A collection of structurally complex and chemically diverse small molecules is a useful tool to explore cell circuitry. In this article, we report the split-pool synthesis of more than 3000 spirooxindoles on high capacity macrobeads. The key reaction to assemble the spirooxindole core stereoselectively is a Lewis acid variant of the Williams' three-component coupling. After formation, the skeleton was elaborated using Sonogashira couplings, amide forming reactions, and N-acylations of gamma-lactams. The final library was analyzed by sampling individual macrobeads and by using binomial confidence limits. It was determined that at least 82% of the library compounds should have better than 80% purity. To demonstrate the utility of our discovery process, a high-throughput chemical genetic modifier screen was performed using stock solutions of the resultant products. A number of positives were identified as enhancers of the cellular actions of latrunculin B, an actin polymerization inhibitor. Through resynthesis, we confirmed one of the positives and demonstrated that, in yeast cells, it has an EC50 in the sub-micromolar range.

As a consequence of the wide-ranging significance of beta-lactams (e.g., use as drugs and as chiral building blocks), a great deal of effort has been dedicated to the development of methods for their stereoselective synthesis. Although considerable progress has been achieved, nearly all of the approaches that have been described are based on the use of chiral precursors; direct catalytic enantioselective routes to beta-lactams are rare as well as limited in scope. In this communication, we establish that, using a new C2-symmetric planar-chiral bis(azaferrocene) ligand, we can generate beta-lactams with very good enantiomeric excess and cis diastereoselection via catalytic enantioselective Kinugasa reactions (couplings of alkynes with nitrones). Appealing attributes of this process include the ready availability of the starting materials, the functional-group tolerance of the reaction, and the convergency of the approach.

The association of the intrinsic optical and biophysical properties of cells to the homeostasis and pathogenesis has long been acknowledged. Defining these label-free cellular features obviates the need for costly...

We report the development and characterization of compound 22 (MK-5046), a potent, selective small molecule agonist of BRS-3 (bombesin receptor subtype-3). In pharmacological testing using diet-induced obese mice, compound 22 caused mechanism-based, dose-dependent reductions in food intake and body weight.

The synthesis of several phosphaferrocene-oxazolines, members of a new family of planar-chiral ligands, is described. These bidentate P, N-ligands are applied to enantioselective palladium-catalyzed allylic alkylations, for which it is shown that the planar-chirality of the phosphaferrocene, not the chirality of the oxazoline, determines the stereochemical outcome of the reaction.

Several C 2 -symmetric bis(phospholyl) adducts of group 4 metals, including the first example of an η 5 -phospholyl complex of hafnium, have been synthesized and structurally characterized. These complexes undergo rac/meso isomerization in a process that is accelerated by Lewis bases. A C 2 -symmetric bis(phospholyl)zirconium dichloride binds as a bidentate ligand to Mo(CO) 4 . In the presence of methylalumoxane, bis(phospholyl)zirconium complexes serve as active catalysts for ethylene-hexene copolymerization reactions.

The stereochemistry of the aldol reaction of seven benzylic nitriles la-g and four aldehydes 2-5 has been studied. In all cases studied the reaction is anti-selective. Good to excellent selectivity (10:1->20:1) can be obtained if aldehydes with bulky secondary or tertiary substituents are used. The resulting aldols 6-9 are easily transformed to the corresponding y-amino alcohols 12-15, which may possess useful antidepressant activity.The stereochemistry of addition of ketone, ester, and amide enolates to aldehydes has been extensively investigated;1 in contrast, very little attention has been given to the stereochemistry of addition of metalated nitriles to aldehydes2 (Scheme 1). This lack of attention is suprising, given the fact that enantiomerically pure /3-hydroxy nitriles 6-9 would be versatile synthetic intermediates.3 Of particular interest is the potential rapid entry into y-amino alcohols 12-15, a functional group present in a number of widely prescribed antidepressants. However, until recently, diastereoselectivities in the nitrile aldol reaction have not been synthetically useful. In 1982, Hamana reported that di-n-butylboron triflate-mediated aldol reaction of phenylacetonitrile and benzaldehyde gave the two diastereomeric aldol products in a 1:1 ratio.4 Kasatkin and co-workers reported that various titanated phenylacetonitriles underwent nonstereoselective aldol reaction with benzaldehyde.5 In a recent chemoselectivity study, Kauffman reported obtaining unassigned mixtures of diastereomers from various metalated propiononitriles and benzaldehyde.6 We recently disclosed that phenylacetonitrile undergoes anti-selective7 aldol reaction with aldehydes.8 We now expand our previous study by examination of other benzylic nitriles and by transformt To whom inquiries concerning the X-ray crystal structures should be directed.

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