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Catalytic Asymmetric Total Synthesis of Macrocyclic Marine Natural Product (–)‐Haliclonin A †
Author(s) -
Luo ShiPeng,
Huang XiongZhi,
Guo LianDong,
Huang PeiQiang
Publication year - 2020
Publication title -
chinese journal of chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.28
H-Index - 41
eISSN - 1614-7065
pISSN - 1001-604X
DOI - 10.1002/cjoc.202000291
Subject(s) - chemistry , enone , enantioselective synthesis , stereocenter , total synthesis , alkene , moiety , nucleophile , allene , stereochemistry , metathesis , intramolecular force , catalysis , organic chemistry , polymer , polymerization
Summary of main observation and conclusion We describe the full details of our total synthesis of haliclonin A, a macrocyclic natural product suggested to originate from a common biosynthetic intermediate as sarain A. Central to our synthetic route is the strategic employment of nitromethane for several purposes: (1) as an umpolung surrogate of an aminomethyl group; (2) as an ideal nucleophile for the highly enantioselective catalytic asymmetric conjugate addition to forge the challenging all‐carbon quaternary stereogenic center that was used to induce the formations of all other chiral centers of the molecule; and (3) as a C 1 N 1 building block to form the 3‐azabicyclo[3.3.1]nonane framework. The realization of this strategy relied on the development of a novel organocatalytic asymmetric conjugate addition of nitromethane to 3‐alkenyl cyclohex‐2‐enone, and the first Pd‐promoted intramolecular coupling of a thiocarbamate moiety onto an electron‐deficient alkene (enone) to form the 3‐azabicyclo[3,3,1]nonane core. The synthesis also features a SmI 2 ‐mediated intermolecular reductive coupling of an enone with an aldehyde, ring‐closing alkene and alkyne metathesis reactions to build the two aza‐macrocycles, and an unprecedented direct transformation of enol into enone.