Total Synthesis of (−)-Batrachotoxinin A: A Local-Desymmetrization Approach

Abstract

An enantioselective total synthesis of (−)-batrachotoxinin A is accomplished based on a key photoredox coupling reaction and the subsequent local-desymmetrization operation. After the expedient assembly of the highly oxidized steroid skeleton, a delicate sequence of redox manipulations was carried out to deliver a late-stage intermediate on gram scaleand ultimately (−)-batrachotoxinin A in an efficient manner.

Strategic Use of Visible-Light Photoredox Catalysis in Natural Product Synthesis

“…It seems assured that the impact of visible-light photocatalysis on the synthesis of structurally elaborate molecules will only increase in the future. Uniting photocatalysis with other diverse catalytic cycles holds enormous potential, beyond the merged organocatalysis ,, and Ni catalysis sequences that are exemplified in syntheses reviewed here. Further progress in addressing the long-standing challenge in radical-based bond constructions, controlling enantioselectivity, will certainly continue to emerge. − One promising approach for controlling enantioselectivity in photoredox reactions involves the use of asymmetric photosensitizers, which has been demonstrated in methods by the Meggers group with bis-cyclometalated rhodium­(III) complexes and recently by Yoon and co-workers with a chiral iridium photosensitizer …”

“…A third total synthesis of (−)-batrachotoxinin A ( 100 ) was reported last year by the Luo group (Scheme ). In this concise synthesis, a key C–C σ-bond and the quaternary carbon of the steroidal C ring were formed by photoredox-catalyzed coupling of a primary α-acyl radical with an enamine intermediate. The synthesis begins with the cis -decalin derivative 101 , an intermediate in Du Bois’s earlier synthesis of 100 .…”

Synthesis of Difluorinated Halohydrins by the Chemoselective Addition of Difluoroenolates to α-Haloketones

“…The tertiary alcohol and secondary chloride on the product 22 display a syn-relationship. This stereochemical configuration is assigned by 1 H NMR data in which the proton of the chloromethylene group (i.e., 4.45 ppm) displays coupling constants of J ax-ax = 10.9 Hz and J ax-eq = 5.2 Hz that support an axial−axial and axial− equatorial coupling, respectively. Analysis of the 1 H− 1 H 2D NOESY and 1 H− 19 F 2D HOESY NMR data also support this assignment.…”

“…The α-halocarbonyl group is an essential building block for assembling complex natural products , and creating other valuable organic structures. − Notable examples of the utility of the α-halocarbonyl group appeared in the total synthesis of batrachotoxin A and palau’amine . This functional group presents two electrophiles, and a typical goal of methodology development is the chemoselective manipulation of the carbonyl group ,, or the halogen. − Although the reactivity of many nucleophiles has been investigated with the α-halocarbonyl group, fluorinated nucleophiles have not been explored with this functionality.…”

“…T he α-halocarbonyl group is an essential building block for assembling complex natural products 1,2 and creating other valuable organic structures. 3−8 Notable examples of the utility of the α-halocarbonyl group appeared in the total synthesis of batrachotoxin A 1 and palau'amine.…”