With the advent of Lewis acid-mediated radical reactions, impressive advances have been made in the last five years in the control of acyclic stereochemistry using chiral auxiliaries. In contrast, enantioselective carbon-carbon bond construction using radical intermediates is still in its infancy. The design of chiral catalytic radical reactions for obtaining high stereoinduction is a challenge. We and others have investigated chiral Lewis acid-mediated enantioselective radical reactions. A few important advancements have been made in this regard in the previous grant period. This continuation (GM-54696) proposal outlines a mixture of new methodology development using free radicals along with application of the newly discovered methods to natural product synthesis. In this proposal we will specifically address: (a) The establishment of one, two, and three chiral centers with relative as well as absolute stereocontrol by intermolecular radical reactions in acyclic systems. The newly developed methodology will be applied to the total synthesis of antiallergenic neolignan magnosalicin, in the formal total synthesis of cytotoxic octalactin A and to the preparation of C-glycosides. (b) The construction of carbo- as well as heterocyclic compounds through intramolecular enantioselective radical cylizations. Processes in which two or more contiguous chiral centers are established will be explored. The application of the methodology to lactone natural products with biological activity will be undertaken. (c) Enantioselective radical annulation reactions will be investigated in detail. Specifically, the formation of medium size rings will be explored. The annulation methodology will constitute a key disconnection in our effort towards the total synthesis of structurally complex tetracyclic diterpenes, the asbestinins, which show promising cytotoxicity against several human cancer cell lines.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM054656-06
Application #
6386542
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1996-07-01
Project End
2004-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
6
Fiscal Year
2001
Total Cost
$225,600
Indirect Cost
Name
North Dakota State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Fargo
State
ND
Country
United States
Zip Code
58108
Sibi, Mukund; Yang, Yong-Hua; Lee, Sunggi (2008) Tin-Free Enantioselective Radical Reactions Using Silanes. Org Lett :
Sibi, Mukund P; Hasegawa, Masayuki (2007) Organocatalysis in radical chemistry. Enantioselective alpha-oxyamination of aldehydes. J Am Chem Soc 129:4124-5
Sibi, Mukund P; Nad, Sukanya (2007) Enantioselective radical reactions: stereoselective aldol synthesis from cyclic ketones. Angew Chem Int Ed Engl 46:9231-4
Lee, Sunggi; Lim, Chae Jo; Kim, Sunggak et al. (2006) Enantioselective conjugate radical addition to alpha'-hydroxy enones. Org Lett 8:4311-3
Sibi, Mukund P; Zimmerman, Jake (2006) Pyrones to pyrans: enantioselective radical additions to acyloxy pyrones. J Am Chem Soc 128:13346-7
Sibi, Mukund P; He, Liwen (2006) Enantioselective Radical Reactions. Formation of Chiral Quaternary Centers. Synlett 2006:689-692
Sibi, Mukund P; Patil, Kalyani (2006) Enantioselective radical reactions. Evaluation of nitrogen protecting groups in the synthesis of beta-amino acids. Tetrahedron Asymmetry 17:516-519
Sibi, Mukund P; Patil, Kalyani (2005) Enantioselective H-atom transfer reaction: a strategy to synthesize formaldehyde aldol products. Org Lett 7:1453-6
Sibi, Mukund P; Petrovic, Goran; Zimmerman, Jake (2005) Enantioselective radical addition/trapping reactions with alpha,beta-disubstituted unsaturated imides. Synthesis of anti-propionate aldols. J Am Chem Soc 127:2390-1
Sibi, Mukund P; Tatamidani, Hiroto; Patil, Kalyani (2005) Enantioselective rhodium enolate protonations. A new methodology for the synthesis of beta2-amino acids. Org Lett 7:2571-3

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