Total Synthesis of Actinophyllic Acid

Abstract

Herein we report at otal synthesis of the indolohydroazocine natural product actinophyllic acid. The target molecule was retrosynthetically deconvoluted to render ag reatly simplified and symmetrical [4.4.1] bicyclic trienone, the desymmetrization of which was carefully examined under av ariety of conditions,i ncluding oxidative,r eductive,a nd transition-metal-catalyzed transformations.U ltimately,t he successful synthetic strategy featured chemoselective catalytic dihydroxylation, desymmetrizing nitrile oxide dipolar cycloaddition, and palladium-catalyzed aminoarylation to sequentially modify the three olefins within the trienone,followed by al ate-stage reductive cascade indolization and alkylation to complete the target molecule. Scheme 1. a) Selected recent examples of desymmetrization in targetoriented synthesis. b) Use of the [4.4.1] bicyclic trienone 2,w ith aplane of symmetry,a saprecursor to actinophyllica cid (1).

Synthesis and Reactivity of 3‐Halo‐4,5‐dihydroisoxazoles: An Overview

“…One point of strength of the use of the 1,3‐dipolar cycloaddition reaction for the synthesis of 3‐bromo 4,5‐dihydroisoxazoles is represented by the key features of DBF. Besides being a handleable and stable precursor of the 1,3‐dipole, DBF is also cheaply available commercially and can be easily synthesized through a one‐pot reaction, by amination of glyoxylic acid with hydroxylamine, followed by decarboxylation and bromination with Br 2 [38,51,59–62] or NBS [37] . These conditions were also optimized by the use of flow‐chemistry reactors [63] …”

“…This reaction also discriminates between more and less reactive olefins. In particular, BrCNO reacts faster with less substituted alkenes [61,72] . During the reaction, which occurs with a concerted mechanism, the two participants are oriented on two parallel planes in which the three orbitals of the dipole and the two of the dipolarophile are combined in a suprafacial/suprafacial way, leading to the formation of a five‐membered isoxazoline ring with syn substituents from alkene cis groups and anti substituents from trans .…”

“…Thus, 3‐bromo‐Δ 2 ‐isoxazolines are a solid choice for the introduction of these peculiar chemical features. Moreover, these moieties have been recently exploited for the total synthesis of different natural products [60,61,66,67,108,113] …”

“…This reaction sequence has been successfully employed with complete regio‐ and stereo‐chemical control for the total synthesis of Pallambin A and B [67] and (−)‐Cocaine [113] (Scheme 17A, 17B). Moreover, throughout the synthesis of Actinophyllic acid [61] (Scheme 17C), the 3‐bromo‐Δ 2 ‐isoxazoline core is inserted with high regioselectivity and giving a single stereoisomer with high yield. Then, the bromine atom is replaced with a methoxy feature by treatment with MeOLi/MeOH, and the 5‐membered nucleus is subsequently oxidized by DDQ to 3‐methoxyisoxazole.…”