Fully Automated Continuous Meso-flow Synthesis of 5′-Nucleotides and Deoxynucleotides

Abstract

The first continuous meso-flow synthesis of natural and non-natural 5′-nucleotides and deoxynucleotides is described, representing a significant advance over the corresponding in-flask method. By means of this mesoflow technique, a synthesis with time consumption and high-energy consumption becomes facile to generate products with great efficiency. An abbreviated duration, satisfactory output, and mild reaction conditions are expected to be realized under the present procedure.

Continuous Flow Organophosphorus Chemistry

“…Ying and co-workers reported the continuous flow preparation of natural and non-natural 5′-nucleotides and deoxynucleotides using a mesofluidic reactor through a phosphorylation/hydrolysis sequence. [59] The process relied on POCl 3 as a phosphorylating agent and directly started from unprotected nucleosides and trimethylphosphate (TMP) as the solvent. Water was subsequently injected in the second reactor to perform the hydrolysis step ( Figure 13).…”

“…Two-step continuous flow sequence for the preparation of natural and non-natural nucleotides starting from nucleosides using phosphoryl chloride as a phosphorylation agent. [59] excellent yields, while non-natural products (generally halogenated) were obtained in lower yields due to side-reactions. Using proton sponge as an additive helped to reduce the presence of these unwanted side-products for the preparation of some nucleotides.…”

“…A series of aldehydes were successfully coupled with diethyl phosphite using the catalyst without the use of any solvent. Next, the procedure was adapted to a cyclic flow process affording the Pudovik product from benzaldehyde (59) and diethylphosphite (60) in 99 % yield using 5 mol-% of PS-BEMP during 2.5 h at 30°C ( Figure 19). MeOH was pumped into the system to wash the catalyst, the product was easily recovered in its pure form after evaporation of the alcohol.…”

“…Next, the procedure was transposed under continuous flow conditions with a packed-bed reactor (Figure 70). Using toluene as a solvent, benzaldehyde (59) and allylborane 266 were mixed and reacted in a packed-bed column containing PS-TRIP and operated at room temperature. An aqueous solution of NaHSO 3 was injected downstream for scavenging any unreacted benzaldehyde (59) and hence avoiding stereochemical drift due to a side-reaction in the collection flask.…”

“…After the demonstration of the acetalization with a large diversity of aldehydes in batch, the procedure was transposed under continuous flow conditions. Benzaldehyde (59) was used as a model compound in methanol and its acetal- Figure 70. Phosphoric acid-catalyzed asymmetric allylboration of benzaldehyde under continuous flow conditions.…”