Synthesis of Naproxen Chiral Auxiliary Approach

The Zambon synthesis of the non-steroidal anti-inflammatory agent (5)-2-(6-methoxy-2-naphthyl)propanoic acid (naproxen) is a landmark-setting application of the chiral auxiliary approach in the industrial stereoselective synthesis of an enantiomerically pure drug [51]. The chiral auxiliary employed, a (2f ,Jf )-dialkyltartrate, is a paradigmatic representative of this class of stereocontroller, being cheap, readily available, easily introduced on the substrate and removed from the product, and eventually recycled (although as its parent acid). 

The process is relatively short and requires five steps from l-(6-methoxy-2-naphthyl)-propan-l-one (Fig. 12). The ketone was converted in high yield into ketal 18, that was then brominated at the carbon a to the ketal carbon atom to give a 94 6 mixture of (5) and (R) epimers of 19. Unfortunately, bromination also occurred in the naphthalene nucleus. 

Ester hydrolysis, performed under basic conditions, proceeded without affecting the d.r. The resulting diacid 20 was subjected to hydrolysis at controlled pH and high temperature to afford acid (5)-21 in 99% e.e. This crucial step involves a 1,2-aryl shift that occurs in a completely stereocontrolled fashion. Debromination of (5)-21 gave naproxen 22 in high overall yield. 

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