Chemistry of some-5-(2-hydroxyalkyl)uracil derivatives and a synthesis of 5-vinyluracil

Abstract

From 5-(2-hydroxyethyl)uracil, its 2-0-methanesulfonate or 2'-0-p-toluenesulfonate, treated with acid or base, a variety of substitution or elimination products can be obtained, depending on the conditions used. Mechanisms for interand intramolecular nucleophilic substitutions, and their competition with elimination of the C-2' groups, are discussed. The decarboxylation of <rons-3-(5-uracilyl)propenoic acid to 5-vinyluracil is described, and the effects of association of the vinylic and propenoic acid side chains with the uracil ring on both the pK* values and ultraviolet and infrared absorption spectra are interpreted. The chemical consequences of these finds in biologically active compounds are considered.Pyrimidines with lipophilic substituents at position 5 display substantial biological activity.2-4 In another lino of investigation a number of N-vinyl derivatives of purines or pyrimidines,5-10 and some O-acryloyl nucleosides11-15 have been useful for studies of intramolecular forces in nucleic acid16-19 and for chromatographic separation of nucleic acid components.20-23We have now extended our synthetic approach to the 5-substitutcd pyrimidines24 to 5-vinyluracil, which is of interest to both of the above areas of investigation. The van der Waals radius of the 5-vinyl substituent is expected to be nearer to that of the methyl of thymine than is that of the ethyl of 5-ethyluracil, which is a thymine analog.25-27The presence of the 5-vinyl substituent should leave the hydrogen-bonding properties of the pyrimidine ring essentially unchanged, so that a polymer of this compound could be uniquely useful as a chromatographic(1) This investigation was supported in part by funds from the National Cancer Institute (Grant No. CA 08748) and the American Cancer Society (Grant No. P 295).(2)

Synthesis of 5-(1-azidovinyl) and 5-[2-(1-azirinyl)] analogs of 2′-deoxyuridine

“…The base-catalyzed intramolecular cyclization reaction of 3a to 6, as illustrated in Scheme 2, is analogous to the reported conversion of 5-[2-[(methylsufonyl)oxy]ethyl]uracil to 2,3-dihydrofurano[2,3-4-pyrimidin-6(5H)-one using t-BuOK in DMSO (9). The mechanism responsible for the formation of the bicyclic compound 5 proceeds via an elimination reaction involving expulsion of HN3 from 6 as illustrated in Scheme 3 since treatment of 6 with a saturated solution of NH, in MeOH gave the bicylic derivative 10, rather than the azido compound 11 (see Scheme 1).…”

“…The in vitro antiviral activities of 5-(1-azidoviny1)-(7), 5-[2-(1-azirinyl)]-2'-deoxyuridine (9), and the related bicyclic For personal use only. (10) provided compounds that were inactive in the in vitro assays against HSV-1, HSV-2, VZV, and CMV.…”

“…The possibility that the 5-[2-(1-azirinyl)] compounds (8, 9) may undergo a [2 + 21 cycloaddition reaction to produce dimeric products 12 was ruled out since the fast atom bombardment (FAB) spectrum of 8a and 9 did not exhibit a molecular ion or mass fragmentation pattern indicating a dimeric structure 12. The FAB spectra (8a, 9) exhibited the expected M + 1, 5-[2-(1-aziriny1)luracil and sugar fragment, ions. Attempts to remove the 3',5'-protecting groups present in compounds 8a-c using NH3 in MeOH (8n, 8c), NaHC03 in dry MeOH (8a, 8b), or p-toluenesulfonic acid (8c) were unsuccessful.…”

“…Attempts to remove the 3',5'-protecting groups present in compounds 8a-c using NH3 in MeOH (8n, 8c), NaHC03 in dry MeOH (8a, 8b), or p-toluenesulfonic acid (8c) were unsuccessful. In contrast, reaction of 86 with nBu,N+F in THF afforded 5-[2-( 1 -azirinyl)]-2'-deoxyuridine (9) in 25% yield. The optimum yield of 9 was obtained by thermal decomposition of 5-(1-azidoviny1)-2'-deoxyuridine (7) in dioxane (37% yield).…”

Hydroxyl-Functionalized DNA: An Efficient Orthogonal Protecting Strategy and Duplex Stability

“…[12,15,16] as described in Scheme 1. The sugar moiety of compounds 2b and 3b was protected with toluoyl group after the glycosylation reaction of the hydroxyl-bearing nucleobases 2a and 3a with 1-chloro-3,5-ditoluoyl-2-deoxypentofuranose (chlorosugar).…”