Divergent enantioselective synthesis of hapalindole-type alkaloids using catalytic asymmetric hydrogenation of a ketone to construct the chiral core structure

Abstract

A divergent enantioselective approach to hapalindole-type alkaloids featuring a ruthenium-catalyzed asymmetric hydrogenation and a switchable sequence of methylation and acetylation/aldol reaction is described.

Enantiospecific Total Syntheses of (+)‐Hapalindole H and (−)‐12‐epi‐Hapalindole U

“…Syntheses of hapalindole K, A and G were also achieved by the Johnston group . Very recently Zhou and co‐workers reported total syntheses of (+)‐hapalindole Q and (+)‐12‐ epi ‐fischerindole U isothiocyanate using the dynamic kinetic resolution (DKR) method . Here, we report the first enantiospecific total synthesis (Figure ) of (+)‐hapalindole H and (−)‐12‐ epi ‐hapalindole U…”

“…Ent ‐ketone 33 was prepared using same synthetic sequence starting from ( S )‐limonene. Ketone 33 and its enantiomer were converted in five steps to (+)‐hapalindole Q ( 6 ) and (+)‐12‐ epi ‐fischerindole U isothiocyanate ( 9 ), respectively, by Zhou and co‐workers . Thus, this constitutes the formal synthesis of these two natural products (Scheme ).…”

A Three-Step Process to Facilitate the Enantioselective Assembly of Cis-Fused Octahydrophenanthrenes with a Quaternary Stereocenter

“…12 However, since Muratake et al 13 reported the first example for the racemic synthesis of cis-fused octahydrophenanthrenes bearing a quaternary stereocenter using the palladium-catalyzed intramolecular enolate arylation of secondary aldehydes with aryl bromides in 1999, there have been no reports of enantioselective constructing such cis-fused tricyclic scaffolds using this efficient quaternary stereocenter-forming method. Motivated by the recent work done on the development of highly efficient asymmetric ketone hydrogenations for the synthesis of bioactive natural products, 14 we have therefore embarked on a program aimed at addressing the challenges of enantioselective constructing cis-fused octahydrophenanthrene scaffolds bearing an all-carbon quaternary stereocenter. Herein, we describe our efforts toward this challenge through a threestep process involving an iridium-catalyzed asymmetric hydrogenation to create C5-stereocenter and a palladium-catalyzed intramolecular enolate arylation to install the all-carbon quaternary stereocenter (Figure 1c).…”

Asymmetric Transfer Hydrogenation of 2,3-Disubstituted Flavanones through Dynamic Kinetic Resolution Enabled by Retro-Oxa-Michael Addition: Construction of Three Contiguous Stereogenic Centers

“…Asymmetric (transfer) hydrogenation of multiple substituted ketones has been regarded as a promising method to synthesize functional chiral alcohol derivatives using transition-metal catalysts. 12,13 Recently, our group observed that 2,3-disubstituted flavanones are easy to proceed retro-oxa-Michael addition 14 under basic conditions, leading to racemization of two stereocenters simultaneously. Then, a palladium-catalyzed asymmetric allylic alkylation with this strategy was achieved, constructing chiral flavanone derivatives with two contiguous stereocenters (including a quaternary stereogenic center).…”