Stereodivergent Synthesis of Biologically Active Spironucleoside Scaffolds via Catalytic Cyclopropanation of 4--Methylene Furanosides.

Cyclopropane fusion of the only rotatable carbon-carbon bond in furanosyl nucleosides (i.e., exocyclic 4'-5') is a powerful design strategy to arrive at conformationally constrained analogues.

Regio- and Stereoselective Synthesis of C-4' Spirocyclobutyl Ribofuranose Scaffolds and Their Use as Biologically Active Nucleoside Analogues.

Novel C-4',C-5' cyclobutane-fused spirocyclic ribonucleoside analogues were prepared. Thermal [2 + 2] cycloaddition between dichloroketene and readily derived 4'--methylene furanoses afforded a first entry to the required constrained ribofuranoses, relying on a carbonyl transposition sequence. Alternatively, an unusual stereoselective ionic [2 + 2] cycloaddition using methyl propiolate promoted by methylaluminoxane gave a complementary, more direct approach to such ribofuranoses.

Synthesis and Reactivity of Spirocarbocycles as Scaffolds for Nucleoside Analogues.

A novel class of substituted spiro[3.4]octanes can be accessed via a [2 + 2]-cycloaddition of dichloroketene on a readily prepared -methylene cyclopentane building block. This reaction sequence was found to be robust on a multigram scale and afforded a central spirocyclobutanone scaffold for carbocyclic nucleosides.

Stereoselective Reductions of 3-Substituted Cyclobutanones: A Comparison between Experiment and Theory.

The stereoselective reduction of carbonyls is of key importance in the total synthesis of natural products and in medicinal chemistry. Nevertheless, models for rationalizing the stereoselectivity of the hydride reductions of cyclobutanones toward cyclobutanols are largely lacking, unlike cyclohexanone reductions. In order to elucidate the factors that control the stereoselectivity of these reductions, we have investigated the effect of the reaction temperature, solvent, substituent, and type of reducing agent using a synergistic experimental-computational approach.