SYNTHESIS OF 5-ALKENYLATED D4T ANALOGUES VIA THE Pd-CATALYZED CROSS-COUPLING REACTION

Abstract

The target compounds 5-[N-(6-amino-hexyl)-acrylamide]-2',3'-didehydro-2',3'-dideoxy-uridine (12) and 5-[N-[5-(methoxycarbonyl)-pentyl]-acrylamide]-2',3'-didehydro-2',3'- dideoxy-uridine (15) were prepared by the palladium acetate-triphenylphosphine-catalyzed reaction of the 5'-O-acetyl-5-iodo-d4T analogue (3). These compounds 12 and 15 can be used to prepare nucleotide probes carrying fluorescent labels and were nevertheless screened for their anti-HIV activity. The biological data demonstrated that none of them were active against HIV-1.

Synthesis of 2,3-Didehydro-2,3-dideoxynucleosides via Nucleoside Route.

“…A variant of the Mattocks reaction using acetyl bromide has been successfully developped by Marumoto [76]. Treatment of uridine (4) and 5-methyluridine (15) with acetyl bromide in acetonitrile afforded the 3',5'-di-O-acetyl-2'-bromo-2'-deoxy derivatives 16 and 17 along with by-products in some cases such as the 5'-bromo derivatives [75,77]. Application of this method to N 4 -acetylcytosine (18) gave the corresponding bromoacetates 19 and 20 in low yield (30%) (see Scheme 9) [78].…”

“…However this methodology was not as successful for the synthesis of the corresponding bromoacetate derivatives. An alternative synthesis of 2-O-acetyl-3'-deoxy-3'-halo nucleosides 22 and 25 was developed via the reaction of 3',5'-di-O-acetyladenosine (24) with boron trifluoride etherate or antimony pentachloride in the presence of anhydrous Several methods for reductive β-elimination of acetoxybromo nucleosides have been described using zinc [74,75,77,78,80,[85][86][87][88][89], chromium [90], viologen [91] Scheme 12. electrochemistry [92][93][94]. Treatment of a 2',3'-transhaloacetate or a 2',3'-cis-haloacetate with zinc dust or zinccopper couple with or without the addition of acetic acid gave good results but sometimes were disadvantaged by failing to reach completion.…”

Modulation of the Electronic Properties of Non-innocent (E,E)-Dibenzylideneacetone for Palladium(0)-Mediated Heck Alkenylation of 5-Iodo-2′-deoxyuridine and Scale-Up Studies

“…Changes in the amount of base, solvent, or additive (TBAB) brought about a slight improvement in yield. To study the catalyst, several different palladium(0) and palladium(II) phosphine free precursors were employed (entries [23][24][25][26][27][28][29]. Most of the palladium(II) precursors failed to furnish the desired product, while an interesting effect was observed in the case of substituted [Pd 2 (dba-4,4′-X) 3 ] complexes.…”

Bifunctional inhibition of HIV-1 reverse transcriptase: A first step in designing a bifunctional triphosphate

“…Substitution at both N-3 and C-5 of AZT (Retrovir) has lead to inactive antiviral compounds 11 . The substitutions at C-5 in d4T (stavudine, Figure 1) yield mixed results, but mostly result in inactive analogs 14,25,28–30 . Attempted modifications to AZT and d4T suggest the difficulty for human thymidine kinase (hTK) to phosphorylate 2′,3′-dideoxythymidine analogs, but there is evidence that C-5 substituted thymidine can be phosphorylated in vivo by thymidine kinase 31–33 .…”