Synthetic studies on the spiroacetal moiety of stenocarpin, a metabolite of Diplodia maydis

Abstract

The fungus Diplodia maydis, (synonym Stenocarpella maydis (Berk)) is worldwide one of the most important cob rot pathogens of maize. The isolation of stenocarpin, a metabolite toxic to ducklings, from maize cultures of D. maydis as the 4,6-0-diacetate derivative and its structure elucidation has been reported in the literature. Detailed NMR studies established the structure as either (3S,4R,6R,7R)- or (3R,4R,6R,7R)-spiro[(4,6, 7-trihydroxy-7-methyl-8-oxo-5,6,7,8-tetrahydroisochromane)-3 ,2' -tetrahydrofuran]. The absolute configuration of the C(3) spiroacetal stereogenic center remained unknown. The aim of the synthetic studies described in this dissertation was to develop a synthetic methodology for the spiroacetal moiety present in stenocarpin in order to establish unambiguously the C(3) absolute configuration. Retrosynthetic analysis of stenocarpin identified two model compounds (5S,lOR)- and (5R,lOR)-1,6-dioxaspiro[4.5]dec-8-en-10-o1 as the synthetic target. In turn the retrosynthetic analysis of these model compounds led to commercially available L-arabinose as starting material. Two strategies, which differ in the timing for the formation of the spiroacetal moiety as well as the initial type of protecting groups, were employed in the development of the synthetic route. In the first route the spirocyclisation reaction of a benzyl protected intermediate followed by the syn elimination of the cis-diol group resulted in the formation of only the (5S, lOR) model compound. The use of the acetonide and TBDPS protecting groups from the outset of the synthetic route and once again a spirocyclisation reaction, led to the formation of two spiro compounds epimeric at the C(5) spiro stereogenic centre, which could be separated and transformed by a syn elimination of the cis-diol group to the two model compounds. The configuration of the spiroacetal intermediates formed in the two synthetic routes and the changes in conformation that occurred in each of the steps were deduced from extensive NMR studies and especially the NOE technique. The results established the 3S configuration for stenocarpin and provided a viable synthesis for the (5S,lOR)-l,6-dioxaspiro[4.5]dec-8-en-1O-ol model compound that is to be used in the total synthesis of stenocarpin. In the dissertation the results of the first steps in a total synthesis, a study on the epoxidation of the double bond, is presented.