A practical synthesis of (S)-2-cyclohexyl-2-phenylglycolic acid via organocatalytic asymmetric construction of a tetrasubstituted carbon center

Article abstract of DOI:10.1021/ol052164w

(Chemical Equation Presented) A concise and enantioselective synthesis of (S)-2-cyclohexyl-2-phenylglycolic acid as a key intermediate for (S)-oxybutynin is reported. The crucial asymmetric tetrasubstituted carbon center was constructed with excellent stereoselectivity through the proline-catalyzed direct asymmetric aldol reaction between cyclohexanone and ethyl phenylglyoxylate under mild conditions.

Full text of DOI:10.1021/ol052164w

ORGANIC
LETTERS
2005
Vol. 7, No. 22
5103-5105
A Practical Synthesis of
(S)-2-Cyclohexyl-2-phenylglycolic Acid
via Organocatalytic Asymmetric
Construction of a Tetrasubstituted
Carbon Center
Osamu Tokuda,†,‡ Taichi Kano,† Wei-Guo Gao,‡ Tetsuya Ikemoto,‡ and
Keiji Maruoka*,†
Department of Chemistry, Graduate School of Science, Kyoto UniVersity,
Sakyo, Kyoto 606-8502, Japan, and Fine Chemical Research Laboratory,
Sumitomo Chemical Co., Ltd., 1-21, Utajima 3-chome, Nishiyodogawa-ku,
Osaka 555-0021, Japan
maruoka@kuchem.kyoto-u.ac.jp
Received September 8, 2005
ABSTRACT
A concise and enantioselective synthesis of (S)-2-cyclohexyl-2-phenylglycolic acid as a key intermediate for (S)-oxybutynin is reported. The
crucial asymmetric tetrasubstituted carbon center was constructed with excellent stereoselectivity through the proline-catalyzed direct asymmetric
aldol reaction between cyclohexanone and ethyl phenylglyoxylate under mild conditions.
Racemic oxybutynin (ditropan) is a widely prescribed
muscarinic receptor antagonist for the treatment of urinary
frequency, urgency, and urge incontinence, but it causes side
effects such as dry mouth, tachycardia, and mydriasis.1 Since
preliminary biological results suggested that (S)-oxybutynin
(S)-1 exhibits an improved therapeutic profile compared to
the racemate, several groups have reported the asymmetric
synthesis of (S)-2-cyclohexyl-2-phenylglycolic acid (S)-2 as
a key intermediate for the preparation of (S)-oxybutynin.2,3
Some of these previous methods, however, require stoichio-
metric amounts of the chiral auxiliary, toxic reagents, or low-
temperature reaction conditions. In this context, it would be
a significant improvement to develop an alternative synthesis
of (S)-2 using an organocatalyst with the environmental ad-
vantages of mild and metal-free conditions in addition to
the operational simplicity. Herein, we report a practical syn-
thetic route to (S)-2-cyclohexyl-2-phenylglycolic acid (S)-2
via a direct asymmetric aldol reaction catalyzed by L-proline.
† Kyoto University.
‡ Sumitomo Chemical Co., Ltd.
(1) Thompson, I. M.; Lauvetz, R. Urology 1976, 8, 452.
(2) (a) Senanayake, C. H.; Fang, Q. K.; Grover, P.; Bakale, R. P.;
Vandenbossche, C. P.; Wald, S. A. Tetrahedron Lett. 1999, 40, 819. (b)
Grover, P. T.; Bhongle, N. N.; Wald, S. A.; Senanayake, C. H. J. Org.
Chem. 2000, 65, 6283. (c) Bakale, R. P.; Lopez, J. L.; McConville, F. X.;
Vandenbossche, C. P.; Senanayake, C. H. U.S. Patent 6140529.
Our retrosynthetic analysis of (S)-2 leads to the â-hydroxy-
ketone 3 having a tetrasubstituted carbon center, which could
10.1021/ol052164w CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/30/2005

be constructed by organocatalytic direct asymmetric aldol
reaction between cyclohexanone and phenylglyoxylate
(Scheme 1).
Table 1. Proline-Catalyzed Asymmetric Aldol Reaction
between Cyclohexanone and Phenylglyoxylate Derivativesa
Scheme 1. Retrosynthetic Analysis of (S)-2
entry
R1
R2
yieldb (%)
drc
% eed
1
2
3
4
Me
Et
Et
Et
H
CF3
Cl
89
>99
95
>20/1
>20/1
>20/1
>20/1
98
97
96
Me
45
>99
a The reaction of phenylglyoxylate (0.25 mmol) with cyclohexanone (0.25
mL, 2.4 mmol) in DMSO (0.25 mL) was carried out in the presence of 30
b
mol % of L-proline at room temperature. Isolated yield after silica gel
To the best of our knowledge, however, such asymmetric
transformation is unprecedented despite a number of recent
reports on the development of the proline-catalyzed direct
asymmetric aldol reactions based on pioneering works by
Wiechert4a and Hajos4b in the early 1970s and by List and
Barbas in 2000.4c-m,5 Accordingly, we first focused on the
development of the proline-catalyzed direct asymmetric aldol
reaction between cyclohexanone and ethyl phenylglyoxylate.
Gratifyingly, in preliminary studies on reaction conditions,
we found that the reaction with a catalytic amount of
L-proline (30 mol %) in DMSO at room temperature gave
the desired aldol adduct 3 in good yield (73%) with excellent
diastereo- and enantioselectivity (dr ) >20:1, 96% ee).
Furthermore, using 50 mol % of L-proline, the yield of 3
was improved to 79% without loss of stereoselectivity
(Scheme 2).
chromatography. c Determined by 1H NMR. d The ee of major isomer was
determined by HPLC on a Chiralpak AD-H column with hexane/2-propanol
(90/10).
With this information in hand, we studied the conversion
of aldol product 3 to (S)-2-cyclohexyl-2-phenylglycolic acid
(S)-2 (Scheme 3). First, attempted reduction of the ketone
carbonyl group of 3 to methylene under Wolff-Kishner
conditions was unsuccessful. In addition, reduction of 3 with
NaBH4 to the diol 4 gave the undesired enone resulting from
the â-hydroxy elimination. On the other hand, the treatment
of 3 with BH3-Me2S in THF at room temperature and
subsequent addition of methanol gave 4 cleanly, which was
reacted with methanesulfonyl chloride and triethylamine at
room temperature to furnish the mesylate 5 in 81% yield
from 3. Unfortunately, however, the reduction of 5 with
Ph3SiH under radical condition gave a complex mixture. We
then turned our attention to induce the olefin formation by
the elimination of methanesulfonic acid from 5. Unexpect-
edly, the elimination of methanesulfonic acid using DBU or
Scheme 2. Proline-Catalyzed Aldol Reaction for the
Construction of a Tetrasubstituted Carbon Center
Scheme 3. Synthesis Route of (S)-2
Similar proline-catalyzed direct asymmetric aldol reactions
between cyclohexanone and phenylglyoxylate derivatives are
also investigated as shown in Table 1. Use of methyl phen-
ylglyoxylate showed excellent diastereo- and enantioselec-
tivity (entry 1). Ethyl phenylglyoxylates possessing electron-
withdrawing groups at the para position were also suitable
substrates for the present reaction (entries 2 and 3). In addi-
tion, a substrate with an electron-donating substituent on the
aromatic ring exhibited a virtually complete stereoselectivity
at the expense of chemical yield (entry 4).
(3) (a) Masumoto, S.; Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron
Lett. 2002, 43, 8647. (b) Gupta, P.; Fernandes, R. A.; Kumar, P. Tetrahedron
Lett. 2003, 44, 4231. (c) Masumoto, S.; Suzuki, M.; Kanai, M.; Shibasaki,
M. Tetrahedron 2004, 60, 10497.
5104
Org. Lett., Vol. 7, No. 22, 2005

KOt-Bu resulted in formation of a mixture of 6a and 6b
accompanied by large amounts of unknown byproducts. In
contrast, substitution of the methanesulfonyloxy group in 5
with NaI or LiBr with concomitant elimination afforded 6a
and 6b in moderate yields (44-54%). Furthermore, the
elimination reaction using LiCl in HMPA proceeded smoothly
to give 6a and 6b in good yield (81%). The resulting olefins
6a and 6b were hydrogenated to 7 at ambient temperature
under hydrogen atmosphere (1 atm) with 10% Pd-C in
ethanol. Hydrolysis of 7 in a mixture of methanol and 1 M
NaOH (3:1, v/v) afforded crude (S)-2-cyclohexyl-2-phenylg-
lycolic acid (S)-2. A single recrystallization from hexane/
CH2Cl2 yielded optically pure (S)-2 in good yield (83%,
>99% ee). The absolute stereochemistry of (S)-2 was
determined by comparison of the optical rotation and the
HPLC retention time with literature values.2a,b
(4) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
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(m) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis: From Biomi-
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Acknowledgment. This work was partially supported
by a Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Suports, Science and Technology,
Japan.
Supporting Information Available: Detailed experi-
mental procedure as well as spectroscopic characterization
of new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
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