Synthesis of Oligonucleotides Containing Thiazole and Thiazole N-Oxide Nucleobases

Abstract

[reaction: see text] The thiazole C-nucleoside analogue was synthesized by the Hantzsch cyclization method to form the thiazole ring and was then converted to the thiazole N-oxide C-nucleoside analogue by peracid oxidation of the heterocycle nitrogen. Incorporation of the thiazole and thiazole N-oxide phosphoramidites into DNA was successful though significant deoxygenation of the N-oxide occurred during DNA assembly. The mechanism proposed for the reduction of the thiazole N-oxide to thiazole involves the formation of an N-oxide phosphite ester.

Synthesis and Properties of DNA Oligomers Containing 2‘-Deoxynucleoside N-Oxide Derivatives

“…The N -oxide function was found to be very stable toward triethyl phosphite for at least 24 h. Interestingly, the reaction of 5 with diphenyl phosphite led to the deoxygenation of the N -oxide moiety ( t 1/2 = 4 h). In connection with our study, Hammer has recently reported the facile reduction of a 2‘-deoxynucleoside analog using a thiazole N -oxide nucleobase with phosphitylating reagents …”

Easy access to the family of thiazole N-oxides using HOF·CH3CN

“…3 Recent studies on the design and synthesis of oligonucleotides containing thiazole N-oxide disclose that this functionality is unique in the sense of introducing a pronounced directional dipole into molecules that is capable of forming specific and strong hydrogen bonds. 4 Such biologically important findings have triggered intensive efforts aimed at the preparation of the thiazole N-oxide moiety, but the built-in limitations of the orthodox routes used did not result in conspicuous success. The synthesis, via cyclization of v-(dialkylamino-oximinomercapto)acetophenone, involves a multi-step reaction and is restricted to specific starting materials, 5 while direct oxidation using meta-CPBA or permaleic acid requires very long reaction times, leading to thiazole N-oxides in yields of 15 to 50% only.…”

“…The synthesis, via cyclization of v-(dialkylamino-oximinomercapto)acetophenone, involves a multi-step reaction and is restricted to specific starting materials, 5 while direct oxidation using meta-CPBA or permaleic acid requires very long reaction times, leading to thiazole N-oxides in yields of 15 to 50% only. 3,4,6,7 There is only one example describing the formation of thiazole N-oxide C-nucleoside in good yield using trifluoroacetic anhydride and hydrogen peroxide-urea complex. 4 Clearly, a general and efficient methodology for the preparation of this important family is needed.…”

“…3,4,6,7 There is only one example describing the formation of thiazole N-oxide C-nucleoside in good yield using trifluoroacetic anhydride and hydrogen peroxide-urea complex. 4 Clearly, a general and efficient methodology for the preparation of this important family is needed.…”