Sialoside clusters as potential ligands for siglecs (sialoadhesins)

Clusters of O- and S-linked alpha-sialosides with valencies of two to four were constructed to serve as potential multivalent inhibitors towards sialoadhesins (siglecs). Thus, O- and S-prop-2-ynyl alpha-sialosides (3, 7), together with 4-iodophenyl sialoside 5 were prepared from acetochloroneuraminic acid derivative I using silver saticylate and propargyl alcohol for 3 and phase-transfer catalysis for 5 and 7, respectively. Oxidative acetylenic homocoupling of 3 and 7 under Glaser conditions (CuCl, O-2) provided 1,3-diynes 8 and 9 in 83-86% yields. Palladium catalyzed cross-coupling of O-prop-2-ynyl sialoside 3 with 5 using Pd-2(dba)(3) and PPh3 gave nonsymmetrical dimer 10 (82%). Alternatively, symmetrical clusters were then prepared as above under Sonogashira cross-coupling conditions with 1,4-diiodobenzene (11), 1,3,5-triodobenzene (14), and finally 1,2,4,6-tetraiodobenzene (17) to provide both O- and S-linked dimers 12 (93%) and 13 (88%), trimers 15 (81%) and 16 (76%), while only O-linked tetramer 18 was prepared in 87% yield. Finally, treatment of the O-linked prop-2-ynyl sialoside 3 with Grubbs' metathesis catalyst Cl2Ru(PCy3)(2)=CHPh (19) gave, as expected, benzeneannulation regioisomeric trimers 20a, 20b in 68% yield.