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.
