Synthesis of Pharmaceutically Relevant Chiral Tetrahydrofurans

Spiroproline derivatives are of interest in biological studies as an inhibitor and mechanistic probe of prolyl-4-hydroxylase. To develop potent inhibitors of angiotensinconverting enzyme (ACE), lipophilic and sterically hindered spiroproline derivatives have been substituted in the structural framework of peptides. In addition, spiroprolines could offer interesting scaffold precursors, particularly in synthesis of combinatorial libraries of peptides. Earlier synthetic efforts aimed at spiroproline analogs involved building the proline nucleus on the structural backbone of the alicyclic system followed by resolution. We decided to try to expand the potential of our synthesis of spirocyclic compounds to pro-line derivatives, with the hitherto unknown 2-aza-spiro[4.4]-nonane carboxylic acid (124) derivative as the target. 

---

This survey describes how the chemistry of lithiated oxygen heterocycles has been fruitfully exploited, particularly over the last 10 years, for the preparation of more (stereodefined) functionalized derivatives and products derived from them. Also, how they have contributed to natural product synthesis and molecules of relevant pharmaceutical interest. The genesis of the reactive lithiated intermediates (especially a- and orf/io-lithiated (hetero)arylepoxides, -oxetanes and -tetrahydrofurans) requires a careful choice of the experimental conditions in terms of solvents and temperature in order them to be successfully intercepted by electrophiles. The study of the aggregation and solvation of certain chiral functionalized lithiated oxygen heterocycles has provided further hints about the factors affecting their configurational stability and... 

---