The assignment of two stereocenters of the natural product haprolid through the application of a profile hidden Markov model (HMM) and its confirmation through total synthesis of the natural product and of two of its diastereomers are reported. The structure elucidation of this polyketide-peptide hybrid natural product is a telling showcase of how difficult it can be to determine the absolute configuration of isolated stereocenters and the benefits of a gene cluster analysis for structure determination. The key steps of the synthesis are a selective epoxidation of a terminal olefin and the stereodivergent macrolactonization strategy. Furthermore, the biological evaluation of all products showed that all diastereomers are potent inhibitors of hepatocellular carcinoma cell lines.

A bisvinylogous Mukaiyama aldol reaction using oxazaborolidinones as a source of chirality was developed. This methodology allows the fast assembly of conjugated dienols by expanding the vinylogy principle by two additional carbons, and can be conducted using a readily available Lewis acid at reasonable reaction times. A broad range of aromatic and aliphatic aldehydes can be used providing access to complex building blocks for polyketide synthesis.

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