Alpha-amino acids are the basic building blocks of peptides and proteins, which are responsible for the structure and function of most living things. They are extensively employed as chiral templates and subunits in the asymmetric construction of many biologically and pharmacologically active compounds. Nonproteinogenic examples are increasingly utilized to study enzyme mechanisms and to modify and enhance protein activity. Alpha-amino phosphonic acids are structural analogs of amino acids and as such exhibit a broad range of biological activities: enzyme inhibitors, antitumor agents, anti-bacterial agents, and fungicides. ? ? The principal objective of the proposed work is to develop practical and efficient methodology for the asymmetric synthesis of functionalized alpha amino acids and alpha amino phosphonic acids by exploiting the diastereoselective addition of CN and phosphite anions to chiral nonracemic sulfinimines [N-sulfinyl imines, R'S(o)N=CR2R3]. Important advantages conferred by the N-sulfinyl group include (i) powerful stereodirecting effects, (ii) activation of the C-N double bond toward addition, and (iii) facile auxiliary removal and hydrolysis of the N-sulfinyl alpha amino nitrile and alpha amino phosphonate to amino acids and amino phosphonic acids under such exceedingly mild conditions that racemization does not occur. ? ? Complementary studies will focus on the synthesis and regioselective and stereoselective ring-opening reactions of N-sulfinyl aziridine 2-phosphonates as sources of novel alpha amino phosphonic acids. The imino-Diels-Alder reactions of 2H-azirine phosphonates, a new chiral dienophile, will be exploited as sources of novel aziridine 2-phosphonates and azabicyclic systems; the latter compounds are important chiral building blocks and exhibit a range of biological activities. Such studies are expected to provide new information on the chemical reactivity/selectivity of the phosphonate group as compared to carboxylate esters. ? ? Concurrently we will employ this chemistry in syntheses of biologically relevant, functionalized alpha amino acids and alpha amino phosphonates that are difficult or impossible to prepare via other methodologies. Targets include cyclic, unsaturated, and, beta substituted derivatives (beta amino, beta hydroxy, and beta fluoro).

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057870-06
Application #
6605011
Study Section
Special Emphasis Panel (ZRG1-SSS-B (01))
Program Officer
Schwab, John M
Project Start
1998-08-01
Project End
2006-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
6
Fiscal Year
2003
Total Cost
$263,375
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
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

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