An asymmetric dihydroxylation route to (S)-oxybutynin

Article abstract of DOI:10.1016/S0040-4039(03)00886-4

An asymmetric synthesis of (S)-oxybutynin 1 is described using the Sharpless asymmetric dihydroxylation of α-cyclohexylstyrene as the key step.

Full text of DOI:10.1016/S0040-4039(03)00886-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4231–4232
An asymmetric dihydroxylation route to (S)-oxybutyninꢀ
Priti Gupta, Rodney A. Fernandes and Pradeep Kumar*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
Received 25 February 2003; revised 27 March 2003; accepted 4 April 2003
Abstract—An asymmetric synthesis of (S)-oxybutynin 1 is described using the Sharpless asymmetric dihydroxylation of
a-cyclohexylstyrene as the key step. © 2003 Elsevier Science Ltd. All rights reserved.
Racemic oxybutynin (Ditropan) is a widely prescribed
muscarinic receptor antagonist for the treatment of
urinary frequency, urgency and urge incontinence.1 It
has been revealed that it exhibits classical antimus-
carinic side effects, such as dry mouth. However, pre-
liminary biological results suggest that (S)-oxybutynin
1 displays an improved therapeutic profile compared to
its racemic counterpart, and it is currently in phase III
clinical trials. Like the majority of muscarinic receptor
antagonists, oxybutynin is composed of a tertiary a-
hydroxy acid as a key component.2 The abundant
occurrence and biological significance of compounds
containing a tertiary a-hydroxy acid2,3 prompted us to
investigate the synthesis of (S)-oxybutynin.
sis of the tertiary a-hydroxy acid 2 employing the
Sharpless asymmetric dihydroxylation of a-cyclohexyl-
styrene as the key step.
Our synthetic strategy for the synthesis of (S)-oxybu-
tynin 1 was envisioned through the retrosynthetic route
shown in Scheme 1. The chiral tert-a-hydroxy acid 2,
one of the components of the target molecule, could be
obtained by the Sharpless asymmetric dihydroxylation
of a-cyclohexylstyrene and subsequent oxidation of the
primary hydroxyl group. The other component 3
required for the oxybutynin synthesis could be easily
derived from 2-butyne-1,4-diol, a readily available
starting material.
A few reports have appeared on the asymmetric synthe-
sis of (S)-acid 24 and (S)-oxybutynin.5 These involve
the use of carbohydrate systems which contain an
asymmetric benzylic center,6 the application of cis-
aminoindanol or related constrained amino alcohols as
highly defined chiral handle,4a a chiral mandelic acid
template4b or catalytic chiral cyanosilylation of a
ketone4c for the preparation of an enantiopure tertiary
a-hydroxy acid. As part of our research programme
aimed at developing enantioselective syntheses of natu-
rally occurring lactones7a–c and amino alcohols,7d–i the
Sharpless asymmetric dihydroxylation8 was envisaged
as a powerful tool to chiral dihydroxy compounds
offering considerable opportunities for synthetic manip-
ulations. While several aryl substituted and a-methyl
styrenes8,9 have been employed in the Sharpless asym-
metric dihydroxylation, there has been no report on the
asymmetric dihydroxylation of a-cyclohexylstyrene. We
have now developed a new and enantioselective synthe-
The synthesis of tert-a-hydroxy acid 2 started from
cyclohexyl phenyl ketone 4 as illustrated in Scheme 2.
Compound
4
was
treated
with
methylene
triphenylphosphorane to give the Wittig product 5 in
92% yield. The asymmetric dihydroxylation of olefin 5
ꢀ NCL Communication No. 6642.
* Corresponding author. Tel.: +91-20-5893300, ext. 2050; fax: +91-20-
5893614; e-mail: tripathi@dalton.ncl.res.in
Scheme 1. Retrosynthetic route to (S)-oxybutynin.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00886-4

4232
P. Gupta et al. / Tetrahedron Letters 44 (2003) 4231–4232
In summary, a practical and short synthesis of (S)-oxy-
butynin has been realized employing the Sharpless
asymmetric dihydroxylation of a-cyclohexylstyrene for
the first time as the key step. The synthetic strategy can
be further extended to the asymmetric synthesis of
(R)-oxybutynin and other related analogs. Currently
studies are in progress in this direction.
Acknowledgements
P.G. and R.A.F. thank the UGC and the CSIR, New
Delhi, for financial assistance, respectively. We are
grateful to Dr. M. K. Gurjar for his support and
encouragement.
Scheme 2. Reagents and conditions: (i) Ph3P+CH3I−, n-BuLi,
THF, 0°C–rt, 8 h, 92%; (ii) (DHQ)2-PHAL, K3Fe(CN)6,
K2CO3, t-BuOH:H2O (1:1), OsO4, 0°C, 18 h, 70%; (iii) (a)
(COCl)2, DMSO, −78°C, Et3N, CH2Cl2 (b) NaClO2,
NaH2PO4·2H2O, 2-methyl-2-butene, t-BuOH, rt, 4 h, 70%.
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with osmium tetroxide and potassium ferricyanide as
cooxidant in the presence of (DHQ)2-PHAL as the
chiral ligand under Sharpless asymmetric dihydroxyla-
tion conditions8,9 gave the crude product which on
recrystallisation twice from EtOAc/pet. ether afforded
the pure diol 6 in 70% yield with 92% ee.10 The subse-
quent Jones’ oxidation of the primary alcohol in 6 in
order to obtain the acid 2 was unsuccessful resulting in
cleavage of the diol affording the starting ketone 4 in a
quantitative yield. Hence we attempted a two-step pro-
cess in the following way. The alcohol 6 was first
oxidized to the corresponding aldehyde under standard
Swern oxidation conditions followed by further oxida-
tion with NaClO2 and NaH2PO4·2H2O to furnish the
acid 2 in 70% yield, [h]2D0=+23.3 (c 1, EtOH) [lit.4a
[h]2D0=+22.6 (c 1.4, EtOH)].
Scheme 3 summarizes the synthesis of 4-N,N-diethyl
aminobut-2-yn-1-ol 3 from the commercially available
2-butyne-1,4-diol 7. The mono hydroxyl protection of 7
as the THP ether was followed by conversion of the
free hydroxyl group into the iodide 9 in good yield.
Displacement of iodide with diethylamine and subse-
quent acid treatment resulted in the formation of the
hydrochloride salt of 3 with concomitant deprotection
of the THP ether. Subsequent neutralization with base
furnished the desired compound 3 in 70% yield.
The final step involved the coupling of acid 2 with
amino alcohol 3 which could readily be performed by
activating the acid as a mixed anhydride and condensa-
tion with 3 as previously described.5
10. The enantiomeric excess was determined by converting the
diol into the mono-Mosher ester and analyzing the 19F
spectrum.