James Erwin Fritz

Use of solid supported nucleophiles and electrophiles for the purification of non-peptide small molecule libraries

Abstract Solid supported nucleophiles and electrophiles are employed to expedite the work-up and purification of a variety of amine alkylations acylacylations. These solid suported scavengers are particularly advantageous for the construction of non-peptide libraries in a parallel array format.

Rapid purification of small molecule libraries by ion exchange chromatography

Abstract Amines and acylated amines are synthesized in traditional solution phase reactions, then rapidly purified by ion exchange chromatography to yield pure products. In some instances, impurities devoid of ionizable functionality can be covalently modified prior to purification. The generic purification sequence is applicable to a variety of reactions, and is amenable to automation with commercially available equipment.

DISCOVERY OF ANTIRHINOVIRAL LEADS BY SCREENING A COMBINATORIAL LIBRARY OF UREAS PREPARED USING COVALENT SCAVENGERS

Abstract Solution phase parallel synthesis of equimolar mixtures of ureas was accomplished using a solid-supported “covalent scavenger” (aminomethylpolystyrene) to remove isocyanate impurities. Screening of these purified mixtures for antirhinoviral activity in a whole cell assay and subsequent deconvolution of hit mixtures afforded novel antirhinoviral agents with low cytotoxicities.

New dipeptide isosteres useful for the inhibition of HIV-1 protease

Abstract A family of readily accessible Phe-Pro mimics has been devised in which ortho-substituted benzamides serve as proline surrogates. When suitably functionalized, these dipeptide isosteres afford potent inhibitors of HIV-1 protease which are also effective in whole cell antiviral assays.

Synthesis of 2′,3′-dideoxy-3′-hydroxymethylcytidine; a unique antiviral nucleoside

Abstract The synthesis of 2′,3′-dideoxy-3′-hydroxymethylcytidine 1 was accomplished using two different approaches. First, uridine and cytidine were used to prepare the key intermediate epoxides 15 and 31 which were opened with cyanide, deoxygenated by elimination to vinyl nitriles 17 and 36, and reduced by 1,4 hydride addition to the saturated nitriles 18 and 37. Secondly, a novel Rh-catalyzed hydroformylation reaction of 2′,3′-didehydro-2′,3′-dideoxycytidine 46 was used to prepare 1 in four steps. The attempted use of 2′-deoxyuridine and 2′-deoxycytidine to prepare 1 is also discussed.

A systematic study of P1–P3 spanning sidechains for the inhibition of HIV-1 protease

Using information obtained from the co-crystal structure of an initial peptidomimetic lead complexed with HIV-1 protease, a series of inhibitors was constructed with substituents designed to span from the P1 to the P3 pockets of the enzyme. In accord with prediction, systematic extension of the P1 substituent with large, lipophilic groups leads to enhancements in binding potencies for this class of inhibitors. Surprisingly, inhibitors with large substituents at both P1 and P3 are also well-tolerated by the enzyme, providing compounds with subnanomolar binding affinities for HIV-1 protease.

Expedited discovery of second generation NK-1 antagonists: identification of a nonbasic aryloxy substituent

Solution-phase, parallel-synthesis techniques were used to optimize a series of nonbasic NK-1 antagonists, resulting in the identification of (R)-26, an orally bioavailable compound with subnanomolar potency.

Synthesis of 2′,3′-dideoxy-3′-hydroxymethylcytidine: A novel hydroformylation route

2′,3′-Dideoxy-3′-hydroxymethylcytidine (1) has been synthesized via stereoselective Rh-catalyzed hydroformylation of 2′,3′-didehydro-2′,3′-dideoxycytidine 3b. This synthesis incorporates the first successful hydroformylation of a nucleoside olefin.

A Convenient, Large Scale Synthesis of N-CBZ-(S-Phenyl)-L-Cysteine

Abstract N-Cbz-(S-phenyl)-L-cysteine (3) has been prepared on a multi-kilogram scale in high yield and optical purity from the β-lactone of N-Cbz-L-serine.