Epi-Quinidine

In two separate routes the aminoepoxides were obtained by highly stereoselective methods. Chlorination of iV -benzoylquinotoxine (5) with iV -chlorodiisopropylamine in 100% phosphoric acid in the dark gave an amorphous mixture of the epimeric a-chloroketones 85 and 86 (Scheme 8) [10). Reduction with sodium borohydride or with lithium tri-i-butoxyaluminum hydride afforded stereoselectively a mixture of the threo chlorohydrins 87 and 88. Treatment of 87 and 88 with aqueous potassium hydroxide at 20°C gave smoothly a mixture of the erythro iV-benzoylepoxides 89 and 90. The benzoyl groups were removed reductively with diisobutylaluminum hydride to give the aminoepoxides 81 and 82 which were cyclized in refluxing toluene-methanol (100 1). This reaction yielded 9-ep -quinine (12) and 9-epi-quinidine (13) in a ratio of 2 1. The overall yield of 12 and 13 from 87 and 88 was 50%. Only traces of the erythro products quinine and quinidine were observed. 

Quinine is the most prevaient aikaioid present in the bark extracts ( 5%) of cinchona. Four stereochemicai centers exist in the moiecuie (at C-3, C-4, C-8, and C-9) (Fig. 39-9). Quinine (absoiute configuration of 3R 4S 8S 9R), quinidine (absoiute configuration of 3R 4S 8R 9S), and their opticai isomers aii have antimaiariai activity, whereas their C-9 epimers (i.e., the epi-series having either 3R 4S 8R 9R or 3R 4S 8S 9S configurations) are inactive. Modification of the secondary aicohoi at C-9, through oxidation, esterification, or similar processes, diminishes activity. The quinuciidine portion is not necessary for activity however, an alkyl tertiary amine at C-9 is important. 

For each configuration at C.8, two isomers are possible which differ in orientation at C.9. Since all of the alkaloids are identical in configuration except at C.8 and C.9, four isomeric substances are possible in each series. Li one series two of these substances are represented by cinchonine and cinchonidine. The other two members are eptcinchonine and eptcinchonidine. Quinine, quinidine, eptquinine and eptquinidine constitute another such series. The normal members of these series are the major natural alkaloids. The epi compounds may occur naturally... 

Figure 6.13 Pseudo-enantiomers 9-amino-9-deoxy-epi-derivatives of quinine 36 and quinidine 38.

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