Synthesis of the Cyclopentyl Nucleoside (−)‐Neplanocin A from D ‐Glucose via Zirconocene‐Mediated Ring Contraction

Two approaches for the conversion of d‐ glucose to (−) ‐neplanocin A ( 2 ), both based on the zirconocene‐promoted ring contraction of a vinyl‐substituted pyranoside, are herein evaluated ( Scheme 1 ). In the first pathway ( Scheme 2 ), the substrate possesses the α ‐ d‐ allo configuration (see 6 ) such that ultimate introduction of the nucleobase would require only an inversion of configuration. However, this precursor proved unresponsive to Cp 2 Zr (=[ZrCl 2 (Cp) 2 ]), an end result believed to be a consequence of substantive nonbonded steric effects operating in a key intermediate ( Scheme 5 ). In contrast, the C(2) epimer (see 7 ) experienced the desired metal‐promoted conversion to an enantiomerically pure polyfunctional cyclopentane (see 5 in Scheme 3 ). The substituents in this product are arrayed in a manner such that conversion to the target nucleoside can be conveniently achieved by a double‐inversion sequence ( Scheme 4 ). Recourse to palladium(0)‐catalyzed allylic alkylation did not provide an alternate means of generating 2 .