Synthesis Of (R)-dimethyl2-(1-benzyl-2-oxopyrrolidin-3-yl)-2-(1H-inden-2-yl) Malonate

(–)-Actinophyllic acid was extracted from the leaves of tree Alstonia actinophylla,growing on the Cape York Peninsula，Far North Queensland by Tony Carroll andco-workers in2005. It was identified as a potent carboxypeptidase unstable (CPU)inhibitor in the coupled enzyme assay, which can inhibit the formation of thrombi. Thenatural product was fascinating for it’s five chiral centers and the unique hesimpler1-azabicyclo [4.4.2]dodecane,-azabicyclo[4.2.1]nonane and octahydropyrrolo [1,2-a]azocine fragments. This thesis was focused on constructing the C15chiral center in(–)-actinophyllic acid by using3-hydroxy-2-pyrrolidinone as bulding block.In this paper, with (R)-4-amino-2-hydroxybutanoic acid61as a chiral source, wecompleted the synthesis of the chiral building block of38by esterification reaction andamidation reaction in two steps. After modifing this building block getting (R)-69,sbstitution of the hydroxyl group on C3in compound (R)-69by using4-nitrobenzenesulfonate as a leaving group offered79b, which underwent nucleophilic substitution withdimethyl malonate to reverse the configuration of C3in79b to produce (S)-78.Malonate (S)-78was converted to81by acylation reaction with o-nitrobenzene acetylchloride. Reduction the nitrol group and intramolecular condensation with carbonyl in81provided indole86. The synthesis of (R)-dimethyl2-(1-benzyl-2-oxopyrrolidin-3-yl)-2-(1H-inden-2-yl) malonate (86) from (R)-4-amino-2-hydroxybutanoic acid wasaccomplished in9steps with4%overall yield. In our work, we not only established anew and practical method to prepare the chiral3-substituted-2-pyrrolidone, but alsosuccessfully provided the useful intermediate for the ongoing asymmetric total synthesisof (–)-actinophyllic acid.