Asymmetric Synthesis of Amino Acids and Amino Phosphonic Acids

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The objective of this research program is to design and synthesize new sulfmimine (N-sulfinyl imine)-derived chiral building blocks, and to invent related methodologies for the asymmetric synthesis of amine structures that are presently difficult to prepare but necessary for the synthesis of biologically important anticancer, antiviral, antibacterial, antifungal, and other bioactive molecules of medicinal relevance. Examples include novel a- and (¿-amino acids, pyrrolidine, and piperidine alkaloids. These amine types are also widely used as chiral building blocks for the enantioselective construction of bioactive materials, including drug and drug candidates. Four sulfinimine-derived chiral building blocks (a-substituted (¿-amino ketones, d-amino (¿- ketophosphonates, 2,¿-diamino esters, and 2-substituted 2H-azirine ¿-carboxylates) will be employed to accomplish our objectives. a-Substituted (¿-amino Weinreb amides, prepared by addition of prochiral Weinreb amides to sulfinimines, on reaction with Grignard reagents, represent a general solution.to the problem of a-substituted (¿-amino ketone synthesis. Using our intramolecular Mannich cyclization protocol, these new (¿-amino ketones will be employed in syntheses of toxic frog skin polysubstituted piperidines not previously prepared. d-Amino (¿-ketophosphonates will be used in new stereocontrolled syntheses of cis- 2,5- and trans-2,5 disubstituted ring functionalized pyrrolidine alkaloids from a common ¿-oxo pyrrolidine 2- phosphonate intermediate. Sulfinimine derived syn- and anti-2,¿-diamino esters are expected to provide access to several biorelevant diamino compounds including the unknown anti isomer of (+)-CP99,994, a potent neurokinin substrate P receptor antagonist. Analogues of the architecturally unique marine antibiotic (-)-agelastatin A will be prepared for biological evaluation. (-)-Agelastatin A has significant activity against a variety of human cancer cell lines, but its mechanism of activity remains undetermined. The reaction of new sulfinimine-derived 2-substituted 2H-azirine ¿-carboxylates with nucleophiles and with dienes in aza-Diels-Alder reactions, will provide unique routes to enantiopure 2-substituted aziridine 2- carboxlates and bicyclic and tricyclic aziridine carboxylates. Stereoselective ring opening of these aziridines affords novel a- and (¿-amino acids not easily assessable by other means. The photodesulfmylation of sulfinamides represents an important new protocol, not requiring acids or bases, for the removal of the valuable amine N-sulfinyl protecting group.