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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56GM057870-09A1
Application #
7477591
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Schwab, John M
Project Start
1998-08-01
Project End
2009-07-29
Budget Start
2007-07-30
Budget End
2009-07-29
Support Year
9
Fiscal Year
2007
Total Cost
$283,225
Indirect Cost
Name
Temple University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Davis, Franklin A; Gaddiraju, Narendra V; Theddu, Naresh et al. (2012) Enantioselective synthesis of cocaine C-1 analogues using sulfinimines (N-sulfinyl imines). J Org Chem 77:2345-59
Davis, Franklin A; Xu, Peng (2011) Asymmetric synthesis of anti-ýý-substituted ýý-amino ketones from sulfinimines. J Org Chem 76:3329-37
Davis, Franklin A; Theddu, Naresh (2010) Asymmetric synthesis of cyclic cis-beta-amino acid derivatives using sulfinimines and prochiral Weinreb amide enolates. J Org Chem 75:3814-20
Davis, Franklin A; Theddu, Naresh; Edupuganti, Ram (2010) Asymmetric total synthesis of (S)-(+)-cocaine and the first synthesis of cocaine C-1 analogs from N-sulfinyl ýý-amino ester ketals. Org Lett 12:4118-21
Davis, Franklin A; Edupuganti, Ram (2010) Asymmetric synthesis of substituted homotropinones from N-sulfinyl beta-amino ketone ketals. (-)-Euphococcinine and (-)-adaline. Org Lett 12:848-51
Davis, Franklin A; Theddu, Naresh; Gaspari, Paul M (2009) Asymmetric synthesis of substituted tropinones using the intramolecular mannich cyclization reaction and acyclic N-sulfinyl beta-amino ketone ketals. Org Lett 11:1647-50
Davis, Franklin A; Zhang, Yanfeng (2009) Asymmetric synthesis of (2S,3R)-(-)-epi-CP-99,994 using sulfinimine-derived anti-2,3-diamino esters. Tetrahedron Lett 50:5205-5207
Davis, Franklin A; Song, Minsoo; Qiu, Hui et al. (2009) Total synthesis of (5R,6R,8R,9S)-(-)-5,9Z-indolizidine 221T using sulfinimine-derived N-sulfinyl beta-amino ketones. Org Biomol Chem 7:5067-73
Davis, Franklin A; Qiu, Hui; Song, Minsoo et al. (2009) Vinylaluminum addition to sulfinimines (N-sulfinyl imines). Asymmetric synthesis of anti-alpha-alkyl beta-amino esters. J Org Chem 74:2798-803