Synthesis and conformational analysis of carbasugar bioisosteres of α- l-iduronic acid and its methyl glycoside

The synthesis of two novel carbasugar analogues of α- l-iduronic acid is described in which the ring-oxygen is replaced by a methylene group. In analogy with the conformational equilibrium described for α- l-Ido pA, the conformation of the carbasugars was investigated by 1H and 13C NMR spectroscopy. Hadamard transform NMR experiments were utilised for rapid acquisition of 1H, 13C-HSQC spectra and efficient measurements of heteronuclear long-range coupling constants. Analysis of 1H NMR chemical shifts and J H,H coupling constants extracted by a total-lineshape fitting procedure in conjunction with J H,C coupling constants obtained by three different 2D NMR experiments, viz., 1H, 13C-HSQC-HECADE, J-HMBC and IPAP-HSQC-TOCSY-HT, as well as effective proton–proton distances from 1D 1H, 1H T-ROE and NOE experiments showed that the conformational equilibrium 4 C 1⇌ 2 S 5a⇌ 1 C 4 is shifted towards 4 C 1 as the predominant or exclusive conformation. These carbasugar bioisosteres of α- l-iduronic acid do not as monomers show the inherent flexibility that is anticipated to be necessary for biological activity.