Asymmetric Total Synthesis of (+)-Hexachlorosulfolipid, a Cytotoxin Isolated from Adriatic Mussels

Abstract

The enantioselective total synthesis of (+)-hexachlorosulfolipid, a cytotoxin found in the Adriatic mussel Mytilus galloprovincialis, is described. The unique chlorinated hydrocarbon motif of the lipid is successfully furnished by a series of dichlorination reactions of chiral epoxides with chlorophosphonium reagent generated in situ from Ph(3)P/NCS. The present total synthesis has allowed the confirmation of the absolute configuration of the natural cytotoxic (+)-hexachlorosulfolipid originally proposed by Fattorusso, Ciminiello, and co-workers.

Diastereoselective Allylation of Carbonyl Compounds and Imines: Application to the Synthesis of Natural Products

“…177 An efficient synthesis of (+)-hexachlorosulfolipid, a cytotoxin found in the Adriatic mussel Mytilus galloprovincialis, has been achieved recently by Yoshimitsu et al Key steps in the synthesis of this hexachlorinated compound are the successive dichlorination of chiral epoxides and the diastereoselective allylation of a chiral α,β-dichloroaldehyde. 178 This aldehyde was quite unstable and decomposed upon thin-layer silica gel chromatography. Consequently, it was prepared in situ from the corresponding alcohol with Dess−Martin periodinane and reacted without purification with allyltrimethylsilane in the presence of boron trifluoride etherate.…”

Stereoselective Halogenation in Natural Product Synthesis

“…[47] For this study, the Markó–Maguire reagent system was employed to generate an uncharacterized active dichlorinating reagent, possibly benzyltriethylammonium trichloride. [48] While stereocontrolled dichlorination of secondary Z -allylic alcohol derivatives might be explained via minimization of A 1,3 -strain, it is not straightforward to rationalize the observed diastereoselectivity of dichlorination of secondary E -allylic alcohol derivatives because of less severe allylic strain.…”

“…[47] A two-step sequence involving epoxide formation from the chlorohydrin followed by deoxydichlorination was more efficient for the production of trichloride 151 than the direct alcohol deoxychlorination, thus demonstrating the synthetic utility of this method.…”

Recent progress toward synthesis of chlorosulfolipids: total synthesis and methodology

“…17 However, 26% of unanticipated syn-1,2-dichloride 17 was formed along with anticipated anti-1,2-dichlorides 15 (38%) and 16 (10%). The anchimeric participation of chlorides in these polychlorinated systems most likely causes the unusual stereoselectivities.…”