The specific aim of the proposed work is to develop the chemistry of alpha-aminoalkylcopper reagents; a type of organocopper reagent that permits functionalization alpha to an amino group using the reactions characteristic of organocopper reagents. The specific objectives are to (1) expand the range of cuprate-electrophile reaction partners, (2) explore the reactivity and thermal stability of these reagents, and the configurational stability of cuprates with a C-Cu stereogenic center, (3) optimize reaction conditions, substrates, and reagents for effecting relative (diastereoselectivity) and absolute (enantioselectivity) asymmetric induction in the characteristic reactions of alpha-aminoalkylcuprates, and (4) develop the synthetic utility of these reagents by developing synthetic strategies for the synthesis of highly substituted 5-membered heterocyclic compounds with a focus on the pyrrolidine aza sugars. The synthetic approach to highly substituted pyrrolines, pyrrolidines, and pyrrolidinones involves the reaction of alpha-aminoalkylcuprates with scalemic propargyl substrates in a controlled anti-SN2' process followed by cyclization of the carbamate nitrogen or free amine onto the resultant allene. The work will extend the scope and synthetic utility of these organocopper reagents. Successful development of alpha-aminoalkylcuprate chemistry will contribute significantly to the synthesis of highly substituted pyrrolidines, piperidines, and their bicyclic analogs (i.e., pyrrolizidines, indolizidines, and quinolizidines). Complex alkaloids and simple nitrogen-containing compounds are biologically active agents representing important classes of antibacterial agents, CSN agents, and antiretroviral compounds. The polyhydroxy analogs (i.e., aza sugars) are an important class of glycosidase inhibitors and immunostimulators and are the focus of intense synthetic activity because of their effects upon glycoprotein processing enzymes. Inhibition of glycoprotein processing is potentially useful against illnesses such as cancers, malaria, diabetes, cystic fibrosis, bacterial, and viral infections including retro-viruses such as the human immunodeficiency virus (HIV). A need exists for a general synthetic approach to the aza sugars that is short, efficient, and which divergently leads to a large number of stereoisomers and analogues from a common intermediate. The proposed synthetic routes to pyrrolidine aza sugars will develop the potential synthetic power of alpha-aminoalkylcuprate chemistry.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM060300-02
Application #
6351316
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2000-02-01
Project End
2003-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
2
Fiscal Year
2001
Total Cost
$125,607
Indirect Cost
Name
Clemson University
Department
Chemistry
Type
Schools of Engineering
DUNS #
042629816
City
Clemson
State
SC
Country
United States
Zip Code
29634
Dieter, R Karl; Chen, Ningyi; Yu, Huayun et al. (2005) Reaction of alpha-(N-carbamoyl)alkylcuprates with propargyl substrates: synthetic route to alpha-amino allenes and delta3-pyrrolines. J Org Chem 70:2109-19
Dieter, R Karl; Oba, Gabriel; Chandupatla, Kishan R et al. (2004) Reactivity and enantioselectivity in the reactions of scalemic stereogenic alpha-(N-carbamoyl)alkylcuprates. J Org Chem 69:3076-86
Dieter, R Karl; Gore, Vinayak K; Chen, Ningyi (2004) Regio- and enantioselective control in the reactions of alpha-(N-carbamoyl)alkylcuprates with allylic phosphates. Org Lett 6:763-6
Watson, Rhett T; Gore, Vinayak K; Chandupatla, Kishan R et al. (2004) Synthesis of (-)-(R)-pyrrolam a and studies on its stability: a caveat on computational methods. J Org Chem 69:6105-14
Dieter, R Karl; Li, ShengJian; Chen, Ningyi (2004) Halogen- and N-haloimide-promoted homo- and heterocoupling of alpha-(N-carbamoyl)alkylcuprates and alpha-(alkoxy)alkylcuprates. J Org Chem 69:2867-70
Dieter, R Karl; Lu, Kai (2002) Alpha-(N-carbamoyl)alkylcuprate chemistry in the synthesis of nitrogen heterocycles. J Org Chem 67:847-55
Dieter, R K; Topping, C M; Chandupatla, K R et al. (2001) Enantioselectivity in the reactions of chiral alpha-(N-carbamoyl)alkylcuprates. J Am Chem Soc 123:5132-3
Dieter, R K; Yu, H (2001) Synthesis of 3-pyrrolines, annulated 3-pyrrolines, and pyrroles from alpha-amino allenes. Org Lett 3:3855-8
Dieter, R K; Yu, H (2000) A facile synthesis of polysubstituted pyrroles. Org Lett 2:2283-6
Dieter, R K; Lu, K; Velu, S E (2000) Conjugate addition reactions of alpha-aminoalkylcuprates with alpha, beta-alkenyl-, alpha,beta-alkynyl-, alpha,beta-beta,gamma-allenyl-, and alpha,beta-gamma,delta-dienyl carboxylic acid derivatives, nitriles, and sulfoxides. J Org Chem 65:8715-24