Parallel medicinal chemistry approaches to selective HDAC1/HDAC2 inhibitor (SHI-1:2) optimization.

The successful application of both solid and solution phase library synthesis, combined with tight integration into the medicinal chemistry effort, resulted in the efficient optimization of a novel structural series of selective HDAC1/HDAC2 inhibitors by the MRL-Boston Parallel Medicinal Chemistry group. An initial lead from a small parallel library was found to be potent and selective in biochemical assays. Advanced compounds were the culmination of iterative library design and possess excellent biochemical and cellular potency, as well as acceptable PK and efficacy in animal models.

Versatile solid-phase synthesis of trisubstituted 1H-pyrido[2,3-d]pyrimidin-4-ones and related heterocycles.

A solid-phase synthesis of trisubstituted 1H-pyrido[2,3-d]pyrimidin-4-ones has been developed. The synthesis utilizes solid-phase bound N-2,6-dichloronicotinoyl-1H-benzotriazole-1-carboximidamides as key intermediates. Sequential substitution of benzotriazole and the two chlorines furnishes the title compounds with regioselectivity and high purity. Application of the method to various disubstituted analogues is also demonstrated.

Combinatorial synthesis of substituted biaryls and heterocyclic arylamines.

In this paper, we report very general conditions that enable palladium-mediated coupling reactions on the solid support. A wide variety of biaryls and arylamines (including pyrimidines) have been synthesized using this protocol. The chemistry facilitates a combinatorial approach to the production of large numbers of medicinally relevant heterocyclic structures.

New developments in chemical library synthesis. Norbornenyl tags for use in phase-switching, sequestration, capture-release and soluble support applications.

A new, general chemical library purification platform is reviewed. This platform makes broad use of (oxa)norbornenyl-tagged reactants, reagents, catalysts, sequestration-enabling reagents and scavengers, in combination with Grubbs catalyst-mediated ring-opening metathesis polymerization (ROMP) reactions as an in situ polymerization purification technique. Extensions of this platform involve the use of preformed ROMP supports in synthesis, and polystyrene-supported Grubbs catalysts, which perform in a boomerang fashion.

Recent advances in chemical library synthesis methodology.

The first part of this review highlights recent advances in polymer-supported reagents, catalysts, reactants and sequestrants. Particular attention is given to recent advances in polymer-supported oxidants, transition metal catalysts and polymer-supported reactants, including acyl groups, guanidinyl groups, alkyl groups and various classes of nucleophiles. This second part of the review highlights recent advances made in the areas of chemical tagging and phase-trafficking techniques, all of which have enabled further advances in the methodology of solution-phase chemical library synthesis.

Titanocene-Catalyzed Reduction of Lactones to Lactols.

A convenient method for the conversion of lactones to lactols is described. The hydrosilylation to lactols is carried out via air-stable titanocene difluoride or a titanocene diphenoxide precatalyst using inexpensive polymethylhydrosiloxane (PMHS) as the stoichiometric reductant. These procedures have been demonstrated with a variety of substrates and proceed in good to excellent yield.

A Practical Titanium-Catalyzed Synthesis of Bicyclic Cyclopentenones and Allylic Amines.

A practical titanium-catalyzed synthesis of bicyclic cyclopentenones and allylic amines is described. The process converts enyne substrates to iminocyclopentenes using 10 mol % of the air- and moisture-stable precatalyst Cp(2)TiCl(2) in the presence of n-BuLi and triethylsilyl cyanide. The resulting iminocyclopentenes can be hydrolyzed to cyclopentenones in good yields or reduced to allylic silylamines with Red-Al or DIBALH. Treatment of the crude silylamines with acetyl chloride allows isolation of allylic amides in excellent yields.