Expedient Diels-Alder assembly of 4-aryl-4-phenylsulfonyl cyclohexanones

The efficient preparation of 4-aryl-4-phenylsulfonyl cyclohexanones, containing a quaternary sulfone-bearing carbon centre, is described. Their synthesis proceeds in 38-78% overall yield by way of three steps: (i) sulfinate alkylation; (ii) methylenation; and (iii) regioselective Diels-Alder condensation with 2-trimethylsiloxybutadiene. The scope and limitations of the one-pot Mannich-type methylenation described were examined.     

Practical asymmetric synthesis of a gamma-secretase inhibitor exploiting substrate-controlled intramolecular nitrile oxide-olefin cycloaddition

A practical asymmetric synthesis of the gamma-secretase inhibitor (-)-1 is described. As the key transformation, a highly diastereoselective intramolecular nitrile oxide cycloaddition forms the hexahydrobenzisoxazole core of 3 in four operations. Other aspects of the route include a highly stereoselective reduction of an isoxazole to form a cis-gamma-amino alcohol, an efficient chemical resolution, a dianion cyclization to construct a sultam ring, and the alpha-alkylation of a sultam with excellent diastereoselectivity. In each instance, the relative stereochemistry was evolved by way of substrate-based induction with > or = 96% ds. Kilogram quantities of the targeted drug candidate (-)-1 were obtained, without recourse to chromatography, by way of 10 isolated intermediates and in 13% overall yield.     

An efficient one-pot synthesis of annulated pyridines utilising a directed ortho-metallation/transmetallation approach

The ortho-alkylation of Boc-protected aminopyridines with α,ω-dihaloalkanes followed by in situ cyclisation, resulted in the corresponding annulated pyridine derivatives in good to excellent yields. The effect of the alkylating and chelating agents, the transmetallation additives and the directing group was examined.     

Synthesis of a NO-releasing prodrug of rofecoxib

[reaction: see text] A newly developed synthesis of a NO-releasing prodrug of rofecoxib is described. The highly productive process consists of five chemical steps and produces prodrug 1 in an overall 64% yield from commercially available 3-phenyl-2-propyn-1-ol (4). The synthesis is highlighted by the carbometalation reaction of propargyl alcohol 4 to generate the tetrasubstituted olefin core, sulfone acid 2. Additionally, two alternate end-game strategies to prepare NO-COXIB 1 from this intermediate were explored and developed: (1) a convergent synthesis where a bromonitrate side chain is introduced in one step and (2) a two-step sequence that first installs the requisite six-carbon ester side chain followed by chemoselective nitration.     

The conformational bias of aryl, arylsulfonyl geminally substituted tertiary carbon centers: applications in substrate-based stereocontrol

Intramolecular nitrile oxide-olefin cycloaddition to form hexahydrobenzisoxazole 14, which engenders a phenylsulfonyl, 2,5-difluorophenyl geminally substituted carbon substructure, proceeds with up to 99% ds. A rationalization of the high level of substrate-based stereo-induction observed in this and related ketone and acrylonitrile metallohydride reductions, supported by single crystal X-ray crystallography, is presented.     

Practical asymmetric synthesis of aprepitant,a potent human NK-1 receptor antagonist,via a stereoselective Lewis acid-catalyzed trans acetalization reaction

A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations.     

A novel crystallization-induced diastereomeric transformation based on a reversible carbon-sulfur bond formation. Application to the synthesis of a gamma-secretase inhibitor

This paper describes a remarkably efficient process for the preparation of gamma-secretase inhibitor 1. The target is synthesized in only five steps with an overall yield of 58%. The key operation is a highly selective and practical, crystallization-driven transformation for the conversion of a mixture of tertiary benzylic alcohols into the desired sulfide diastereomer with 94:6 dr. This unprecedented process is based upon a reversible carbon-sulfur bond formation under acidic conditions.     

Regioselective synthesis of N-substituted-4-substituted isothiazolidine-1,1-dioxides

A novel and efficient synthesis of a range of racemic and enantioenriched N-substituted-4-substituted isothiazolidine-1,1-dioxides from epoxides and sulfonamides is described. The critical choice of the activating group for the cyclization event is discussed. The application of this methodology to the synthesis of N-substituted-4,5-disubstituted derivatives is also described.     

A practical synthesis of a gamma-secretase inhibitor

A practical and scaleable synthesis of the gamma-secretase inhibitor 1 is reported. The inhibitor consists of a central trisubstituted cyclohexane core with appended propionic acid, 2,5-difluorophenyl, and 4-chlorophenylsulfonyl moieties. Two alternative synthetic strategies, proceeding by way of a common disubstituted cyclohexanone derivative 5, were studied. In the preferred route, conjugate reduction of acrylonitrile derivative 4 with L-Selectride configures the desired relative stereochemistry of the cyclohexane core with >99.9:0.1 dr. A second strategy, based on catalyst-controlled hydrogenation of racemic cyclohexene derivative 2, is more convergent but less diastereoselective (up to 75:25 dr). The common cyclohexanone intermediate 5 was constructed by a regioselective Diels-Alder condensation of a 1,1-disubstituted vinyl sulfone 6 with 2-trimethylsiloxybutadiene.