Xianglin Shi
Chemical Process R&D, Biogen Idec, USA
Title: Development of Novel Petasis Reaction Methodologies for Efficient and Scalable Synthesis of Biologically Interesting Compounds
Biography
Biography: Xianglin Shi
Abstract
BIIB042, a g-secretase modulator, was pursued for its potential in the treatment of Alzheimer’s Disease. Med. Chem. synthesis consisted of four chemical reactions. A mixture of four diastereomers were made in the first step and carried through to the end of the synthesis. BIIB042 was obtained in ~4% overall yield via chiral HPLC separation. A seven-step process was developed for delivery of kilograms of BIIB042. A racemic mixture made in the first step was separated using SMB chromatography. Second chiral center was introduced in the last step by stereoselective hydrogenation reaction to afford BIIB042 in 95-96% ee. This route afforded the API in ~9% overall yield. Further improved synthesis included synthesis of 2 by Petasis reaction of enantioenriched aldehyde 1 followed by its conversion into BIIB042 in two steps (Scheme 1). Development of a mild and efficient Petasis reaction condition made synthesis of 2 in high yield without loss of ee possible. This new Petasis reaction condition was applicable to a variety of substrates (Shi, X, et al. J. Org. Chem. 2012, 77, 1154).