Stereoselective synthesis of the imidazole alkaloids (+)‐pilocarpine and (+)‐isopilocarpine. (Imidazole chemistry, Part IX)

Abstract

A novel synthesis of (+)‐pilocarpine (10a) is described. L‐Histidine is converted into methyl (R)‐2‐bromo‐3‐(l‐methyl‐5‐imidazolyl)propionate (5) in which the configuration has been inverted. Alkylation of dibenzyl ethylmalonate with 5 yields the imidazole compound 6, again with inversion. Finally, 6 is converted into a mixture of (+)‐pilocarpine (10a) and (+)‐isopilocarpine (10b), the separation of which is well established.

Concise Synthesis of Both Enantiomers of Pilocarpine

“…However, the content of (+)-1 is very low in the leaves of different species of trees of the genus Pilocarpus ; it ranges from 0.12–0.6% in P. racemosous [ 30 , 31 , 32 ] and from 0.45% in P. microphyllus [ 33 , 34 , 35 ] and P. pennatifolius [ 36 , 37 ] to 0.8% in P. jaborandi [ 38 , 39 ]. Due to the low content of the alkaloid in the plant material as well as a laborious extraction procedure [ 40 ], a number of syntheses have been described for this interesting molecule [ 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. Many of them, however, are multi-step and laborious, often of low yield, or they yield a racemic product.…”