A practical enantioselective synthesis of odanacatib, a potent Cathepsin K inhibitor, via triflate displacement of an alpha-trifluoromethylbenzyl triflate.

An enantioselective synthesis of the Cathepsin K inhibitor odanacatib (MK-0822) 1 is described. The key step involves the novel stereospecific S(N)2 triflate displacement of a chiral alpha-trifluoromethylbenzyl triflate 9a with (S)-gamma-fluoroleucine ethyl ester 3 to generate the required alpha-trifluoromethylbenzyl amino stereocenter. The triflate displacement is achieved in high yield (95%) and minimal loss of stereochemistry.

Stereoselective syntheses of highly functionalized bicyclo[3.1.0]hexanes: a general methodology for the synthesis of potent and selective mGluR2/3 agonists.

[Chemical reaction: See text] A Et3Al mediated intramolecular epoxide opening, cyclopropanation reaction is described. The transformation provided highly functionalized bicyclo[3.1.

Preparation of enamides via palladium-catalyzed amidation of enol tosylates.

[reaction: see text] A Pd-catalyzed coupling of enol tosylates and amides has been developed. Ligand screening revealed dipf as the most general ligand for this transformation. A variety of enol tosylates were coupled to an array of enamides in 58-97% yield.

Unprecedented catalytic asymmetric reduction of N-H imines.

[Reaction: see text] Addition of lithium bis(trimethylsilyl)amide to perfluorinated ketones 1a-j affords (E)-N-TMS-ketimines 2a-j that are reduced in situ to afford racemic perfluoromethylated amine hydrochloride salts 3a-j in 54-97% yields. Solvolysis of the N-Si bond in MeOH leads to formation of bench-stable, isolable N-H imine Z/E isomer mixtures along with a methanol adduct. Enantioselective reduction of these three-component mixtures provides the first catalytic asymmetric synthesis of trifluoromethylated amines in 72-95% yields and 75-98% ee.

An efficient synthesis of an alphavbeta3 antagonist.

A practical preparation of an alpha(v)beta(3) antagonist is reported. The antagonist consists of three key components, a tetrahydronaphthyridine moiety, a beta-alanine moiety, and a central imidazolidone moiety. The tetrahydronaphthyridine component was prepared using two different methods, both of which relied on variations of the Friedländer reaction to establish the desired regiochemistry.

Oxazolidine ring opening and isomerization to (E)-imines. Asymmetric synthesis of aryl-alpha-fluoroalkyl amino alcohols.

[reaction: see text] A base-induced ring opening/imine isomerization/diastereoselective organometallic addition sequence on 4-substituted 2-perfluoroalkyl-1,3-oxazolidines has been developed for the asymmetric synthesis of aryl alpha-perfluoroalkylamine derivatives. This practical method provides chiral amino alcohols in 60-95% yield with uniformely high diastereoselectivities ranging from 35:1 to >100:1.

Palladium-catalyzed amidation of enol triflates: a new synthesis of enamides.

[reaction: see text] The palladium-catalyzed coupling of a range of enol triflates with amides, carbamates, and sulfonamides has been developed. This offers a simple and widely applicable synthesis of enamides, which may not be readily available by other means.