Sequential C-H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11β-HSD-1 Inhibitor

J Am Chem Soc. 2016 Nov 30;138(47):15473-15481. doi: 10.1021/jacs.6b09764. Epub 2016 Nov 17.

Abstract

A concise asymmetric synthesis of an 11β-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C-H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl]2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • Catalysis
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydrogenation
  • Iridium / chemistry
  • Molecular Conformation
  • Palladium / chemistry
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Stereoisomerism

Substances

  • Enzyme Inhibitors
  • Piperidines
  • Iridium
  • Palladium
  • piperidine
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1