A practical and scaleable total synthesis of the jaborandi alkaloid (+)-pilocarpine

The total synthesis of (+)-pilocarpine (as its nitrate salt) has been achieved in nine steps and 30% overall yield starting from racemic 2-(2',2'-dimethoxyethyl)propane-1,3-diol, which was desymmetrised via all enzymatic protocol. A high yielding synthesis of a key alpha-ethylidene lactone precursor has been developed, which involves the palladium-catalysed decarboxylation/carbonylation of a 1,3-dioxan-2-one for formation or the gamma-butyrolactone ring. Subsequent hydrogenation of the alpha-ethylidene lactone introduces the C(3)-stereochemistry to give a 72 28 mixture of (+)-pilocarpine and (+)-isopilocarpine, which are readily separable via recrystallisation of the (-)-pilocarpine nitrate salt (C) 2009 Elsevier Ltd All rights reserved