Ian W. Davies
University of Bath
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Featured researches published by Ian W. Davies.
Journal of Organic Chemistry | 2011
Stéphane G. Ouellet; Amélie Roy; Carmela Molinaro; Remy Angelaud; Jean-François Marcoux; Paul D. O’Shea; Ian W. Davies
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.
Journal of Organic Chemistry | 2011
Zhiguo J. Song; David M. Tellers; Michel Journet; Jeffrey T. Kuethe; David R. Lieberman; Guy R. Humphrey; Fei Zhang; Zhihui Peng; Marjorie S. Waters; Daniel Zewge; Andrew Nolting; Dalian Zhao; Robert A. Reamer; Peter G. Dormer; Kevin M. Belyk; Ian W. Davies; Paul N. Devine; David M. Tschaen
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.
Journal of The Chemical Society-perkin Transactions 1 | 1992
Timothy Gallagher; Ian W. Davies; Sw Jones; David Lathbury; Mary F. Mahon; Kieran C. Molloy; Robert W. Shaw; Peter Vernon
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.
Tetrahedron Letters | 1990
Varinder K. Aggarwal; Ian W. Davies; John Maddock; Mary F. Mahon; Kieran C. Molloy
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.
Journal of Organic Chemistry | 2010
Danny Gauvreau; Sarah J. Dolman; Greg Hughes; Paul O'shea; Ian W. Davies
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.
Journal of Organic Chemistry | 2009
Francis Gosselin; Stephen Lau; Christian Nadeau; Thao Trinh; Paul O'shea; Ian W. Davies
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.
ACS Medicinal Chemistry Letters | 2016
Santhosh Francis Neelamkavil; Sony Agrawal; Thomas Bara; Chad E. Bennett; Sathesh Bhat; Dipshikha Biswas; Linda Brockunier; Nicole Buist; Duane Burnette; Mark Cartwright; Samuel Chackalamannil; Robert Chase; Mariappan V. Chelliah; Austin Chen; Martin C. Clasby; Vincent J. Colandrea; Ian W. Davies; Keith Eagen; Zhuyan Guo; Yongxin Han; John A. Howe; Charles Lee Jayne; Hubert Josien; Stacia Kargman; Karen Marcantonio; Shouwu Miao; Randy R. Miller; Andrew Nolting; Patrick A. Pinto; Murali Rajagopalan
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.
Journal of The Chemical Society, Chemical Communications | 1992
Ian W. Davies; Timothy Gallagher; R. Brian Lamont; David I. C. Scopes
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.
Organic Letters | 2010
Danny Gauvreau; Greg Hughes; Stephen Lau; Daniel J. McKay; Paul D. O’Shea; Rick R. Sidler; Bing Yu; Ian W. Davies
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.
Journal of The Chemical Society-perkin Transactions 1 | 1994
Varinder K. Aggarwal; Ian W. Davies; Richard J. Franklin; John Maddock; Mary F. Mahon; Kieran C. Molloy
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.