Application of conformation design in acyclic stereoselection: total synthesis of borrelidin as the crystalline benzene solvate.
The total synthesis of (-)-borrelidin (treponemycin), a structurally distinct 18-membered macrolide antibiotic, has been achieved. It was isolated as the crystalline benzene solvate, and its structure was confirmed by a single-crystal X-ray analysis. The deoxypropionate subunit consisting of four alternating C-methyl groups with a C(4)-C(10) syn/syn/anti orientation was elaborated by a new method of iterative cuprate additions to acyclic alpha,beta-unsaturated esters relying on two consecutive 1,3-inductions and starting with d-glyceraldehyde as the chiral progenitor. The unique Z/E cyanodiene unit was obtained as a single isomer by application of the Still-Gennari olefination protocol. The gamma-hydroxycyclopentane carboxylic acid subunit was prepared from L-malic acid utilizing a sequential introduction of C-vinyl and C-allyl groups, capitalizing on 1,2-induction in an acyclic alpha,beta-unsaturated ester and carbocyclization by a Grubbs ring closure metathesis reaction. The prevalence of 1,3-syn-disposed deoxypropionate triads in the cuprate additions is rationalized on the basis of minimized syn-pentane interactions in the transition states. A virtual diamond lattice was used as a visual tool to portray the low-energy conformations of the acyclic substrates, and corroborated by (1)H NMR homodecoupling studies.
Department of Chemistry, Université de Montréal, P.O. Box 6128, Station Centre-ville Montréal, Province of Quebec H3C 3J7, Canada. stephen.hanessian@umontreal.ca
Stephen
S
Hanessian
Yang
Y
Yang
Simon
S
Giroux
Vincent
V
Mascitti
Jianguo
J
Ma
Franck
F
Raeppel
D018360:Crystallography, X-Ray; D003517:Cyclopentanes / Q000737:chemistry; D005233:Fatty Alcohols / Q000138:chemical synthesis*; D008958:Models, Molecular; D008968:Molecular Conformation; D011422:Propionates / Q000737:chemistry; D013237:Stereoisomerism
D003517:Cyclopentanes; D005233:Fatty Alcohols; D011422:Propionates; C005066:borrelidin; C029658:propionic acid