Study of Oseltamivir Synthesis from D-Serine

• Main Authors: Joshua Lai, 賴怡禎
• Other Authors: Jim-Min Fang
• Format: Others
• Language: en_US
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/69237575531269921217

博士 === 國立臺灣大學 === 化學研究所 === 99 === Recently, influenza has just swept worldwide and resulted in a severe crisis to human beings. Taking advantage of two mutation mechanisms---antigenic drift and antigenic shift, influenza virus can generate hybrid and highly pathogenic strains. The lack of immunities to these new influenza strains poses human into an unequal battle and even causes a worldwide panic. Hoffmann La-Roche Ltd. and GlaxoSmithKline have developed two neuraminidase inhibitors---Tamiflu and Relenza against influenza virus. By mimicking the transition state of neuraminidase in the cleavage of sialic acid, these two drugs can block the release of the budding progenitors of influenza virus. However, the oral bioavailability of Relenza is relatively low due to the highly polar functionalities. The administration of Relenza is therefore limited in nasal inhalation which is not convenient to the elders and the infants. As a result, Tamiflu is the only orally available drug in the treatment of influenza virus. The industrial manufacture of oseltamivir, the active pharmaceutical ingredient of Tamiflu, starts from shikimic acid, which is mainly produced by extraction of star anise, a natural herb. When there were a pandemic, the limited resource of natural herb may not satisfy the demand for manufacturing oseltamivir in sufficient amount. For this reason, we design a new synthetic route to oseltamivir using commercially available D-serine as the starting material. The stereogenic center of D-serine not only controls the syn stereochemistry in the vinyl addition to Garner''s aldehyde but also secures the three consecutive chiral centers in anti--anti relationship for oseltamivir. In this synthesis, we successfully integrate the following key reactions: (a) Zn2+ chelated vinyl addition to Garner''s aldehyde, (b) indium promoted Reformatsky reaction of $alphaup$-(bromomethyl)acrylate in aqueous media, and (c) ring-closure metathesis.