Broadening the scope of 1,2,4-triazine synthesis by the application of microwave technology

By the application of microwave technology, a general protocol has been developed for the rapid synthesis of diverse 3,5,6-trisubstituted 1,2,4-triazines in excellent yield and purity, including many previously unknown 3-heterocyclic-1,2,4-triazines.     

An alkylsilyl-tethered, high-capacity solid support amenable to diversity-oriented synthesis for one-bead, one-stock solution chemical genetics

The synthesis and use of an alkylsilyl-tethered large (500-600 microm) polystyrene resin (1) are disclosed. An optimized Suzuki coupling of bromine-functionalized polystyrene and a silicon-functionalized alkylborane generates the silicon-substituted polystyrene 1 in large scale (>100 g). Resin loading is accomplished by activation as the silyl triflate, which can accommodate even sterically encumbered secondary alcohols and phenols. Treatment with HF/pyridine for linker cleavage is mild, efficient, and amenable to an automated, large-scale distribution system. This platform delivers, minimally, 50 nmol of each small molecule derived from a diversity-oriented, split-pool synthesis on a per bead basis for use in both forward and reverse chemical genetic assays. This technology satisfies many requirements of a one bead-one stock solution approach to chemical genetics.     

Development of a custom high-throughput preparative liquid chromatography/mass spectrometer platform for the preparative purification and analytical analysis of compound libraries

Solution-phase parallel synthesis has had a profound impact on the speed of compound synthesis delivering relatively pure compounds (>80%) in short order. However, to develop structure activity relationships (SAR) for a compound series, each library member should preferably be >95% pure. Historically, achieving and quantifying such high-purity criteria for each library member proved to be the slow step for most lead discovery groups. To address this issue, significant modifications have been made to a commercial Agilent preparative LC/MS system to allow for the general mass-guided purification of diverse compound libraries. The custom modifications include (1) the "DMSO slug" approach for the purification of samples with poor solubility; (2) an active splitter to reduce system back-pressure, reduce the delay volume, and allow for a variable split ratio; (3) a sample loading pump for the quick purification of large, dilute samples; (4) a preparative column-selection valve to quickly change column selectivity or sample loading; and (5) an analytical injector with a separate flow path for crude reaction or fraction analyses.     

Rasta silanes: new silyl resins with novel macromolecular architecture via living free radical polymerization

Heating TEMPO-methyl resin with dialkylsilane styrenes affords larger resin beads via living free radical polymerization. The new silyl resins prepared by this solvent-free suspension polymerization protocol have been coined "Rasta silanes". Rasta silanes have a novel macromolecular architecture typified by long straight chain polymers bearing the silanes which emanate from the phenyl rings of a cross-linked polystyrene core. By careful selection of comonomers during the polymerization step, loading capacity, silane spacing, and the relative distance of the silane moieties from the resin core can be controlled. The consistently high-loading Rasta silane resins produced can be easily converted into either a reactive silyl chloride or triflate to subsequently anchor alcohols and phenols to the solid phase. Cleavage from the resin can be mediated by treatment with HF.pyridine, TFA solutions, or TBAF.     

Enantioselective synthesis of C2-functionalized, N-protected morpholines and orthogonally N,N'-protected piperazines via organocatalysis

In this Letter, we describe a novel three-step, one-pot procedure for the enantioselective synthesis of N-benzyl protected morpholines and orthogonally N,N'-protected piperazines with chiral alkyl groups installed at the C2 position of each heterocyclic core via organocatalysis. This methodology allows for the rapid preparation of functionalized morpholines and piperazines that are not readily accessible through any other chemistry in good to excellent % ee (55-98% ee).     

Efficient synthesis of imidazoles from aldehydes and 1,2-diketones using microwave irradiation

[reaction: see text] A simple, high-yielding synthesis of 2,4,5-trisubstituted imidazoles from 1,2-diketones and aldehydes in the presence of NH(4)OAc is described. Under microwave irradiation, alkyl-, aryl-, and heteroaryl-substituted imidazoles are formed in yields ranging from 80 to 99%. Short syntheses of lepidiline B and trifenagrel illustrate the utility of this approach.     

MAOS ls for the general synthesis and lead optimization of 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines

General, high-yielding MAOS protocols for the expedient synthesis of functionalized 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines are described amenable to an iterative analog library synthesis strategy for the lead optimization of an M1 antagonist screening hit. Optimized compounds proved to be highly selective M1 antagonists.