Synthesis and conformational analysis of carbasugar bioisosteres of a-L-iduronic acid and its methyl glycoside

摘要

The synthesis of two novel carbasugar analogues of a-L-iduronic acid is described in which the ring-oxygen is replaced by a methylene group. In analogy with the conformational equilibrium described for a-LIdopA, 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 JH,H coupling constants extracted by a total-lineshape fitting procedure in conjunction with JH,C coupling constants obtained by three different 2D NMR experiments, viz., 1H,13C-HSQC-HECADE, J-HMBC and IPAPHSQC- TOCSY-HT, as well as effective proton–proton distances from 1D 1H,1H T-ROE and NOE experiments showed that the conformational equilibrium 4C12S5a1C4 is shifted towards 4C1 as the predominant or exclusive conformation. These carbasugar bioisosteres of a-L-iduronic acid do not as monomers show the inherent flexibility that is anticipated to be necessary for biological activity.