A Flexible, Efficient Synthesis of (±)-Carbocyclic Phosphonic Acid Nucleoside Derivatives

Abstract

An efficient and flexible synthesis of cyclopentane and hydroxylated cyclopentane phosphonic acid analogues is described.The key step involves the opening of an epoxide with either a nucleoside base or a selenyl anion to access the target molecules.Chemotherapies based on the administration of analogues of nucleosides and deoxynucleosides 1 have proved successful against a range of cancers and viral infections such as HIV, cytomegalovirus, and herpes virus. 1 In each case, intracellular processing of the nucleoside to its triphosphate 2 generates the active form of the nucleoside. 2 This phosphorylation sequence is often stepwise, and performed by more than one cellular kinase, and the initial formation of the nucleoside monophosphate is often the most difficult step in the sequence. Strategies to facilitate or bypass this first phosphorylation step have included the use of prodrugs of the pre-formed monophosphate. 3 Phosphonic acids 3 are rather more chemically stable analogues of the monophosphate which in some cases can still undergo phosphorylation and generate effective mimics of a nucleoside triphosphate ( Figure 1). 4 Figure 1Nucleosides, nucleoside triphosphates, and carbocyclic phosphonic acid nucleoside mimics.We have been investigating synthetic procedures which would allow us to access a range of phosphonic acid analogues of carbocyclic nucleosides. 5 Herein, we wish to report a flexible synthesis of hydroxy, dihydroxy and dideoxy versions using an efficient epoxide-opening strategy outlined in Scheme 1. Carbocyclic ribose analogues have been synthesised in a variety of ways, usually starting with ribose itself or a substituted cyclopentane derivative. 6 Such routes could be adapted to access phosphonic acids, however, we wished to maximise the flexibility of our route, and chose to synthesise all targets via the readily prepared epoxy-alcohol 4. In this strategy, nucleoside bases can be added to the meso-trans-epoxy-phosphonylmethyl cyclopentane 5 to generate directly 3¢-deoxycarbocyclic nucleosides 7. Conversely, the cis-epoxyphosphonylmethyl cyclopentane 6 could be converted to an allyl species onto which bases could be appended using Pd-p-allylation chemistry, 7 providing access to a range of ribose 10, arabinose 11, cyclopentane 9 and cyclopentene 8 analogues. This article describes how this strategy was put into practice.Scheme 1 An epoxide-opening strategy to access cyclopentene 8, cyclopentane 9, hydroxycyclopentane 7, cis-dihydroxycyclopentane 10 and trans-dihydroxycyclopentane 11 phosphonic acid nucleoside mimics.The trans-epoxy-alcohol 4a 8 was synthesised in six straightforward steps (Scheme 2) from dimethyl malonate, by a sequence of allylation, RCM, 8a saponification, reduction, alcohol silyl-protection and a trans-selective epoxidation. 9 The latter process afforded a 3:1 mixture of trans:cis epoxides from which the trans-isomer was isolated in 40% yield following silica gel column chromatography. Compound 4a was converted to the corresponding iodide 10 and then to the diisopropyl phosp...