Biomedical subjects

Michael C Hillier

Publications and source records attributed to Michael C Hillier.

6 recordsLinked to original sources

PubMed2006

A one-pot preparation of 1,3-disubstituted azetidines.

A straightforward synthesis of 1,3-disubstituted azetidines has been accomplished via the alkylation of a primary amine with the bis-triflate of a 2-substituted-1,3-propanediol species. This transformation is carried out in one reaction vessel, and elimination of the alkylating reagent is generally not a major byproduct. The scope of this methodology has been investigated using a variety 2-substituted-1,3-propanediols and amine nucleophiles.

Alkylation↗

PubMed2006

Stereoselective preparation of a cyclopentane-based NK1 receptor antagonist bearing an unsymmetrically substituted sec-sec ether.

A highly efficient synthesis of the potent and selective NK-1 receptor antagonist 1 is described. The key transformation involved the etherification reaction between cyclopentanol 12 and chiral imidate 30 which was catalyzed by HBF4 to initially give ether 14 as a 17:1 mixture of diastereomers and in 75% combined yield. The diastereoselectivity was upgraded to 109:1 by crystallization of the triethylamine solvate 44 which was isolated in 54% yield from 12. Mechanistic studies confirmed that the etherification reaction proceeds through an unprecedented S(N)2 reaction pathway under typical S(N)1 reaction conditions.

Cyclopentanes↗

PubMed2005

Stereoselective formation of carbon-carbon bonds via SN2-displacement: synthesis of substituted cycloalkyl[b]indoles.

A general asymmetric synthesis of substituted cycloalkyl[b]indoles has been accomplished. The key features of this approach are (1) the utilization of a Japp-Klingemann condensation/Fischer cyclization to prepare cycloalkyl[b]indolones, (2) the asymmetric borane reduction of these heterocyclic ketones with (S)-OAB to obtain enantiomerically pure alcohols, and (3) the stereoselective S(N)2-displacement of these indole alcohol substrates with a carbon nucleophile under Mitsunobu conditions to set the C1 or C3 tertiary carbon stereocenter. The use of trimethylphosphine (PMe3) and bis(2,2,2-trichloroethyl) azodicarboxylate (TCEAD) was found to have an effect on the Mitsunobu dehydrative alkylation.

Carbon↗

PubMed2004

Stereoselective carbon-carbon bond formation via the Mitsunobu displacement of chiral secondary benzylic alcohols.

[reaction: see text] The stereoselective displacement of a variety of chiral benzylic alcohols with triethylmethanetricarboxylate (TEMT) under Mitsunobu conditions (DEAD, PMe(3)) has been demonstrated to proceed in good yield (70-94%) and with a high degree of inversion. Subsequent saponification and decarboxylation of the products thus obtained provide chiral 3-aryl-3-substituted propanoic acids without racemization.

Journal Article↗

PubMed2002

Asymmetric synthesis of 1,2,3-trisubstituted cyclopentanes and cyclohexanes as key components of substance p antagonists.

An efficient asymmetric synthesis of 1,2,3-trisubstituted cyclopentanes and cyclohexanes is described. Three methods were developed for the preparation of the 2,3-disubstituted cyclopentenones and cyclohexenones, which are key achiral building blocks. These intermediates are reduced catalytically with (R)-2-methyloxazaborolidine in high yield (82-98%) and excellent ee (89-96%). Directed reduction of the chiral allylic alcohols using Red-Al gives exclusively the 1,2-anti stereochemistry (>99:1). Epimerization of the ester center followed by saponification/crystallization affords the desired hydroxyacids in good yield (65-70%) and in high enantiomeric excess (>99%).

Catalysis↗

PubMed2002

Stereoselective synthesis from a process research perspective.

The process chemists' primary responsibility is to develop efficient and reproducible syntheses of pharmaceutically active compounds. This task is complicated when dealing with chiral molecules that often must be made as single isomers according to regulatory guidelines. The presence of any isomeric impurity in the final product, even in small amounts, is usually not acceptable. This requirement necessitates an exquisite understanding of the methods employed in the construction of chiral drugs. However, the chemistry available for this purpose is sometimes limited and often requires a significant amount of effort and creativity to be made both functional and consistent.

Animals↗