APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P 1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P 1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.

Abstract-Novel hydroxy-functionalized phosphabenzenes were synthesized, which provide the possibility to prepare chiral phosphabenzene-phosphites. These systems act as bidentate ligands toward rhodium centers and the corresponding metal complexes were applied in the rhodium-catalyzed asymmetric hydrogenation of prochiral substrates. Ó 2006 Elsevier Ltd. All rights reserved.Phosphabenzenes (phosphinines, phosphorines), the higher homologues of pyridines, have been known for many decades, due to the pioneering work of Märkl and Ashe in the late 1960s.1,2 These heterocycles are planar, aromatic systems in which one -CH-group of the aryl moiety is substituted by an isoelectronic phosphorus atom, thus exhibiting lone pair electrons suitable for r-coordination to a metal center.3 In comparison to aryl phosphines and aryl phosphites, which are frequently applied as ligands in metal-catalyzed reactions under homogeneous reaction conditions, 4 phosphabenzenes act qualitatively as r-donor and p-acceptor ligands with electronic properties somewhat more similar to phosphites.5 However, their application in homogeneous catalysis is still limited or even neglected, 5,6 despite the fact that very interesting results in terms of activity and selectivity were obtained in the hydroformylation of alkenes, as reported by Breit and co-workers.6a,b Even though a few examples of chiral bidentate ligands based on phosphabenzenes have been reported as well, no enantioselectivity in asymmetric catalytic reactions has been observed so far. 7 We report here a synthetic route to novel hydroxy-functionalized phosphabenzenes, which can be easily converted into chiral, bidentate ligands. Results on their coordination chemistry and application in asymmetric hydrogenations are presented, and demonstrate a promising step forward in developing these truly unique phosphines to their full potential.Reaction of the methoxy-functionalized pyrylium salts 1a/b 8 with an excess of BBr 3 in CH 2 Cl 2 9 gave, in a clean and quantitative reaction, the corresponding hydroxysubstituted compounds 2a/b after aqueous work-up (Scheme 1).The complete removal of the -CH 3 groups was confirmed by 1 H NMR spectroscopy. No resonances were observed by 19 F NMR spectroscopy, suggesting loss of the BF À 4 anion during aqueous work-up. In fact, the reaction with H 2 O produced substantial amounts of HBr, which led to anion exchange of BF À 4 for Br À , yielding quantitatively the pyrylium salts 2a/b as red and yellow solids, respectively. Red crystals of 2a, suitable for X-ray crystallography, were obtained by slow crystallization from methanol and the molecular structure is 0040-4039/$ -see front matter Ó

Two distinct and scalable enantioselective approaches to the tricyclic indole (R)-2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate, an important synthon for a preclinical S1P(1) receptor agonist, are reported. Route 1 employs a modified version of Smith's modular 2-substituted indole synthesis as the key transformation. Route 2 involves a highly enantioselective CuH-catalyzed 1,4-hydrosilylation as the stereodefining step. Both routes can be performed without chromatography to provide multigram quantities of the tricycle in ≥98% ee.

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