A Concise and Highly Enantioselective Total Synthesis of (+)‐anti‐ and (−)‐syn‐Mefloquine Hydrochloride: Definitive Absolute Stereochemical Assignment of the Mefloquines

Abstract

Aconcise asymmetric (> 99:1 e.r.)total synthesis of (+ +)-anti-and (À)-syn-mefloquine hydrochloride from ac ommon intermediate is described. The key asymmetric transformation is aSharpless dihydroxylation of an olefin that is accessed in three steps from commercially available materials.T he Sharpless-derived diol is converted into either atrans or cis epoxide,a nd these are subsequently converted into (+ +)-anti-and (À)-syn-mefloquine,r espectively.T he synthetic (+ +)-anti-and (À)-syn-mefloquine samples were derivatized with (S)-(+ +)-mandelic acid tert-butyldimethylsilyl ether,a nd ac rystal structure of each derivative was obtained. These are the first X-ray structures for mefloquine derivatives that were obtained by coupling to ak nownc hiral, nonracemic compound, and provide definitive confirmation of the absolute stereochemistry of (+ +)-anti-as well as (À)-syn-mefloquine.

Catalytic Enantioselective Pyridine N-Oxidation

“…Nonetheless, methodologies for achieving "asymmetric", or enantioselective, syntheses of pyridines are essential given the extant and growing number of pyridine-containing chiral molecules now found in drugs and drug candidates (Fig. 1A) (5)(6)(7)(8)(9).…”