Efficient Synthesis of 4′-Cyclopropylated Carbovir Analogues with Use of Ring-Closing Metathesis from Glycolate

Abstract

The first synthetic route of novel 4'-cyclopropylated carbovir analgues is described. The construction of cyclopropylated quaternary carbon at 4'-position of carbocyclic nucleosides was successfully made via sequential Johnson's orthoester rearrangement and ring-closing metathesis (RCM) starting from ethyl glycolate. Synthesized compounds 15 and 16 showed moderate antiviral activity without any cytotoxicity up to 100 micromol.

Synthesis and Anti-Hepatitis C Virus Activity of 2′(β)-Hydroxyethyl and 4′(α)-Hydroxymethyl Carbodine Analogues

“…[10] The aldehyde was condensed with the lithium reagent prepared from three equivalents of 3-bromo-but-3-enyloxyt-butyldimethylsilane 7 and 2.5 equivalents of butyl lithium in THF at −110 • C to yield the diene analogue 8. [11] The diene analogue 8 was subjected to ring-closing metathesis (RCM) conditions [12] using secondsgeneration Grubbs catalysis to provide cyclopentenol 9 as a racemic mixture (Scheme 1).…”

The Orthoester Johnson–Claisen Rearrangement in the Synthesis of Bioactive Molecules, Natural Products, and Synthetic Intermediates – Recent Advances

“…These compounds display greater metabolic stability to phosphorylase enzymes. Stimulated by this finding, Hong and co-workers [92] developed 4Јcyclopropylated carbovir analogues with the aid of Johnson-Claisen rearrangement and ring-closing metathesis. Stimulated by this finding, Hong and co-workers [92] developed 4Јcyclopropylated carbovir analogues with the aid of Johnson-Claisen rearrangement and ring-closing metathesis.…”

A synergistic approach to polycyclics via a strategic utilization of Claisen rearrangement and olefin metathesis

“…To this end, Hong and co-workers have demonstrated a convenient procedure for making 4¢-cyclopropylated carbovir analogues (440) using a sequential Johnson's orthoester CR and RCM protocol (Scheme 70). 81 Srikrishna and co-workers reported the total synthesis of (±)-1,14-herbertenediol 449 through (±)-11-epi-herbertenolide 448 via a simple and efficient methodology based on Johnson CR and RCM as key steps. The starting compound 2-methoxy-5-methylphenyl acetate 441 has been transformed to cinnamyl alcohol 442 and orthoester rearrangement of 442 with triethylorthoacetate and propionic acid followed by RCM furnished (±)-11-epi-herbertenolide 448.…”