An efficient asymmetric synthesis of (S)-2-cyclohexyl-2-phenylglycolic acid, the acid segment of oxybutynin

Article abstract of DOI:10.1016/j.tetlet.2006.07.101

An innovative and facile synthesis of the title compound has been developed starting from (R)-cyclohexylidene glyceraldehyde. The key step in the synthesis is a chiral template-driven Grignard addition with absolute diastereocontrol. The other attractive features are the operational simplicity and the use of inexpensive compounds/reagents.

Full text of DOI:10.1016/j.tetlet.2006.07.101

Tetrahedron Letters 47 (2006) 7067–7069
An efficient asymmetric synthesis
of (S)-2-cyclohexyl-2-phenylglycolic acid,
the acid segment of oxybutynin
Siddharth Roy,a Anubha Sharma,b Nilmadhav Chattopadhyaya
and Subrata Chattopadhyayb,*
aNAA Unit, Central Forensic Science Laboratory, Bhabha Atomic Research Centre, Mumbai 400 085, India
bBio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
Received 15 May 2006; revised 10 July 2006; accepted 20 July 2006
Abstract—An innovative and facile synthesis of the title compound has been developed starting from (R)-cyclohexylidene glycer-
aldehyde. The key step in the synthesis is a chiral template-driven Grignard addition with absolute diastereocontrol. The other
attractive features are the operational simplicity and the use of inexpensive compounds/reagents.
Ó 2006 Elsevier Ltd. All rights reserved.
Tertiary hydroxy acids and their derivatives are impor-
tant intermediates in the asymmetric synthesis of a vari-
ety of medicinal agents1 and natural products.2 One
such compound, oxybutynin (Ditropan) (1), is widely
prescribed in racemic form for the treatment of urinary
frequency, urgency and urge incontinence,3 although its
(S)-enantiomer displays a better therapeutic profile de-
void of antimuscarinic side effects.4 In view of the medic-
inal importance, oxybutynin and its congeners have
become important targets for organic chemists leading
to several asymmetric syntheses of (S)-15a–e and its con-
stituent acid segment 2.6a Further, various congeners of
1 with improved receptor subtype selectivity and less
side effects have also been synthesized.1b,6b–d
in the presence of various additives to a chiral keto-
amide or a ketoester possessing a rigid benzocycloalk-
l-ene-derived vicinal amino alcohol platform was also
reported.6a For our part, we have developed a practical
synthesis of 2 with excellent enantioselectivity and high
yield.
Earlier, we found7a–c that addition of Grignard reagents
to easily accessible glyceraldehyde derivative 3 pro-
ceeded efficiently to furnish the diastereomeric alkane-
triol derivatives. It was envisaged that extension of a
similar strategy with a suitable glyceraldehyde-derived
ketone might be an efficient alternative for the synthesis
of 2. It was anticipated that the bulky cyclohexyl group
in the chiral ketone might provide good diastereomeric
bias for the Grignard addition, while the acetal func-
tionality of the resultant compound would ensure its
easy conversion to the required acid moiety.
Earlier, the key acid subunit (S)-2 was synthesized using
a chiral Gd-complex-mediated asymmetric cyanosilyla-
tion of a suitable ketone,5a,c Sharpless asymmetric
dihydroxylation,5b organometallic addition to a chiral
mandelic acid template5d and via a proline-catalyzed
asymmetric aldol reaction.5e In addition, its asymmetric
synthesis by addition of a cyclohexyl Grignard reagent
Thus, we reacted 3 with phenylmagnesium bromide to
furnish 4 in excellent yield as a mixture of two chro-
matographically separable diastereomers. Since the
stereochemical course of the reaction was of no conse-
quence to the present synthesis, we did not assess the
diastereoselectivity of the reaction. Oxidation of 4 with
buffered pyridinium chlorochromate (PCC)8 afforded
ketone 5. Reaction of 5 with cyclohexylmagnesium
bromide proceeded uneventfully to afford tertiary alco-
hol 6a in excellent yield, and as a single diastereomer
Keywords: Asymmetric synthesis; (R)-cyclohexylidene glyceraldehyde;
Oxybutynin; a-Hydroxy acid.
*
Corresponding author. Tel.: +91 22 25593703; fax: +91 22
5505151; e-mail addresses: schatt@barc.gov.in; schatt@apsara.barc.
gov.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.101

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S. Roy et al. / Tetrahedron Letters 47 (2006) 7067–7069
O
O
CO2H
HO
HO
NEt2
(S)-1
(S
)-2
R
R
O
O
R
R1O
R
R
R
O
R
R
O
O
iii
i
ii
O
Ph
OH
O
Ph
O
CHO
4
6a R1 = H
O
3
5
6b R1 = Bn
iv
R,R = Cyclohexylidene
HO
OH
CHO
RO
RO
v
vi
viii
(S)-2
7a R = H
8a R = H
7b R = Bn
vii
8b R = Bn
Scheme 1. Reagents and conditions: (i) PhMgBr/THF (88%), (ii) PCC/NaOAc/CH2Cl2 (84%), (iii) cyclohexylmagnesium bromide/THF (87%), (iv)
BnBr/NaH/THF/D (88%), (v) 1% HCl–MeOH (77% and 92% from 6a and 6b, respectively), (vi) NaIO4/MeCN/H2O (45% and 81% from 7a and 7b,
respectively), (vii) DDQ/CH2Cl2/45 °C (88%), (viii) NaClO2 (68%).
as revealed from its 1H and C NMR spectra.9
Attempted hydrolysis of the acetal function of 6a with
25–70% aqueous trifluoroacetic acid or 5–30 mol % Cu-
Cl2ÆH2O/MeOH10 resulted in either decomposition of
6a, or very low yields of the required product 7a. Sur-
prisingly, the desired transformation could be achieved
in the presence of 1% HCl in methanol to give 7a in
an acceptable (77%) yield. This on treatment with
NaIO4 in aqueous CH3CN provided aldehyde 8a along
with benzoylcyclohexane5b formed by further cleavage
of the a-hydroxyaldehyde function of 8a. Carrying out
the reaction at 0 °C, and adding NaIO4 in batches did
not suppress this side reaction, and 8a was obtained in
ꢀ45% yield. Oxidation of 8a with NaClO2 gave the tar-
get acid (S)-2 (70%), which was characterized from its
spectral data which matching those reported.6a The
[a]D value of our synthetic sample compared very well
with the reported value confirming the absolute stereo-
chemistry as (S). The enantiomeric excess (98%) of
(S)-2 was determined by HPLC (Chiracel OD-H col-
umn, mobile phase 95% hexane/5% IPA) analysis.
the synthesis of (R)-2 by altering the sequence of the
Grignard addition or using the easily accessible11 (S)-3
as the chiral template.
13
Acknowledgements
S.R. thanks the Directorate of Forensic Science (DFS),
Ministry of Home Affairs, Government of India for
awarding the fellowship, and the Director, DFS, as well
as the Director, Chemistry Group, BARC, for their
encouragement.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2006.
07.101.
References and notes
In view of the low yield of 8a, an alternative strategy for
the synthesis of (S)-2 was developed. Thus, alcohol 6a
was benzylated to give 6b, which was converted to diol
7b in excellent yield (92%) as above. Reaction of 7b with
NaIO4 proceeded uneventfully to give 8b (81%), which
on debenzylation with DDQ afforded 8a. This was then
oxidized with NaClO2 to furnish (S)-2 in 68% yield.
Although the alternative scheme requires two additional
steps, the overall yield of the target compound was high-
er (Scheme 1).
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22
9. Data for 6a: ½aꢁD +20.97 (c 1.03, CHCl3); IR: 3349, 3060,
1588, 1480 cmꢂ1 1H NMR (200 MHz, CDCl3): d 1.08–
;
1.25 (m, 8H), 1.40–1.68 (m, 12H), 2.08–2.14 (m, 1H), 2.59
(s, D2O exchangeable, 1H), 3.35–3.52 (m, 2H), 4.64 (t,
J = 8.6 Hz, 1H), 7.18–7.31 (m, 5H); 13C NMR (50 MHz,
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47.6, 65.1, 75.5, 78.0, 109.5, 124.7, 125.9, 126.9, 141.0.
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