A Convenient Method for the Modification of 8-Bromoguanine via Its N⁹-Tetrahydrofuranyl Derivative

Abstract

M o d i f i c a t i o n o f 8 -B r o m o g u a n i n e v i a I t s N 9 -T e t r a h y d r o f u r a n y l D e r i v a t i v e Abstract: A simple and straightforward method for the introduction of some N-and O-protecting groups into 8-bromoguanine has been developed using 2-acetylamino-8-bromo-6-oxo-9-(tetrahydrofuran-2-yl)-purine as a key intermediate.

Synthesis of Lipophilic Guanine N-9 Derivatives: Membrane Anchoring of Nucleobases Tailored to Fatty Acid Vesicles

“…Using Mitsunobu conditions, alcohols can be used as substrates for the N-9 alkylation of guanine. This method can be used for noncanonical purines as well (for example, in the modification of 8-bromoguanine as reported by Madre et al, 30 further confirming the utility of 2-N-acetyl-6-O-DPC protection). Below, we report the synthetic routes to guanines modified with a C 10 lipophilic anchor, linked via an N-9 butyl spacer and either an ether, amide, or triazole moiety.…”

The Determinative Influence of the O6-(Diphenylcarbamoyl) Group on the Exocyclic Nitrogen Benzylation in 2-Amino-6-oxopurine Derivatives

“…A reasonable choice seemed to be the tosyloxy moiety, due to its convenient introduction and subsequent removal. Therefore, a model compound, 9-[(2-acetoxyethoxy)methyl]-2-(acetylamino)-8-bromo-6-(tosyloxy)-9H-purine (11) was synthesized 3 and reacted with bromide 2e under the same conditions as in the case of purines 1, 9a-c. 9-[(2-Acetoxyethoxy)methyl]-2-[acetyl(2-bromobenzyl)amino]-8-bromo-1,9-dihydro-6H-purin-6-one (12) was isolated as the product in 37% yield (Scheme 3). It indicated that apart from benzylation at the exocyclic nitrogen, a partial or complete loss of tosyl function at the exocyclic oxygen occurred during either the benzylation reaction or the product isolation process.…”

“…As our previous attempts to synthesize the target compound from 2-(acetylamino)-8-bromo-1,9-dihydro-6H-purin-6-one and benzyl bromide resulted in the formation of N-benzylated regioisomers, 2 we decided to improve the process by using as a substrate 2-(acetylamino)-8-bromo-6-(diphenylcarbamoyloxy)-1H-purine (1) synthesized by us earlier. 3 The choice was motivated by the well-established fact that constraining 2-amino-6oxopurine from its dominant 6-lactam structure to its lactim (enolate) form by a suitable protecting group at O 6 has a beneficial effect on the regioselectivity of alkylation. 4 In this paper we present the results of the arylalkylation of purine derivative 1 and various substituted analogues.…”

Acyclic Twisted Amides

“…N -Monoacyl activated twisted amides with τ values of 40–90° are presented in Figures and . ,,− Three points of amide bond geometry should be considered when discussing structures of acyclic twisted amides: (1) N -acyl activating substituent, (2) the other N-substituent, and (3) substitution at the α-carbon. It is important to note that when both of the N–C­(O) groups are acyclic, geometric distortion of the more twisted bond represents a balance between the optimum geometry for the two acyl bonds, which often leads to the flattening of the other N -acyl bond …”

“…Examination of the examples in Figures and ,,− shows that N -acyl substituents that result in a substantial twist of the amide bond include acyclic C­(O)­R, such as aromatic (aryl, 3.1 , 3.21 ; anthracenyl, 3.6 , 3.13 ), vinyl ( 3.9 , 3.39 , 3.59 ), heterocyclic ( 3.5 , 3.15 ), 1° aliphatic ( 3.14 , 3.17 , 3.23 , 3.44 , 3.55 , 3.60 – 3.61 , 3.64 ), 2° aliphatic ( 3.34 , 3.41 – 3.42 , 3.45 ), and CF 3 ( 3.51 – 3.52 ). Furthermore, the activating acyclic acyl group can be C­(S)­R (such as 3.7 , 3.11 , 3.16 , 3.24 , 3.38 ), CO 2 R (such as 3.10 , 3.35 , 3.48 , 3.50 , 3.54 , 3.57 – 3.58 , 3.62 ), C­(S)­OR (such as 3.25 ), or CONR 2 (such as 3.29 ).…”