Strategies for the dessymmetrization of cyclopentene scaffolds using the enantioselective Heck-Matsuda reaction and their potential synthetic applications.

Abstract

The synthesis of sphingosine-1-phosphate (S1P) analogues has been an important subject in medicinal chemistry because of its action as selective agonists for S1P receptors. These compounds act as second messengers in the immune response controlled by the activation of T-lymphocytes. The compound VPC01091, disclosed recently by Abbott has demonstrated high selectivity for S1P1 receptors, thus making this drug a superior treatment of multiple sclerosis. Using the catalytic Heck-Matsuda reaction the research group of prof. Carlos Roque has recently demonstrated to be possible to synthesize these compounds in a concise manner. Nevertheless, so far those syntheses have been restricted to racemic compounds. Aiming at the total enantiomeric synthesis of the most active stereoisomers of compound VPC01091 in a concise manner, the present proposal has as its main objective to develop an enantioselective Heck-Matsuda arylation process applicable to symmetrical and functionalized cyclopentene systems. The catalytic arylating process employs bisoxazolines and/or pyridino-oxazolines as main chiral ligand to achieve the syntheses of advanced intermediates and/or the total synthesis of VPC01091. The conceived route is flexible and should also allow for the synthesis of new analogues.