Diastereocontrolled Synthesis of Highly Functionalized Spiroketals: Application to the Synthesis of a Precursor of the C-12-C-25 Fragment of Bafilomycin A₁

Abstract

Studies dealing with the diastereoselective installation of nine stereogenic centers of the C-12-C-25 subunit of bafilomycin A₁ 1 are described. A spiroketal precursor has been chosen as a rigid scaffold owing to the central spiro center, the configuration of which is dictated by predictable anomeric effects. A strategy using a previously described anti-Danishefsky condensation of chiral anti-aldehyde 6( O TES) with pentan-2,4-dione bis(trimethylsilyl)ether 7 (M = TMS), followed by an oxalate condensation to the other end of the pentanedione unit, afforded the required spiroketalic enone precursor 24. After generating the C-18 and C-17 centers through an enolate methylation reaction-Luche reduction sequence followed by a Mitsunobu inversion to give 27, the remaining C-16 methyl group was achieved via a hydroxy-directed cyclopropanation-reductive opening sequence to give the fully functionalized C-15-C-25 spiroketal 35. Further elongation at the C-14 center involved a Felkin-Ahn stereocontrolled addition of trimethylsilyl­acetylene followed by a one-pot O-methylation-desilylation, affording the acetylenic subunit 44, ready to be transformed into the vinylstannne required for the subsequent Stille coupling reaction with a C-1-C-11 subunit of bafilomycin A₁. A 15-epi spiroketal intermediate has also been synthesized, as well as various 18-des­methyl analogues for comparative studies.

macrocycles - stereoselective synthesis - aldol reactions - diastereoselectivity - spiro compounds

References

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New address: Jean-Pierre Férézou, IPD-Farma, Avenida Churchill, 129; sl. 1003, CEP 20020-050 - Centro - Rio de Janeiro, RJ, Brazil. E-mail: [e-mail].

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