Syntheses of the racemic jaborandi alkaloids pilocarpine, isopilocarpine and pilosinine
Davies SG., Roberts PM., Stephenson PT., Thomson JE.
The synthesis of racemic pilocarpine has been achieved in high overall yield. Two alternative approaches for the formation of the γ-butyrolactone ring are described: the first involves a palladium-catalysed carbonylation reaction of a homopropargylic alcohol, whereas the second involves the palladium-catalysed decarboxylation/carbonylation of a 1,3-dioxan-2-one. Subsequent hydrogenation of an α-ethylidene lactone introduces the C(3)-stereochemistry to give a mixture of pilocarpine and isopilocarpine, its C(3)-epimer, which are readily separable by recrystallisation of their hydrochloride or nitrate salts. A concise synthesis of racemic pilosinine is also disclosed (37% overall yield in six steps); this also represents an alternative, formal synthesis of racemic pilocarpine. © 2009 Elsevier Ltd. All rights reserved.