Conformational and configurational analysis in the study and synthesis of chlorinated natural products.

The first detailed study of the J-based configuration analysis method in chlorinated hydrocarbons and chlorohydrins is presented along with the development of a spectroscopic database that facilitates configurational assignment of these structures. The data are generated through the investigation of model structures in solution by NMR spectroscopic methods and in the solid state by X-ray crystallography. Consequently, complete conformational analysis of trichlorinated hexane-1,2- and -1,3-diols is presented. The investigations in chlorinated systems for the first time attest to the relevance, reliability, and accuracy of the spectroscopic approach in configurational assignment, which had been otherwise developed for polyketides. During the synthesis of the various molecules that constitute the database and exemplify the various possible stereochemical patterns, a number of observations were made that underscore the unique features of these chlorinated systems. Thus, certain diastereomeric subclasses of 4,5-dichloro-2,3-epoxyhexane-1-ols display a propensity to undergo ring-opening reactions at C-3 with concomitant inversion of configuration at the neighboring C-Cl at C4, implicating the intermediacy of chloronium ions. The observations of positional and stereochemical scrambling in polychlorinated hydrocarbons underscore the necessity of a spectroscopic database that enables rapid, reliable configurational assignment of chlorinated natural products and intermediates en route to these.

Total synthesis of a chlorosulpholipid cytotoxin associated with seafood poisoning.

Each year, there are many cases of seafood poisoning in humans worldwide. Among the various toxins isolated that contribute to these poisonings, the chlorosulpholipids are particularly intriguing because of their structural and stereochemical complexity. The mechanism of biological activity remains unknown and, although chlorosulpholipids are associated with membranes in the organisms from which they are isolated, little is understood about their role within biological membranes. The lack of availability of the natural products has impaired more in-depth biochemical studies. So far, none of the chlorosulpholipids have been obtained from total synthesis, and efficient routes to their synthesis would be desirable for the preparation of material for pharmacological characterization and proper evaluation of the risk to human health. Despite the notable advances in the science of organic synthesis, reliable methods for stereoselective construction of polychlorinated acyclic substrates are lacking, although some preliminary investigations have appeared. Here we report the synthesis of a chlorosulpholipid cytotoxin, leading to confirmation of the proposed structure and the discovery of unanticipated reactivity of polychlorinated hydrocarbons. The concise synthetic approach should enable the preparation of material in sufficient quantities to facilitate biological studies.

Reduction of 2,3-dihydroisoxazoles to beta-amino ketones and beta-amino alcohols.

[chemical reaction: see text]. We report the reduction of 2,3-dihydroisoxazoles to beta-amino ketones and beta-amino alcohols. The latter are obtained in high diastereoselectivity with preference for the syn isomer.