Molbank 2007, M522 | www.mdpi.org/molbank/ |
Electrophilic Substitution at
C(7) of a Protected 7-Deaza-2’-deoxyguanosine –
The
2’-Deoxyribonucleoside Parent Analogue of Queuosine #
Most naturally occurring 7-deazapurine ribonucleosides [1,2] – both of the adenosine as well as of the guanosine type – carry substituents at the 7-position, and many of them which are found in tRNA represent Mannich bases such as the nucleoside “Q” {2-amino-5-(4,5-cis-dihydroxy-1-cyclopenten-3-yl-trans-aminomethyl-(7-ß-D-ribofuranosyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, Queuosine, 1}. Many attempts have been made to direct a Mannich side chain regioselectively into position 7. In contrast to 7-deazaadenosine derivatives [3,4] this is not an easy task for 7-deazaguanosine precursors [5] and requires chemical detours [6]. For example, regioselective C(7) Mannich alkylation (morpholine, HCOH/HOAc) can be performed at 3’,5’-bis-O-toluoylated 6-methoxy-2-(methylthio)-7-deazapurine 2’-deoxy-ß-D-ribonucleoside, followed by a three-step aglycone conversion to 7-deazaguanine and deprotection of the glycone [7].
It has been reported for 7-deazaguanines that the position of electrophilic substitution strongly depends on the particular substituent pattern of the base as well as of the reaction conditions [8-10]. Of decisive importance is the observation that a free 2-amino group directs the electrophilic attack into the undesired 8-position (position 6 using systematic numbering) of the 7-deazaguanine moiety. This is the result of mesomeric stabilization of the σ-complex formed during electrophilic attack at the 8-position. On the other hand, 2-acylamino-7-deazaguanine derivatives form the desired 7-substituted compounds [8]
In this communication we disclose that reaction of the fully protected 7-deaza-2’-deoxy-7-deazaguanosine derivative 2 [8] with N,N-dimethyl-methyleniminium iodide (Eschenmoser’s salt) afforded the C(7) alkylated Mannich compound 4 in moderate yield. This reaction presents a new and alternative route to 7-deazapurine nucleosides with a Mannich side chain in position 7. The structure of 4 was unequivocally assigned by 1H- and 13C-NMR spectroscopy as well as by 1H-NMR NOE difference spectroscopy (see Experimental Procedure). 13C-NMR resonances were assigned applying DEPT-135 and [C,H]HETCOR spectra.
A further transformation of the tertiary amino group of 4 into other Mannich compounds can be accomplished after quarternization. Furthermore, the synthetic or enzymatic incorporation of Mannich bases derived from compounds such as compound 4 allows the introduction of reporter groups in a favourable position of a DNA molecule because the Mannich side chain protrudes into the major groove of a B-DNA double helix.
Experimental Procedure# Purine numbering has been used within the General Part of the manuscript, systematic numbering within the Experimental Part.
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