Reserpic acid lactone

Immediate sodium borohydride (NaBfLt) reduction gave lactam 44. Bischler-Napieralski cyclization of 44 followed by NaBfLt reduction yielded ( )-methyl-0-acetyl-isoreserpate (45). The correct stereochemistry at C-3 was obtained by first lactonizing compound 45 epimerization with pivalic acid then resulted in ( )-reserpic acid lactone (47). Treatment with base followed by acylation with TMBCI yielded racemic reserpine. The stereochemical considerations involved in the epimerization reaction will be discussed later. 

Fig. (13). Stereoformulas of isoreserpic acid lactone (46) and reserpic acid lactone (47).

A brief, selective review of epimerizations in the isoquinoline and indole alkaloid series inevitably gives prominence to epimerizations at C-3 of tetrahydro-/3 -carbo-line derivatives, in particular of reserpine and reserpic acid lactone the epimerizations involved in Brown s synthesis33/ of Afa-methyl-tetrahydroalstonine and 3/3-H,20/3 -H-lVa-methyldihydrogeissoschizine, from ATb-benzyl-lVa-methylvincoside, are also discussed.69... 

Much of the chemistry of reserpine and its congeners becomes clear and compelling if the conformational mobility of the CDE rings of its 3-epialloyohimbane nucleus is remembered (134). It was the gradual realization of this property and how to take advantage of it that led to the very elegant experiments which established the complete relative stereochemistry of the reserpine molecule (135, 136). Not unexpectedly, it is found that reserpine under normal conditions prefers the cis-trans-cis CDE conformation (137, 138), but this does not prevent it from assuming the trans-trans-cis shape to make possible the formation of reserpic acid lactone (125) and the quaternary salt III (136). 

Similarly to reserpic acid lactone, in rauniticine, the epiallo system, specifically the trans-trans-cis conformer, is favoured under acid equilibrating conditions because it releases the molecule from the steric crowding of the axial 19j3-methyl upon the lone pair nitrogen orbital and the 14j3-proton in both the alio form and the cis-trans-cis epiallo conformer. 

The absolute chemistry of reserpine has been derived directly (135), by making use of Klyne s extension of the Hudson lactone rule (147) as applied to reserpic acid and its lactone, as well as by the application of Prelog s asymmetric synthesis (148) to methyl reserpate (149). These results are in agreement with the conclusions obtained by more indirect but no less accurate means (91). 

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