A concise asymmetric route for the synthesis of a novel class of glucocorticoid mimetics containing a trifluoromethyl-substituted alcohol.
An asymmetric route was developed for the synthesis of a class of novel glucocorticoid receptor ligand derivatives 1. The key step of this synthesis involves a diastereoselective addition of chiral sulfoxide anion to a trifluoromethyl ketone precursor. The resulting diastereomers are readily separable and can be converted to the corresponding chiral epoxide and chiral alkyne intermediates (2 and 3). This sequence of reactions is suitable for large-scale preparation of these chiral intermediates and derivatives of 1. The absolute stereochemistry of the biologically active enantiomer of these GR ligands has also been determined.
Lee
Thomas W
TW
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA. tlee2@rdg.boehringer-ingelheim.com
Proudfoot
John R
JR
Thomson
David S
DS
D000438:Alcohols / Q000737:chemistry* / Q000494:pharmacology; D000480:Alkynes / Q000737:chemistry; D018360:Crystallography, X-Ray; D005466:Fluorocarbons / Q000737:chemistry* / Q000494:pharmacology; D005938:Glucocorticoids / Q000138:chemical synthesis* / Q000494:pharmacology; D008024:Ligands; D008956:Models, Chemical; D018716:Molecular Mimicry; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D013237:Stereoisomerism
D000438:Alcohols; D000480:Alkynes; D005466:Fluorocarbons; D005938:Glucocorticoids; D008024:Ligands; D011965:Receptors, Glucocorticoid