A multistep scalable synthesis of the clinically important hepatitis C virus (HCV) protease inhibitor BILN 2061 (1) is described. The synthesis is highly convergent and consists of two amide bond formations, one etherification, and one ring-closing metathesis (RCM) step, using readily available building blocks 2-5. The optimization of each step is described at length. The main focus of the paper is the study of the RCM step and the description of the main problems faced when scaling up to pilot scale this highly powerful but very challenging synthetic operation. Eventually, the RCM reaction was smoothly scaled up to produce >400 kg of cyclized product.

Combinatorial and structure-based medicinal chemistry strategies were used together to advance a lead compound with an activity of K(i) = 58 microM via a potency enhancement of >70 000-fold to an analogue with an activity of K(i) = 0.8 nM against influenza neuraminidase (A/Tokyo/67). Lead optimization was initiated using molecular modeling and combinatorial chemistry. Protein crystal structures revealed that inconsistent structure-activity relationship (SAR) data resulted from different binding orientations of the inhibitor core five-membered rings from one series to another. Binding modes for a series of compounds showed up to a 180 degrees variation in orientation of the five-membered ring within the active site. Potent analogues were only achieved with chemical series that were observed to bind in the same orientation and yielded consistent SAR. In one series, consistent binding was obtained by an unprecedented occupation of a negatively charged binding pocket by a neutral methyl ester unit. The structural rationale for this novel SAR variation, based on protein crystallographic data, is given.

A general, efficient, and highly diastereoselective method for the synthesis of structurally and sterically diverse P-chiral phosphine oxides was developed. The method relies on sequential nucleophilic substitution on the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide, which features enhanced and differentiated P-N and P-O bond reactivity toward nucleophiles. The reactivities of both bonds are fine-tuned to allow cleavage to occur even with sterically hindered nucleophiles under mild conditions.

N-Acyl enamides are useful compounds in organic synthesis. In the realm of catalytic asymmetric hydrogenation, they are among the most exhaustively studied class of substrates, and provide access to valuable chiral amine building blocks. [1] These substrates have also demonstrated broad utility in catalytic asymmetric CÀC bond forming processes such as aza-ene, [2] Michael, [3] Friedel-Crafts, [4] cycloaddition, [5] and arylation [6] reactions. Despite the extensive applications of Nacyl enamides, their preparation remains challenging. The direct condensation of acetamide with ketones, while attractive in its simplicity, proceeds either in low yields or not at all for the majority of ketone substrates.[7] The Pd-catalyzed cross-coupling of vinyl electrophiles with amides [8] and the Heck reaction of N-vinylacetamide with aryl halides [9] often require additional steps for preparation of coupling precursors and employ a costly transition metal catalyst.[10] The addition of alkyl magnesium or alkyl lithium reagents to nitriles followed by trapping with Ac 2 O or AcCl has limited functional-group tolerance [11] and requires low reaction temperatures.[12] By far the most commonly employed procedure is the two-step conversion of ketones through ketoximes (Scheme 1). [13] This reaction was first described in 1975 by Barton and coworkers. After a first step of oxime formation, the ketoxime was then treated with Ac 2 O and either pyridine at reflux, Cr(OAc) 2 , or Ti(OAc) 3 for reductive acylation.[13] Subsequently, numerous alternative reducing agents were developed.[14] The most commonly employed reductant is Fe powder, which was first demonstrated by Barton and Zard in 1985 [14a] and subsequently developed by Burk and Zhang in 1998. [14b,c] From a large scale perspective, the use of highenergy hydroxylamine, generating a high-energy oxime intermediate, and reducing the oxime at high temperatures present safety concerns. In addition, the workup of the Fe process is often tedious, requiring filtration of large amounts of inorganic salts. While several alternatives to Fe metal have emerged recently, these still rely on the same overall two-step process through a ketoxime.[14d-g] Our own requirements for large-scale synthesis of N-acetyl enamides for asymmetric hydrogenation prompted us to develop a more direct and process-friendly alternative in which hydroxylamine is replaced with ammonia. Herein we describe a direct, redoxfree synthesis of enamides from ketones, ammonia, and Ac 2 O mediated by Ti(OiPr) 4 . In addition, we introduce the use of edte (N,N,N',N'-tetrakis(2-hydroxyethyl)ethylenediamine) to effect water solubilization of the Ti and allow a simple extractive workup.Our strategy for enamide synthesis was based on condensation of a ketone with ammonia to give an N-unsubstituted imine or enamine, followed by N-acetylation on addition of Ac 2 O. The imine formation presented a challenge due to the volatility of ammonia, which excluded the common method for imine formation by azeotropic distillation for remo...

S-Alkyl, S-aryl, and S-vinyl thiosulfate sodium salts (Bunte salts) react with Grignard reagents to give sulfides in good yields. The S-alkyl Bunte salts are prepared from odorless sodium thiosulfate by an SN2 reaction with alkyl halides. A Cu-catalyzed coupling of sodium thiosulfate with aryl and vinyl halides was developed to access S-aryl and S-vinyl Bunte salts. The reaction is amenable to a broad structural array of Bunte salts and Grignard reagents. Importantly, this route to sulfides avoids the use of malodorous thiol starting materials or byproducts.

Carbamoyl anions, generated from N,N-disubstituted formamides and lithium diisopropylamide, add with high diastereoselectivity to chiral N-sulfinyl aldimines and ketimines to provide α-amino amides. The methodology enables the direct introduction of a carbonyl group without the requirement of unmasking steps as with other nucleophiles. The products may be converted to α-amino esters or 1,2-diamines. Iterative application of the reaction enabled the stereoselective synthesis of a dipeptide. Spectroscopic and computational studies support an anion structure with η(2) coordination of lithium by the carbonyl group.

[chemical reaction: see text]. Direct addition of Grignard reagents to acid chlorides in the presence of bis[2-(N,N-dimethylamino)ethyl] ether proceeds selectively to provide aryl ketones in high yields. A possible tridentate interaction between Grignard reagents and bis[2-(N,N-dimethylamino)ethyl] ether moderates the reactivity of Grignard reagents, preventing the newly formed ketones from nucleophilic addition by Grignard reagents.

A mild and general procedure for reduction of primary, secondary, and tertiary amides using catalytic triruthenium dodecacarbonyl and 1,1,3,3-tetramethyldisiloxane as reductant is described. The reaction is tolerant of numerous functional groups, and the amine products can often be isolated by direct crystallization as hydrochloride salts. The catalyst and silane are commercially available, air stable, and inexpensive, making the procedure accessible for both laboratory and large-scale applications.