Stereoselective Syntheses of 3'-Hydroxyamino- and 3'-Methoxyamino-2',3'-Dideoxynucleosides.

Sritama Bose,David R W Hodgson

doi:10.1021/acs.orglett.9b03474

Sritama Bose, David R W Hodgson

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https://doi.org/10.1021/acs.orglett.9b03474

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Journal: Organic Letters	Publication Date: Oct 31, 2019
License type: cc-by

Affiliation: Durham University

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Aminonucleosides are used as key motifs in medicinal and bioconjugate chemistry; however, existing strategies toward 3′-hypernucleophilic amine systems do not readily deliver deoxyribo-configured products. We report diastereoselective syntheses of deoxyribo- and deoxyxylo-configured 3′-hydroxyamino- and 3′-methoxyamino-nucelosides from 3′-imine intermediates. The presence or absence of the 5′-hydroxyl-group protection dictates facial selectivity via inter- or intramolecular delivery of hydride from BH3 (borane). Protecting group screening gave one access to previously unknown 3′-methoxyamino-deoxyguanosine derivatives.

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Aminonucleosides are used as key motifs in medicinal and bioconjugate chemistry; existing strategies toward 3′-hypernucleophilic amine systems do not readily deliver deoxyribo-configured products
The growth of L1210 cells was shown to be inhibited by 2′-deoxy-2′-(hydroxyamino) cytidine with an IC50 of 1.84 μM; synthesis was achieved indirectly, via a uridine derivative.1b Tronchet et al.[2] explored the synthesis of 3′-methoxyamino- and 3′-hydroxyamino-derivatives by stereoselective reduction of 3′-imines
The deoxyribo-isomers, on the other hand, were usually minor products or absent, where syntheses have only been achieved via indirect, multistep methods

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Introduction

Aminonucleosides are used as key motifs in medicinal and bioconjugate chemistry; existing strategies toward 3′-hypernucleophilic amine systems do not readily deliver deoxyribo-configured products. They readily obtained deoxyxylo-configured systems as major or exclusive products across a range of reduction conditions. Stereoselective reduction of 3′-keto nucleosides to ribonucleosides via intramolecular delivery of hydride, tethered through a free 5′-hydroxyl group, has been reported.[9] Matsuda and co-workers1b reported that 3′(hydroxyamino) uridine with a ribo-configuration 5a can be obtained from the corresponding 3′-hydroxyiminouridine 4a by treatment with NaBH4/AcOH (Scheme 2).

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