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.
Highlights
Podophyllotoxin is probably the most prominent representative of lignan natural products
The reaction can be conducted on 2 g scale, and the enzyme allows tailoring of the initial, “natural” structure and transforms various nonnatural derivatives
While significant efforts have been dedicated to cytochrome P450 monooxygenases (CYPs),[3] 2-oxoglutaratedependent dioxygenases (2-ODDs) have gained rather moderate attention far.[4]
Summary
Reaction conditions: Cell-free extract (CFE, 44 v %), 20 mm substrate, 2-oxoglutarate (1.75 equiv), sodium ascorbate (3 equiv), 23 % DMSO as cosolvent. [a] Determined by peak area integration of the HPLC-UV chromatogram (at 215 nm). [b] Yields of isolated, chromatographically pure, and fully characterized products are reported; [c] ee was determined via HPLC-UV on a chiral stationary phase (for details see the Supporting Information). [d] With 37 % of diastereoisomer 3. [e] 20 % of compound 3 were isolated from the same batch; [a]D20 values for 11 a and 3 are in full consistency with literature values.[24] [f ] The experiment was conducted on 50 mg substrate scale. The enzyme overrides the substrate-controlled stereopreference for the ring formation.[18a] The diastereomeric mixture complicated the purification process, and pure products were obtained only by preparative HPLC. These results encouraged us to challenge the biocatalyst with a substrate congener with an additional chiral center, such as the hydroxy group present in podophyllotoxins northern benzylic position (Figure 1). Kinetic measurements imply that the reaction occurs over two to four hours only (see Tables S13 a and S13 b in the Supporting Information; the upscale experiment was performed for 16 h) This leads to a space–time yield of 1.6–0.8 g LÀ1 hÀ1 for the analytical scale, and we assume that similar numbers can be obtained in upscale experiments. Preparation of podophyllotoxin (1) from its epi-congener 10 b
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
