derivative (S)-711 in 60% yield. The alcohol was converted
to the chloroethylpyrrolidine coupling partner with thionyl
chloride in chloroform at 60 °C,12 which returned the
amine hydrochloride (S)-2a·HCl13 in 92% yield.
Scheme 1. Retrosynthesis of Clemastine
(R)-2a·HCl was made by a parallel route starting with
N-Boc pyrrolidine 8, which was lithiated with s-BuLi in
the presence of (-)-sparteine, and the resulting complex
was quenched with dry CO214 to yield N-Boc-(R)-proline
(R)-9 in 55% yield and >99:1 er after crystallization.15
As a result of the incompatibility of the Boc group with
the conditions used for diazoketone formation, a protecting
group swap16 was necessary, which was achieved using
2 M HCl followed by benzyl chloroformate. The product
(R)-4 was taken through the same series of transformations
to yield (R)-2a·HCl.
A small amount of 2a·HCl was converted to its free base
2a by purification on an SCX cartridge,17 but we found that
prolonged storage of 2a either neat or in solution led to the
formation of significant quantities of the bicyclic ammonium
salt 10+Cl-. The same cyclization was observed in good yield
on attempted purification of 2a by distillation.12 Cyclization
to 10+·TsO- was likewise observed on attempted formation
of the tosylate derivative of 7. In general therefore we chose
to store and use 2a as its stable hydrochloride salt.
of our synthetic (S,S)-clemastine and its fumarate salt with
literature data furthermore confirms the invertive nature
of the aryl migration.
Both enantiomers of the pyrrolidine fragment 2a were
made by homologation of N-Cbz-proline 4 using an
Arndt-Eistert reaction (Scheme 2).7 For the (S) enanti-
Scheme 2. Pyrrolidine Fragment (S)-2
In view of this instability, an alternative coupling partner
lacking a basic nitrogen atom, the CBz-protected iodide 2b,
was also made. Selective reduction of 6 with lithium
borohydride in THF18 gave the alcohol 11, which was
converted to the iodide 2b with triphenylphosphine and
iodine. At 0 °C, 2b was formed in good yield and was stable
to prolonged heating at 100 °C.
The tertiary alcohol (S)-3a was made from p-chloroac-
etophenone 12, which was reduced by the method of
Noyori19 using formic acid in the presence of the ruthenium
complex (S,S)-13 to provide the alcohol (S)-14a20 in 91%
yield and >99:1 er. This alcohol was converted to its
carbamate derivative 15a by reaction with phenyl isocyanate
and methylation with sodium hydride and methyl iodide
(Scheme 3).6 For the purpose of stereochemical confirmation
(11) Nikiforov, T.; Stanchev, S.; Milenkov, B.; Dimitrov, V. Hetero-
cycles 1986, 24, 1825.
(12) Wu, Y.; Corrigan, J. R.; Feldkamp, R. J. Org. Chem. 1961, 26,
1531. Bourquin, J. P.; Schwarb, G.; Gamboni, G.; Fischer, R.; Ruesch, L.;
Guldimann, S.; Theus, V.; Schenker, E.; Renz, J. HelV. Chim. Acta 1958,
151, 1072.
omer, Cbz-L-proline (S)-4 was converted to its acid
chloride with oxalyl chloride and then treated with
trimethylsilyldiazomethane to generate, after 5 h at 0 °C,
the diazoketone (S)-57 in 80% yield. Decomposition of
the diazoketone with silver benzoate in the presence of
methanol and base8 returned the chain-extended methyl
ester (S)-69 in 78% yield. Lithium aluminum hydride in
THF at 45 °C reduced both the ester and the carbamate
protecting group,10 giving the hydroxyethylpyrrolidine
(13) Japanese patent JP53046967, 1993.
(14) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994,
116, 3231.
(15) The er was determined by conversion to the 3-5-dimethylanilides
( Pirkle, W. H.; McCune, J. E. J. Chromatogr. 1989, 479, 419) and HPLC
ꢀ-GEM/Regis, 250 mm × 4.6 mm, with a flow rate of 1 mL/min and a
detection wavelength of 254 nm. tR: (R) 23.9 min, (S) 21.2 minThe method
of Mani et al. ( Deng, X.; Mani, N. S Tetrahedron Asymmetry 2005, 16,
661), quenching the lithiopyrrolidine with ethylene oxide, was unsuccessful
in our hands.
(16) Rispens, M. T.; Gelling, O. J.; de Vries, A. H. M.; Meetsma, A.;
van Bolhuis, F.; Feringa, B. L. Tetrahedron 1996, 52, 3521.
(17) SCX (Strong Cation Exchange) cartridges are manufactured by
Biotage and contain an immobilized benzenesulfonic acid.
(18) Campbell, J. A.; Rapoport, H. J. Org. Chem. 1996, 61, 6313.
(19) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1996, 118, 2521.
(7) Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981, 29, 3249. Podlech,
J.; Seebach, D. Liebigs Ann. 1995, 1217.
(8) Newman, M. S.; Beal, P. F. J. Am. Chem. Soc. 1950, 72, 5163.
(9) Hanessian, S.; Sharma, R. Heterocycles 2000, 52, 1231.
(10) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc.
1987, 109, 7111.
(20) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature
(London) 2008, 456, 778.
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