Total Synthesis of (−)-Actinophyllic Acid Enabled by a Key Dual Ir/Amine-Catalyzed Allylation

Abstract

A synthetic strategy for the catalytic asymmetric total synthesis of (-)-actinophyllic acid is described. This highly efficient and enantioselective approach allows the rapid installation of the four contiguous chiral centers (C16, C15, C20, and C19) by way of a dual Ir/amine catalytic allylation of 2-indolyl vinyl carbinol 6 and an aldol reaction of resultant chiral aldehyde 4a with 2-pyrrolidinone 5. The key indol-3-ylmethanamine moiety and 1-azabicyclo[4.2.1]nonane ring system were readily generated through a selective Mannich-like cyclization and an intramolecular N-alkylation, respectively.

Preparation of Stereodefined 2-(3-Oxoindolin-2-yl)-2-Arylacetonitriles via One-Pot Reaction of Indoles with Nitroalkenes

“…1 H -Indole-2-acetic acid derivatives with stereogenic center at C-2′ are omnipresent in nature, representing several classes of indoline alkaloids − with important biological properties. Compounds of this type serve as important synthetic intermediates in the preparation of natural products and non-natural biologically active compounds. − It is not surprising that these compounds remain the focus of attention of many research groups all around the world, while selective methods for their preparation are exceedingly desirable. We have recently described a highly diastereoselective route toward 4′ H -spiro­[indole-3,5′-isoxazoles] ( 3 ) proceeding via unusual formal [4 + 1] cycloaddition reaction involving a nitroalkene ( 2 ) as a 1,4-CCNO dipole and the nucleophilic C-3 of an indole ( 1 ) as the dipolarophilic C 1 moiety (Scheme ).…”

Catalytic, Enantioselective Formal Synthesis of Monoterpene Indole Alkaloid (−)-Alstoscholarine

“…At this point, we conjectured that indole 4 and its hemiaminal ring-opened precursor indole 5 could in turn be prepared by functional operation of the indole derived, chiral aldehyde 6 . Accordingly, aldehyde 6 could be generated from 3-indolyl vinyl carbinol derivative 7 and aldehyde 8 through our recent methodology, which stemmed from Carreira’s original work on the Ir-amine dual catalyzed asymmetric allylation. , …”

Direct Conversion of 3-(2-Nitroethyl)-1H-Indoles into 2-(1H-Indol-2-yl)Acetonitriles

“…This reaction was repeated in a preparative scale and, after isolation and purification, afforded the target nitrile in 72% yield. Further optimization attempts were unproductive and led to a decreased product yield (entries [15][16][17][18][19][20].…”

“…Derivatives of 1H-indole-2-acetic acid are common, naturally occurring indoline alkaloids with important bioactivities [1][2][3][4][5][6][7][8][9][10]. These compounds were used as key intermediates in total syntheses of several natural products and nonnatural pharmaceutical agents [11][12][13][14][15][16][17]. Thus, synthetic methods for selective preparation of these 1H-indole derivatives remain the focus of many research groups.…”