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With the goal of identifying inhibitors of hepatitis C virus (HCV) NS3/4a protease that are potent against a wide range of genotypes and clinically relevant mutant viruses, several subseries of macrocycles were investigated based on observations made during the discovery of MK-5172. Quinazolinone-containing macrocycles were identified as promising leads, and optimization for superior cross-genotype and mutant enzyme potency as well as rat liver and plasma concentrations following oral dosing, led to the development of MK-2748. Additional investigation of a series of bis-macrocycles containing a fused 18- and 15-membered ring system were also optimized for the same properties, leading to the discovery of MK-6325. Both compounds display the broad genotype and mutant potency necessary for clinical development as next-generation HCV NS3/4a protease inhibitors.

The minimising of torsional strain and non-bonding interactions is proposed as the explanation of high diastereoselectivity observed in the epoxidation of cycloalkenyl alcohols, reported for twenty three examples. The resulting 2,3-epoxyalcohols are key intermediates in the synthesis of tricyclic 1,2-diols and β-hydroxy ketones.

2,3-epoxyalcohols are shown to undergo stereoselective reactions in the presence of tin tetrachloride. The resulting diols when treated with acid are converted into polycyclic aromatic hydrocarbons or polycyclic ketones.

The furanoid fatty acid Fg has been synthesized using a mercury(II) catalyzed isomerization of 2-(1,2-oxiranylcyclododecyl)-3-nonyn-2-ol. (C) 1997 Elsevier Science Ltd. All rights reserved.

A versatile procedure for the preparation of synthetically valuable 2,5-disubstituted and 2,3,5-trisubstituted furans via mercury(II)-mediated isomerization of 1-alkynyl-2,3-epoxy alcohols is described. Mercury(II)-catalyzed isomerization of alkynyl epoxides 3a-k derived from cyclic Phi-alkynyl allylic alcohols furnishes 2,3,5-substituted furans bearing an aldehyde or keto group on the C-2 side chain. The reaction is used in a succinct and efficient synthesis of the furanoid fatty acid F-5. In contrast, the mercury(II)-catalyzed reaction of a series of alkynyl epoxides 3m-p lacking ring fusion affords difurylmethanes 5, presumably by the dimerization of intermediate 2-(alpha-hydroxyalkyl)furans 4.

A six-step, high yielding synthesis of the title compound, which can be regarded as a model compound for the preparation of aza-analogues of taxanes, is described.

5,6-Dihydroxypyrimidine-4-carboxylic acids are a promising series of hepatitis C virus (HCV) NS5B polymerase inhibitors that bind at the active site of the enzyme. Here we report a simple 2-thienyl substituted analogue that shows 10-fold improved activity over the original lead, and which allowed us to further delineate the key elements of the pharmacophore of this class of inhibitor. This work led to the identification of a trifluoromethyl acylsulfonamide group as a viable replacement for the C4 carboxylic acid in this series.