An innovative and sustainable procedure for the synthesis of morpholino nucleosides Marta Papis, Gianluigi Broggini Università degli Studi dell'Insubria, Italy Synthetic oligonucleotide-based therapies currently represent one of the most active areas of clinical research. The wide variety of possible modifications to the nucleotide scaffold makes them virtually active against any disease, for which the responsible nucleotide sequence is known.[1] Morpholine derivatives, obtained from natural ribonucleosides, proved to be advantageous in therapeutical applications, offering realistic perspectives for the treatment of diseases involved in gene expression (Figure 1, path a).[2] The strategy proposed by Summerton can be suitable for canonic nucleosides, but the use of modified nucleosides places limitations in terms of availability. As to the best of our knowledge, any procedure in the literature describes the direct morpholine functionalization with a nucleic base. In this communication, our efforts toward the development of an innovative synthetic protocol for nucleobase-modified morpholino monomers will be reported. The key step of the process involves the condensation of 1 , which is the common precursor of target nucleoside analogs, with model nucleic bases as nucleophiles under mild Lewis acid-promoted glycosylation reaction conditions (Figure 1, path b). The proposed strategy gives access to optically pure compounds whose stereochemistry is strictly related to the geometry of the starting epoxide. This de novo synthesis allows for a variety of b-morpholino nucleosides in good yields and anomeric ratios starting from readily available substrates.
Figure 1 References 1. K.L. eley-Radtke and M.K. Yates Antiv. Res. , 2018 , 154 , 66. 2. Summerton and D. Weller Antisense Nucleic Acid Drug Dev ., 1997 , 7 , 187.
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