Asymmetric synthesis of (+)-mequitazine from quinine

Article abstract of DOI:10.1021/ol2012567

The first asymmetric synthesis of the antihistaminic drug mequitazine is reported. Our approach started from quinine, a Cinchona alkaloid, whose chiral information was exploited for setting up the stereogenic center of (+)-mequitazine.

Full text of DOI:10.1021/ol2012567

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3549–3551
Asymmetric Synthesis of (þ)-Mequitazine
from Quinine
†
‡
‡
Sebastien Leroux, Laurent Larquetoux, Marc Nicolas, and Eric Doris*
,†
ꢀ
CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, 91191 Gif-sur-Yvette, France,
ꢀ
and Les Laboratoires Pierre Fabre, Centre de Developpement et de Chimie Industrielle,
16 rue Jean Rostand, 81600 Gaillac, France
eric.doris@cea.fr
Received May 17, 2011
ABSTRACT
The first asymmetric synthesis of the antihistaminic drug mequitazine is reported. Our approach started from quinine, a Cinchona alkaloid, whose
chiral information was exploited for setting up the stereogenic center of (þ)-mequitazine.
Mequitazine 1 is a potent antihistaminic drug currently
in use for the treatment of allergic conditions such as
itching, rhinitis, urticaria, hay fever, and Quincke’s edema.1
Mequitazine is an H-receptor antagonist which competes
with histamine on effector cells.2 It belongs to the second
generation of antihistaminic drugs and is currently mar-
keted, as racemate, under various brand names such as
Primalan. Several approaches have been reported in the
literature for the synthesis of mequitazine, most of which
have been patented. Strategies that have been devised so
far relied on the coupling of a quinuclidine derivative
with phenothiazine (Scheme 1). For example, alkylation
of phenothiazine with 3-substituted quinuclidine electro-
philes 2 permitted the efficient formation of the key C9ꢀN
bond.3 Also, nucleophilic attack of a phenothiazine anion
on epoxide 3, followed by elimination of the resulting
tertiary alcohol and double bond hydrogenation, allowed
the multistep synthesis of mequitazine.4 The most recent
synthetic route reported to date for the synthesis of
mequitazine is from the group of Baati who described
the palladium catalyzed alkylation of phenothiazine by
allylic acetate 4.5 The latter was prepared starting either
from epoxide 3 by β-elimination or by using the Shapiro
reaction. This approach permittedthe elegant and straight-
forward construction of mequitazine’s skeleton.
Scheme 1. Known Synthetic Approaches to rac-Mequitazine
† CEA.
However, the above strategies only provide access to rac-
mequitazine and no enantioselective synthesis has yet been
reported. Optically active mequitazine has nevertheless been
obtained by kinetic resolution of a racemic synthetic inter-
mediate, but this approach inexorably leads to 50% loss of
‡ Pierre Fabre.
(1) Persi, L.; Dupin, O.; Arnaud, B.; Trinquand, C.; Michel, F. B.;
Bousquet, J. Allergy 1997, 52, 451.
(2) Nicholson, A. N.; Stone, B. M. Eur. J. Clin. Pharmacol. 1983, 25,
563.
(3) (a) Gueremy, C.; Labey, R.; Wirth, D.; Auclair, M. US Patent
3987042, 1976. (b) Guminski, Y.; Imbert, T.; Lesimple, P. WO Patent
9929692, 1999.
(4) (a) Iki, M.; Hayashi, T. JP Patent 4169583, 1992. (b) Iki, M.;
Hayashi, T.; Yamazaki, S. JP Patent 5140157, 1993. (c) Yamazaki, S.;
Yumoto, H.; Igi, M. EP Patent 1074552, 2003.
(5) (a) Mioskowski, C.; Gonnot, V.; Baati, R.; Nicolas M. WO Patent
107545, 2008. (b) Gonnot, V.; Nicolas, M.; Mioskowski, C.; Baati, R. Chem.
Pharm. Bull. 2009, 57, 1300.
r
10.1021/ol2012567
2011 American Chemical Society
Published on Web 06/09/2011

material.6 In the present paper we would like to disclose the
first asymmetric synthesis of (þ)-mequitazine.
alcohol. The peculiar reactivity of the quinuclidinone
intermediate 8 toward nucleophilic ring-opening can be
rationalized by the intrinsic ring strain of the twisted
amide that prevents classical stabilization by π-electron
delocalization.10 Meroquinene 9, whose stereocenters were
unaffected by the autoxidation step, was nevertheless
exploited for the continuation of our synthesis of (þ)-
mequitazine.
Stereochemistry of the C3 position is usually difficult to
control because of the high symmetry of the quinuclidine
core. This prompted us to investigate a novel synthetic
route starting from widely available Cinchona alkaloids
(Scheme 2).7 Ourchoice wasgovernedby the factthatthese
alkaloids (e.g., quinine 5) already incorporate a C3-stereo-
genic center of the same absolute (R) configuration as
that of (þ)-mequitazine. The C3-borne vinyl group of the
Cinchona alkaloid could afterward be transformed by
oxidative cleavage and reduction for subsequent cou-
pling with phenothiazine. Albeit, this pathway calls for
the removal of the “superfluous” quinoline side chain
linked to C8 in order to provide the required quinoline-
free quinuclidine.
Scheme 3. Stage 1: Isolation of the Quinuclidine Core from
Quinine
Scheme 2. Strategy for the Synthesis of (þ)-Mequitazine Start-
ing from Quinine
To remove the pendant side chain, we conceived that the
carbonꢀcarbon bond connecting the quinuclidine to the
quinoline part could be cleaved by an autoxidation pro-
cess, as originally demonstrated by Doering in 1946 for
quininone.8 The synthetic plan was thus divided into two
stages: (i) isolation of the quinuclidine core from the
Cinchona alkaloid and (ii) interconversion of the vinyl
group for ultimate coupling with phenothiazine.
We chose quinine 5 as the starting alkaloid. Our synth-
esis thus commenced from 5 which was cleanly trans-
formed to quininone 6 by Swern oxidation (Scheme 3).
The resulting ketone was then reacted with potassium tert-
butanolate in the presence of oxygen to induce autoxida-
tion of the enolate. Fragmentation of the transient cy-
cloadduct 7 however failed to give quinuclidinone 8 but
rather provided meroquinene tert-butyl ester 9.9 The latter
resulted from the in situ ring-opening of 8 by tert-butyl
Lithium aluminum hydride reduction of the tert-butyl
ester of 9 gave the corresponding alcohol 10 which was
treated with thionyl chloride to produce chlorinated qui-
nuclidine precursor 11. Intramolecular cyclization of 11 in
refluxing acetonitrile finally afforded optically active vinyl
quinuclidine 12.
At this stage, we formally isolated the vinyl quinuclidine
part from the quinoline part of quinine, while keeping
intact the C3 stereogenic center. With vinyl quinuclidine 12
in hand, we next had to convert the olefinic side chain into
an activated leaving group for the final coupling with
phenothiazine. This transformation involved the ozone-
mediated oxidative cleavage of the double bond (Scheme 4).
The strongly basic nitrogen atom of 12 was first protected
as the corresponding trifuoroacetate salt to prevent
N-oxide formation and further side reactions. The proto-
nated vinyl quinuclidine was then reacted with ozone
at ꢀ78 °C in methanol, and to minimize potential risks
of epimerization, the transient ozonide was directly re-
duced in situ at low temperature with sodium borohydride.
Quinuclidine methylalcohol 13was recovered in63% yield
but of unknown optical purity as enantiomeric excess
(6) Renault, C.; Le Fur, G. FR Patent 8203667, 1982.
(7) Hoffmann, H. M. R.; Frackenpohl, J. Eur. J. Org. Chem. 2004,
4293.
(8) Doering, W. E.; Chanley, J. D. J. Am. Chem. Soc. 1946, 68, 586.
(9) (a) Martinelli, M. J.; Peterson, B. C.; Khau, V. V.; Hutchison,
D. R.; Sullivan, K. A. Tetrahedron Lett. 1993, 34, 5413. (b) Clark, J. S.;
Townsend, R. J.; Blake, A. J.; Teat, S. J.; Johns, A. Tetrahedron Lett.
2001, 42, 3235. (c) Hutchison, D. R.; Khau, V. V.; Martinelli, M. J.;
Nayyar, N. K.; Peterson, B. C.; Sullivan K. A. Org. Synth. 2004, Coll.
Vol. 10, 35.
(10) Clayden, J.; Moran, W. J. Angew. Chem., Int. Ed. 2006, 45, 7118.
Org. Lett., Vol. 13, No. 13, 2011
3550

20 °C) to be compared to ꢀ40.5 (c 0.93, EtOH, 24 °C) for
(ꢀ)-mequitazine (obtained by chiral resolution).11 The
enantiomeric excess of (þ)-1 was ultimately measured by
chiral HPLC which indicated an ee value greater than
99%. These results unambiguously indicate that the C3
stereocenter of the starting Cinchona alkaloid was fully
preserved throughout our synthesis of (þ)-mequitazine
which was achieved in eight linear steps.
Scheme 4. Stage 2: Completion of the Synthesis of (þ)-Mequit-
azine by Coupling with Phenothiazine
The strategy we have developed to meet the synthetic
challenge of the first asymmetric synthesis of mequitazine
may be viewed as a general route for the preparation of
optically active substituted quinuclidines from Cinchona
alkaloids. The devised synthetic scheme permitted the
straightforward access to (þ)-mequitazine 1 of C3(R)
absolute configuration.
measurements by chiral HPLC were not feasible due to the
lack of UV absorption of the substrate. The synthesis was
nevertheless continued by activation of the alcohol as the
corresponding mesylate 14 before phenothiazine was
added. The coupling reaction proceeded in the presence
of potassium tert-butanolate in refluxing THF to give (þ)-
mequitazine 1 in 72% yield.
Spectral data (1H and 13C NMR) of (þ)-1 are consistent
with those of authentic mequitazine, and optical rotation
measurement gave an RD value of þ43.4 (c 0.098, EtOH,
Acknowledgment. S.L. thanks the CEA and “Les La-
boratoires Pierre Fabre” for a CTCI PhD grant.
Supporting Information Available. Experimental pro-
cedures and copies of 1H and 13C NMR. This material is
available free of charge via the Internet at http://pubs.acs.
org.
(11) Guminski, Y.; Fabre, V.; Lesimple, P.; Imbert, T. Org. Prep.
Proc. Int. 1999, 31, 319.
Org. Lett., Vol. 13, No. 13, 2011
3551