A New Synthetic Route to (North)-Methanocarba Nucleosides (I) Designed as A3 Adenosine Receptor Agonists.

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS Bethesda, Maryland 20892, USA.
The Journal of Organic Chemistry (Impact Factor: 4.72). 02/2005; 70(2):439-47. DOI: 10.1021/jo0487606
Source: PubMed


Activation of the A3 adenosine receptor (AR) is associated with cerebroprotective, cardioprotective, and anticancer effects. Among potent and selective A3 AR agonists are novel methanocarba adenosine analogues in which the conformation of a pseudo-ribose moiety is locked in the North (N) hemisphere of the pseudorotational cycle. 5'-Uronamide (N)-methanocarba nucleosides, such as MRS1898 and MRS2346, are examples of full agonists of the human A3 AR. An improved convergent approach from easily accessible 2,3-O-isopropylidene-d-erythrose (2b), and the combination of a strategic intramolecular cyclopropanation step plus the acid-catalyzed isomerization of an isopropylidene group, provided a suitable pseudosugar precursor (23) for the synthesis of MRS1898, MRS2346, and related analogues. This new synthetic route uses readily available building blocks and opens the way for the preparation of a variety of targets on a reasonable scale.

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