A Pauson–Khand Approach to New Carbocyclic Nucleoside Analogs

Abstract

AbstractThe synthesis of three new carbocyclic nucleoside analogs (CNAs) with the nucleobase attached to a 3′‐hydroxymethylcyclopent‐2′‐en‐1′‐yl scaffold is reported. A variety of symmetric dienynes (propargylic acetals of type 11) were used as substrates in a cobalt‐mediated Pauson–Khand (PK) reaction to give bicyclic cyclopentenone derivatives of type rac‐12 with high diastereoselectivity. These compounds are valuable building blocks for the synthesis of structurally diverse CNAs with a high biological potential as apoptosis‐inducing agents. Starting from the PK product rac‐12a, the synthesis of 4′‐trialkylsilyloxyethyl‐substituted nucleosides rac‐18 and rac‐19 (with 5‐bromouracil and 6‐chloropurine as a nucleo‐base, respectively) was accomplished in seven steps (28 % and 37 % overall yield). The regio‐ and diastereoselective nucleobase (NB) introduction was achieved by Pd0‐catalyzed allylic substitution. Starting from the PK product rac‐12e, the 2′‐phenyl‐4′‐trialkylsilyloxymethyl‐substituted CNA rac‐17 was prepared (6 steps, 29 % yield)by exploitingan alternative protocol — a Mitsunobu reaction — for the NB introduction. The key intermediates 12a and 12e were obtained in virtually enantiopure form by kinetic resolution by means of oxazaborolidine‐catalyzed borane reduction (CBS reduction) in the presence of a (R)‐diphenylprolinol‐derived B‐methyl oxazaborolidine catalyst. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)