I. Utilization of the 1-ferrocenyl-2-methylpropyl substituent as a chiral auxiliary in the asymmetric syntheses of the benzophenanthridine alkaloids (+)- and (-)-corynoline. II. The syntheses of intercalating agents with linker chains for the attachment to oligodeoxyribonucleotides

Jer-Kang Chen, Purdue University

Abstract

Part I. The synthesis of optically pure (+)- and ($-$)-corynoline was achieved by the condensation reaction of the chiral Schiff bases (+)- and ($-$)-$N$-piperonylidene-1-ferrocenyl-2-methylpropylamine, S-(+)-78 and R-($-$)-78, with 3,4-(methylenedioxy)-7-methylhomophthalic anhydride 36 to afford the chiral isoquinolones, (+)- and ($-$)-108. The chiral auxiliary, 1-ferrocenyl-2-methylpropyl group, thus influences both the relative and absolute configurations of two asymmetric centers. Removal of the chiral auxiliary from these chiral isoquinolones and further transformations lead to optically pure (+)- and ($-$)-corynoline. The overall yield of (+)- or ($-$)-corynoline from piperonal was 16.5%. The intermediates and products were determined to be optically pure within the limits of detection by HPLC on a covalent $(R)$-$N$-((3,5j-dinitrobenzoyl)phenyl) glycine column. Part II. It has been known that intercalating agents covalently linked to oligodeoxyribonucleotides provide compounds which can bind to nucleic acid with high base-sequence specificity and high binding affinity. This concept is then applied to the syntheses of anti-viral agents. Fagaronine chloride (2) and an indenoisoquinoline analog (3) of nitidine chloride were chosen as the primary intercalating moieties. This study aims to covalently attach linker chains to these molecules to give intermediates which can then be linked to oligodeoxyribonucleotides at a later stage. For fagaronine chloride (2), the free phenolic group is the site for the attachment of linker chains. In the case of the indenoisoquinoline analog (3) of nitidine chloride, the quaternary nitrogen ultimately may serve as the site of attachment. The condensation reaction of Schiff base and anhydride was used in the synthesis of the key intermediate 42, which was then $N$-alkylated with linker chains. This synthetic sequence is to be developed as a general methodology which can be applied to synthesize other active quaternary benzophenanthridines or their analogs covalently attached to a wide variety of linker chains on the quaternary nitrogen.

Degree

Ph.D.

Advisors

Cushman, Purdue University.

Subject Area

Pharmacology

COinS