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DOI: 10.1039/A901141B (Paper) Reference Section for: J. Chem. Soc., Perkin Trans. 1, 1999, 1495-1504

Chemoenzymatic preparation of the novel antifolate thymidylate synthase inhibitor N-(4-{N-[(6S[hair space])-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoyl)-L-glutamic acid and its glutamyl cleavage product

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Jonathan H. Marriott, Stephen Neidle, Zbigniew Matusiak, Vassilios Bavetsias, Ann L. Jackman, Camille Melin and F. Thomas Boyle

Abstract

5-Aminoindane was converted in six steps to the cyclopenta[g]quinazoline ketone 13. Condensation of 13 with diethyl 4-aminobenzoyl-L-glutamate, followed by in situ reduction, produced the secondary amine 15. N-Propargylation of 15, followed by deprotection, gave the diacid 17 as a mixture of diastereoisomers. Treatment of 17 with the bacterial enzyme carboxypeptidase G2 resulted in removal of the L-glutamic acid residue from (6R)-17 to give a chromatographically separable mixture of the monoacid 18 and the antifolate 5 [(6S[hair space])-17], which was assayed as an inhibitor of thymidylate synthase (Kiapp = 3 nM). Treatment of isolated diacid 5 with carboxypeptidase G2 produced the monoacid 19 in ca. 98% enantiomeric excess. The (6S[hair space]) stereochemistry of compound 19 has been established by X-ray crystal structure determination of the amide derivative 24.

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