Modulating the Stability of 2-Pyridinyl Thermolabile Hydroxyl Protecting Groups via the “Chemical Switch” Approach

Abstract

A novel and effective method is presented for modulating the stability of 2-Pyridinyl Thermolabile Protecting Groups (2-Py TPGs) in the "chemical switch" approach. The main advantage of the discussed approach is the possibility of changing the nucleophilic character of pyridine nitrogen using different switchable factors, which results in an increase or decrease in the thermal deprotection rate. One of the factors is transformation of a nitro into an amine group via reduction with a low-valent titanium in mild conditions. The usefulness of our approach is corroborated using 3'-O-acetyl nucleosides as model compounds. Their stability in various solvents and temperatures before and after reduction is also examined. Pyridine N-oxide and pH are other factors responsible for the nucleophilicity and stability of 2-Pyridinyl Thermolabile Protecting Groups in thermal deprotection. Protonation of 4-amino 2-Pyridinyl Thermolabile Protecting Groups is demonstrated by (1)H-(15)N HMBC and HSQC NMR analysis.

Experimental and computational studies on a protonated 2-pyridinyl moiety and its switchable effect for the design of thermolytic devices

“…Compound for NMR studies, 4-amino-2-pyridinyl-N-benzylaminoethanol (4-APyBzOH) was synthesized according to previously reported method [ 10 ]. 4-APyBzOH was diluted in DMSO-d6 (dried over 4Å molecular sieves).…”

“…Based on the above considerations, we developed two systems with reversible processes: “ click-clack ” (intramolecular cyclization and decyclization) [ 9 ] and “ chemical switch ” (transformation of a nitro into an amine group) [ 10 ] and demonstrated their usefulness in the regulation of thermolytic deprotection rates of 2-Pyridinyl Thermolabile Protecting Groups (2PyTPGs) [ 11 ]. The use of chemical modification to enable switching properties of 2PyTPGs increases the protecting group’s attractiveness.…”

“…Recently, we have shown the advantage of 2PyTPG as a perfect thermocontrolled group cleaved from the hydroxyl [ 14 ] and phosphate functions [ 15 ] in nucleosides and nucleotide chemistry [ 11 ]. Moreover, protonation of 2PyTPGs can be enabled by controlling their thermolabile properties [ 10 ]. We also proved that we were able to control this deprotecting process via intramolecular cyclization and modulation of the four factors: i) temperature, ii) electron distribution in the pyridine ring by various substituents on 4 position, iii) pH levels [ 16 ], and iv) steric effect [ 17 ].…”

“…Nucleophilicity of pyridinic nitrogen is the driving force behind the thermocyclization process initiated by an attack of endocyclic nitrogen on the α-methylene bridge in the aminoethanol linker of potential 2PyTPG ( S1 Fig ). Therefore, through temperature or pH adjustments, we were able to control the rate of the intramolecular cyclization via protonation of N 1 nitrogen [ 10 ] Although pyridinic nitrogen N 1 participates in thermocyclization and its nucleophilicity determines this process, the role of other nitrogens, i.e. N 2 from the aminoethanol substituent or N4 from the 4-amino group, should not be neglected.…”

2-Pyridinyl-N-(2,4-difluorobenzyl)aminoethyl Group As Thermocontrolled Implement for Protection of Carboxylic Acids

“…26 The presence of the bicyclic product 3 confirms the mechanism known from carbonate thermocyclization. 27 Table 2 shows the data of the deprotection rate for protected carboxyl moieties 2a−e which are presented in time position (1 and 2 h heating) and include room (25 °C), lower (60 °C), and higher (90 °C) temperatures.…”