Synthesis of l‑Iduronic Acid Derivatives via [3.2.1] and [2.2.2] l‑Iduronic Lactones from Bulk Glucose-Derived Cyanohydrin Hydrolysis: A Reversible Conformationally Switched Superdisarmed/Rearmed Lactone Route to Heparin Disaccharides

l-Idofuranoside cyanohydrin 1 is converted
on large scale into a mixture of l-IdoA methyl pyranosides
and furanosides, which is converged to provide short 2-step routes
to bicyclic [3.2.1] or [2.2.2] l-iduronate lactones. The
former is obtained via a 100 g scale synthesis of 3-OBn l-IdoA. A two-step conversion of this mixture provides either pure
anomer of the novel [2.2.2] l-iduronate thioglycoside lactones.
Both [3.2.1] and [2.2.2] lactones are converted into GlcN-IdoA heparin
precursor disaccharides. The [2.2.2] lactone enables a scalable 3-step
route from 1 to a new type of highly disarmed O-4 iduronate
thioglycoside, which is an effective acceptor with glucoazide thioglycoside
donors. The resulting new iduronic [2.2.2] lactone disaccharides are
readily rearmed by mild methanolysis to provide GlcN-IdoA thiophenyl
disaccharide donors, intercepting their established utility for the
assembly of both heparin- and heparan sulfate-like oligosaccharides.
The [2.2.2] lactonization acts as a conformational switch to superdisarm
iduronate components, reversible by lactone ring opening. In addition,
the separated 2,4-diacetates also provide short access to all four
anomeric and ring size isomers of l-iduronic acid methyl
glycosides, including the first syntheses of the parent idofuranosides.
X-ray structures are reported for a [2.2.2] iduronate lactone and
examples of both methyl l-idopyranoside and novel methyl-l-idofuranoside systems.