Chiral nonracemic amines containing nitrogen attached to a stereogenic carbon are ubiquitous in nature and found in many biologically active materials including drugs and drug candidates. Relevant examples include proteinogenic and nonproteinogenic alpha- and beta-amino acids and diverse alkaloids. Such amines are also widely used as chiral building blocks for the enantioselective construction of bioactive materials. The principal objective of the proposed work is to employ enantiopure sulfinimines [N-sulfinyl imines, R1S(O)N=CR2R3] and four sulfinimine-derived building blocks--beta-amino Weinreb amides, delta-amino beta-ketoesters, 3,4-dihydroisoquinolines, and 3,5-dihydro-1(2H)-isoquinolones--in new methodology for the enantioselective syntheses of biologically relevant amines and alkaloids. Important advantages conferred by the N-sulfinyl auxiliary include (i) powerful stereodirecting effects; (ii) activation of the C=N bond toward nucleophilic addition; (iii) ability to be removed under mild conditions without epimerization; and (iv) ready availability of single enantiomers via separation of diastereomeric intermediates. Beta-amino Weinreb amides will be used in new syntheses of beta-amino aldehydes and ketones that in turn will be employed in the asymmetric syntheses of 1,3-amino alcohols and 1,3-diamines, important ligands and structural units of natural products. New methods for the enantioselective synthesis of polyfunctionalized piperidine and pyrrolidine alkaloids will utilize delta-amino beta-ketoesters as building blocks. In this context new chemistry will be devised for the construction of trans 2,6- and 2,5-disubstituted analogs. Addition of laterally lithiated nitriles and amides to sulfinimines provide 3,4-dihydroisoquinolines and 3,5-dihydro-1 (2H)-isoquinolones, building blocks with substitution patterns not easily accessible by other means. A further major objective in these studies is elucidation of the factors responsible for molecular recognition. Concurrently we will exploit this new chemistry in concise syntheses of biologically relevant molecules or their chiral nonracemic precursors. Targets include (i) densely substituted piperidine and pyrrolidine alkaloids, classes of compounds that exhibit diverse biological activities; (ii) polysubstituted prolines, important building blocks and modifiers of proteins; and (iii) tetrahydroisoquinolines, medicinally valuable alkaloids.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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Temple University
Schools of Arts and Sciences
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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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