The stereochemistry of the aldol condensation of preformed lithium enolates of a variety of ethyl ketones and propionic acid derivatives with aldehydes has been investigated. It is found that certain compounds give completely or nearly completely one diastereomeric enolate and that the stereostructure of the resulting aldol is correlated with the stereostructure of the enolate from which it is formed. The observed stereochemistry may be understood in terms of an ordered transition state in which both oxygens are oriented in more or less the same direction. It is shown that the observed stereochemistry is kinetically controlled. In many cases, the initial aldol adduct equilibrates to furnish predominantly a threo isomer. The rate of equilibration varies widely, ranging from very fast at -60 °C with the propiophenone-benzaldehyde adduct to slow at 25 °C for the ethyl fert-butyl ketonebenzaldehyde adduct. The equilibration behavior of lithium ketolates is compared with that of the zinc ketolates, and some differences are noted. A method for achieving erythro-threo equilibration via a chloral hemiacetal is presented. A new reagent is introduced (trimethylsilyloxy ketone 36) which may be used to stereoselectively homologate an aldehyde to an erythro -methyl-d-hydroxy acid. As an application of the use of stereoselective aldol condensations in synthesis, (±)-ephedrine (48) has been synthesized from benzaldehyde in 71% overall yield.

Pyrazole-based inhibitors of the transforming growth factor-beta type I receptor kinase domain (TbetaR-I) are described. Examination of the SAR in both enzyme- and cell-based in vitro assays resulted in the emergence of two subseries featuring differing selectivity versus p38 MAP kinase. A common binding mode at the active site has been established by successful cocrystallization and X-ray analysis of potent inhibitors with the TbetaR-I receptor kinase domain.

Transforming growth factor beta (TGF-beta) signaling pathways regulate a wide variety of cellular processes including cell proliferation, differentiation, extracellular matrix deposition, development, and apoptosis. TGF-beta type-I receptor (TbetaRI) is the major receptor that triggers several signaling events by activating downstream targets such as the Smad proteins. The intracellular kinase domain of TbetaRI is essential for its function. In this study, we have identified a short phospho-Smad peptide, pSmad3(-3), KVLTQMGSPSIRCSS(PO4)VS as a substrate of TbetaRI kinase for in vitro kinase assays. This peptide is uniquely phosphorylated by TbetaRI kinase at the C-terminal serine residue, the phosphorylation site of its parent Smad protein in vivo. Specificity analysis demonstrated that the peptide is phosphorylated by only TbetaRI and not TGF-beta type-II receptor kinase, indicating that the peptide is a physiologically relevant substrate suitable for kinetic analysis and screening of TbetaRI kinase inhibitors. Utilizing pSmad3(-3) as a substrate, we have shown that novel pyrazole compounds are potent inhibitors of TbetaRI kinase with K(i) value as low as 15 nM. Kinetic analysis revealed that these pyrazoles act through the ATP-binding site and are typical ATP competitive inhibitors with tight binding kinetics. More importantly, these compounds were shown to inhibit TGF-beta-induced Smad2 phosphorylation in vivo in NMuMg mammary epithelial cells with potency equivalent to the inhibitory activity in the in vitro kinase assay. Cellular selectivity analysis demonstrated that these pyrazoles are capable of inhibiting activin signaling but not bone morphogenic protein or platelet-derived growth factor signal transduction pathways. Further functional analysis revealed that pyrazoles are capable of blocking the TGF-beta-induced epithelial-mesenchymal transition in NMuMg cells, a process involved in the progression of cancer, fibrosis, and other human diseases. These pyrazoles provide a foundation for future development of potent and selective TbetaRI kinase inhibitors to treat human disease.

Indazoles are unselectively protected under strongly basic conditions to give a mixture at N-1 and N-2. Under mildly acidic conditions, regioselective protection at N-2 takes place. Thermodynamic conditions lead to regioselective protection at N-1. This trend applies to various substituted indazoles. Protected 5-bromoindazoles participate in Buchwald reactions with a range of amines to generate novel derivatives.

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