부산대학교 도서관

Presented herein is a total synthesis of cinchona alkaloids including quinine (1) and quinidine (2). The intermediate we have designed is the piperidine 5, which was synthesized from the cyclopentenyl monoacetate 6 as disclosed in Scheme 1. Installation of the necessary two side chains on the cyclopentene ring of 6 was accomplished by Pd-catalyzed reaction with malonate anion and subsequent Claisen rearrangement with CH_2=CHOEt/Hg^<2+> to afford cyclopentene 9, which, after functional group manipulation, was submitted to oxidative cleavage at the double bond followed by construction of the piperidine ring to produce 11. Finally, Wittig reaction of the aldehyde derived from 14 with the quinoline phosphonate furnished the intermediate 5. Transformation of 5 to quinine (1) was carried out through dihydroxylation with AD-mix-β, transformation of the resulting diol 16a to epoxide 17a, and an intramolecular reaction shown in 18a (Scheme 2). Similarly, quinidine (2) was synthesized from 5. In order to replace the above method of constructing the vinyl group, allylic substitution of 19 with CH_2=CHMgBr was studied to afford 20 satisfactory (Scheme 3). In a similar way, we synthesized various analogues with i-Pr, c-Hex, and Ph groups (Scheme 4).