Organic Letters
Organic Letters
5 years ago

Stereoselective Synthesis and Evaluation of C6″-Substituted 5a-Carbasugar Analogues of SL0101 as Inhibitors of RSK1/2

Stereoselective Synthesis and Evaluation of C6″-Substituted 5a-Carbasugar Analogues of SL0101 as Inhibitors of RSK1/2
Mingzong Li, Deborah A. Lannigan, Zachary M. Sandusky, George A. O’Doherty, Katarzyna A. Ludwik, Yu Li
A convergent synthesis of 5a-carbasugar analogues of the n-Pr-variant of SL0101 is described. The analogues were synthesized in an effort to find compounds with potent in vivo efficacy in the inhibition of p90 ribosomal s6 kinase (RSK1/2). The synthesis derived the desired C-4 L-rhamnose stereochemistry from quinic acid and used a highly selective cuprate addition, NaBH4 reduction, Mitsunobu inversion, and alkene dihydroxylation to install the remaining stereochemistry. A Pd-catalyzed cyclitolization stereoselectively installed the aglycon at the anomeric position. The analogues were evaluated as RSK1/2 inhibitors and found to have 3- to 6-fold improved activity.

Publisher URL: http://dx.doi.org/10.1021/acs.orglett.7b00945

DOI: 10.1021/acs.orglett.7b00945

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