Chemoenzymatic Total Synthesis of Deoxy-, epi-, and Podophyllotoxin and a Biocatalytic Kinetic Resolution of Dibenzylbutyrolactones

Abstract

Podophyllotoxin is probably the most prominent representative of lignan natural products. Deoxy-, epi-, and podophyllotoxin, which are all precursors to frequently used chemotherapeutic agents, were prepared by a stereodivergent biotransformation and a biocatalytic kinetic resolution of the corresponding dibenzylbutyrolactones with the same 2-oxoglutarate-dependent dioxygenase. The reaction can be conducted on 2 g scale, and the enzyme allows tailoring of the initial, "natural" structure and thus transforms various non-natural derivatives. Depending on the substitution pattern, the enzyme performs an oxidative C-C bond formation by C-H activation or hydroxylation at the benzylic position prone to ring closure.

Keywords: 2-oxoglutarate-dependent dioxygenases; biocatalysis; lignans; podophyllotoxin; total synthesis.