Mitsunobu with thioacetic acid

The synthesis of the second building block [62] for meropenem starts from trans-hydroxyproline. First, the amino acid is protected on both, the amino and the carboxyl group. By reaction with thioacetic acid m a Mitsunobu esterification, the thiol ftmction is introduced, and the carboxyl group is then selectively deprotected with trifluoroacetic add. The dimethylamino-group is introduced with the aid of isopropyl chloroformate, and the thiol acetate is finally hydrolysed with aqueous sodium hydroxide. 

A modified Mitsunobu procedure in which 63 is first treated with the preformed complex 68 (prepared by reaction of triphenylphosphine and diisopropyl azodicarboxylate) and then cesium thioacetate leads to significant racemization [17]. However, if the free acid is reacted instead with an appropriate thioacid (rather than the ester and a cesium salt), optical yields improve significantly. Thus, thioacetylation of (S)-l can be accomplished by treating it with 68 followed by the addition of thioacetic acid in THF to provide in 48% yield (5)-2-(acet-ylthio)-2-phenylacetic acid (69) with 84% ee after recrystallization. The low yield is due in part to the unavoidable formation to the extent of at least 50% of a viscous, polymeric material. The reaction is complete in minutes, however, and proceeds with retention of configuration. Presumably this is a result of a double inversion mechanism that passes through an a-lactone. Interestingly, the corresponding reaction with lactic acid does occur with inversion [18]. 

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