Diastereoselective hydrogenation of 2'-deoxy-2'-exo-methyleneuridine was carried out under homogeneous conditions using a low loading of a chiral Rh catalyst. This, coupled with improvements in the synthesis of the substrate, allowed the smooth pilot plant preparation of the title compound on >10 kg scale.

The key macrocyclization step in the synthesis of simeprevir, a hepatitis C virus (HCV) antiviral drug, was studied. N-Boc substitution on the diene precursor changes the site of insertion of the metathesis catalyst and, consequently, the kinetic model of the ring closing metathesis (RCM), enabling a further increase in the macrocyclization efficiency under simulated high dilution (SHD) conditions. NMR of the inserted species of both first and second generation RCM catalysts are reported and discussed.

A series of tetrasubstituted fluoroalkenes were synthesized in good yield and high E/Z selectivity (up to 96/4) by Wittig reaction between α-heterosubstituted ketones and α-fluorophosphonium ylides. A detailed study of factors that control stereoselectivity in these reactions shows that stereoselectivity is the result of stabilizing CH···F and N···C═O interactions in the addition TS leading to the E isomer. This analysis provides a rationale for the observed decrease in selectivity for reactions of stabilized ylides with α-alkoxy aldehydes.

In the article they were spelled incorrectly as Didier Shilds and Wim Vermuelen.

The synthesis of an anti-infective nucleoside intermediate was accomplished through direct iodine displacement at C-5′ by a tetrabutylammonium carboxylate. This approach constitutes a more efficient alternative to the traditional oxidative displacement.4′-Azidonucleosides have attracted much attention as experimental drugs in the therapy of HIV 1,2 and HCV 3-5 (hepatitis C virus). We were interested in developing a practical, economical, and robust synthesis of a novel class of anti-HCV agents, represented by 4′-azido-2′-deoxy-2′-C-methylcytidine and its diester prodrugs, 6 in order to support a clinical program.We have recently described a practical synthesis of (2′R)-2′-deoxy-2′-C-methyluridine. 7 This synthesis provided us with hundreds of kilograms of the key intermediate 1 (Scheme 1). Following the literature precedent, 1 was smoothly dehydrated to 2 in two steps. The functionalization of the double bond in 2 to our drug candidate 3 can be carried out according to two distinct methods (Scheme 2): A recent publication details the epoxidation of vinyl ether 2 followed by ring opening with TMSN 3 (path a). 8,9 This approach is scalable, but epoxide instability and the hazard associated with handling TMSN 3 make it challenging. 10 The second method (path b) begins with the regioand stereoselective addition of IN 3 to the vinyl ether double bond of 2a. This addition is described as proceeding with complete Markovnikov regioselectivity and a face selectivity of 9:1 in a similar substrate, 1 and we were therefore confident that we could achieve this step regioand stereoselectively. Indeed, our first attempts to adopt the published procedure to our substrate 2a led to 6 in 85-87% isolated yield. 11 We determined the diastereomeric ratio as 95:5 in solution. Isolation by crystallization led to 6 contaminated by only 2-3% of its C-4′ epimeric analogue 6′. 11