Donald P. Matthews

Stereospecific synthesis of 1-fluoro olefins via (fluorovinyl)stannanes and an unequivocal NMR method for the assignment of fluoro olefin geometry

Abstract (E)- and (Z)-Fluorovinyl sulfones (II) form (fluorovinyl)stannanes (III) on treatment with two equivalents of tributyltin hydride and a catalytic amount of AIBN; the free radical catalyzed reaction proceeds with retention of configuration for 2,2-disubstituted fluorovinyl sulfones (IIa and IIb). Conversion of III to 1-fluoro olefins (IV) is a stereospecific reaction and provides a general method to (E) and (Z) fluoro olefins. The utility of this method is exemplified by the synthesis of the deutero fluoro olefin 27, nucleosides 32 and 34, and the amino acids 43 and 47. Proton observe, 19F irradiated (1H-19F) NOE difference specroscopy was used for the first time as an unequivocal method for the assignment of olefin geometry for fluorovinyl sulfones, (fluorovinyl)stannanes and fluoro olefins.

A new method for the electrophilic fluorination of vinyl stannanes

Abstract A new method for the electrophilic fluorination of vinyl stannanes using commercially available 1-chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane bis-(tetrafluoroborate) (1) has been developed.

The Application of High-Throughput Synthesis And Purification To The Preparation Of Ethanolamines

Abstract A 48 compound library of structurally diverse ethanolamines was prepared using a parallel synthesis approach. The synthetic paradigm employed a solution phase epoxide-opening reaction followed by rapid purification by ion exchange chromatography to yield products with near-analytical purity. An array of epoxides and primary amines, arranged in an 8×6 matrix, were reacted in the presence of an in situ silylating agent to form 48 individual compounds with an average yield of 75% and an average purity of 92.3%.

A facile synthesis of aromatic trifluoromethyl compounds via orthothio esters

Abstract Aromatic trifluoromethyl compounds ( 2 ) are prepared by treatment of aromatic orthothio esters ( 1 ) with 1,3-dibromo-5,5-dimethylhydantoin (DBH) or N-bromosuccinimide (NBS) followed by HF/pyridine complex. The starting materials ( 1 ) were readily obtained by literature methodology.

The synthesis of (1-fluorovinyl)tributyltin: A synthetic equivalent for the 1-fluoroethene anion

Abstract The synthesis of (1-fluorovinyl)tributyltin ( 1b ) is reported, and the utility of 1b as a synthetic equivalent for the 1-fluoroethene anion 2 through palladium-catalyzed couplings is demonstrated.

A new route to 2-fluoro-1-olefins utilizing a synthetic equivalent for the 1-fluoroethene anion

Abstract The preparation of (E)-tributyl(1-fluoro-2-trimethylsilyl)vinylstannane ( 10 ), a synthetic equivalent for the 1-fluoroethene anion, and its utility for the synthesis of nucleoside 20 , and other 2-fluoro-1-olefins is described.

Improved Synthesis of (E)-2′-Deoxy-2′-(fluoromethylene)cytidine - A Potent Inhibitor Of Ribonucleotide Diphosphate Reductase

Abstract An improved synthesis of 1 is reported that utilizes cytidine as starting material and incorporates the stereospecific method to fluoro olefins as in the original process. The new route is five steps, compared to the seven step original procedure, with an overall yield of 29%. Several intermediates are crystalline and readily purified.

The use of high-throughput synthesis and purification in the preparation of a directed library of adrenergic agents

A library of potential agonists and antagonists for adrenergic receptors was prepared using high-throughput solution-phase parallel synthesis. Traditional solution-phase reductive amination reactions followed by rapid purification by ion exchange chromatography yielded products with near-analytical purity. An array of ketones and amines, arranged in an 8 × 12 matrix, were combined to form 96 individual compounds.

Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm

Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cat S may provide a new treatment for AAA. To date, several classes of Cat S inhibitors have been reported, many of which form covalent interactions with the active site Cys25. Herein, we report the discovery of a novel series of noncovalent inhibitors of Cat S through a medium-throughput focused cassette screen and the optimization of the resulting hits. Structure-based optimization efforts led to Cat S inhibitors such as 5 and 9 with greatly improved potency and drug disposition properties. This series of compounds binds to the S2 and S3 subsites without interacting with the active site Cys25. On the basis of in vitro potency, selectivity, and efficacy in a CaCl2-induced AAA in vivo model, 5 (LY3000328) was selected for clinical development.

(E) and (Z)5′-fluoro olefin carbocyclic nucleosides: effect of olefin geometry on inhibition of s-adenosyl-l-homocysteine hydrolase

Abstract (E) and (Z) 4′,5′-Didehydro-5′-deoxy-5′-fluoroaristeromycin ( 9a and 9b ) were synthesized utilizing the fluoro-Pummerer reaction . Fluoro olefin 9a was a time-dependent inhibitor of S-adenosyl-L- homocysteine hydrolase whereas 9b was a competitive inhibitor. The effects of 9a and 9b on T cell proliferation are presented.