Syntheses of the racemic jaborandi alkaloids pilocarpine, isopilocarpine and pilosinine

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.