Guy Humphrey | Merck - Academia.edu (original) (raw)
Papers by Guy Humphrey
Journal of The Chemical Society-perkin Transactions 1, 1995
Organic letters, Nov 3, 2017
A practical and asymmetric synthesis of a functionalized trans-cyclopropoxy building block for th... more A practical and asymmetric synthesis of a functionalized trans-cyclopropoxy building block for the preparation of the HCV NS3/4a protease inhibitor grazoprevir is reported. Intramolecular SN2 displacement-ring closure, followed by a Baeyer-Villiger oxidation, yields the desired trans-cyclopropanol with full control of diastereoselectivity. A terminal alkyne is then effectively installed using LiNH(CH2)2NEt2. Starting from (S)-epichlorohydrin, the cyclopropoxy building block is prepared in 51% overall yield with >99.8% optical purity without isolation of any intermediates.
Green Chem.
The increasing employment of palladium-catalyzed reactions in the synthesis of active pharmaceuti... more The increasing employment of palladium-catalyzed reactions in the synthesis of active pharmaceutical ingredients (APIs) has created a pressing need for ultra-efficient palladium removal of the resulting metal contaminants.
Journal of the American Chemical Society, Aug 9, 2017
A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been deve... more A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C2-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,β-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4-dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues.
Organic Process Research & Development, 2016
Organic Letters, 2016
The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease in... more The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.
Organic Process Research & Development, 2010
ABSTRACT An efficient asymmetric synthesis of a unique sulfenylated prostaglandin DP receptor ant... more ABSTRACT An efficient asymmetric synthesis of a unique sulfenylated prostaglandin DP receptor antagonist candidate is described. The synthesis is characterized by a novel intramolecular Friedel−Crafts cyclization of an imino-pyrrole to prepare the azaindole core. Other key steps include a highly selective Horner−Wadsworth−Emmons olefination of a tricyclic ketone intermediate and subsequent catalytic asymmetric hydrogenation of a trisubstituted α,β-unsaturated ester to install the chirogenic center. Finally, a new indole sulfenylation protocol was developed to install the aromatic thioether functionality in good yield.
The Journal of Organic Chemistry, 2006
An efficient, practical, and high yielding synthesis of (R)-2-methylpyrrolidine is described. The... more An efficient, practical, and high yielding synthesis of (R)-2-methylpyrrolidine is described. The sequence allows for the scalable preparation of the target compound in just four synthetic steps and proceeds in 83% overall yield and >99% optical purity from readily available starting materials.
Organic Letters, 2004
[reaction: see text] A facile preparation of chiral alpha-aryloxy carboxylic acids via asymmetric... more [reaction: see text] A facile preparation of chiral alpha-aryloxy carboxylic acids via asymmetric hydrogenation of the corresponding unsaturated acids has been discovered. A number of catalysts have been identified that give high product enantioselectivity, and the scope of the reaction has been examined with respect to substitution on the aromatic ring and olefin.
The Journal of Organic Chemistry, 2016
The development of a practical asymmetric total synthesis of the potent HIV-1 integrase inhibitor... more The development of a practical asymmetric total synthesis of the potent HIV-1 integrase inhibitor 5 is described. Key transformations include construction of the naphthridine core in a highly efficient manner followed by cyclization of the 8-membered ring. Control of the atropisomers of intermediates and final compound 5 is also described.
Bioorg Medicinal Chem Letter, 1993
Abstract Palladium catalyzed addition of lactate esters or phenethyl alcohols to acyloxyazetidino... more Abstract Palladium catalyzed addition of lactate esters or phenethyl alcohols to acyloxyazetidinones gives 4-oxy-substituted β-lactams with 6-9: 1 diastereoselectivity. The stereochemistry of the major products was established as S* S* by X-ray crystallography.
Journal of The Chemical Society-perkin Transactions 1, 1995
Organic letters, Nov 3, 2017
A practical and asymmetric synthesis of a functionalized trans-cyclopropoxy building block for th... more A practical and asymmetric synthesis of a functionalized trans-cyclopropoxy building block for the preparation of the HCV NS3/4a protease inhibitor grazoprevir is reported. Intramolecular SN2 displacement-ring closure, followed by a Baeyer-Villiger oxidation, yields the desired trans-cyclopropanol with full control of diastereoselectivity. A terminal alkyne is then effectively installed using LiNH(CH2)2NEt2. Starting from (S)-epichlorohydrin, the cyclopropoxy building block is prepared in 51% overall yield with >99.8% optical purity without isolation of any intermediates.
Green Chem.
The increasing employment of palladium-catalyzed reactions in the synthesis of active pharmaceuti... more The increasing employment of palladium-catalyzed reactions in the synthesis of active pharmaceutical ingredients (APIs) has created a pressing need for ultra-efficient palladium removal of the resulting metal contaminants.
Journal of the American Chemical Society, Aug 9, 2017
A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been deve... more A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C2-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,β-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4-dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues.
Organic Process Research & Development, 2016
Organic Letters, 2016
The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease in... more The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.
Organic Process Research & Development, 2010
ABSTRACT An efficient asymmetric synthesis of a unique sulfenylated prostaglandin DP receptor ant... more ABSTRACT An efficient asymmetric synthesis of a unique sulfenylated prostaglandin DP receptor antagonist candidate is described. The synthesis is characterized by a novel intramolecular Friedel−Crafts cyclization of an imino-pyrrole to prepare the azaindole core. Other key steps include a highly selective Horner−Wadsworth−Emmons olefination of a tricyclic ketone intermediate and subsequent catalytic asymmetric hydrogenation of a trisubstituted α,β-unsaturated ester to install the chirogenic center. Finally, a new indole sulfenylation protocol was developed to install the aromatic thioether functionality in good yield.
The Journal of Organic Chemistry, 2006
An efficient, practical, and high yielding synthesis of (R)-2-methylpyrrolidine is described. The... more An efficient, practical, and high yielding synthesis of (R)-2-methylpyrrolidine is described. The sequence allows for the scalable preparation of the target compound in just four synthetic steps and proceeds in 83% overall yield and >99% optical purity from readily available starting materials.
Organic Letters, 2004
[reaction: see text] A facile preparation of chiral alpha-aryloxy carboxylic acids via asymmetric... more [reaction: see text] A facile preparation of chiral alpha-aryloxy carboxylic acids via asymmetric hydrogenation of the corresponding unsaturated acids has been discovered. A number of catalysts have been identified that give high product enantioselectivity, and the scope of the reaction has been examined with respect to substitution on the aromatic ring and olefin.
The Journal of Organic Chemistry, 2016
The development of a practical asymmetric total synthesis of the potent HIV-1 integrase inhibitor... more The development of a practical asymmetric total synthesis of the potent HIV-1 integrase inhibitor 5 is described. Key transformations include construction of the naphthridine core in a highly efficient manner followed by cyclization of the 8-membered ring. Control of the atropisomers of intermediates and final compound 5 is also described.
Bioorg Medicinal Chem Letter, 1993
Abstract Palladium catalyzed addition of lactate esters or phenethyl alcohols to acyloxyazetidino... more Abstract Palladium catalyzed addition of lactate esters or phenethyl alcohols to acyloxyazetidinones gives 4-oxy-substituted β-lactams with 6-9: 1 diastereoselectivity. The stereochemistry of the major products was established as S* S* by X-ray crystallography.