ChemInform Abstract: Stereoselective Synthesis of Pyrrolo(2,3‐d)pyrimidine α‐ and β‐D‐Ribonucleosides from Anomerically Pure D‐Ribofuranosyl Chlorides: Solid‐Liquid Phase‐Transfer Glycosylation and 15N NMR Spectra.

Abstract

Solid-liquid phase-transfer glycosylation (KOH, tris[2-(2-methoxyethoxy)ethyl]amine ( = TDA-I ), MeCN) of pyrrolo[2,3-djpyrimidines such as 3a and 3b with an equimolar amount of 5-U-[( 1, I-dimethylethy1)dimethylsilyl~-2,3-U-(l-methylethylidene)-a -D-ribofuranosyl chloride (1) [6] gave the protected 8-o-nucleosides 4a and 4b, respectively, stereoselectively (Scheme). The B-o-anomer 2 [6] yielded the corresponding a -D-nucleosides 5a and 5b with traces of the 8-D-compounds. The 6-substituted 7-deazapurine nucleosides 6a, 7a, and 8 were converted into tubercidin (10) or its a -D-anomer (1 1). Spin-lattice relaxation measurements of anomeric ribonucleosides revealed that T , values of H-C(8) in the a-o-series are significantly increased compared to H-C(8) in the B-D-series while the opposite is true for T , of H-C(1'). I5N-NMR data of 6-substituted 7-deazapurine o-rihofuranosides were assigned and compared with those of 2'-deoxy compounds. Furthermore, it was shown that 7-deaza-2'-deoxyadenosine ( = 2'-deoxytubercidin; 12) is protonated at N( l), whereas the protonation site of 7-deaza-2'-deoxyguanosine (20) is N(3).Introduction. -Pyrrolyl anions have been proved to be effective in regioselective glycosylation of pyrrolo[2,3-d]pyrimidines. They were employed first by Goto during the synthesis of queosine and were generated with NaH [ 11.In 1983, the synthesis of 7-deazaguanosine and -inosine has been reported by our laboratory using liquid-liquid phase-transfer conditions for anion generation and employing benzyl-protected D-ribofuranosyl bromide during glycosylations [24]. According to the configuration of the bromo sugar, predominant formation of a -D-configurated glycosylation products was observed (a //? 5 : 2). Nevertheless, it was recognized that glycosylation proceeded stereoselectively and was controlled by the anomeric ratio of halogenoses present in the reaction mixture. Unfortunately, it was not possible to generate the anomerically pure bromo sugar separately. Moreover, all attempts to use acyl-protected halogenoses failed. While acyloxonium ions are formed as intermediates, nucleophilic attack of the nucleobase resulted in orthoamides which were not rearranged to nucleosides [ 51. As a consequence, neighbouring-group participation which directs the incoming nucleobase into the /?-face cannot be exploited.Recently, Wilcox and coworkers have described the preparation of a -and /?-D-configurated 2,3-U-isopropylidene-5-0-[(terf-butyl)dimethylsilyl]-~-ribofuranosyl chlorides 1 and 2, respectively [6]. As these halogenoses can be prepared as pure anomers and do not contain a participating substituent at C(2), we have employed them for the synthesis of pyrrolo[2,3-d]pyrimidine D-ribofuranosides. In the following, we describe the stereoselective synthesis of either /?-or a -D-configurated tubercidin (10 and 11, resp.) employing the halogenose 1 or 2 upon solid-liquid phase-transfer glycosylation. As now pyrrolo[2,3-d]pyrimidine D-ribonucleosides as well as 2'-deoxy-~-ribonucleosides are available in sufficient...

Fluorinated 7-Deazapurine 2′-Deoxyribonucleosides: Modification At The Nucleobase And The Sugar Moiety

“…[6] The same strategy was used to synthesize the fluorinated pyrrolo[2,3-d]pyrimidine derivatives 12 and 13 by utilizing lower temperature conditions than used for 11. The nucleobase-anion glycosylation reaction [7,8] of the base (11-13) afforded the 7-fluorinated inosine derivatives 4a,b, as well as the 7-deaza-7-fluoro-2 -deoxyguanosine (5), 7-deaza-7-fluoro-2 -deoxyisoguanosine (7), and 7-deaza-7-fluoro-2 -deoxyxanthosine (8). Glycosylation of 11 with the halogenose 14a,b gave the nucleosides 15a,b, which were deprotected in NaOCH 3 to afford the 6-methoxy derivatives 1a,b.…”

“…[5] In a similar way, compounds 12 and 13 were glycosylated with 14a to form the nucleosides 16 and 17, which were deprotected in NaOMe/MeOH to give the intermediate methoxy derivatives 2 and 3. Consequently, 2 and 3 were converted to 7-deaza-7-fluoro-2 -deoxyguanosine (5) and 7-deaza-7-fluoro-2 -deoxyxanthosine (8) in aqueous NaOH or with Me 3 SiCl/NaI in MeCN. The isodG derivative 7 was obtained from 6 by photochemically induced displacement reaction performed in water (30% yield) (Scheme 3).…”

pH-Dependent mismatch discrimination of oligonucleotide duplexes containing 2′-deoxytubercidin and 2- or 7-substituted derivatives: protonated base pairs formed between 7-deazapurines and cytosine

“…Possible protonation sites are only nitrogen-1 or nitrogen-3 (Scheme 4). Rosemeyer and Seela (43) reported that 15 N-NMR studies on 7-deazaadenine nucleosides show that the protonation site of 1a is N-1 ( 1ap ; Scheme 4, right). Therefore, the 1a -dC or 1d -dC base pairs should form according to bidentate motifs viia,b with nucleosides 1a or 1d in the N-1 protonated state (Figure 6).…”

Progress in 7-Deazapurine - Pyrrolo[2,3-d]pyrimidine - Ribonucleoside Synthesis

“…Since then, the 7deazapurine 2'-deoxyribonucleosides could be prepared in a stereo-controlled manner, with the exclusive formation of β-D-2'-deoxyribonucleosides [25,26]. Later on, this protocol was applied to the synthesis of other base-modified 2'deoxyribonucleosides [25,[28][29][30] as well as to 7-deazapurine ribonucleosides [31][32][33][34][35]. This was of particular value because the common glycosylation methods developed for purine nucleosides can not be applied efficiently to the synthesis of the corresponding 7-deazapurine nucleosides.…”

“…Tubercidin and its derivatives were prepared by this method. The glycosylation of nucleobase 37a or 100 with the sugar derivative 68 resulted in the intermediates 87a or 101 (Scheme 28) [34]. Treatment of 87a or 101 with 90% aqueous TFA yielded the deprotected compound 88a or 102.…”