Enzymatic desymmetrization of a centrosymmetric diacetate

Article abstract of DOI:10.1016/S0957-4166(02)00787-5

An enantiomerically pure cyclohexanol was synthesized starting from para-xylene 1. The key steps are a stereoselective twofold hydroboration and a pig liver esterase (PLE)-catalyzed desymmetrization of the centrosymmetric cyclohexanediacetate 4.

Full text of DOI:10.1016/S0957-4166(02)00787-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 71–74
Enzymatic desymmetrization of a centrosymmetric diacetate
C. Bo¨hm, W. F. Austin and D. Trauner*
Center for New Directions in Organic Synthesis, Department of Chemistry, University of California, Berkeley, CA 94720, USA
Received 13 August 2002; accepted 2 September 2002
Abstract—An enantiomerically pure cyclohexanol was synthesized starting from para-xylene 1. The key steps are a stereoselective
twofold hydroboration and a pig liver esterase (PLE)-catalyzed desymmetrization of the centrosymmetric cyclohexanediacetate 4.
© 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
hexanol featuring an enzymatic hydrolysis of the corre-
sponding centrosymmetric diacetate.
The desymmetrization of readily available meso com-
pounds to yield enantiomerically enriched products has
proven to be a valuable synthetic operation.1 While this
strategy has been widely applied to Cs symmetrical
substrates, few examples of the desymmetrization of
molecules belonging to the molecular point group Ci
(=S2), or other centrosymmetric substrates, have been
described. As early as 1958, Prelog et al. reported the
enantiotopos-selective reduction of a centrosymmetric
decalin-dione using baker’s yeast.2 Very recently, the
desymmetrization of a Ci-symmetrical bis-epoxide via
metal-catalyzed epoxide hydrolysis was disclosed.3 We
now report a route to an enantiomerically pure cyclo-
2. Results and discussion
Birch-reduction of para-xylene 14 yielded 1,4-dimethyl-
cyclohexa-1,4-diene 2, which subsequently underwent
hydroboration with excess 9-BBN-H. Oxidative workup
gave the crystalline centrosymmetric diol 3 as the only
isolated diastereomer and regioisomer in 39% overall
yield. No C2-symmetric diol was observed. Presumably,
the high diastereoselectivity of the reaction results from
preferential addition of the second borane molecule to
the side opposite the bulky 9-BBN moiety in the
Scheme 1. Preparation of the centrosymmetric diacetate 4. Reagents and conditions: (a) Na, NH3, MeOH, THF; (b) i. 9-BBN (3
equiv.), THF, ii. H2O2, NaOH, 39%; (c) Ac2O, NEt3, DMAP, CH2Cl2, 98%; (d) n-BuLi (1 equiv.), Ac2O, 54%.
* Corresponding author. E-mail: trauner@cchem.berkeley.edu
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00787-5

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C. Bo¨hm et al. / Tetrahedron: Asymmetry 14 (2003) 71–74
monoadduct. Upon treatment with Ac2O in the pres-
ence of NEt3 and DMAP, the diol 3 was converted into
the diacetate 4 in 98% yield. Monodeprotonation of the
diol 3 with n-BuLi (1 equiv.) followed by addition of
Ac2O, gave the racemic monoacetate 5 in 54% yield
(Scheme 1).
Arguably, esterases such as pig liver esterase (PLE)
have proven to be the most widely successful enzymes
in asymmetric synthesis.5 They are cheap, stable, do not
require a coenzyme and tolerate a wide variety of
substrates. The PLE-catalyzed hydrolysis of 4 gave rise
to the enantiomerically pure cyclohexanediol monoac-
etate (+)-5 in 95% yield and >99.5% e.e. (Table 1).
Importantly, no further hydrolysis of the second acetate
to afford 3 could be detected (by GC). This implies that
the high e.e. does not result from kinetic resolution
following the initial enantiotopos-discriminating
hydrolysis.6
Scheme 2. Determination of the absolute configuration of
(+)-5.
Table 1. Enzymatic hydrolysis of the diacetate 4
Figure 1. X-Ray structure of (−)-7.
Entry
Additive
–
Conversion
(%)a
React. time E.e.b (%)
(h)
1
2
100
20
17
\99.5
\99.5
3. Conclusion
10% DMSO 100
In summary, we have achieved an asymmetric synthesis
of the cyclohexanol (+)-5 from readily available racemic
starting materials in a highly enantioselective fashion.
Our work demonstrates the usefulness of PLE for the
desymmetrization of centrosymmetric diacetates. Stud-
ies on the scope and limitations of this methodology
and its application to the total synthesis of natural
products are underway and will be reported in due
course.
a Reaction was monitored by GC.
b ee was determined by chiral GC.
It has been reported that the presence of various
organic cosolvents have a dramatic effect on the rate
and selectivity of enzyme-catalyzed reactions.7,8 How-
ever, we observed only moderate rate enhancement for
the hydrolysis of 4 in the presence of 10% DMSO and
no significant impact on the enantioselectivity (Table
1).
4. Experimental
4.1. General
The absolute configuration of our enantiomerically
pure monoacetate (+)-5 was established by X-ray crys-
tallography. Unfortunately, the para-bromo-benzoate
of (+)-5 did not yield high quality single crystals. There-
fore, the camphanic acid ester derivative (−)-7 was
synthesized in 76% yield using standard conditions
(Scheme 2). The latter was crystallized and analyzed by
X-ray diffraction (Fig. 1).9 The X-ray structure shows
that the pro-(R)-acyl group is preferentially hydrolyzed
by PLE. This is in accordance with the results of
Schneider and Laumen, who examined the enzymatic
hydrolysis of Cs-symmetric prochiral diesters.10
Unless otherwise noted, all reagents were purchased
from commercial suppliers and used without further
purification. PLE was purchased from Sigma. Melting
points were measured on a Bu¨chi melting point appara-
tus and are uncorrected. 1H NMR and 13C spectra were
recorded on a Bruker DRX 500 or Bruker AMX 300.
Optical rotations were measured on a Perkin–Elmer
241 polarimeter. Mass spectra were recorded on a VG
ProSpec. Silica gel chromatography was carried out
,
using ICN SiliTech 32–63 D 60 A. Thin-layer chro-
matography (TLC) was performed with Merck Silica

C. Bo¨hm et al. / Tetrahedron: Asymmetry 14 (2003) 71–74
73
Gel 60 plates. Elemental analysis was performed by the
Microanalytical Laboratory operated by the UCB Col-
lege of Chemistry. X-Ray analysis was performed on a
Bruker SMART CCD area-detector diffractometer.
170.8; MS (EI): 228 [M+] (5), 169 [M+−HOAc] (50), 108
(100); IR (KBr): w=3428, 2930, 1731, 1373, 1246, 1108,
1025 cm−1. Anal. calcd for C10H18O3: C, 64.49; H, 9.74.
Found: C, 64.25; H, 10.09%. The e.e. was determined
by GC on a chiral column: HP 6850 Series GC system,
HP 7683 Series Injector, detector: FID, 250°C, column:
Astec 71023, b-cyclodextrin, 30.0 m×250 mm×0.25 mm,
method: 90°C, 5 min; +5°C/min, 135°C, 70 min, −15°C/
min. Retention time: 34.2 min.
4.2. Compounds
4.2.1. 2,5-Dimethylcyclohexan-1,4-diol, 3. To a nitrogen-
purged reaction flask containing a solution of 9-BBN in
THF (0.5 M, 18 mL, 9.0 mmol, 3 equiv.) was added
diene 2 (324 mg, 3 mmol, 1 equiv.). The solution was
heated to reflux for 24 h. After cooling to 0°C, aqueous
NaOH (2.5 M, 5 mL) and 30% aqueous H2O2 (5 mL)
was added carefully. Upon complete addition, the mix-
ture was heated to reflux for an additional hour, cooled
to 0°C, and satd aq. NaCl (25 mL) and EtOAc (25 mL)
were added. The layers were separated, and the
aqueous layer was extracted with EtOAc (3×20 mL),
dried with MgSO4, filtered, and concentrated. The
crude product was purified by chromatography (hex-
anes/EtOAc, 1:2 v/v) to provide the desired diol 3 as a
colorless solid (170 mg, 39%). Mp 156°C; 1H NMR
(300 MHz, CDCl3): l=1.03 (d, J=6.5 Hz, 3H, CH3),
1.45 (m, 2H), 1.51 (m, 2H), 1.93 (m, 1H), 3.20 (dd,
J=11.0, 4.5 Hz, 1H); 13C NMR (75 MHz, CDCl3):
l=18.1, 38.5, 41.9, 75.3. MS (EI): 144 [M+], 126 [M+−
H2O] (90), 71 (50), 57 (100); IR (KBr): w=3308, 2923,
1453, 1033 cm−1. Anal. calcd for C8H16O2: C, 66.63; H,
11.18. Found: C, 67.01; H, 11.53%.
4.2.4. (−)-Camphanic acid (4-acetoxy-2,5-dimethyl)-
cyclohexyl ester, (−)-7. A solution of alcohol (+)-5 (18.6
mg, 0.1 mmol, 1 equiv.), acid chloride (−)-6 (26.0 mg,
0.12 mmol, 1.2 equiv.), and NEt3 (21 mL, 0.15 mmol,
1.5 equiv.) in dry CH2Cl2 (5 mL) was stirred first at 0°C
for 1 h, then at rt for 15 h. The solvent was evaporated,
and the crude residue purified by chromatography (hex-
anes/EtOAc 1:1 v/v) to provide 27.8 mg (76%) ester
(−)-7 as a colorless solid. Mp 134°C; [h]D=−8.7 (c 0.85,
CH2Cl2); 1H NMR (500 MHz, CDCl3): l=0.92 (d,
J=6.5 Hz, 6H, 2CH3), 0.96 (s, 3H, CH3), 1.05 (s, 3H,
CH3), 1.11 (s, 3H, CH3), 1.16 (m, 1H), 1.22 (m, 1H),
1.66–1.83 (m, 3H), 1.92 (ddd, J=15.3, 10.7, 4.6 Hz,
1H), 2.00–2.10 (m, 3H), 2.05 (s, 3H, CH3), 2.40 (ddd,
J=14.9, 10.7, 4.2 Hz, 1H), 4.42 (dt, J=10.8, 4.3 Hz,
1H), 4.56 (dt, J=10.8, 4.3 Hz, 1H); 13C NMR (125
MHz, CDCl3): l=9.7, 16.8, 16.9, 17.8, 17.9, 29.0, 30.7,
35.2, 35.4, 37.7, 37.8, 54.1, 54.8, 76.2, 78.1, 91.1, 167.2,
170.8, 178.1; MS (FAB pos.): 367 [M+H+] (25), 109
(100); IR (KBr): w=2967, 1789, 1729, 1451, 1375, 1243
cm−1.
4.2.2. 1,4-Diacetoxy-2,5-dimethylcyclohexane, 4. To an
ice-cooled solution of diol 3 (200 mg, 1.4 mmol, 1
equiv.) in dry CH2Cl2 (20 mL) was added NEt3 (870
mL, 6.24 mmol, 4.5 equiv.) followed by Ac2O (590 mL,
6.24 mmol, 4.5 equiv.) and a trace of DMAP. After
stirring at rt for 3 h (TLC) the solution was concen-
trated and the crude material purified by chromatogra-
phy (hexanes/EtOAc, 1:1 v/v) to provide the diacetate 4
Acknowledgements
C.B. is grateful to C. H. Heathcock for financial sup-
port and Dr. Frederick J. Hollander and Dr. Allen G.
Oliver for the crystal structure determination of com-
pound (−)-7.
1
as a colorless solid (310 mg, 98%). Mp 96°C; H NMR
(300 MHz, CDCl3): l=0.90 (d, J=6.5 Hz, 3H, CH3),
1.14 (m, 2H), 1.70 (m, 1H), 2.04 (s, 3H, OAc), 4.41 (dd,
J=11.0, 4.5 Hz, 1H); 13C NMR (75 MHz, CDCl3):
l=17.8, 21.1, 35.4, 37.8, 76.4, 170.8; MS (EI): 228 [M+]
(5), 169 [M+−HOAc] (50), 108 (100); IR (KBr): w=
2957, 1727, 1372, 1243, 1025 cm−1. Anal. calcd for
C12H20O4: C, 63.14; H, 8.83. Found: C, 63.30; H,
9.00%.
References
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7.5) at rt. The reaction was monitored by GC analysis
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1
(c 0.42, CH2Cl2); H NMR (300 MHz, CDCl3): l=0.90
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2.04 (s, 3H, OAc), 4.41 (dd, J=11.0, 4.5 Hz, 1H); 13C
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74
C. Bo¨hm et al. / Tetrahedron: Asymmetry 14 (2003) 71–74
largest diff. peak: 0.70 and −0.55 e A−3. The crystallo-
graphic data for (−)-7 have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication number CDCC 186333. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge, CB2 1 EZ, UK [fax:
+44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.
uk].
,
9. X-Ray analysis for (−)-7 (crystallized from CH2Cl2/hex-
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space group: P11, unit cell dimensions: a=6.309(1), b=
,
6.668(1), c=12.406(3) A, h=96.895(3), i=102.879(3),
3
,
k=98.669(3)°, V=496.5(2) A , Z=1, density=1.226 g/
cm3, absorption coefficient=0.89 cm−1, F(000)=198.0;
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,
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R