A practical and scaleable total synthesis of the jaborandi alkaloid (+)-pilocarpine
Davies SG., Roberts PM., Stephenson PT., Storr HR., Thomson JE.
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 an enzymatic protocol. A high yielding synthesis of a key α-ethylidene lactone precursor has been developed, which involves the palladium-catalysed decarboxylation/carbonylation of a 1,3-dioxan-2-one for formation of the γ-butyrolactone ring. Subsequent hydrogenation of the α-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. © 2009 Elsevier Ltd. All rights reserved.