Synthesis using ring closure metathesis and effect on nucleoside transport of a (N)-methanocarba S-(4-nitrobenzyl)thioinosine derivative

Abstract

[reaction: see text] A new synthetic route to ring-constrained (N)-methanocarba nucleosides and nucleotides is presented. Ring closure of a diene intermediate using Grubbs catalyst provides a new avenue for the preparation of the cyclopentenone derivative 6, which is a versatile intermediate for various carbocycles. The product was almost as potent an inhibitor of es-mediated nucleoside transport as the parent compound, inhibiting initial rates of uptake of uridine into cultured CCRF-CEM cells by 50% at approximately 30-50 nM.

Scheme 1^a

^a (a) (COCl)₂, DMSO, THF, −78 °C, then TEA, rt. (b) PPh₃CH₃Br, n-BuLi, THF. (c) TBAF, CH₃CN. (d) (COCl)₂, DMSO, THF, −78 °C, then TEA, rt. (e) Vinylmagnesium bromide, THF, −78 °C. (f) 4, CH₂Cl₂. (g) MnO₂, CHCl₃.

Scheme 2^a

^a (a) 6-Cl-purine, DEAD, Ph₃P, THF. (b) (i) BCl₃, CH₂Cl₂, −78 °C, (ii) DMP, acetone, pTsOH. (c) (i) 10, NaOMe, MeOH, reflux, (ii) TFA, wet MeOH, 60 °C.