4
5
6
CAL-B
CRL
BCL
ANL
PPL
7
20
28
144
144
144
94
95
88
g98
g98
g98
(1R,3S)
(1R,3S)
(1R,3S)
PLE
a CAL-B ) Candida antarctica lipase B, CRL ) Candida rugosa
lipase, BCL ) Burkholderia cepacia lipase, ANL ) Aspergillus niger
lipase, PPL ) porcine pancreatic lipase, PLE ) pig liver esterase. For
reaction conditions, see Experimental Section. b Isolated yield.
c Determined by GC on chiral phase.
The stereoselective acetylation of meso-2,2-dimethyl-1,3-
cyclohexanediol by vinyl acetate in the presence of three
lipases gave the (1R,3S)-monoester in high enantiomeric
excess (ee g 98%). The hydrolysis of the corresponding
meso-diacetate in the presence of Candida antarctica lipase
in phosphate buffer provided the opposite enantiomer.
Optically active monoacetates were converted to both enan-
tiomers of 3-hydroxy-2,2-dimethylcyclohexanone, a versatile
chiral building block.
reduction is carried out by the addition of the hydride donor
catecholborane (1.8 equiv) to a cold (-60 °C) toluene solution
of diketone 2, an oxazaborolidine catalyst (0.1 equiv), and N,N-
diethylaniline (0.5 equiv) to give 1 (yield ) 69%, ee ) 92%).
Herein, we report the synthesis of both enantiomers of 1 via
the enzymatic desymmetrization of meso-cis-2,2-dimethylcy-
clohexane-1,3-diol (3) and the corresponding meso-diacetate 4.
2,2-Dimethylcyclohexane-1,3-dione (2), which was prepared
by methylation of commercially available 2-methylcyclohexane-
1,3-dione or cyclohexane-1,3-dione,2,4,5 was reduced with
NaBH4 in ethanol to yield a mixture of cis-trans diastereomeric
2,2-dimethylcyclohexane-1,3-diols. The major cis isomer, meso-
3, was easily purified by recrystallization5 (Scheme 1). Diacetate
4 was prepared by the acylation of 3 with acetic anhydride in
pyridine.
Then, we examined both the acylation (transesterification)
of meso-diol 3 and the hydrolysis of meso-diacetate 4 in the
presence of commercially available hydrolases under various
conditions. The reactions were monitored by TLC and termi-
nated when all of the starting material (diol or diacetate) was
consumed (conversion ) 100%). The enantiomeric excess (ee)
of monoacetate 5 was measured by gas chromatography on a
chiral phase column. The absolute configuration of monoester
5 was determined by chemical correlation with compound 1 of
known absolute configuration.
Optically active 3-hydroxy-2,2-dimethylcyclohexanone (1)
has been used as a chiral building block for the synthesis of a
large number of natural products or biologically active
compounds.1,2 The (S)-enantiomer is usually prepared by baker’s
yeast (Saccharomyces cereVisiae) reduction of 2,2-dimethyl-
cyclohexane-1,3-dione (2).2 Recently, Corey et al. reported the
enantioselective preparation of 1 by a modified CBS reduction
of 2, giving access to both enantiomers.3 This three-component
(1) (a) Gorobets, E.; Stepanenko, V.; Wicha, J. Eur. J. Org. Chem. 2004,
783–799. (b) Iwamoto, M.; Miyano, M.; Utsugi, M.; Kawada, H.; Nakada, M.
Tetrahedron Lett. 2004, 45, 8647–8651. (c) Zhang, J.; Duan, W.; Cai, J.
Tetrahedron 2004, 60, 1665–1669. (d) Tsujimori, H.; Mori, K. Biosci. Biotechnol.
Biochem. 2000, 64, 1410–1415. (e) Stepanenko, W.; Wicha, J. Tetrahedron Lett.
1998, 39, 885–888. (f) Kinoshita, Y.; Kitahara, T. Tetrahedron Lett. 1997, 38,
4993–4996. (g) Mori, K.; Koga, Y. Liebigs Ann. Chem. 1995, 1755–1763. (h)
Mori, K.; Koga, Y. Bioorg. Med. Chem. Lett. 1992, 2, 391–394. (i) Watanabe,
H.; Mori, K. J. Chem. Soc., Perkins Trans. 1 1991, 2919–2934. (j) Mori, K.;
Tamura, H. Liebigs Ann. Chem. 1990, 361–368. (k) Mori, K.; Suzuki, N. Liebigs
Ann. Chem. 1990, 287–292. (l) Haiza, M.; Lee, J.; Snyder, J. K. J. Org. Chem.
1990, 55, 5008–5013. (m) Mori, K.; Takaishi, H. Liebigs Ann. Chem. 1989,
695–697. (n) Mori, K.; Takaishi, H. Liebigs Ann. Chem. 1989, 939–943. (o)
Yamamoto, H.; Oritani, T.; Yamashita, K. Agric. Biol. Chem. 1988, 52, 2203–
2208. (p) Murai, A.; Tanimoto, N.; Sakamoto, N.; Masamune, T. J. Am. Chem.
Soc. 1988, 110, 1985–1986.
The results of the hydrolase-mediated acylation of substrate
3 using vinyl acetate in ether as acyl donor are summarized in
Table 1. Candida antarctica lipase B (CAL-B) not only showed
the best performance in the analytical runs but also gave
(2) For a survey of the syntheses reported before 1988, see: Mori, K.; Mori,
H. Organic Synthesis; Wiley: New York, 1989; Vol. 68, pp 56-63.
(3) Yeug, Y. Y.; Chein, R. J.; Corey, E. J. J. Am. Chem. Soc. 2007, 129,
10346–10347.
(4) Hoffmann, J.; Holst, H.; Volz, W.; Voss, J. J. Chem. Res. (S) 1989, 40–
41.
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3247–3255.
10.1021/jo801954v CCC: $40.75
Published on Web 11/08/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9501–9503 9501

TABLE 2. Enzymatic Desymmetrization (Hydrolysis) of Diacetate
4
SCHEME 2
monoester 5
diol 3
entry enzymea time (h) yieldb (%) eec (%) abs conf yieldb (%)
2). The reaction took also place with TEMPO and sodium
hypochlorite as terminal oxidant, but the yield was lower.
Hydrolysis of the acetate group with aqueous HCl-methanol
provided the title compound (R)-1. In the same manner,
(1S,3R)-5 was transformed into (S)-1.
1
2
3
4
5
6
CAL-B
BCL
PPL
PLE
CRL
ANL
30
39
6
4
6
94
99
93
57
53
g98
g98
71
53
56
(1S,3R)
(1R,3S)
(1S,3R)
(1R,3S)
(1S,3R)
38
40
The present procedure complements the two other methods
for the preparation of 1. Although it involves more steps, it
provides both enantiomers in high ee, requires inexpensive
reagents, and may prove to be a more practical method for large-
scale preparations. The oxazaborolidine-mediated reduction
requires substantial quantities of expensive catalyst (0.1 equiv)
and reagent catecholborane (1.8 equiv) at low temperature (-60
°C). The bioreduction with baker’s yeast provide only the (S)-
enantiomer and has several drawbacks: high ratio of biomass
and source of carbon (saccharose) to substrate, low yield due
to side reactions, and tedious workup due to large volumes and
foaming. In summary, we have developed syntheses of (R)- and
(S)-3-hydroxy-2,2-dimethylcyclohexanone 1 from cyclohexane-
1,3-dione 2. The key step is the enzymatic desymmetrization
of meso-cis-2,2-dimethylcyclohexane-1,3-diol and the corre-
sponding meso-diacetate. The title compound 1 and intermedi-
ates 5 and 6, obtained in both enantiomeric forms with high ee,
are valuable synthons in asymmetric synthesis.
110
a CAL-B ) Candida antarctica lipase B, CRL ) Candida rugosa
lipase, BCL ) Burkholderia cepacia lipase, ANL ) Aspergillus niger
lipase, PPL ) porcine pancreatic lipase, PLE ) pig liver esterase. For
reactions conditions, see Experimental Section. b Isolated yield.
c Determined by GC on chiral phase.
excellent results (yield ) 94%, ee g 98%) for the acylation of
3 on a preparative scale (entry 1). This highly (R)-selective
acylation was also observed for Candida rugosa lipase (CRL)
andBurkholderiacepacialipase(BCL,formerlynamedPseudomo-
nas cepacia), although in the latter cases the reaction was slower
(entries 2 and 3). The reaction stopped after one acylation, and
overacylation to diacetate 4 was negligeable. Aspergillus niger
lipase (ANL), porcine pancreatic lipase (PPL), and pig liver
esterase (PLE) were not active (entries 4-6).
The enzymatic hydrolysis of diacetate 4 was performed in
phosphate buffer-hexanes in the presence of various hydrolases
(Table 2). The addition of a secondary solvent (hexanes) is to
assist the solubility of the diacetate in the two-phase reaction
medium. CAL-B showed good activity, and (S)-monoacetate
(1S,3R)-5 was obtained in high yield and excellent enantiose-
lectivity (ee g 98%, entry 1). Unexpectedly, hydrolysis and
acylation with BCL afforded the same enantiomer (entry 2).
When both the alcohol and the corresponding ester are substrate
for a hydrolase, acylation and hydrolysis are usually comple-
mentary and give opposite enantiomers. Although acylation and
hydrolysis represent reactions in opposite directions, the hy-
drolase favors the same enantiomer or the same prochiral group
in both cases. This empirical rule applies to kinetic resolutions
and desymmetrizations, but exceptions have been reported.6 PPL
was very active but moderately enantioselective (entry 3). With
both PLE and CRL, extensive overhydrolysis to achiral diol 3
occurred, and monoester 5 was obtained in poor yield and low
ee (entry 4 and 5). Compound 4 was not a substrate for ANL
(entry 6).
Experimental Section
Enzymatic Desymmetrization (Acylation) of Diol 3. Typical
Procedure. To a solution of 3 (1.5 g, 10.4 mmol) in diethyl ether
(75 mL) were added vinyl acetate (15 mL) and CAL-B (4000 units).
The mixture was stirred at room temperature. The reaction was
monitored by TLC and quenched by filtration of the enzyme when
all starting material was consumed (14 h). Evaporation of the
solvents gave (1R,3S)-3-hydroxy-2,2-dimethylcyclohexyl acetate 5
(1.88 g, 96%) as a colorless oil, which was further processed without
purification. For analytical purposes a sample was purified by flash
column chromatography (hexanes-ethyl acetate, 4:1): [R]23D -9.5
1
(c 0.92, CHCl3), (ee g 98%); H NMR (CDCl3) δ 4.53 (dd, J )
9.9 and 3.4 Hz, 1H), 3.33 (dd, J ) 9.7 and 3.2 Hz, 1H), 2.05 (s,
3H), 1.60-1.80 (m, 3H), 1.30-1.55 (m, 3H), 0.99 (s, 3H), 0.91
(s, 3H); 13C NMR (CDCl3) δ 170.8, 78.0, 75.9, 40.1, 29.5, 26.3,
24.4, 21.1, 19.3, 13.8; HRMS (CI, NH3) m/z calcd for C10H19O3
(M + H)+ 187.1334, found 187.1341.
cis-3-(Acetoxy)-2,2-dimethylcyclohexyl Acetate 4. To a solution
of diol 3 (250 mg, 1.75 mmol) in pyridine (25 mL) were added
DMAP (5 mg, 0.2 mmol) and acetic anhydride (1.5 mL). The
solution was stirred overnight at room temperature. The mixture
was diluted with methylene chloride (100 mL), and the organic
phase was washed with water (3 × 20 mL), dried (MgSO4), and
Thus, both enantiomers of monoester 5 have been obtained
in high yield and excellent ee. Chiral 1,3-diols and derivatives
such as 5 are important building blocks in asymmetric synthe-
sis.7 Several examples of desymmetrization of meso- cyclohex-
anediols using enzymatic reactions have been previously
8
reported.
(8) (a) Fransson, A. B. L.; Xu, Y.; Leijondahl, K.; Ba¨ckvall, J. E. J. Org.
Chem. 2006, 71, 6309–6316. (b) Hilpert, H.; Wirz, B. Tetrahedron 2001, 57,
681–694. (c) Matsumoto, T.; Konegawa, T.; Yamaguchi, H.; Nakamura, T.;
Sugai, T. Synlett 2001, 1650–1652. (d) Zhao, Y.; Wu, Y.; De Clercq, P.;
Vandewalle, M.; Maillos, P.; Pascal, J. C. Tetrahedron: Asymmetry 2000, 11,
3887–3900. (e) Luzzio, F. A.; Fitch, R. W. J. Org. Chem. 1999, 64, 5485–5493.
(f) Dumortier, L.; Carda, M.; Van der Eycken, J.; Snatzke, G.; Vandewalle, M.
Tetrahedron: Asymmetry 1991, 2, 789–792. (g) Suemune, H.; Takahashi, M.;
Maeda, S.; Xie, Z. F.; Sakai, K. Tetrahedron: Asymmetry 1990, 1, 425–428. (h)
Andersch, P.; Schneider, M. P. Tetrahedron: Asymmetry 1993, 4, 2135–2138.
(i) Eberle, M.; Egli, M.; Seebach, D. HelV. Chim. Acta 1988, 71, 1–23.
Monoester (1R,3S)-5 underwent smooth oxidation with py-
ridinium dichromate (PDC) affording ketoester (R)-6 (Scheme
(6) (a) Cheˆnevert, R.; Jacques, F.; Gigue`re, P.; Dasser, M. Tetrahedron:
Asymmetry 2008, 19, 1333–1338. (b) Izquierdo, I.; Plaza, M. T.; Rodriguez,
M.; Tamayo, J. Tetrahedron: Asymmetry 1999, 10, 449–455. (c) Morgan, B.;
Dodds, D. R.; Zaks, A.; Andrews, D. R.; Klesse, R. J. Org. Chem. 1997, 62,
7736–7743.
(7) Bode, S. E.; Wolberg, M.; Mu¨ller, M. Synthesis 2006, 557–588.
9502 J. Org. Chem. Vol. 73, No. 23, 2008

evaporated to give diacetate 4 (369 mg, 95%) as a solid: mp 63-65
Method 2. To a solution of (1R,3S)-5 (1.00 g, 5.32 mmol) in
CH2Cl2 (10 mL) at 0 °C was added an aqueous solution of KBr (3
N, 5 mL) followed by addition of TEMPO (80 mg, 0.52 mmol).
The mixture was stirred at 0 °C during the addition of aqueous
sodium hypochlorite (10-15%, 50 mL). The mixture was stirred
at room temperature for 20 h and extracted with CH2Cl2 (2 × 50
mL). The organic phase was washed with brine (3 × 50 mL), dried
(MgSO4), and evaporated. The crude product was purified by flash
chromatography (hexanes-ethyl acetate, 4:1) to give (R)-6 (600
1
°C, H NMR (CDCl3) δ 4.55 (dd, J ) 9.9 and 3.4 Hz, 2H), 2.05
(s, 6H), 1.70-1.77 (m, 3H), 1.40-1.47 (m, 3H), 0.97 (s, 3H), 0.90
(s, 3H); 13C NMR (CDCl3) δ 170.5, 77.3, 39.3, 26.4, 24.3, 21.1,
19.7, 14.0; HRMS (ES) m/z calcd for C12H20O4Na (M + Na)+
251.1259, found 251.1254.
Enzymatic Desymmetrization (Hydrolysis) of Diacetate 4.
Typical Procedure. A mixture of diacetate 4 (200 mg, 0.80 mmol),
CAL-B (700 units), phosphate buffer (30 mL, pH 7.2), and hexane
(5 mL) was stirred at room temperature. The reaction was monitored
by TLC (hexanes-ethyl acetate, 4:1) and terminated when the
substrate had disappeared. The mixture was filtrated through a Celite
pad, diluted with CH2Cl2 (20 mL), and washed with brine (2 × 5
mL) and water (10 mL). The organic phase was dried and
evaporated to yield (1S,3R)-5 (136 mg, 91%) as a colorless oil,
which was further processed without further purification. For
analytical purposes a sample was purified by flash column chro-
mg, 61%): [R]23 -9.21 (c 1.5, CHCl3); spectral data as above.
D
3-Hydroxy-2,2-dimethylcyclohexanone (1). To a solution of
(R)-6 (700 mg, 3.80 mmol) in methanol-water (1:1, 50 mL) was
added concentrated HCl (2 mL). The solution was stirred overnight
at room temperature. The solution was neutralized (pH < 8) with
a saturated aqueous solution of NaHCO3. The solution was
evaporated with addition of methanol to form an azeotrope. The
residue was dissolved in CH2Cl2 and filtered, and the solvent was
matography (hexanes-ethyl acetate, 4:1): [R]23 +9.13 (c 0.9,
evaporated to give (R)-1 (512 mg, 92%) as a colorless oil: [R]25
D
D
-23.7 (c 1.5, CHCl3); lit.3 [R]25D -22.1 (c 1.0, CHCl3); 1H NMR
(CDCl3) δ 3.71 (dd, J ) 7.5 and 2.2 Hz, 1H), 2.38-2.42 (m, 2H),
1.99-2.04 (m, 2H), 1.93 (br s, 1H), 1.79-1.90 (m, 2H), 1.60-1.70
(m, 1H), 1.16 (s, 3H), 1.12 (s, 1H); 13C NMR (CDCl3) δ 215.1,
77.9, 51.4, 37.4, 29.1, 22.9, 20.8, 19.7. The (S)-enantiomer showed
identical physical and spectroscopic data except for the sign of the
optical rotation.
CHCl3); spectral data as above.
2,2-Dimethyl-3-oxocyclohexylacetate (6). Method 1. To a
solution of (1R,3S)-5 (500 mg, 2.66 mmol) in CH2Cl2 (30 mL) at
0 °C was added pyridinium dichromate (1.20 g, 3.2 mmol). The
mixture was stirred at room temperature overnight. Silica gel (500
mg) was added to the mixture, and stirring was continued for 1 h.
The mixture was filtered through a Celite pad, and the solvent was
evaporated. The crude product was purified by flash chromatography
(hexanes-ethyl acetate, 4:1) to give (R)-6 (396 mg, 81%) as an
oil: [R]23D -9.36 (c 1.45, CHCl3), lit.9 [R]20D +8.62 (c 0.58, CHCl3)
for the (S)-enantiomer. 1H NMR (CDCl3) δ 4.92 (dd, J ) 6.2 and
2.4 Hz, 1H), 2.35-2.50 (m, 2H), 2.03 (s, 3H), 1.72-2.00 (m, 4H),
1.16 (s, 3H), 1.07 (s, 3H); 13C NMR (CDCl3) δ 213.5, 170.5, 79.4,
49.5, 37.4, 26.0, 23.5, 21.2, 20.9, 20.4. The (S)-enantiomer showed
identical physical and spectroscopic data except for the sign of the
optical rotation.
Acknowledgment. Financial support from the Natural Sci-
ences and Engineering Research Council of Canada (NSERC)
is gratefully acknowledged.
Supporting Information Available: General experimental
procedures and 1H and 13C NMR spectra for new compounds 4
and 5. This material is available free of charge via the Internet
at http://pubs.acs.org.
(9) Lu, Y.; Barth, G.; Kieslich, K.; Strong, P. D.; Duax, W. L.; Djerassi, C.
J. Org. Chem. 1983, 48, 4549–4554.
JO801954V
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