Total Synthesis and Reassignment of the Structures of the Antimicrobial Lipodepsipeptides Circulocin γ and δ.

The structures of the naturally occurring antimicrobial lipodepsipeptides circulocin γ and circulocin δ have been reported to comprise a common cyclic depsipeptide core attached to 3-hydroxy,ω-guanidino fatty acid chains differing in length by two methylene units, but analysis of the reported data suggested that the originally reported structures had incorrect side chain lengths. The total synthesis of both side chain epimers of the originally reported structure of circulocin γ bearing a 19-guanidino-3-hydroxynonadecanoyl (GHND) side chain has been accomplished using a modular approach involving synthesis of the cyclic depsipeptide and side chain fragments followed by a late stage coupling reaction. This revealed that the originally reported structure for circulocin γ bearing the GHND side chain is incorrect and that this structure is actually that of circulocin δ. It has also enabled the absolute configuration of the side chain hydroxy group of the natural product to be assigned as (R). Subsequent synthesis of the analogue bearing a 17-guanidino-3-(R)-hydroxyheptadecanoyl (GHHD) side chain provided confirmation that this revised structure is that of circulocin γ.

Concise synthesis of complicated polypropionates through one-pot dissymmetrical two-directional chain elongation.

Herein, a major breakthrough in a sulfur dioxide-mediated oxyallylation cascade reaction is reported that allows the preparation of complex long-chain polyketide fragments with more than ten stereogenic centers through a carefully designed desymmetrization process. An allylbissilane is combined, under the appropriate reaction conditions, with two different 1,3-dioxy-1,3-dienes permitting the construction of a 13-membered polypropionate precursor in one pot. Four stereocenters are selectively created during this process. The so-obtained pseudo-C(2)- or -C(S)-symmetric products are desymmetrized through selective deprotection and can be selectively elongated in both directions using aldol chemistry.

Total asymmetric syntheses of ß-hydroxy-δ-lactones via Umpolung with sulfur dioxide.

Cyclic stereotriads and stereotetrads of the ß-hydroxy-δ-lactone type, e.g. prelactones B and E, common in polyketides and polypropionates, are prepared via SO(2)-induced oxyallylations of enoxysilanes with (1E,3Z)-1-(1-phenylethoxy)penta-1,3-dien-3-yl carboxylates. Using (Z)- or (E)-enoxysilanes both 4,5-cis- or 4,5-trans-δ-lactones are obtained. Depending on the reduction method applied to the obtained aldol intermediates 5,6-trans or 5,6-cis-derivatives are formed. The δ-lactones can be prepared in both their enantiomeric forms depending on the (1R)- or (1S)-configuration of the starting 1-(1-phenylethoxy)penta-1,3-dienes.

Synthesis of (E,Z)-1-alkoxy-3-acyloxy-2-methylpenta-1,3-dienes via Danishefsky-type dienes or O-acylation of enones.

1-Alkoxy-2-methyl-3-acyloxy-(E,E)-penta-1,3-dienes have been prepared applying among others a modified Danishefsky's general method, including chiral, racemic, and achiral derivatives.