Purines. XXIX. Syntheses of 9-alkyl-2-deuterio-N6-methoxyadenines and 2-deuterio-N6,9-dimethyladenine: Tautomerism in 9-substituted N6-alkoxyadenines.

Abstract

Cyclizations of the alkoxyamidines 7a, i with formic acid gave N6-methoxy-9-methyladenine (8a) and 9-benzyl-N6-methoxyadenine (8i). Replacement of formic acid by formic-d acid-d in these cyclizations afforded the 2-deuterated species 13a and 13i. A similar cyclization of 22, obtained from 21 by alkaline hydrolysis, with formic-d acid-d yielded 2-deuterio-N6-methoxy-1,9-dimethyladenine (24). The N6-methyl isomer 19 was prepared from 13a by treatment with NaH and MeI.Comparison of the proton nuclear magnetic resonance ('H-NMR) spectrum of 8a in with that of .13a revealed that 8a exists as an equilibrated 1 : 3.5 mixture of the amino (type 14 or 15) and the imino (type 16 or 17) forms. The deuterated species 19 and 24 were utilized for interpretation of the 'H-NMR spectra of the amino-form model 18 and the imino-form model 23. The existence of amino-imino tautomerism in 8a was also supported by ultraviolet and infrared spectroscopic evidence. Such tautomerism, with a preference for the imino form, in Me2S0-d6 was found to be common to 13 other 9-substituted N6-alkoxyadenines (type 8) including adenosine analogues. On the other hand, comparison of the 1H-NMR spectra of 11, N6,9-dimethyladenine (12), and N6,N6,9-trimethyladenine (36) indicated that 12 exists solely in the amino form in CDC13 or Me2S0-d6. KeywordsN6-alkoxy-9-alkyladenine; N6-alkoxyadenosine; 9-alky1-2-deuterio-N6-methoxyadenine; 2-deuterio-N6,9-dimethyladenine; amino-imino tautomerism; 11-1-NMR; UV; IR An alkoxy group at the N6-position of adenine (1:R1 = H) and substituted adenines has been found of considerable synthetic utility because of its unique directivity in alkylation and substantial removability under hydrogenolytic conditions.2m The synthesis of 7,9-dialkyladeninium salts by us2a,c-e) from N6-alkoxy-9-alkyladenines (type 8) is a representative of such synthetic utility, culminating in the elegant syntheses of agelasine B, a sea sponge bicyclic diterpene with the 9-methyl-7-adeninylium moiety, and analogues by Tokoroyama's group.4) In 1966, we synthesized the N6-alkoxyadenines 8 for the first time and found that unambiguous assignments of the NH and the purine-ring proton signals in their nuclear magnetic resonance (NMR) spectra were difficult in many cases because of the complexity or dullness of the low-field signals. In order to interpret these spectra, we synthesized several 2-deuterated species and measured their 1 H-NMR spectra in the present study.The synthesis of the 2-deuterated species 13a and 13i was planned on the basis of our knowledge3) concerning fission and reclosure of the adenine ring, employing an alkoxy group at the 1-position, and of our recent success6) in synthesizing 9-substituted 2-deuterioadenines (type 5) from 9-substituted adenines (type 1) through the intermediates 2, 3, 4, 7, and 6 (Chart 1). Thus, the monocycle 7a5b) was treated with formic-d acid-d (of over 99% isotopic purity) in boiling MeCN for 6 h, giving 13a in 52% yield. The 1-benzyl analogue 7i6) was likewise cyclized to produce 13i in 63% yield. This...

Synthetic Studies Directed towards Agelasine Analogs – Synthesis, Tautomerism, and Alkylation of 2‐Substituted N‐Methoxy‐9‐methyl‐9H‐purin‐6‐amines

“…-95 ppm in imines 2Ј (relative to MeNO 2 at 0 ppm), as reported for 2aЈ previously. [3] All iminopurines 2Ј are drawn with the NH at N-1 and in their most probable double bond configuration (syn, Scheme 2), in accordance with earlier NMR [3,10,11] and UV [10] studies of imine 2aЈ and other 6-(methoxyamino)purines. We have no indication that chromatographic separation of any of the tautomer pairs would be possible.…”

Crystallization and preliminary analysis of a DNA dodecamer of d(CGCGmo6AATCCGCG) containing 2′-deoxy-N 6-methoxyadenosine: change in crystal packing with different humidity

“…In the case of an adenine derivative methoxylated at N(6), it has been shown that this modi®cation allows the adenine base to tautomerize between amino and imino forms with the latter more stabilized under hydrophilic conditions (Stolarski et al, 1984;Fujii et al, 1987). Matsuda and his colleagues showed by an in vitro polymerase incorporation assay that when a DNA fragment containing the modi®ed adenosine was used as a template, not only complementary thymidine residues but also cytidine residues were incorporated into the newly synthesized opposite DNA strand (Nishio et al, 1992).…”

Polymerase recognition of synthetic oligodeoxyribonucleotides incorporating degenerate pyrimidine and purine bases

“…The purine analogues N 6 -methoxyadenine (mo 6 A) (Z) and N 6 -methoxy-2,6-diaminopurine (K) correspondingly showed specific pairing with cytosine (C) and thymine (T) in duplexes (15)(16)(17). The analogue K gave greater duplex stabilities and so was chosen for further studies.…”