Asymmetric Synthesis of (+)-Mequitazine from Quinine

Abstract

The first asymmetric synthesis of the antihistaminic drug mequitazine is reported. Our approach started from quinine, a Cinchona alkaloid, whose chiral information was exploited for setting up the stereogenic center of (+)-mequitazine.

Chemistry of Bridged Lactams and Related Heterocycles

“…154 Oxidation of quinine under Swern conditions provided the required quininone. This intermediate was reacted with potassium tert -butoxide in the presence of oxygen to deliver, after alcoholysis of the transient bridged amide bond, the vinyl piperidine in 60% yield.…”

“…Nonplanar amides have been frequently employed to investigate fundamental properties of amide bonds, such as proton exchange, − bonding, − rotational barriers, , and chemical reactivity. − The effect of amide distortion has been leveraged to control chemical transformations − including hydrolysis, − acylation, − desymmetrization, and kinetic resolution , of alcohols. Bridged lactams have been applied as intermediates in the synthesis of bioactive natural products − and are even present in the structures of several alkaloids. − …”

“…Bridged lactams have been used on several occasions in the total synthesis of natural products. − The ability to provide a rigid molecular framework and to attenuate the basicity of a nitrogen atom are among the strategic advantages of applying bridged lactams in target-oriented synthesis. Moreover, in recent years, a number of natural products containing bridged amide bonds have been isolated, − suggesting that bridged lactams may be more prevalent in nature than had been previously considered.…”

“…Recently, Doris and co-workers reported the total synthesis of (+)-mequitazine using oxidative degradation of quinine via an unisolated bridged lactam, 5-vinylquinuclidin-2-one, as the key step (Scheme ) . Oxidation of quinine under Swern conditions provided the required quininone.…”

“…The conditions used for the Heck reactions had a significant effect on the outcome of the pivotal cyclization; the neutral conditions employing PPh 3 and Et 3 N in DMF led to the disubstituted Z-olefin 602, while under cationic conditions (dppp, Ag 2 CO 3 , toluene) the anti-Bredt olefin 603 was formed as a mixture of E and Z Recently, Doris and co-workers reported the total synthesis of (+)-mequitazine using oxidative degradation of quinine via an unisolated bridged lactam, 5-vinylquinuclidin-2-one, as the key step (Scheme 177). 154 Oxidation of quinine under Swern conditions provided the required quininone. This intermediate was reacted with potassium tert-butoxide in the presence of oxygen to deliver, after alcoholysis of the transient bridged amide bond, the vinyl piperidine in 60% yield.…”