Enantioselective Total Synthesis and Absolute Configuration Assignment of (+)‐Tronocarpine Enabled by an Asymmetric Michael/Aldol Reaction

Abstract

We present the first asymmetric total synthesis and absolute configuration determination of (+)‐tronocarpine. The [6.5.7.6.6] pentacyclic core was constructed at an early stage by using a sequential cyclization strategy through a newly developed catalytic asymmetric Michael/aldol cascade to build the aza[3.3.1]‐bridged cycle and a tandem reduction/hemiamidation procedure to assemble the seven‐membered lactam. The side‐chain functionalities were incorporated at a late stage by several appropriately orchestrated manipulations under mild conditions. The synthesis of enantiomerically pure (+)‐tronocarpine was achieved through a 20‐step longest linear sequence from tryptamine.

A Divergent Enantioselective Total Synthesis of Post‐Iboga Indole Alkaloids

“…To this end, two synthetic strategies with respect to N 4 ‐C 21 bond forming reactions were devised, featuring the aza‐Michael addition from H to F , and the S N 2′‐type or Tsuji–Trost‐type reaction from I to G, respectively. Finally, simplification of H or I led to the aza‐[3.3.1]‐bridged cycle B which could be prepared by executing our previously established asymmetric Michael/aldol cascade reactions …”

“…Therefore, our investigations commenced with the exploration of the feasibility for the construction of the polycyclic system through the N 4 ‐C 21 bond forming reaction. We first explored the aza‐Michael addition protocol by using racemic enone 16 (Scheme ) as a model substrate, which could be easily prepared from 13 via a three‐step transformation including the TMG‐mediated Michael/aldol reaction, Dess–Martin oxidation, and Pd‐catalyzed oxidative dehydrogenation by modifying the conditions reported by Stahl . Unfortunately, an exhaustive examination based on the conditions reported in literature showed that the reaction was ineffective.…”

“…In early 2019, a semi‐synthesis of (+)‐dippinine B (ent‐ 3 ), the enantiomer of the naturally occurring (−)‐dippinine B, from the iboga (+)‐catharanthine ( 12 ) was reported . Very recently, we successfully realized the asymmetric total synthesis and absolute configuration determination of the naturally occurring (+)‐tronocarpine ( 10 ), which represents the first example of the total synthesis of naturally occurring dippinine‐chippiine alkaloids.…”

“…11 ). Thus, to further exploit the potential application of the new methodology as well as to continue our constant interest in the synthesis of indole natural products, we set the dippinine‐chippiine alkaloids 1 – 9 and 11 as the target for synthesis. One of the major structural differences between the compounds 1 – 9 and our previously synthesized tronocarpine ( 10 ) arises from the skeletal connection of the N‐containing seven‐membered ring.…”

Concise Total Synthesis of Tronocarpine

“…In 2020, Han and co-workers reported the first asymmetric total synthesis of (+)-1 from tryptamine using elegant reactions. [8] They constructed the azabicyclo- [3.3.1]nonane core by utilizing asymmetric Michael/aldol reactions, and formed the pentacyclic skeleton of 1 in the early stages of the synthesis. The remainder of the carbon side chains were then introduced in the later stages under mild conditions to avoid unexpected side reactions.…”