Olefin Cross‐Metathesis for the Synthesis of Alkenyl Acyclonucleoside Phosphonates

Abstract

The detailed synthetic protocol for the straightforward, efficient synthesis of various alkenyl acyclonucleosides, including challenging trisubstituted alkenyl acyclonucleoside phosphonates, is described. The key step of those syntheses is an olefin cross-metathesis reaction between two olefins selected based on their reactivity using well-defined ruthenium alkylidene catalysts.

Preparation of Pyrimidine Alkenyl Acyclic Nucleoside Phosphonoamidates

“…(E)-N 1 -(4 -dimethoxyphosphinyl-2 -butenyl) thymine (see Basic Protocol 1 of Bessières et al, 2001) Dry argon (Ar) Anhydrous acetonitrile (CH 3 CN, Sigma-Aldrich) Bromotrimethylsilane (TMSBr) (Sigma-Aldrich) Anhydrous pyridine (Py, Sigma-Aldrich) L-Alanine neopentyl ester tosylate (see Support Protocol in Serpi, Madela, Pertusati, & Slusarczyk, 2013) Phenol (PhOH, Sigma-Aldrich) Triethylamine (Et 3 N, Sigma-Aldrich) Aldrithiol-2 (Sigma-Aldrich) Triphenylphosphine (PPh 3 , Sigma-Aldrich) Figure 1 Synthesis of S P and R P isomer of (E)-N 1 -(4 -O-phenyl-(neopentyloxy-L-alanine)phosphinyl-but-2-enyl)thymine (3a and 3b). Pileggi et al Additional reagents and equipment for thin-layer chromatography (Meyers, 2001) Prepare phosponoamidate 3 1.…”

“…This unit presents two different synthetic strategies for the synthesis of alkenyl acyclic nucleoside phosphonoamidate prodrugs. The first methodology (Basic Protocol 1) consists in the preparation of linear (E)-but-2-enyl pyrimidine ProTide via the bis-trimethylsilyl ester of the parent alkenyl dimethylphosphonate nucleoside, synthetized following the procedure reported in Basic Protocol 1 of Bessières et al (2001), another unit of Current Protocols in Nucleic Acid Chemistry. This intermediate, obtained by treatment of the parent nucleoside with an excess of trimethylsilyl bromide (TMSBr), is reacted, without purification, with the desired amino acid ester and an excess of phenol in pyridine in the presence of triethylamine, aldrithiol-2, and triphenylphosphine.…”

Expedient synthesis and biological evaluation of alkenyl acyclic nucleoside phosphonate prodrugs

“…Among these synthetic strategies, quite recently, Agrofoglio's group has elaborated a novel, efficient and straightforward synthesis of C5-alkenyl substituted ANPs via olefin cross-metathesis. [36][37][38][39][40][41][42] Although structure-activity relationship (SAR) studies on acyclic nucleosides have not clarified their pharmacophore model, the introduction of a rigid structural element such as the double bond has proved to be extremely important for their antiviral activity. 43,44 Precisely, the trans-alkene skeleton is able to mimic the three-dimensional geometry of the ribose ring maintaining also an electronic contribution similar to the one provided by the oxygen.…”