Bicyclo[3.1.0]Hexane Nucleosides

Various approaches for the synthesis of conformationally locked methanocarba LNAs bearing the pseudosugar bicyclo[3.1.0]hexane template are described. These nucleosides are conformationally rigid and reside exclusively in the North or South hemisphere of the pseudorotational cycle. The parameters that define the preferred boat conformation of the pseudosugar template control the anti or syn disposition of the attached nucleobases and the associated energy barriers between rotamers. These studies revealed a strict association between North/anti and South/syn conformations with energy barriers between rotamers exceeding those typical of conventional nucleosides. The syntheses of enantiomerically pure methanocarba LNAs, including 2′-deoxyribo and ribo versions, incorporate strict chemical methods as well as combined chemico-enzymatic approaches at different stages of the synthesis. Efficient enantioselective methods to obtain methanocarba LNAs are indispensable for the dissection of the critical biological problems studied in the succeeding chapters.