Seetharaman Jayaraman

Synthesis of cyclosporin analogs

The invention is directed to isomeric mixtures of cyclosporine analogues that are structurally similar to cyclosporine A. The mixtures possess enhanced efficacy and reduced toxicity over the individual isomers and over naturally occurring and other presently known cyclosporines and cyclosporine derivatives. Embodiments of the present invention are directed toward cis and trans-isomers of cyclosporin A analogs referred to as ISATX247, and derivatives thereof. ISATX247 isomers and alkylated, arylated, and deuterated derivatives are synthesized by stereoselective pathways where the particular conditions of a reaction determine the degree of stereoselectivity. Stereoselective pathways may utilize a Wittig reaction, or an organometallic reagent comprising inorganic elements such as boron, silicon, titanium, and lithium. The ratio of isomers in a mixture may range from about 10 to 90 percent by weight of the (E)-isomer to about 90 to 10 percent by weight of the (Z)-isomer, based on the total weight of the mixture.

Three-carbon ring expansion of boracyclanes

Abstract (α-Chloroally)lithium, generated in situ from LiNR 2 and allyl chloride, reacts with cyclic borinates to furnish ring-expanded allylic boracyclenes. The undesired protonolysis by the amine generated during metalation has been overcome either by increasing the steric bulk of the alkoxy group on boron or by addition of BF 3 .OEt 2 to deactivate the amine. The synthetic utility of the allylic B-alkoxy-3-boracyclenes has been demonstrated.