The role of nucleophilic catalysis in chemistry and stereochemistry of ribonucleosideH-phosphonate condensation

Abstract

The efficiency and stereoselectivity of condensation of ribonucleoside 3 0 -H-phosphonates with alcohols were investigated as a function of amines used for the reaction. It was found that irrespective of the presence or absence of nucleophilic catalysts, the Dynamic Kinetic Asymmetric Transformation (DYKAT) was the major factor responsible for the stereoselective formation of the D P (S P ) isomers of the H-phosphonate diesters, and a mechanistic rationalization of this observation was proposed. In addition, studies on the reactions carried out in the presence of various bases led to the conclusion that certain sterically hindered pyridines, e.g. 2,6-lutidine, may act as nucleophilic catalysts in the condensation of ribonucleoside 3 0 -H-phosphonates with alcohols.

Stereochemistry of Internucleotide Bond Formation by theH-Phosphonate Method. 5. The Role of Brønsted and H-Bonding Base Catalysis in RibonucleosideH-Phosphonate Condensation—Chemical and Stereochemical Consequences

“…In contrast to many pyridine derivatives, [15,22] for most of the tertiary amines investigated, including these of relatively low basicity, the condensations were not quantitative and usually ca. 5-30% of the starting H-phosphonate monoester 1 remained unreacted (Table 1).…”

“…A variety of pyridine derivatives promote efficient and highly stereoselective condensations of H-phosphonate 1, most probably due to their ability to act as mild nucleophilic catalysts. [22] In contrast, the analogous reactions performed in the presence of more powerful nucleophilic catalysts, for example, 4-dimethylaminopyridine (DMAP) or Nmethylimidazole (NMI), suffered from decreased stereoselectivity and low yields that were attributed to side reactions at nucleobases and the phosphorus center. [11,22,[29][30][31] Interestingly, in the corresponding condensations in which tertiary aliphatic amines (triethylamine, TEA; diisopropylethylamine, DIPEA) were used as bases, the reactions were rapid, and stereoselectivity was usually higher than that observed for nucleophilic catalysts; however, the yields were not quantitative.…”

“…[22] In contrast, the analogous reactions performed in the presence of more powerful nucleophilic catalysts, for example, 4-dimethylaminopyridine (DMAP) or Nmethylimidazole (NMI), suffered from decreased stereoselectivity and low yields that were attributed to side reactions at nucleobases and the phosphorus center. [11,22,[29][30][31] Interestingly, in the corresponding condensations in which tertiary aliphatic amines (triethylamine, TEA; diisopropylethylamine, DIPEA) were used as bases, the reactions were rapid, and stereoselectivity was usually higher than that observed for nucleophilic catalysts; however, the yields were not quantitative. [22,23] This unusual observation prompted us to study in more detail H-phosphonate condensations proceeding in the presence of non-nucleophilic amines.…”

“…[11,22,[29][30][31] Interestingly, in the corresponding condensations in which tertiary aliphatic amines (triethylamine, TEA; diisopropylethylamine, DIPEA) were used as bases, the reactions were rapid, and stereoselectivity was usually higher than that observed for nucleophilic catalysts; however, the yields were not quantitative. [22,23] This unusual observation prompted us to study in more detail H-phosphonate condensations proceeding in the presence of non-nucleophilic amines. In this article, we present mechanistic investigations on the influence of general base and acid catalysis on chemistry and stereochemistry of ribonucleoside H-phosphonate condensations.…”

“…[18][19][20][21][22][23] For instance, it was found that by decreasing contents of pyridines in the reaction mixture, stability of the reactive H-phosphonate intermediates involved was increased by orders of magnitude, while the condensations with nucleophilic species were still rapid and effective. [15,18,20,21,24] An advantage of low concentration of a base in the reaction mixture is suppression of the rate of side reactions associated with an overactivation of H-phosphonate monoesters.…”