Russell E. Pike

Discovery of Narlaprevir (SCH 900518): A Potent, Second Generation HCV NS3 Serine Protease Inhibitor

Boceprevir (SCH 503034), 1, a novel HCV NS3 serine protease inhibitor discovered in our laboratories, is currently undergoing phase III clinical trials. Detailed investigations toward a second generation protease inhibitor culminated in the discovery of narlaprevir (SCH 900518), 37, with improved potency (∼10-fold over 1), pharmacokinetic profile and physicochemical characteristics, currently in phase II human trials. Exploration of synthetic sequence for preparation of 37 resulted in a route that required no silica gel purification for the entire synthesis.

Total synthesis and absolute stereochemistry of the antifungal dipeptide Sch 37137 and its 2S,3S - isomer

Abstract The absolute stereochemistry of the epoxide moiety in Sch 37137 has been established as 2R, 3R by its synthesis from L-tartaric acid. .

Highly stereoselective access to novel 2,2,4-trisubstituted tetrahydrofurans by halocyclization: Practical chemoenzymatic synthesis of Sch 51048, a broad-spectrum orally active antifungal agent

A convenient synthesis of (−)-(2R)-cis-tosylate 2 is reported via stereoselective 5-exo iodocyclization of the optically active 2,2-disubstituted olefin 9a. Enzymatic desymmetrization of the homoallylic diol 4 with Novo SP435 allowed optimal pro-(S) selectivity to provide the desired (−)-(S)-monoacetate 9a. Under the irreversible reaction conditions, the presence of a bulky aryl substituent on the 2,2-disubstituted olefin seems to determine stereochemical outcome of these halocyclizations.

Enantioselective synthesis of the optical isomers of broad-spectrum orally active antifungal azoles, Sch 42538 and Sch 45012

Abstract Sharpless-Katsuki asymmetric epoxidation of 1 provided the (R)-(+)- and (S)-(−) epoxy alcohols 2R and 2S as key intermediates towards all six stereoisomers of the title compounds. Sch 50001 and Sch 50002 (the “eutomers” of Sch 45012) are novel antifungals which display greatly improved oral activity over itraconazole and saperconazole.

A novel synthesis of cis-1-[[6-chloro-3-[(2-chloro-3-thienyl)methoxy]-2,3-dihydrobenzo[b]thien-2-yl]methyl]1h-imidazole: A new class of azole antifungal agents

Abstract Ring contraction of cis -3-bromo-7-chloro-3,4-dihydro-2H-1-benzothiopyran-4-ol 4 in the presence of imidazole results in formation of cis -6-chloro-2,3-dihydro-2-(1H-imidazol-1-ylmethyl) benzo[b]thiophene-3-ol 8 as the major product. The structure of 8 was defined unequivocally by X-ray analysis of a solvated (ethyl acetate) and an unsolvated crystal form. Alkylation of 8 with 3-(bromomethyl)-2-chlorothiophene gave cis -1-[[6-chloro-3-[(2-chloro-3-thienyl)methoxy]-2,3-dihydrobenzor[b] thien-2-yl]methyl]lH-imidazole 9 , a representative of a new class of azole antifungal agents.

Sch 51048, a novel broad-spectrum orally active antifungal agent: Synthesis and preliminary structure-activity profile

Abstract Synthesis of Sch 51048, a novel orally active azole antifungal, is described. Based on its superior oral efficacy over other available agents against a variety of fungal pathogens in normal and immunocompromised animal infection models, Sch 51048 is a subject for possible clinical evaluation.

Aqueous Diels-Alder reactions of electron deficient 2-arylfurans: a highly stereoselective route to 2,2,5-trisubstituted tetrahydrofurans towards a novel class of orally active azole antifungals

Aqueous Diels-Alder reactions 1 of halogenated 2-arylfurans with acetylenedicarboxylates made available previously inaccessible adducts (2, 2a, 7, and 8) which were successfully elaborated in a general stereocontrolled route to the title compounds

Ring contraction reactions of 2-O-methanesulfonates of α-hydroxy-γ-lactones in aqueous medium to oxetane-2-carboxylic acids: A convenient synthesis of 3′-O-methyloxetanocin and a formal synthesis of oxetanocin

Abstract Barton decarboxylative rearrangement 15 of thiohydroxamic ester 17 directly provided the key oxetanosyl-thiopyridyl glycosides 18 which were successfully coupled to N-benzoyladenine. A two-step ring contraction of the tosylate 7 to the oxetane-2-carboxamide 23 is described. Attempted ring contraction of the triflate 24 gave the unexpected products 25 and 26 . A ring expansion reaction (e.g. 14a → 21a ) was also observed.