Chiral nonracemic amines containing nitrogen attached to stereogenic carbon are ubiquitous in nature. Examples include protein and non-protein alpha- and beta-amino acids as well as allylic and homoallyic amines. These amines are also widely used as chiral synthons for the enantioselective construction of bioactive materials including aziridines, beta-lactams, peptide antibiotics, amino sugars, HIV-1 protease inhibitors and alkaloids. Of particular significance is the absolute stereochemistry, upon which biological activity often critically depends. The principal objective of the proposed work is to employ chiral nonracemic sulfinimines [ArS(O)N=CRR'] in new methodology for the enantioselective synthesis of biologically relevant primary amines (RR'R""""""""C-NH2) and their derivatives. To this end, we will explore the diastereoselective addition of organometallic reagents and enolates to sulfinimines (chiral ammonia-imine synthons). Important advantages conferred by the N-sulfinyl group include, (i) powerful stereodirecting effects, (ii) activation of the C-N double bond toward addition, (iii) configurational stability of the sulfinamide product [ArS(O)-NHCRR'R""""""""] and (iv) removal under mild conditions without racemization. A second major objective is the elucidation of the factors responsible for the molecular recognition. New and improved methods for the synthesis of enantiopure sulfinimines will also be devised. Complementary studies will focus on the chemistry of the product sulfinamides including N-sulfinyl alpha- and beta-amino acids, aziridines, and allylic and homoallylic amines. Here we will survey the compatibility of the N-sulfinyl auxiliary with various functional group transformations and assess its usefulness as a stereodirecting group. Concurrently we will exploit this chemistry in syntheses of biologically relevant molecules or their chiral nonracemic precursors. Targets include (i) vinyl glycines, which inhibit amino acid decarboxylase enzymes, (ii) alpha-hydroxy-beta-amino acids, constituents of antifungal and antitumor agents, intermediates in the synthesis of beta-lactams and the aminosaccharide fragments of the anticancer drugs daunorubicin and adrimycin, and (iii) syn-beta-hydroxy-alpha-amino acids, components of numerous peptide antibiotics. Improved enantioselective approaches to these bioactive amines are expected to result.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM051982-02
Application #
2190806
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1995-07-01
Project End
1999-06-30
Budget Start
1995-09-01
Budget End
1996-06-30
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Temple University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Davis, Franklin A; Ramachandar, Tokala (2008) alpha-Amino 1,3-Dithioketal Mediated Asymmetric Synthesis of Piperidines (L-733,060) and Tetrahydrofuran Glycines. Tetrahedron Lett 49:870-872
Davis, Franklin A; Zhang, Junyi; Qiu, Hui et al. (2008) Asymmetric synthesis of cis- and trans-2,5-disubstituted pyrrolidines from 3-oxo pyrrolidine 2-phosphonates: synthesis of (+)-preussin and analogs. Org Lett 10:1433-6
Davis, Franklin A; Xu, He; Zhang, Junyi (2007) Asymmetric synthesis of ring functionalized trans-2,6-disubstituted piperidines from N-sulfinyl delta-amino beta-keto phosphonates. total synthesis of (-)-myrtine. J Org Chem 72:2046-52
Davis, Franklin A; Deng, Jianghe (2007) Asymmetric synthesis of 2H-azirine 3-carboxylates. Org Lett 9:1707-10
Davis, Franklin A; Zhang, Yanfeng; Li, Danyang (2007) Sulfinimine-derived 2,3-diamino esters in the asymmetric synthesis of piperidine (2S,3S)-(+)-CP-99,994. Tetrahedron Lett 48:7838-7840
Davis, Franklin A; Song, Minsoo (2007) Asymmetric synthesis of syn-alpha-substituted beta-amino ketones by using sulfinimines and prochiral Weinreb amide enolates. Org Lett 9:2413-6
Davis, Franklin A; Song, Minsoo; Augustine, Alexander (2006) Asymmetric synthesis of trans-2,5-disubstituted pyrrolidines from enantiopure homoallylic amines. Synthesis of pyrrolidine (-)-197B. J Org Chem 71:2779-86
Davis, Franklin A; Melamed, Jeffrey Y; Sharik, Steven S (2006) Total synthesis of (-)-normalindine via addition of metalated 4-methyl-3-cyanopyridine to an enantiopure sulfinimine. J Org Chem 71:8761-6
Davis, Franklin A; Zhang, Junyi; Li, Yingxin et al. (2005) Asymmetric synthesis of 2,4,5-trisubstituted piperidines from sulfinimine-derived delta-amino beta-ketoesters. Formal synthesis of pseudodistomin B triacetate. J Org Chem 70:5413-9
Davis, Franklin A; Yang, Bin (2005) Asymmetric synthesis of alpha-substituted beta-amino ketones from sulfinimines (N-sulfinyl imines). synthesis of the indolizidine alkaloid (-)-223A. J Am Chem Soc 127:8398-407

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