Synthesis and Absolute Configuration Assignments of Enantiomeric Forms Of Ifosphamide, Sulfosphamide, and Trofosphamide

K. Pankiewicz, R. Kinas, W. J. Stec, A. B. Foster, M. Jarman, Jan M.S. Van Maanen

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46 Scopus citations

Abstract

Using N-(S)-α-or N-(R)-α-methylbenzyl-3-aminopropan-l-ol as the starting material, the diastereomers of 2-chioro-3-[(S)-α-or (R)-α-methylbenzyl]tetrahydro-2H-l, 3, 2-oxazaphosphorine 2-oxide were obtained in the ratio 80 : 20. Their conversion via P-aziridines (14) into 2-chloroethylamino derivatives (15) and separation of the latter into diastereo-metrically pure forms allowed the further synthesis of enantiomers of ifosphamide (2-(2-chloroethylamino)-3-(2-chloroethyl)- tetrahydro-2H-l, 3, 2-oxazaphosphorine 2-oxide] and sulfosphamide (2-(2-mesyloxyethylamino)-3-(2-chloroethyl)tetrahydro-211-1, 3, 2-oxazaphosphorine 2-oxide]. Chloroacetylation of previously reported enantiomers of ifosphosphamide {2-[bis(2-chloroethyl)amino]tetrahydro-2H-l, 3, 2-oxazaphosphorine 2-oxide} and conversion of the N-chloroacetyl group into an N-(2-chloroethyl) group gave both enantiomers of trofosphamide {2-[bis(2-chloroethyl)amino]-3-(2-chloroelhyl)tetrahydro-2W-1, 3, 2-oxazaphosphorine 2-oxide]. Absolute configurations were assigned as (+)-2(R),( + )-3(S),( + )-4(R) by the following chemical transformations : 2 was related to 1 by the stereospecific synthesis from the common intermediate 15 and. independently, by conversion into a common bicyclic product 21, 3 by direct synthesis from 1, and 4 by synthesis of its enantiomers and those of 2 from common intermediates.

Original languageEnglish (US)
Pages (from-to)7712-7718
Number of pages7
JournalJournal of the American Chemical Society
Volume101
Issue number26
DOIs
StatePublished - Feb 1 1979

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