Regio- and Stereoselective Synthesis of C-4' Spirocyclobutyl Ribofuranose Scaffolds and Their Use as Biologically Active Nucleoside Analogues

  • Org Lett. 2021 Nov 19;23(22):8828-8833. doi: 10.1021/acs.orglett.1c03334.
Lucile Jouffroy  1 ,  Jonas Verhoeven  2  3 ,  Marta Brambilla  2 ,  Guido Verniest  2  3 ,  Hanchu Kong  4 ,  Yongbin Zhao  4 ,  Wenbin Wang  4 ,  Lieven Meerpoel  2 ,  Jan Willem Thuring  2 ,  Johan M Winne  1
Affiliations
  • 1. Department of Organic and Macromolecular Chemistry, Ghent University, Campus Sterre, Krijgslaan 281-S4, 9000 Gent, Belgium.
  • 2. Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • 3. Research Group of Organic Chemistry (ORGC), Department of Chemistry and Department of Bio-engineering Sciences, Faculty of Science and Bio-engineering Sciences, Vrije Universiteit Brussel (VUB), Pleinlaan 2, 1050 Brussels, Belgium.
  • 4. Department of Synthetic Chemistry, Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, People's Republic of China.
PMID: 34730365 DOI: 10.1021/acs.orglett.1c03334
Abstract

Novel C-4',C-5' cyclobutane-fused spirocyclic ribonucleoside analogues were prepared. Thermal [2 + 2] cycloaddition between dichloroketene and readily derived 4'-exo-methylene furanoses afforded a first entry to the required constrained ribofuranoses, relying on a carbonyl transposition sequence. Alternatively, an unusual stereoselective ionic [2 + 2] cycloaddition using methyl propiolate promoted by methylaluminoxane gave a complementary, more direct approach to such ribofuranoses. Further conversion to the constrained adenosine analogues revealed promising structure-dependent inhibition of the protein methyltransferase PRMT5:MEP50 complex in the (sub)micromolar range.

Products