Asymmetric Total Synthesis of (–)‐Gracilamine Using a Bioinspired Approach

Abstract

The asymmetric total synthesis of optically pure (–)‐gracilamine (1) was achieved by employing a bioinspired approach. The strategy involved elaboration of 3a‐arylhexahydroindole 7, a designed precursor, to 3a‐formylarylhexahydroindole 5, which upon heating with l‐leucine ethyl ester gave (–)‐1 efficiently.

Dearomative logic in natural product total synthesis

“…291 Gao's 2014 synthesis forged this critical asymmetric carbon center through photo-Nazarov cyclization ( 240 → 241 ), 292 while a 2016 formal synthesis from Snyder utilized an intramolecular [4 + 2]/ retro -[4 + 2] cycloaddition of a pyrone ( 242 → 243 ). 293 More exotic strategies from Yu (formal synthesis, 2016), 294 Pandey (2017), 295 and Banwell (2017) 296 construct this stereocenter through Rh-catalyzed [3 + 2 + 1] cycloaddition ( 244 → 245 ), ring opening of an aza-norbornene derivative ( 246 → 247 ), and Pd-catalyzed intramolecular Alder-ene reaction ( 248 → 249 ), respectively. In 2017, Zhou and Xie published a notable semisynthesis of (+)-gracilamine from a crinine derivative that proceeds through oxidative cleavage, Schiff-base formation with l -leucine, and intramolecular 1,3-dipolar cycloaddition, lending strong support to the proposed biosynthesis.…”

“…Although only a recent addition to the family of Amaryllidaceae alkaloids, the rare pentacyclic dinitrogenous base gracilamine (200)-isolated in 2005-has been the subject of no fewer than eight synthetic efforts within the past ten years. [290][291][292][293][294][295][296][297][298] The intriguing structure of gracilamine is proposed to derive biosynthetically from (+)-epicrinine (235, Fig. 27).…”

Diversity-Oriented Approach Toward the Syntheses of Amaryllidaceae Alkaloids via a Common Chiral Synthon

“…Based upon our previous experiences of building natural products by utilizing the chiral ketone scaffold 2 , we sought to exploit it to design a retrosynthetic route to the common divergent intermediate 1 , which is outlined in Scheme . We planned to build the requisite hydroindole moiety from selective ring opening of aryl-substituted sterically congested 7-azabicyclo heptenesulfone followed by an intramolecular amination reaction.…”

“…We planned to build the requisite hydroindole moiety from selective ring opening of aryl-substituted sterically congested 7-azabicyclo heptenesulfone followed by an intramolecular amination reaction. The strained bicyclic framework plays an interesting role in controlling the stereoselectivity by allowing the nucleophile to attack only from the exo -face, while blocking the endo -face . This reaction serves as a boon for the synthetic design as it fixes the stereochemistry of the crucial quaternary center in the early stages of the synthesis.…”

“…The bicyclic core 1B synthesized from ( − ) -2 represents a versatile precursor for many of the Amaryllidaceae alkaloids including the structurally complex dinitrogenous pentacyclic cage like alkaloid (−)-gracilamine, which was synthesized in 6 steps from this advanced intermediate . Alkaloids (−)-crinine ( 3 ) and (−)-amabiline ( 4 ) were synthesized from 1B via N-Boc deprotection followed by Pictet–Spengler type cyclization using formic acid and paraformaldehyde, obtaining 19 in a high yield (95%) .…”