High-yield synthesis of 3′-amino-3′-deoxynucleosides. Conversion of adenosine to 3′-amino-3′-deoxyadenosine

Nucleotides, Part LIX, Synthesis, Characterization, and Biological Activities of New Potential Antiviral Agents: (2′ - 5′)Adenylate Trimer Analogs Containing 3′-Deoxy-3′-(hexadecanoylamino)adenosine at the 2′-Terminus

“…In our preparative-scale synthesis of 15 starting from adenosine (1), we were able to reach an overall yield of 53% over 8 steps (1 3 14). Including the last debenzylation step (14 3 15; 69%), we can claim only 37% (1 3 15) instead of 66% obtained by Samano and Robins [2].…”

“…± The successful synthesis of the four new trimers 33 ± 36 was based on the availability of 3'-amino-3'-deoxyadenosine (15) for which several synthetic approaches have been described in literature. Till 1989 when Samano and Robins [2] reported an efficient nine-step synthesis of 15 in a 66% overall yield, this biologically active compound was isolated either from microbiological cultures or was prepared in very low yields (`2 ± 20%) by chemical means, as, e.g. by transformation [15] [16] of adenosine into 3'-azido-3'-deoxyadenosine (12 steps, overall yields`5%) and further reduction to the 3'-amino component [17], or by coupling reactions of suitable protected purine bases with glucose or xylose derivatives [18] [19] (overall yield2 0%).…”

“…We chose the first route [2] starting from adenosine (1), but realized that the described synthetic approach has to be discussed in more detail, since, in our hands, most steps have to be modified to achieve good yields of 15 (Scheme 1). It is recommended to treat dry 1 first with freshly prepared a-acetoxyisobutyryl bromide (2) [21] [22] in moist MeCN [2] [23] [24] leading to a mixture of 9-(2-O-acetyl-3-bromo-3-deoxy-b-d-xylofuranosyl)-and 9-(3-O-acetyl-2-bromo-2-deoxy-b-d-arabinofuranosyl)adenines 3a ± d in which the 5'-OH group is present either in the orthoester function derived from 2,5,5-trimethyl-1,3-dioxol-4(5H)-one (3a, 3c) or in unprotected form (3b, 3d) [15] [16].…”

“…It is recommended to treat dry 1 first with freshly prepared a-acetoxyisobutyryl bromide (2) [21] [22] in moist MeCN [2] [23] [24] leading to a mixture of 9-(2-O-acetyl-3-bromo-3-deoxy-b-d-xylofuranosyl)-and 9-(3-O-acetyl-2-bromo-2-deoxy-b-d-arabinofuranosyl)adenines 3a ± d in which the 5'-OH group is present either in the orthoester function derived from 2,5,5-trimethyl-1,3-dioxol-4(5H)-one (3a, 3c) or in unprotected form (3b, 3d) [15] [16]. The dioxolone and acetyl protecting groups can either be sequentially removed by mild acidic treatment to give from 3a the hydrolysed compound 3b and finally 4 [15] [16] [25], or the mixture of the trans-3'(2')-bromo-2'(3')-acetoxy derivatives 3a ± d was directly treated without further separation with Dowex 1 Â 2 (OH À ) resin in MeOH to give 2',3'-anhydroadenosine (4) in high yield [23 ± 26].…”

“…Furthermore, 8 was obtained by treatment of 9-(3-bromo-3-deoxyb-d-xylofuranosyl)adenine (9) [11] [22] with tbdps-Cl in pyridine within 19 h in 89% isolated yield. In subsequent reactions, the 2'-OH group of 8 was selectively protected by treatment with benzyl isocyanate under Et 3 N activation for 3 days at room temperature [2] [32] to give compound 10 in 93% yield after flash chromatography (silica gel). The reaction time could be shortened to a few hours if 8 was first suspended in THF/MeCN and then reacted with benzyl isocyanate and Et 3 N at 808 to give, within 15 min, a clear solution; further stirring for 75 min and usual workup gave 10 (78% yield) and some unreacted starting material 8 (14%).…”