Rapid Synthesis of l‐Idosyl Glycosyl Donors from α‐Thioglucosides for the Preparation of Heparin Disaccharides

Abstract

A new methodology for the synthesis of the most challenging heparin building block has been developed. Orthogonally protected l‐idosyl glycosyl donors were prepared by C5 epimerization of the corresponding thioglucosides using the hydroboration/oxidation method followed by a 4,6‐acetal formation. The α‐anomeric configuration was crucial, and the bulky C4 substituent was advantageous for the high l‐ido diastereoselectivity. The 4,6‐arylmethylene group proved to be a directing element in glycosylation, whereby stereoselective α‐idosylation could be achieved by using idosyl donors without a C‐2 participating group.

Short Synthesis of Idraparinux by Applying a 2‐O‐Methyl‐4,6‐O‐arylmethylene Thioidoside as a 1,2‐trans‐α‐Selective Glycosyl Donor

“…(The structure of 6 and 9 was identified on the basis of the MS data and NMR spectra of their inseparable mixture.) The observed high stereo‐ and chemoselectivity of the hydroboration/oxidation of the α‐thioglycoside is in line with our previous results . A third by‐product, the 6‐fluoro derivative ( 10 ) of the initial glucose compound was also isolated from the reaction mixture in an 11 % yield.…”

“…It was followed by the key step of the synthesis, glycosylation of monosaccharide acceptor 12 with the new, non‐participating l ‐idosyl donor 11 . We demonstrated earlier that glycosylation reaction between the 2,3‐di‐ O ‐benzyl congener of 11 and a GlcNAc acceptor of low reactivity proceeded with full 1,2‐ trans ‐α‐selectivity . However, it was questionable whether donor 11 was able to ensure complete stereoselectivity when reacting with an acceptor of higher reactivity.…”

“…We have developed an efficient synthetic strategy for idraparinux and related pentasaccharides, which was based on the coupling of an FGH acceptor and a DE donor, both containing a non‐oxidized precursor of the hexuronic acid unit, and formation of the uronic acids was performed in one step at the pentasaccharide level. While keeping this post‐glycosylation oxidation strategy, we devised a significantly shortened synthesis for the GH building block by utilizing a new, non‐participating l ‐idosyl glycosyl donor which is readily available from a suitably protected α‐thioglucoside by our recent method …”

“…While this reaction sequence had proceeded both in high yield and high stereoselectivity starting from 2,3‐di‐ O ‐benzyl α‐thioglucosides, upon dehydrohalogenation of the 2,3‐di‐ O ‐methylated 7 with sodium hydride a number of byproducts were observed by TLC and, after hydroboration/oxidation, the expected l ‐idose derivative 8 was only formed in low 41 % yield (Scheme , Route A). Thus, we attempted to produce the 5,6‐unsaturated 7a derivative by another method using silver fluoride in dry pyridine (Scheme , Route B).…”

“…Very recently, we published a straightforward new synthesis of l ‐idosyl glycosyl donors starting from orthogonally protected α‐thioglucosides . The key steps include C5 epimerization by hydroboration/oxidation of the corresponding 5‐enopyranosides followed by a 4,6‐ O ‐acetal formation of the obtained l ‐idosides.…”