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.

Biocatalytic routes to anti-viral agents and their synthetic intermediates

“…379 Recently, both Fuchs et al and Renata et al have independently employed the dioxygenase from Podofyllum hexandrum (2-ODD-PH) to achieve the synthesis of podophyllotoxin itself. 380,381 Multigram scale resolution of racemic hydroxy-yatein (300) through selective conversion of (À)-hydroxy-yatein to epipodophyllotoxin (epi-299) using 2-ODD-PH had been shown by Fuchs and co-workers (Scheme 60B). Subsequent chemical steps furnished podophyllotoxin (299) in 32% overall yield.…”

Enzymatic Kinetic Resolution by Addition of Oxygen

“…In the first, Kroutil and Fuchs reported an impressive large-scale enzymatic kinetic resolution of rac-48 via enantioselective ring-closing C-C bond formation. [95] Although this transformation was shown not to proceed through a hydroxylated intermediate, the authors reported initial results in 10.1002/anie.202011468…”

Asymmetric Chemoenzymatic Synthesis of Podophyllotoxin and Related Aryltetralin Lignans

“…During the preparation of this manuscript, Kroutil, Fuchs and coworkers reported a complementary chemoenzymatic synthesis of deoxypodophyllotoxin, epi-podophyllotoxin and podophyllotoxin via biocatalytic kinetic resolution of racemic dibenzylbutyrolactone precursors. 7 In contrast, our approach establishes the absolute stereochemistry of the dibenzylbutyrolactone precursor at an early stage and does not require a kinetic resolution process to provide the enantioenriched tetracyclic product in the key enzymatic cyclization step. Biosynthetically, podophyllotoxin arises from oxidative dimerization of coniferyl alcohol (7, Figure 1B).…”