Mimicking Noncanonical Oxidations with Redox-Neutral Photocatalysis

Abstract

Noncanonical oxygenases are a family of Fe-containing enzymes that catalyze oxidative radical cyclizations. Despite creating key structural features that often define a natural product's complexity, the mechanisms of these oxidations remain poorly understood and difficult to mimic. In this work, we show that noncanonical cyclizations from lignan biosynthesis can be recreated when presumed biosynthetic radicals are generated using photocatalysis. These conditions afford the ensuing electron rich radicals sufficient time to undergo challenging 5-or 11-membered ring formation that create the defining structural features of the highly oxidized lignans taiwankadsurins A, B and kadsuphilin N. By showing that these cyclizations can occur without enzymatic assistance, we provide a more general strategy for mimicking noncanonical transformations that should broaden their use in organic synthesis. Scheme 2. (A) Biosynthetic hypothesis for 1-3 via noncanonical oxidation. (B) Previous studies of the 5-membered spirocyclization. (C) This work: mimicking biosynthetic noncanonical oxidations using photoredox catalysis.While there has not been a total synthesis of an oxidized DBCOD family member, there have been three studies examining the 5-membered spirocyclization (Scheme 2B). A radical mechanism consists of a stereoelectronically allowed 5-exo-trig cyclization, but requires a nucleophilic carbon centered radical to add to an electron rich aromatic ring. This is an uncommon, polarity mismatched radical addition 19,21 that was investigated by Whiting and coworkers in 1998. 22 Using Barton's conditions for the generation of the phenoxy-methyl radical and a 2,4-dinitro Scheme 3. Retrosynthetic analysis for the atroposelective biaryl bond formation.Our syntheses of 16 and 17 began by a 4-step preparation of (E)-Cy 2 B-enolate 25, in which the benzylic stereocenter at C6 (DBCOD numbering) was set in 93% ee using North's catalytic asymmetric hydrocyanation (Scheme 4A). 31 This stereocenter was then used to control the ensuing anti-aldol (TS-I) with good 1, 3-syn-induction (20:1 dr) to provide 27 in 66% yield and high enantiopurity (>99% ee) following recrystallization on 13 g scale. Tertiary alcohol 28 was then prepared under Bartoli's conditions in a 70% yield with 3:1 diastereoselectivity on 14 g scale by pseudo-axial addition of a methyl nucleophile to the 6-membered titanium chelate (TS-II). 32 In preparation for the ensuing biaryl bond formation, we installed a cyclic borinic ester to tether the C9-alcohol over a two-step sequence, and then selectively deprotected the phenol to direct halogenation at C16. 33 The ensuing intramolecular Suzuki coupling was then catalyzed by Buchwald's SPhos Pd G2 pre-catalyst 34 in conjunction with additional ligand and potassium phosphate (K 3 PO 4 ) to afford 30 in 87% yield on 6 g scale. Given the well-documented challenges of forming tetrasubstituted biaryl bonds stereoselectively, 28 the efficiency of these conditions is noteworthy. We believe that the (P)-configuration of the chiral axis r...