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Synthesis 2003(3): 0375-0382
DOI: 10.1055/s-2003-37353
PAPER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of All Stereoisomers and Some Congeners of Isocytoxazone

Zdenko Hameršaka, Dragan Šepaca, Dinko Žiherb, Vitomir Šunjić*a
a Ruđer Bošković Institute, Bijenič ka c. 54, POB 180, 10002 Zagreb, Croatia
Fax: +385(1)4680195; e-Mail: sunjic@rudjer.irb.hr;
b PLIVA Research and Development Institute, Ul. Baruna Filipovića 25, 10000 Zagreb, Croatia
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Publication History

Received 23 October 2002
Publication Date:
19 February 2003 (online)

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Abstract

cis-Isocytoxazone 2a and trans-isocytoxazone 2b, structural isomers of the antiasthmatic agent cytoxazone (-)-1, and their 5-substituted congeners 23-28 have been prepared. Aldol reaction of para-substituted benzaldehydes with 7-chloro-1-methyl-5-phenyl-1,4-benzodiazepin-2-one, followed by separation of diastereomeric racemates afforded 3-10. Acid-catalyzed 1,4-benzodiazepine ring opening, and transformation of the methyl esters of β-aryl-β-hydroxy-α-amino acids (11-16) via 4-methoxycarbonyl derivatives of 1,3-oxazolidin-2-one (17-22) and their reduction afforded the target oxazolidin-2-one derivatives 23-28. Racemic isocytoxazones 2a and 2b were prepared by an independent route starting from 4-methoxystyrene epoxide. Pure enantiomers of these diastereomeric racemates were separated by HPLC chromatography on chiral stationary phases. Their CD spectra, along with those of previously prepared enantiomers of cis-cytoxazone 1a and trans-cytoxazone 1b are discussed.

Key words

1,4-benzodiazepines - ring opening - oxazolidin-2-ones - chiral HPLC