Ian W. Davies

Preparative Scale Synthesis of the Biaryl Core of Anacetrapib via a Ruthenium-Catalyzed Direct Arylation Reaction: Unexpected Effect of Solvent Impurity on the Arylation Reaction†

In this report, we disclose our findings regarding the remarkable effect of a low-level impurity found in the solvent used for a ruthenium-catalyzed direct arylation reaction. This discovery allowed for the development of a robust and high-yield arylation protocol that was demonstrated on a multikilogram scale using carboxylate as the cocatalyst. Finally, a practical, scalable, and chromatography-free synthesis of the biaryl core of Anacetrapib is described.

Synthesis of Vaniprevir (MK-7009): Lactamization To Prepare a 22-Membered Macrocycle

Development of a practical synthesis of MK-7009, a 20-membered [corrected] macrocycle, is described. A variety of ring-closing strategies were evaluated, including ring-closing metathesis, intermolecular palladium-catalyzed cross-couplings, and macrolactamization. Ring closure via macrolactamization was found to give the highest yields under relatively high reaction concentrations. Optimization of the ring formation step and the synthesis of key intermediates en route to MK-7009 are reported.

Electrophile-mediated cyclisations involving the allene π-system. Stereoselectivity and synthetic utility of PdII-catalysed heteroatom cyclisation reactions. X-Ray molecular structure of methyl 2-[trans-3-phenyl-N-(p-tolylsulfonyl)pyrrolidin-2-yl]acrylate

PdII-Mediated cyclisation and methoxycarbonylation of the phenyl-substituted allenic sulfonamides 4,5 and 6 gave the corresponding N-sulfonyl 2,3-, 2,4- and 2,5-disubstituted pyrrolidines 9, 10 and 11, respectively. With the exception of compound 4, cyclisations were not highly selective and similar trends were observed with the α-amino allenic esters 7 and 8. Some improvement, both in yield and diastereoselectivity, was apparent when cyclisations were carried out in the presence of an excess of Et3N. The isolation of acyclic by-products 14 and 15 from α-amino allenic ester 7 suggests that chloropalladiation may play a key role in the mechanism of this cyclisation sequence and similar byproducts were obtained from cyclisation of the unsubstituted allenic sulfonamides 16 and 20 leading to 6- and 7-membered rings, respectively. Other synthetic aspects of this palladium-based chemistry, including efforts directed towards coupling of the cyclisation step with a Heck-type olefination, are also described.

Additions of aldehydes to metallated trans-1,3-Dithiane-S,S-dioxide under conditions of kinetic and thermodynamic control

Abstract The chiral acyl anion equivalent (1) can be metallated with n-BuLi/py and reacts with aldehydes to give adducts in high yield. At −78δC the reaction is under kinetic control whereas at 0δC equilibration occurs with PhCHO and t-BuCHO resulting in good yields of single diastereoisomers.

Scalable Synthesis of a Prostaglandin EP4 Receptor Antagonist

The evolution of scalable, economically viable synthetic approaches to the potent and selective prostaglandin EP4 antagonist 1 is presented. The chromatography-free synthesis of multikilogram quantities of 1 using a seven-step sequence (six in the longest linear sequence) is described. This approach has been further modified in an effort to identify a long-term manufacturing route. Our final synthesis involves no step requiring cryogenic (< -25 degrees C) conditions; comprises a total of four steps, only three of which are in the longest linear synthesis; and features the use of two consecutive iron-catalyzed Friedel-Crafts substitutions.

A Practical Synthesis of m-Prostaglandin E Synthase-1 Inhibitor MK-7285

A practical, kilogram-scale chromatography-free synthesis of mPGE synthase I inhibitor MK-7285 is described. The route features a convergent assembly of the core phenanthrene unit via amide-directed ortho-metalation and proximity-induced anionic cyclization, followed by imidazole synthesis and late-stage cyanation.

Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.

We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.

Asymmetric synthesis of functionalised pyrrolidines. Highly diastereoselective cyclisations mediated by sulfide and sulfoxide ligands

Silver(I)-catalysed cyclisation of sulfide 1b and sulfoxides 4 and 5 to give the corresponding 2-vinylpyrrolidines 2b, 6a and 7a, respectively proceeds with a high (up to 99% diastereoisomeric excess) level of diastereoselectivity; in all of these cases the sense of asymmetric induction observed has been shown to be the same.

Practical Synthesis of a Renin Inhibitor via a Diastereoselective Dieckmann Cyclization

A scalable synthesis of a potent renin inhibitor (1) is described. The absolute stereochemistry is set via an unprecedented diastereoselective Dieckmann cyclization directed by a remote chiral protecting group. This transformation enables preparation of chiral 1,3-[3.3.1]-diazabicyclononenes by desymmetrization of alkyl-esters, with selectivities ranging from 4 to 17:1.

Studies on the oxidation of 1, 3-dithiane and 5, 5-disubstituted analogues including X-ray crystal structure, equilibration studies and pKa measurements on selected oxides

Oxidation of 1,3-dithiane has been carried out using eight different oxidants under several different reaction conditions. The most favourable conditions for obtaining the required trans-1,3-dithiane 1,3-dioxide were to use either MCPBA in Et2O or NaIO4 in MeOH–H2O. Other 5,5-disubstituted 1,3-dithianes were also prepared and subjected to similar oxidations. For these compounds the best oxidant for obtaining the trans-dioxides was O3. A rationalisation for the stereochemical outcome of the oxidations is presented and requires that trans-1,3-dithiane 1,3-dioxide is more stable than cis-1,3-dithiane 1,3-dioxide. This is borne out by equilibration studies of the two diastereoisomeric sulfoxides using N2O4. A rationalisation for the greater stability of the trans compared to the cis isomer is also presented and fits with the pKa values and melting points of the two compounds.