Approach to the synthesis of Macrolactin A: New, non-racemic 1,3-diol synthons.

Abstract

A unique synthetic strategy towards the natural marine product, Macrolactin A 1, is described. This 25-membered lactone contains a structurally intriguing architecture. Areas of particular interest are the conjugated (2Z,4E)- and the (8E,10Z)-olefin regions and the (13S,15R)-1,3-diol fragment. Based on the retrosynthetical analyses, the synthesis of the aglycone has been broken down into five key fragments, four of which coincide with the two discussed routes. Several key intermediates are stereoselectively synthesized including (1E,6S)-((1,1-dimethylethyl)dimethylsilyl)oxy-1-tri-n-butylstannyl-1-heptene 16, (5R)-5-(tris(1-methylethyl)silyl)oxyhexyl phenyl sulfone 66, and (5R)-5-((1,1-dimethylethyl)-dimethylsilyl)oxyhexyl phenyl sulfone 14. En route to exploring this synthesis, new, bifunctional 1,3-diol synthons were developed. Specifically, an efficient five step synthesis to each of the four optically pure diastereomers of (S$\rm\sb{R}$)-4,5-epoxy-2-hydroxy p-tolyl sulfoxide 34, 35, 42, and 43 is described. The route is based on an initial stereoselective BINAP mediated reduction of ethyl 4-chloroacetoacetic ester and Solladie's stereoselective reduction of $\beta$-ketosulfoxides. The overall yield for these synthons is greater than 70% with diastereomeric excesses greater than 95%. The synthons were shown to open regiospecifically and in practically quantitative yields with higher order cuprates. In particular, 42 was subjected to the butyl, methyl, phenyl, (E)-2-tri-n-butylstannyl ethene, and vinyl higher order cuprates. The application of synthon 35 in the synthesis of Macrolactin A is detailed. A large segment of the aglycone containing the 1,3-diol fragment and the (8E,10Z)-olefin region was constructed in one step and in high yield using the vinyl tellurides, (1Z,3E)-5-((1,1-dimethylethyl)dimethylsilyl)oxy-1,3-pentadienyl butyl telluride 23 or (1Z,3E)-5-(tetrahydropyranyl)oxy-1,3-pentadienyl butyl telluride 22. The ability of these vinyl tellurides to act as (Z)-vinyl nucleophiles and contain a large degree of functionality was paramount to the success of the approach to the target molecule. Further elaboration of the carbon skeleton will combine the key fragments listed above and the key intermediates resulting from the reaction of 35, with 22 and 23.