FFA2, also called GPR43, is a G-protein coupled receptor for short chain fatty acids which is involved in the mediation of inflammatory responses. A class of azetidines was developed as potent FFA2 antagonists. Multiparametric optimization of early hits with moderate potency and suboptimal ADME properties led to the identification of several compounds with nanomolar potency on the receptor combined with excellent pharmacokinetic (PK) parameters. The most advanced compound, 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid 99 (GLPG0974), is able to inhibit acetate-induced neutrophil migration strongly in vitro and demonstrated ability to inhibit a neutrophil-based pharmacodynamic (PD) marker, CD11b activation-specific epitope [AE], in a human whole blood assay. All together, these data supported the progression of 99 toward next phases, becoming the first FFA2 antagonist to reach the clinic.

A direct ruthenium-catalyzed radical chloroalkylation of N-acyl oxazolidinones capitalizing on valence tautomerism of titanium enolates has been developed. The chloroalkylation method served as the centerpiece in the enantioselective total synthesis of trichloroleucine-derived marine natural product neodysidenin.Among more than four thousand halogenated natural products identified to date, 1 neodysidenin and other trichloroleucine-derived marine metabolites comprise a unique group. 2 For the majority of chlorinated natural products, a reasonable biosynthetic pathway involving an electrophilic chlorination can be proposed. 3 On the other hand, the trichloromethyl group in neodysidenin and related compounds arises from a remarkable direct chlorination of the pro-R methyl group of L-leucine carried out by nonheme Fe II halogenases requiring oxygen, chloride, and α-ketoglutarate for their activity. 4 In contrast, availability of synthetic methods for stereoselective trichloromethylation is highly limited, 5 whereas chlorinated natural products are attracting increasing attention as targets for chemical synthesis. 6 In this communication we describe a practical, efficient method for highly stereoselective direct chloroalkylation of titanium enolates and its application in the total synthesis of neodysidenin zakarian@chem.ucsb.edu. Supporting Information Available:Experimental procedures and copies of 1 H and 13 C NMR spectra. This information is available free of charge via the Internet at http://pubs.acs.org. that can be readily adopted for the synthesis of other bioactive natural products in this class. 7 Guided by an extension of the classic Kharasch reaction8 described by Eguchi and coworkers, 9 our early efforts involved Ru(II)-catalyzed 10 redox trichloromethylation of trimethylsilyl enol ethers generated from chiral N-acyl oxazolidinones such as 1 (Scheme 1). 11 Although encouraging results were obtained with silyl ketene acetals (~50% yields, ds 3:1), the recent characterization of valence tautomerism in titanium enolates provided a conceptual foundation for the development of a direct radical chloroalkylation of N-acyl oxazolidinones. NIH Public Access 12,13The unconventional biradical character of titanium enolates described by Moreira and coworkers suggests that these intermediates should be efficient radical acceptors. 7 Indeed, when the Ti enolate derived from 1 14 was treated with BrCCl 3 in the presence of [Ph 3 P] 3 RuCl 2 as a readily available redox catalyst (7 mol%), product 2 was obtained in an essentially quantitative yield with exquisite stereocontrol (Scheme 1). The the mechanistic hypothesis in Scheme 1 is based on well-established redox activity of [Ph 3 P] 3 RuCl 2 widely used in atom-transfer radical polymerization (ATRP) 15 and is similar to that proposed by Eguchi for a related process with silyl enol ethers.9 A major advantage, however, is that the radical addition product should be stabilized by electron delocalization onto titanium, not feasible with silyl enol ethers. Th...

A series of 5-alkylindolobenzazepin-7-ones was synthesized by Suzuki coupling between 3-iodoindole-2-carboxylates and the appropriate alpha-alkylbenzylamino o-boronic acids followed by cyclization to the lactam. Derivatives having a linear alkyl chain at C5 were found to be highly cytotoxic to KB cells with IC50 values in the 30-80 nM range. These compounds also inhibited the polymerization of tubulin with IC50's of 1-2 microM. Compound 4f (( S)-5-ethyl) showed comparable antiproliferative activities (IC50's of 30-70 nM) in a variety of cancer cell lines, cell growth being arrested at the G2/M phase. Compound 4f induced apoptosis in a dose-dependent manner in three different cancer cell lines and was shown to affect cell morphology in a manner consistent with its inhibitory action on tubulin polymerization. Using the experimental model of glioma grafted on the chick chorio-allantoic membrane, local treatment with compound 4f markedly reduced tumor progression.

Twofold versatility: An efficient intermolecular oxyamidation of indoles relies on the application of rhodium(II)‐catalyzed nitrene transfers. The cis or trans products are exclusively isolated in very good yields (up to 88 %) by changing the nucleophile. Control of the regioselectivity of the addition is also possible by modifying the substitution of the indole double bond (see scheme).