ABSTRACT
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.
Subject(s)
Biphenyl Compounds/chemical synthesis , Cathepsins/antagonists & inhibitors , Hydrocarbons, Fluorinated/chemistry , Protease Inhibitors/chemical synthesis , Alcohols/chemistry , Biphenyl Compounds/chemistry , Cathepsin K , Esters/chemistry , Hydrolysis , Protease Inhibitors/chemistry , Stereoisomerism , Substrate SpecificityABSTRACT
[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.
Subject(s)
Bridged Bicyclo Compounds/chemical synthesis , Hexanes/chemical synthesis , Receptors, Metabotropic Glutamate/agonists , Bridged Bicyclo Compounds/chemistry , Chromatography, High Pressure Liquid , Hexanes/chemistry , Indicators and Reagents , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , StereoisomerismABSTRACT
[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.
Subject(s)
Amides/chemical synthesis , Combinatorial Chemistry Techniques , Palladium/chemistry , Tosyl Compounds/chemistry , Molecular StructureABSTRACT
[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.
Subject(s)
Amines/chemistry , Hydrogen/chemistry , Imines/chemistry , Nitrogen/chemistry , Catalysis , Hydrogen/metabolism , Hydrogen Bonding , Nitrogen/metabolism , Oxidation-Reduction , StereoisomerismABSTRACT
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.
Subject(s)
Imidazoles/chemical synthesis , Integrin alphaVbeta3/antagonists & inhibitors , Naphthyridines/chemical synthesis , beta-Alanine/analogs & derivatives , Catalysis , Cyclization , Molecular Structure , Stereoisomerism , beta-Alanine/chemical synthesisABSTRACT
[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.
ABSTRACT
[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.
