Synthesis of (¹⁵N₂)[¹⁷O]Urea, (¹⁵N₂)[O², O⁴‐¹⁷O₂]Uridine, and (¹⁵N₃)[O²‐¹⁷O]Cytidine

Abstract

A general synthetic approach for the synthesis of "Nand 170-doubly labelled pyrimidine nucleosides is described. The I5N isotopes in uridine and the I7O isotope in the urea-derived carbonyl group of uridine and cytidine originate from (15N2)['70]urea (5) which was synthesized from "NH,CI, thiophosgene (I), and H,['70]. The third "N isotope of cytidine in 4-position stems from the substitution of the 1,2,4-triazole moiety of ('SN3[02-170]uridine derivative 8a/b with "NH,OH. Hydrolysis of the same key intermediate 8a/b with Na[170]H/H2[170] introduced the second I7O isotope into the 4-position of uridine. The "Nand I70-NMR spectra of the target compounds 12 and 14 in phosphate-buffered H,O serve as references for heteronuclear NMR spectra of labelled RNA fragments.

Conversion of N-acyl amidines to amidoximes: a convenient synthetic approach to molnupiravir (EIDD-2801) from ribose

“…Silylation of nucleobases with hexamethyldisilazane (HMDS) in catalytic amount of TMSOTf prior to coupling with sugar donors is well known Silyl Hilbert–Johnson reaction which is reported mostly for the synthesis of uridine derivatives. 15 But, mostly cytidine is obtained from uridine after a series of steps which involves chlorination with POCl 3 and substituent installation of 1,2,4-triazole to get amine with the treatment of hydroxylamine 16 ( Scheme 3A ). For direct access of cytidine Raffaele et al reported microwave accelerated glycosylation approach from N -benzoyl cytosine with 50% yield 17 ( Scheme 3B ), So in order to improve the yield further optimization of reaction was needed.…”

Synthesis of a bifunctional cytidine derivative and its conjugation to RNA for in vitro selection of a cytidine deaminase ribozyme

“…Among the procedures described for conversion of uridine into cytidine derivatives [ 31 – 34 ] we have chosen the path via a triazolyl activated uridine [ 31 ], because the triazolyl derivatives are known being stable enough to allow convenient handling and isolation, and they have shown very good reactivity with aliphatic amines. Synthon 3 could be isolated by recrystallization in 76% yield.…”

Specific labelling of nucleosides and nucleotides with 13C and 15N

“…With the appropriate selection of leaving groups postsynthetic N4 labelling of cytidine and N6 labelling of adenosine was achieved with good yield. 98 Usually the source of 15 N was labelled ammonia (either as a water solution, 70,[98][99][100][101][102][103] or generated in situ from its salt 22,74,75,[104][105][106][107] ). Another possibility is the use of 15 N-labelled phthalimide 108,109 or 15 N-benzylamine 110-114 as a nucleophile (Scheme 10).…”

“…The exception is the situation, when the label source contains more than one isotope atom and several labels are introduced simultaneously. An example of such a case are the syntheses starting from [ 13 C 6 ]-dglucose 13,14,93,94 or the synthesis of [1,[3][4][5][6][7][8][9][10][11][12][13][14][15] 102 where the authors applied a multiple-isotope-labelled urea as a substrate. Usually, however, multilabelling (either with several atoms of the same isotope or with different isotopes) means a combination of single-labelling syntheses described above.…”