Highly concise synthesis of 3'-"up"-ethynyl-5'-methylbicyclo- [3.1.0]hexyl purine and pyrimidine nucleoside derivatives using rhodium(II) carbenoid cycloaddition and highly diastereoselective Grignard reaction

Abstract

Synthesis of north-5'-methylbicyclo[3.1.0]hexyl purine and pyrimidine nucleosides with an ethynyl group at C-3' position has been successfully accomplished by a facile method. Methylbicyclo[3.1.0]hexanone (±)-5 having three contiguous chiral centers was remarkably simply constructed only by four steps containing a carbenoid insertion reaction in the presence of rhodium(II) acetate dimer and CuSO 4, giving a correct relative stereochemistry of the generated three chiral centers. Upon Grignard reaction of (±)-5 with ethynylmagnesium bromide, exclusive diastereoselectivity was observed. Condensation of glycosyl donor (±)-9 with purine nucleobase afforded only the desired N9-alkylated nucleoside, while condensation with pyrimidine, N 3-benzoylated uracil gave the desired N1-alkylated nucleoside (±)-13 with the undesired O 2-alkylated nucleoside (±)-14. Probably, (±)-14 would be formed due to steric hindrance caused upon approaching for N1-alkylation. © 2009 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.