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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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University of Illinois at Chicago
Schools of Arts and Sciences
United States
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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