Enantioselective Total Synthesis of (−)-Misramine

Abstract

The enantioselective total synthesis of an unusual pentacyclic proaporphine alkaloid, (-)-misramine, was achieved. The synthetic strategy relied on an enantioselective intramolecular Friedel-Crafts-type 1,4-addition using an asymmetric organocatalyst to construct a spiroindane skeleton containing an all-carbon quaternary stereocenter and a double reductive amination of the keto-aldehyde to form a piperidine ring toward the end of the synthesis. This work is the first example of asymmetric synthesis of a proaporphine alkaloid.

Enantioselective Total Synthesis of Pentacyclic Proaporphine Alkaloid (−)‐Misramine

“…The structures and relative stereochemistry of these two alkaloids were determined by NMR spectroscopy, and further confirmed via enantioselective total synthesis by Yoshida and Takao et al. in 2018 [4] . The synthesis represents the only total synthesis of pentacyclic proaporphine alkaloids, in which an organocatalyzed asymmetric intramolecular Friedel‐Crafts‐type 1,4‐addition was used as the key step for the construction of the spirocyclic structure, and (−)‐misramine was synthesized in 24 steps with 2.0% overall yield from commercially available 2,4,6‐tribromoanisole.…”

Recent Applications of Asymmetric Organocatalytic Methods in Total Synthesis

“…In 2018, Yoshida, Takao, and co‐workers reported an enantioselective total synthesis of (−)‐misramine ( 289 , Scheme 31). [58] They established an organocatalytic intramolecular Friedel‐Crafts‐type Michael addition of cyclohexenone‐resorcinol derivative 281 using cinchonine‐derived amine 282 as the catalyst to obtain the spiroindane skeleton 283 , which served as the key intermediate for the total synthesis. Further synthetic maneuvers afforded eventually (−)‐misramine ( 289 ) via a multistep sequence (Scheme 31).…”

“…Further synthetic maneuvers afforded eventually (−)‐misramine ( 289 ) via a multistep sequence (Scheme 31). [58] …”

“…Further synthetic maneuvers afforded eventually (À )-misramine (289) via a multistep sequence (Scheme 31). [58] In 2017, Kádas and co-workers reported an enantioselective total synthesis of (À )-trans-dihydronarciclasine (296) starting from a simple organocatalytic Michael addition of nitromethane (164) to butenone derivative 290, using a quininederived amine (291) as the catalyst (Scheme 31). [59] The reaction led to the formation of nitropentanone derivative 292, which was extensively elaborated to afford the natural product (À )trans-dihydronarciclasine (296, Scheme 32).…”

Evolutionary chemical space exploration for functional materials: computational organic semiconductor discovery

“…21 Solid-state electron affinities were approximated from calculated gas phase adiabatic electron affinities by taking advantage of the known linear correlation between the two quantities. 22,23 The relationship was calibrated for 12 molecules against experimental lowenergy inverse photoemission spectroscopy (LEIPS) values for thin-lms organic semiconductors; see ESI † for details.…”