The successful development of methods for catalytic asymmetric C-C bond formation is one of the most fundamentally important endeavors in synthetic organic chemistry. During the last two decades, the dirhodium(II)-catalyzed intramolecular insertion of alpha-diazocarbonyl compounds into unactivated C-H bonds has emerged as a particularly powerful method for the construction of both carbocyclic and heterocyclic systems. When this insertion process occurs at a C-H bond adjacent to an ether oxygen, beta- alkoxycarbonyl products are obtained and consequently this transformation can be considered to be a synthetic alternative to aldol-type reactions. Since 1,3-diols or derivatives thereof are found in a large number of biologically active natural products the development of this transformation is of considerable importance. The long-term objective of this project is therefore to successfully develop a unique C-H bond insertion strategy which can be applied to the synthesis of a range of pharmacologically active natural products.
The specific aims of this project are: i) to investigate the use of a dirhodium(II)-catalyzed asymmetric intramolecular metal carbene C-H insertion reaction as an efficient method for the preparation of the synthetically useful 2,8-dioxabicyclo[3.2.1]octane ring system; ii) to develop this reaction as a novel method for the simultaneous functionalization and asymmetric desymmetrization of meso 1,3-diol systems; iii) to illustrate the potential of this chemistry through its application to the synthesis of a diverse range of biologically active target molecules, including the antihypercholesterolaemic agent zaragozic acid A/squalestatin S1 and the potent antifungal agent sphingofungin E; and iv) to develop a novel method for the synthesis of branched-chain carbohydrates by extending this chemistry to the direct functionalization of various pyranoside systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059157-04
Application #
6519980
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1999-06-01
Project End
2004-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
4
Fiscal Year
2002
Total Cost
$187,320
Indirect Cost
Name
University of Illinois at Chicago
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Wardrop, Duncan J; Komenda, John P (2012) Dehydrative fragmentation of 5-hydroxyalkyl-1H-tetrazoles: a mild route to alkylidenecarbenes. Org Lett 14:1548-51
Wardrop, Duncan J; Waidyarachchi, Samanthi L (2010) Synthesis and biological activity of naturally occurring ?-glucosidase inhibitors. Nat Prod Rep 27:1431-68
Bowen, Edward G; Wardrop, Duncan J (2009) Total synthesis of the alpha-glucosidase inhibitors schulzeine A, B, and C and a structural revision of schulzeine A. J Am Chem Soc 131:6062-3
Wardrop, Duncan J; Fritz, Joseph (2006) Total synthesis of (+/-)-magnofargesin. Org Lett 8:3659-62
Wardrop, Duncan J; Zhang, Wenming; Fritz, Joseph (2002) Stereospecific entry to [4.5]spiroketal glycosides using alkylidenecarbene C-H insertion. Org Lett 4:489-92
Wardrop, D J; Velter, A I; Forslund, R E (2001) Template-directed C-H insertion: synthesis of the dioxabicyclo[3.2.1]octane core of the zaragozic acids. Org Lett 3:2261-4
Wardrop, D J; Zhang, W (2001) N-methoxy-N-acylnitrenium ions: application to the formal synthesis of (+/-)-desmethylamino FR901483. Org Lett 3:2353-6
Wardrop, D J; Basak, A (2001) N-methoxy-N-acylnitrenium ions: application to the formal synthesis of (-)-TAN1251A. Org Lett 3:1053-6