A convenient, large scale synthesis of trans-(+)-sobrerol

Article abstract of DOI:10.1081/SCC-120021040

A convenient and highly efficient synthesis of optically pure trans(+)-sobrerol (1), starting from methyl 3,5-dihydroxy-4-methyl benzoate 2 in 8 steps with overall yield 26%, is reported. The key intermediate 4 is prepared in remarkably high yield by selectively esterification of 3 using lipase as catalyst. A critical step to stereoselectively inverse the configuration of 7 is realized under Mistunobu conditions.

Full text of DOI:10.1081/SCC-120021040

This article was downloaded by: [University of California Santa Cruz]
On: 11 November 2014, At: 03:39
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
A Convenient, Large Scale Synthesis of trans-(+)-
Sobrerol
Qiuan Wang a , Yanlin Li a & Qingqi Chen b
a College of Chemistry and Chemical Engineering , Hunan University , Changsha, P.R. China
b Biomarin Pharmaceutical Inc. , Vancouver, Canada
Published online: 17 Aug 2006.
To cite this article: Qiuan Wang , Yanlin Li & Qingqi Chen (2003) A Convenient, Large Scale Synthesis of trans-(+)-Sobrerol,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:12,
2125-2134, DOI: 10.1081/SCC-120021040
To link to this article: http://dx.doi.org/10.1081/SCC-120021040
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONSꢀ
Vol. 33, No. 12, pp. 2125–2134, 2003
A Convenient, Large Scale Synthesis
of trans-(Q)-Sobrerol
Qiuan Wang,1 Yanlin Li,1 and Qingqi Chen2,
*
1College of Chemistry and Chemical Engineering,
Hunan University, Changsha, P.R. China
2Biomarin Pharmaceutical Inc., Vancouver, Canada
ABSTRACT
A convenient and highly efficient synthesis of optically pure trans-
(þ)-sobrerol (1), starting from methyl 3,5-dihydroxy-4-methyl benzo-
ate 2 in 8 steps with overall yield 26%, is reported. The key
intermediate 4 is prepared in remarkably high yield by selectively
esterification of 3 using lipase as catalyst. A critical step to
stereoselectively inverse the configuration of 7 is realized under
Mistunobu conditions.
*Correspondence: Qingqi Chen, Biomarin Pharmaceutical Inc., 2386 East Mall,
Vancouver, BC, V6T 1Z3, Canada; E-mail: qchen@synapse-tech.com.
2125
DOI: 10.1081/SCC-120021040
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2126
Wang, Li, and Chen
INTRODUCTION
The trans-(þ)-sobrerol (1, trans-p-menth-6-ene-2,8-diol) is a well-
known mucolytic drug.[1] Many other important biological activities
of this compound have recently been found and attracted increasing
attention.[2–3] For example, sobrerol was found to have chemopreventive
activity to induce tumor cell apoptosis, and/or to inhibit the post-
translational isoprenylation of cell growth-regulating proteins,[2] and to
inhibit farnesyltransferase regulating the development of pulmonary
hypertension.[3] More interestingly, trans-sobrerol (1) is also a versatile
chiral tool in the asymmetric synthesis of a number of natural products.[4]
trans-(Æ)-Sobrerol is commercially available from Aldrich-Sigma.
However, reports on the preparation of its optical active isomer, trans-
(þ)-sobrerol, are scarce. Literature methods on the synthesis of
compound 1, including acid-catalyzed cleavage[4] or RuCl3 mediated
ring-open[5] of (þ)-2,3-epoxy-cis-pinane in aqueous systems, and kinetic
resolution of (Æ)-trans-sobrerol by lipase-catalyzed acetylation,[1] suffer
from either low yield or poor optical purity, and are not suitable for large
scale preparation. Herein, we wish to report a convenient and highly
efficient stereogenic synthesis of optically pure 1 using readily available
starting materials (Sch. 1).
RESULTS AND DISCUSSION
Methyl 3.5-dihydroxy-4-methyl benzoate (2) is converted in 65%
yield to all-cis-3.5-dihydroxy-4-methyl-1-(methoxycarbonyl)cyclohexane
(3) by Rh/Al2O3 catalyzed hydrogenation as described previously,[6,7]
which is then esterified using vinyl acetate to generate 93% enantiomeri-
cally pure monoacetate (4) under enzyme catalyzed condition using lipase
(Ps. Fluorescens, Fluka).
The enantiomeric excess is determined by subcritical fluid chromato-
graphy (SFC).[8] The absolute configurations of 3 and 4 could be deduced
by the structure of cis-(À)-sobrerol 11, which is prepared in two steps from
4 as outlined in Sch. 2. Compound 4 is dehydrated under Mitsunobu
conditions,[9] and converted to the corresponding cyclohexene 10, and
further to cis-(-)-sobrerol, 11, upon reaction with MeMgBr.[10]
Treating 4 tert-butyldiphenylsilyl chloride (TBDPS-chloride) and
subsequently with K2CO3 in dry methanol, the expected TBDPS ether 5
is obtained in 84% yield, which is dehydrated under Mitsunobu conditions
to give the corresponding TBDPS-cyclohexenol 6 in 92% yield. Removal
of the TBDPS group of 6 using tetrabutylammonium fluoride (TBAF) in

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Optically Pure trans-(Q)-Sobrerol
2127
Scheme 1. Reagents and conditions: a) H2, 5%Rh/Al2O3, ethanol, 105œ for
24 h, 65%. b) lipase (Ps. fluorescens), r.t. for 72 h, 93%. c) (1) t-BuPh2SiCl,
imidazole, DMAP, DMF, r.t. for 20 h. (2) K2CO3, MeOH, r.t. for 7 h, 84%. d)
Ph3P, DEAD, THF, r.t. for 15 h, 92%. e) TBAF, THF, r.t. for 20 h, 90%. f )
p-Nitrobenzoic acid, Ph3P, DEAD, toluene, r.t. for 9 h, 78%. g) K2CO3, MeOH,
r.t. for 8h, 93%. h) MeMgBr, THF, À78œ for 6 h, 85%.
Scheme 2. Reagents and conditions: a) Ph3P, DEAD, THF, r.t. for 15 h, 92%.
b) MeMgBr, THF, À78œ for 6 h, 86%.
THF at room temperature gives 7 in 90%. The key conversion to 8 is
achieved in 78% yield using triphenylphosphine and p-nitrobenzoic acid
in the presence of diethylazodicarboxylate at room temperature for 9 h.
Deprotection of the p-nitrobenzoate ester 8 with anhydrous K2CO3 and

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2128
Wang, Li, and Chen
dry MeOH give 9 in 93% yield, which is further to converted the target
compound, trans-(þ)-sobrerol 1 in 85% yield with ee > 99% upon
treatment with MeMgBr in THF at À78œ. The structure of 1 is confirmed
by NMR, MS, combustion analysis, which are identical with the literature
report.[1,2]
In summary, we here have reported a very convenient, highly efficient
method for the synthesis of trans-(þ)-sobrerol (1), which is suitable for
larger scale synthesis.
EXPERIMENTAL SECTION
Column chromatography was performed on silica gel. HPLC separa-
tions were performed on a Knauer 64 or a Kontron 420 delivery system
with RI detection. Optical rotations were measured with a Perkin-Elmer
421 polarimeter. IR spectra were recorded on a Perkin-Elmer FTIR-1600
1
spectrometer, mass spectra on a HP-5988 Spectrometer. The H NMR
spectra were recorded at 500 MHz (Brucker AN-500), the 13C NMR
Spectra at 50 MHz (Varian Gemini-200). The chemical shifts ( ꢀ ) are
reported in parts per million with reference at 0 ppm (Me4Si) or
7.26 ppm (CHC13) for the proton and at 77.0 ppm (centered on the
signal of CDCl3) for the carbon. Elemental analyses were carried out
on a Perkin-Elmer 240B microanalyzer. Enantiomeric excess (ee) values
are determined by SFC (Column chiralpak AD, Diacel, Japan, eluent
CO2 modified with 5% MeOH). All solvents and reagents are purchased
from Aldrich, Sigma, or Fluka. Ester 3 is prepared according to the
previous reports.[6,7]
(1R,3S,4S,5R)-5-Acetoxy-3-hydroxy-4-methyl-1-
(methoxycarbonyl)cyclohexane (4)
A mixture of diol 3 (1.0 g, 5.5 mmol) and lipase (Ps. fluorescens)
(650 mg, 42.5 U/mg) in vinyl acetate (30 mL) was stirred in the dark
at room temperature. The reaction was monitored by TLC
(H3PO4/12MoO3 solution as indictor). After 72 h, the reaction mixture
was filtered through a pad of celite. The filtrate was concentrated, and
purified on a short (2.5 cm  10 cm) silica gel column (i-octane/EtOAc,
v/v, 5/5) to give a colorless oil (11.8 g, 93%). Rf 0.36 (i-octane/EtOAc,
25
D
v/v, 5/5). ½ꢁŠ ¼ À21.9(c 0.81, CHCl3), ee ꢀ 99%. IR (film): ꢂ ¼ 3437,
2953, 1730, 1472, 1439, 1365, 1242, 1197, 1178, 1078, 1026, 981,

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Optically Pure trans-(Q)-Sobrerol
2129
875 cmÀ1
.
1H NMR (500 MHz, CDCl3, ꢀ ¼ 4.8 (m, 1H), 3.8 (m, 1H),
3.69 (s, 3H), 2.4 (m, 1H), 2.30 (d, J ¼ 6.4 Hz, 1H), 2.05 (s, 3H), 1.9
(m, 2H), 1.8 (m, 3H), 0.96 (d, J ¼ 7.0 Hz, 3H) ppm. 13C NMR
(50 MHz, CDCl3, ꢀ ¼ 174.6, 170.3, 72.1, 69.6, 52.0, 38.0, 37.6, 30.5,
27.3, 21.2, 6.21 ppm. MS: m/z ¼ (%): 231 (Mþþ1,1), 213 (2), 199 (4),
186 (5), 170 (15), 152 (21), 127 (60), 111 (70), 93 (75), 87 (25), 82 (20),
43 (100). Anal. Calcd. for C11H18O5, required: C, 57.38; H, 7.88%.
Found: C, 57.21; H, 7.95%.
(1S,R,4R,5S)-5-t-Butyldiphenylsilyloxy-3-hydroxy-4-methyl-1-
(methoxy-carbonyl)cyclochexane (5)
To a stirred solution of 4 (8.1 g, 35.2 mmol), imidazole (7.2 g,
105.7 mmol) and DMAP (2.2 g) in dry DMF (120 mL) was added
dropwise tert-butyldiphenyl silyl chloride (TBDPSCl, 18 mL,
70.4 mmol). The mixture was stirred for 20h at room temperature
before pouring into water-EtOAc (600 mL, v/v, 1/1). The organic
layer was separated and then the aqueous layer was extracted with
EtOAc (200 mL Â 3). The combined extracts were washed with brine
(150 Â 3 mL), dried over anhydrous MgSO4 and concentrated to give
the crude product, which was then dissolved in 150 mL dry MeOH,
and treated with K2CO3 (600 mg). The mixture was stirred at room
temperature for 10 min. before the second portion K2CO3 (380 mg)
was added. The mixture was allowed to stir for 6h at room temperature,
then partitioned with EtOAc (300 mL) and water (200 mL). The
organic phase was separated and aqueous phase was extracted
with EtOAc (300 mL Â 3). The organic phase and extracts were
combined, dried over anhydrous magnesium sulfate, and concen-
trated under vacuum to give the crude product, which was further
purified by flash chromatography over silica gel (i-octane/EtOAc,
v/v, 9/1) to offer
(i-octane/EtOAc, v/v, 8/2), ½ꢁŠ ¼ þ33.0 (c 0.62, CHCl3). IR (film):
5 (6.9 g, 98%) as a colorless oil. Rf 0.16
25
D
ꢂ ¼ 3448, 2954, 2858, 1737, 1654, 1472, 1362, 1279, 1240, 1173, 1008,
1
852, 822, 795, 741, 702, 611 cmÀ1. H NMR (500 MHz, CDCl3, ꢀ ¼ 7.6
(m, 4H), 7.4 (m, 2H), 7.4 (m, 4H), 3.70 (m, 1H), 3.64 (s, 3H), 3.5 (m,
1H), 2.2 (m, 1H), 2.1 (m, 1H), 1.8 (m, 1H), 1.69 (t, J ¼ 8.9 Hz, 2H), 1.56
(q, J ¼ 12.4 Hz, 1H), 1.37 (d, J ¼ 5.3 Hz, 1H), 1.06 (s, 9H), 1.02
(d, J ¼ 7.0 Hz, 3H). MS: m/z (%): 409 (1), 369 (7), 337 (7), 309 (5),
291 (35), 199 (100), 156 (85), 181 (17), 153 (34), 121 (23), 93 (68), 57
(47). Anal. Calcd. for C25H34O4 Si, required: C, 70.38; H, 8.03%.
Found: C, 70.55; H, 7.91%.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2130
Wang, Li, and Chen
(4S,6S)-6-t-Butyldiphenylsilyloxy-1-methyl-4-
(methoxycarbonyl)cyclohexene (6)
To
a stirred solution of 5 (19.0 g, 45.0 mmol) and Ph3P
(57.7 g, 220 mmol) in THF (300 mL) at r.t., was added dropwise
diethylazodicarboxylate (DEAD, 41 mL, 220 mmol). After stirring
overnight at room temperature, the solution was concentrated. The
residue was purified by flash chromatography over silica gel (i-
octane/EtOAc, v/v, 95/5) to afford the expected compound 6 (16.7 g,
25
92%) as colorless oil. Rf 0.31 (i-octane/ EtOAc, 95:5), ½ꢁŠ ¼ þ81.8 (c
D
l.52, CHCl3). IR (film): ꢂ ¼ 2952, 2857, 1738, 1589, 1472, 1429, 1362,
1
1308, 1247, 1169, 1111, 1062, 1000, 934, 821, 740, 703 cmÀ1. H NMR
(500 MHz, CDCl3, ꢀ ¼ 7.7 (m, 10H), 5.4 (m, 1H), 4.24 (s, 1H), 3.59 (s,
1H), 2.4 (m, 1H), 2.3 (m, 3H), 1.7 (m, 1H), 1.66 (s, 3H), 1.07 (s, 9H)
ppm 13C NMR (50 MHz, CDCl3), ꢀ ¼ 175.2, 137.5, 136.1, 134.4, 133.7,
129.6, 127.6, 121.9, 71.4, 51.6, 38.9, 35.2, 27.9, 27.1, 20.2, 19.5 ppm MS:
m/z (%): 408 (Mþ, 1), 354 (8), 351 (Mþ-57, 20), 299 (5), 273 (6), 213 (100),
183 (75), 137 (70). Anal. Calcd. for C25H32O3 Si, required: C, 73.49; H,
7.89%. Found: C, 73.25; H, 7.74%.
(4S,6S)-6-Hydroxyl-1-methyl-4-
(methoxycarbonyl)cyclohexene (7)
To a stirred solution of 6 (13.7 g, 34 mmol) in THF (200 mL) was
added TBAF (180 mL, 1M in THF). The mixture was stirred for 20 h
at room temperature. THF was evaporated, the residue was purified
by flash chromatography over silica gel (i-octane/EtOAc, v/v, 8/2) to
give the desired compound 7 (5.2 g, 90%) as a colorless oil. Rf 0.18 (i-
octane/EtOAc, v/v, 8/2). To a stirred solution of 6 (13.7 g, 34 mmol) in
THF (200 mL) was added TBAF (180 mL, 1 M in THF). The mixture
was stirred for 20 h at room temperature. THF was evaporated, the
residue was purified by flash chromatography over silica gel (i-
octane/EtOAc, v/v, 8/2) to give the desired compound 7 (5.2 g, 90%)
25
as a colorless oil. Rf 0.18 (i-octane/EtOAc, v/v, 8/2). ½ꢁŠ ¼ þ16.8 (c
D
0.66, CHCl3). IR (film): ꢂ ¼ 3432, 2951, 2850, 1735, 1455, 1435, 1382,
1
1247, 1185, 1170, 1035, 925 cmÀ1. H NMR (500 MHz, CDCl3, ꢀ ¼ 5.45
(t, J ¼ 1.5 Hz, 1H), 4.08 (t, J ¼ 6.2 Hz, 1H), 3.68 (s, 3H), 2.7 (m, 1H),
2.3 (m, 3H), 2.15 (brs, 1H), 1.9 (m, 1H), 1.78 (s, 3H). MS m/z (%):
170 (Mþ, 3), 152 (20), 137 (15), 111 (30), 93 (100), 77 (30), 43(50).
Anal. Calcd. for C9H14O3 (170.21): C, 63.51; H, 8.29%. Found: C,
63.31; H, 8.40%.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Optically Pure trans-(Q)-Sobrerol
2131
(4S,6R)-1-Methyl-6-(40-nitrobenzoyloxy)-4-
(methoxycarbonyl)cyclohexene (8)
To a stirred solution of 7 (3.5 g, 16.5 mmol), 4-nitrobenzoic acid
(3.04 g, 18.2 mmol) and Ph3P (4.76 g, 18.2 mmol) in THF (200 mL) was
added dropwise DIAD (34 mL, 18.2 mmol) over a period of 30 min at
0–10œ, then the reaction mixture was stirred at room temperature for
9 h before filtering through a pad of celite and washing with ethyl acetate.
The yellow filtrate was evaporated. The residue was further purified by
flash chromatography over silica gel (i-octane/EtOAc, v/v, 9/1) to afford
4-nitrobenzoate ester 8 (5.12 g, 78%) as a colorless oil. Rf 0.3 (i-
25
octane/EtOAc, v/v, 9/1). ½ꢁŠ ¼ þ281.5 (c l.38, CHCl3), IR (film):
D
ꢂ ¼ 2950, 1719, 1607, 1527, 1436, 1343, 1267, 1196, 1167, 1101, 1013,
1
946, 921, 873, 848, 720 cmÀ1. H NMR (500 MHz, CDCl3 ꢀ ¼ 8.29 (d,
J ¼ 7.9 Hz, 2H), 8.22 (d, J ¼ 7.9 Hz, 2H), 5.79 (brs, 1H), 5.54 (s, 1H), 3.69
(s, 3H), 2.8 (m, 1H), 2.45 (d, J ¼ 17.8 Hz, 1H), 2.32 (d, J ¼ 11.6 Hz, 1H),
2.25 (t, J ¼ 13.2 Hz, 1H), 2.0 (m, 1H), 1.75(s, 3H) pp. 13C NMR (50 MHz,
CDCl3): ꢀ ¼ 175.5, 164.5, 150.8, 135.9, 127.1, 123.7, 77.8, 77.2, 76.5, 71.2,
52.0, 35.1, 28.0, 20.9 ppm. MS m/z (%): 319 (Mþ, 1), 259 (8), 152 (20), 150
(75), 121 (20), 93 (100). 77 (40), 50 (30). Anal. Calcd. for C16H17NO6,
required: C, 60.18; H, 5.37; N, 4.39%. Found: C, 59.87; H, 5.11; N, 4.01%.
(4S,6R)-6-Hydroxyl-1-methyl-4-
(methoxycarbonyl)cyclohexene (9)
To the solution of 4-nitrobenzoate ester 8 (5.0 g, 15.7 mmol) in
MeOH (200 mL) was added K2CO3 (108 g, 7.85 mmol). The mixture
was stirred at room temperature for 8 h before partitioning with EtOAc
(300 mL) and water (200 mL). The organic layer was separated, the aqu-
eous layer was extracted with EtOAc (3 Â 100 mL). The combined
organic layer and extracts were washed with brine (3 Â 60 mL), dried
over anhydrous magnesium sulfate and concentrated under vacuum.
The residue was purified by flash chromatography over silica gel (i-
octane/EtOAc, v/v, 8/2) to yield the expected product 9 (2.48 g, 93%)
25
as a colorless oil. Rf 0.22 (i-octane/EtOAc, v/v, 8/2). ½ꢁŠ ¼ þ156.3 (c 0.6,
D
CHCl3). IR (film): ꢂ ¼ 3406, 2952, 1734, 1437, 1250, 1197, 1053, 966,
809 cmÀ1
.
1H NMR (500 MHz, CDCl3): ꢀ ¼ 5.56 (q, J ¼ 1.4Hz, 1H),
4.05 (brs, 1H), 3.69 (s, 3H), 2.7 (m, 1H), 2.2 (m, 2H), 1.79 (m, 4H),
1.61 (s, 1H). 13C NMR (50 MHz, CDCl3): ꢀ ¼ 176.0, 134.4, 123.8, 67.3,
51.8, 34.3, 34.2, 27.9, 20.8 ppm, MS m/z (%): 170 (Mþ,15), 139 (15), 120
(10), 110 (70), 95 (100), 77 (70), 67 (50), 55 (80), 43 (70). Anal. Calcd.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2132
Wang, Li, and Chen
for C9H14O3 (170.21): required: C, 63.51; H, 8.29%. Found: C, 63.42;
H, 8.37%.
(4S,6R)-6-Hydroxyl-4-(1-hydroxyisopropyl)-1-
methylcyclohexene (1) (trans-(Q)-Sobrerol) (1)
To a stirred solution of 9 (2.5 g, 11.8 mmol) in THF (60 mL) at À78œ
was added dropwise MeMgBr (66 mL, 3.0 M in Et2O). The mixture was
stirred for 6 h at À78œ before slowly warming up room temperature. The
mixture is further stirred overnight at room temperature. The reaction was
quenched with aqueous saturated NH4Cl (50 mL) and extracted with
EtOAc (3 Â 200 mL). The combined organic layers were washed with
brine (3 Â 100 mL), dried over anhydrous magnesium sulfate and
concentrated under vacuum. The residue was purified by flash chromato-
graphy (i-octane/EtOAc, v/v, 6/4) and crystallized from CH2Cl2 to give the
desired compound 1 (1.68 g, 85%) as colorless needle. m.p. 130–132œ, Rf
25
D
0.22 (i-octane/EtOAc, v/v, 1/1)œ ½ꢁŠ ¼ þ133.4 (c 0.31, CHCl3),
ee ꢀ 99%. IR (film)œ ꢂ ¼ 3274œ2973œ1629œ1468œ1425œ1376œ
1294 œ1251œ1156œ1052œ984œ920œ824œ761œ662œ611 œ468 cmÀ1
.
1H NMR (500 MHz, CDCl3): ꢀ ¼ 5.58 (q, J ¼ 1.4 Hz, 1H), 4.05 (s, 1H), 2.1
(m, 1H), 2.01 (dd, J ¼ 13.4, 1.4 Hz, 1H), 1.80(s, 3H), 1.8 (m, 1H), 1.54 (br
s, 2H),1.4 (m, 2H), 1.22 (s, 2H), 1.19 (s, 3H) ppm. 13C NMR (50 MHz,
CDCl3): ꢀ ¼ 133.5, 125.5, 72.4, 68.8, 39.0, 32.9, 27.7, 27.2, 21.0 ppm. MS:
m/z (%): 152(Mþ-18,6), 149 (7), 137 (10), 119 (5), 109 (55), 97 (8), 95 (15),
79 (50), 69 (25), 59 (90), 55 (35), 43 (100). Anal. Calcd for C10H18O2
(170.25): C, 70.55; H, 10.66%. Found: C, 70.61; H, 10.85%.
(4R,6R)-6-Acetoxy-1-methyl-4-
(methoxycarbonyl)cyclohexene (10)
To a stirred solution of monoacetate 4 (420 mg 1.67 mmol) and Ph3P
(1.32 g, 5.02 mmol) in THF (30 mL) at room temperature was added
dropwise DIAD (0.93 mL, 5.02 mmol). After stirring overnight at room
temperature, the solution was concentrated under vacuum. The residue
was purified by column chromatography over silica gel (i-octane/EtOAc,
v/v, 95/5) to afford 10 (356 mg, 92%) as a colorless oil. To a stirred
solution of monoacetate 4 (420 mg, 1.67 mmol) and Ph3P (1.32 g,
5.02 mmol) in THF (30 mL) at room temperature was added dropwise
DIAD (0.93 mL, 5.02 mmol). After stirring overnight at room tempera-
ture, the solution was concentrated under vacuum. The residue was
purified by column chromatography over silica gel (i-octane/EtOAc,

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Optically Pure trans-(Q)-Sobrerol
2133
v/v, 95/5) to afford 10 (356 mg, 92%) as a colorless oil. Rf 0.35
25
(i-octane/EtOAc, v/v, 9/1). ½ꢁŠ ¼ À50.5 (c 0.72, CHC13). IR (film):
D
ꢂ ¼ 3070, 2951, 2850, 1736, 1456, 1436, 1370, 1343, 1239, 1170, 1074,
1028, 987, 932 cmÀ1
.
1H NMR (500 MHz, CDCl3): ꢀ ¼ 5.48 (d,
J ¼ 1.5 Hz, 1H), 5.35 (br s, 1H), 3.67 (s, 3H), 2.7 (m, 1H), 2.4 (m, 3H),
2.05 (s, 3H), 1.8 (m, 1H), 1.63 (s, 3H) ppm. 13C NMR (50 MHz, CDCl3):
ꢀ ¼ 174.7, 170.8, 132.6, 124.7, 71.1, 51.7, 37.6, 31.0, 27.3, 21.0, 19.1 ppm.
MS m/z (%): 212 (Mþœ5) œ199 (8), 184 (8), 170 (95), 152 (85), 139 (62),
121 (45), 111 (75), 93 (100), 77 (80). Anal. Calcd. for C11H15O4, required:
C, 62.55; H, 7.16%. Found: C, 62.18; H, 7.23%.
(4R,6R)-6-Hydroxy-4-(1-hydroxyisopropyl)-1-
methylcyclohexene (cis-(2)-Sobrerol (11)
This compound was prepared as the same method as described for
compound 1. Yield: 86%. M.p. 109–110œ. Rf 0.18 (i-octane/EtOAc, v/v,
25
D
25
D
5/5). ½ꢁŠ ¼ À20.1 ( c 0.72, CHCl3 ) {lit.[7] ½ꢁŠ ¼ À16}. IR (film): ꢂ ¼ 3283,
2969, 2944, 2886, 2849, 1454, 1383, 1320, 1256, 1167, 1148, 1109, 1037,
974, 922 cmÀ1. 1H NMR (500 MHz, CDCl3): ꢀ ¼ 5.47 (t, J ¼ 1.45 Hz, 1H),
4.16 (brs, 1H), 2.2 (m, 1H), 2.05 (m, 1H), 1.89 (m, 1H), 1.74 (s, 3H), 1.6 (m,
1H), 1.54 (brs, 2H), 1.32 (m, 1H), 1.19 (s, 3H) ppm. 13C NMR (50 MHz,
CDCl3): ꢀ ¼ 136.3, 123.6œ 72.2, 70.8, 43.8, 34.2, 27.3, 26.9, 26.4,
18.7 ppm. MS m/z (%): 169 (Mþ-1,4), 152 (13), 149 (4), 137 (16), 119
(11), 109 (59), 94 (57), 79 (60), 69 (34), 59 (100). Anal. Calcd. for
C10H18O2 (170.25): C, 70.55; H, 10.66%. Found: C, 70.38; H, 10.72%.
ACKNOWLEDGMENTS
Q.W. thanks Professor M. Vandewalle (University of Gent, Belgium),
in whose laboratory part of this work was initiated.
REFERENCES
1. (a). Carrea, G.; Ottolina, G.; Riva, S. Role of solvents in the control of
enzyme selectivity in organic media. Trends in Biotech. 1995, 13 (2),
63–70; (b) Scuri, R.; Giannetti, P.; Paesano, A. 2-(2,3-Dihydro-5-acet-
oxy-4,6,7-tribenzofuranyl)acetic acid (IRFI-016)—a new antioxidant
mucoactive drug. Drug Exp. Clin. Res. 1990, 16 (12), 649–656.
2. (a) Crowell, P.L. Monoterpenes in breast cancer chemoprevention.
Breast Cancer Res. Treat. 1997, 46 (2–3), 191–197; (b). Ellebgbed, J.A.;

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2134
Wang, Li, and Chen
Maltzman, T.H.; Elson, C.E.; Gould, M.N. Effects of anticarcino-
genic monoterpenes on phase-II hepatic metabolizing enzymes.
Carcinogenesis 1993, 14 (6), 1221–1223; (c). Crowell, P.L.;
Kennan, W.S.; Haag, J.D.; Ahmad, S.; Vedejs, E.; Gould, M.N.
Chemoprevention of mammary carcinogenesis by hydroxylated
derivatives of D-limonene. Carcinogenesis 1992, 13 (7), 1261–1264;
(d). Maltzman, T.H.; Christou, M.; Gould, M.N.; Jefcoate, C.R.
Effects of monoterpenoids on in vivo DMBA-DNA adduct forma-
tion and on phase I hepatic metabolizing enzymes. Carcinogenesis
1991, 12 (11), 2081–2087.
3. Touvay, C.; Vilain, B.; Carre, C.; Menciahuerta, J.M.; Braquet, P.
Effect of limonene and sobrerol on monocrotaline-induced lung
alterations and pulmonary-hypertension. Int. Arch Allergy
Immunol. 1995, 107 (1–3), 272–274.
4. (a) William, F.E. The absolute configurations of the monoterpenes.
In Chemistry of the Monoterpenes an Encyclopedic Handbook,
Willian, F.E., Ed.; Marcel Dekker, Inc.: New York, 1985;
215–217; (b). William, F.E. The pinane monoterpenes. In
Chemistry of the Monoterpenes an Encyclopedic Handbook;
Willian, F.E., Ed.; Marcel Dekker, Inc.: New York, 1985; 969–971.
5. Rothenberg, G.; Yatziv, Y.; Sasson, Y. Comparative autoxidation of
3-carene and alpha-pinene: factors governing regioselective hydrogen
abstraction reactions. Tetrahedron 1998, 54 (3–4), 593–598.
6. Manchand, P.S.; Towsend, J.M.; Belica, P.S.; Wong, H.S. A con-
venient synthesis of 3,5-dimethoxy-4-methylbenzoic acid. Synthesis
1980, (4), 409–410.
7. Wang, P.; Adams, J. Model studies of the stereoelectronic effect in
Rh(II) mediated carbenoid C-H insertion reactions. J. Am. Chem.
Soc. 1994, 116 (8), 3296–3305.
8. Medvedovici, A.; Sandra, P.; Toribo, L.; David, F. Chiral packed
column subcritical fluid chromatography on polysaccharide and
macrocyclic antibiotic chiral stationary phases. J. Chromatography
A 1997, 785 (1–2), 159–171.
9. Mitsunobu, O. The use of diethyl azodicarboxylate and triphenyl-
phosphine in synthesis and transformation of natural products.
Synthesis 1981, (1), 1–28.
10. Mori, K.; Igarashi, Y.; Synthesis of the enantiomers of alpha-
phellandren-8-ol ( p-menth-1,5-dien-8-ol), a monoterpene from
bark beetles. Liebigs. Ann. Chem. 1988, (1), 93–95.
Received in the USA September 16, 2002