RESUMEN
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. The overall synthesis of 1 is completed in 6 steps in 61% overall yield.
Asunto(s)
Compuestos de Bifenilo/síntesis química , Catepsinas/antagonistas & inhibidores , Hidrocarburos Fluorados/química , Inhibidores de Proteasas/síntesis química , Alcoholes/química , Compuestos de Bifenilo/química , Catepsina K , Ésteres/química , Hidrólisis , Inhibidores de Proteasas/química , Estereoisomerismo , Especificidad por SustratoRESUMEN
[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.
Asunto(s)
Amidas/síntesis química , Técnicas Químicas Combinatorias , Paladio/química , Compuestos de Tosilo/química , Estructura MolecularRESUMEN
[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.
Asunto(s)
Aminas/química , Hidrógeno/química , Iminas/química , Nitrógeno/química , Catálisis , Hidrógeno/metabolismo , Enlace de Hidrógeno , Nitrógeno/metabolismo , Oxidación-Reducción , EstereoisomerismoRESUMEN
[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.
RESUMEN
[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.
RESUMEN
[Chemical reaction: See text] A Et3Al mediated intramolecular epoxide opening, cyclopropanation reaction is described. The transformation provided highly functionalized bicyclo[3.1.0]hexane systems in high efficiency and with perfect H or F endo selectivity. Application of this reaction to the synthesis of mGluR2/3 agonist 1 (43% overall yield) and a few intermediates suitable for the synthesis of other bicyclo[3.1.0]hexane mGluR2/3 agonists is discussed.
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Hexanos/síntesis química , Receptores de Glutamato Metabotrópico/agonistas , Compuestos Bicíclicos con Puentes/química , Cromatografía Líquida de Alta Presión , Hexanos/química , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , EstereoisomerismoRESUMEN
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. The beta-alanine component was prepared using Davies' asymmetric 1,4-addition methodology as the key stereo-defining step. The central imidazolidone portion was created from these two components using an effective three-step cyclization protocol. Thus, a highly convergent process for the drug candidate was defined.