The power of visual imagery in synthesis planning. Stereocontrolled approaches to CGP-60536B, a potent renin inhibitor.
Two strategies were developed toward the stereocontrolled synthesis of 8-aryl-3-hydroxy-4-amino-2,7-diisopropyloctanoic acids with predetermined stereogenic centers. This is a generic motif in a new class of potent inhibitors of the enzyme renin, exemplified by CGP-60536B. The synthesis relies on the utilization of L-pyroglutamic acid as chiron, and proceeds through the incorporation of required functionality by exploiting internal induction. One of the strategies shows the power of visual imagery in synthesis planning, akin to a Dali-like representation of objects that can be viewed in more than one way. Thus, the entire carbon skeleton of the target molecule is encompassed in a partially functionalized bicyclic indolizidinone precursor. In a second strategy, an intermediate common to the first approach is elaborated into an appended gamma-lactone which is alkylated through enolate chemistry and ultimately transformed into the intended target compound. X-ray crystallography was used to corroborate the structures and stereochemistries of several intermediates.
Hanessian
Stephen
S
Department of Chemistry, Université de Montréal, C.P. 6128, Succursale Centre-ville, Québec H3C 3J7, Canada. stephen.hanessian@umontreal.ca
Claridge
Stephen
S
Johnstone
Shawn
S
D000478:Alkylation; D000840:Anisoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006639:Histidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000840:Anisoles; D004151:Dipeptides; D004791:Enzyme Inhibitors; D006639:Histidine; D007093:Imidazoles; D009025:Morpholines; D009842:Oligopeptides; D000092502:Renin Inhibitors; C410082:CGP 60536; C056622:enalkiren; C060150:CGP 38560; C083010:FK 906; C065581:remikiren