ASYMMETRIC SYNTHESIS OF BIOACTIVE PRIMARY AMINES

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DESCRIPTION: (Applicant's Abstract) Chiral nonracemic amines containing nitrogen attached to a stereogenic carbon are ubiquitous in nature. Examples include proteinogenic and nonproteinogenic alpha and beta-amino acids and structurally diverse alkaloids. Such amines are also widely used as chiral building blocks for the enantioselective construction of bioactive materials including aziridines, beta-lactams, peptide antibiotics, amino sugars and HIV-1 protease inhibitors. Of particular significance is the absolute stereochemistry, upon which biological activity often critically depends. The principal objective of the proposed work is to employ enantiopure sulfinimines (R1S(O)N-CR2R3) and four new sulfinimine- derived building blocks, N-sulfinyl aziridine carboxylate esters, isoquinolones, densely functionalized amino acids, and glyoxylate N-sulfinyl imines, in new methodology for the enantioselective synthesis of biologically relevant alpha and beta-amino acids and alkaloids. Important advantages conferred by the N-sulfinyl auxiliary include: (i) powerful stereodirecting affects; (ii) activation of the C=N bond toward nucleophilic addition; (iii) removal under mild conditions without epimerization; ad (iv) ready availability of enantiopure products via separation of diastereomeric intermediates. Regio-and stereoselective ring- opening reactions of N-sulfinyl aziridine carboxylate esters will be used to synthesize alpha and beta-amino acids and their difficult-to-prepare beta, beta'-disubstituted and alpha- substituted analogs. Isoquinolones and densely functionalized amino acids will provide efficient entry into biologically active alkaloid systems with substitution patterns not easily accessible by other means. Glyoxlate N-sulfinyl imines, new chiral heterodinenophiles and glycne cation equivalent, will be employed in the aza Diels-Alder and imino ene synthesis of amino acids. A second major objective is the elucidation of the factors responsible for the molecular recognition in thee processes. Concurrently we will exploit this chemistry in syntheses of biologically relevant molecules or their chiral nonracemic precursors. Targets include: (i) aryl alanines, constitutents of peptides and antitumor antibiotics; (ii) beta-hydroxy alpha-amino acids, components of numerous peptide antibiotics such as vancomycin; (iii) beta-amino acids, important peptidomimetics and fragments of antitumor drugs such as taxol; and (iv) isoquinolines, medicinally valuable alkaloids, and HIV inhibitors. New and improved enantioselective approaches to these bioactive amines are expected to result.