Total synthesis of cruentaren B

Abstract

A convergent total synthesis of the cytotoxic natural product cruentaren B is completed in 26 steps (longest linear sequence) with an overall yield of 7.1%. For the construction of the C₁-C₁₁ benzolactone fragment of the molecule, the key steps used were O-methylation, using a Mitsunobu reaction, a Stille coupling method to construct the C₇-C₈ bond, and a Brown's asymmetric crotylboration reaction for the direct enantioselective installation of the two chiral centers present in this fragment. For diastereoselective installation of the chiral centers in the C₁₂-C₂₀ polyketide fragment, an Evans syn aldol reaction on a chiral aldehyde, derived from methyl (R)-3-hydroxyl-2-methylpropionate, and subsequently a Mukaiyama aldol reaction were employed. For the construction of the C₂₁-C₂₈ tail, a "non-Evans" syn aldol reaction was used. The three fragments were coupled by an S_N2 reaction and a Wittig olefination reaction followed by standard functional group manipulations to furnish the target molecule.