Heparin, a highly sulfated polysaccharide, has been used as an anticoagulant for more than 75 years. While commercial heparin is currently prepared by porcine tissue extraction, there is no efficient method to synthesize heparin from a non-animal source. The varying sulfo group patterns and locations within the heparin chain make it an extremely difficult target to synthesize chemically. Here, we show our efforts to synthesize heparin oligosaccharides using a chemoenzymatic approach.  First, an acceptor disaccharide with a fluorous protecting group was synthesized in less than 15 steps. The disaccharide was then extended to an oligosaccharide with the desired number of sugar residues using glycosyltransferases. Finally, heparin and heparan sulfate biosynthetic enzymes, including O-sulfotransferases and N-sulfotransferase, and C5-epimerase, were used to introduce sulfo groups and to epimerize glucuronic acid to iduronic acid, both of which are crucial to heparin's anticoagulant activity.

Chemoenzymatic synthesis of fluorous-tagged heparin oligosaccharides

243rd National Meeting (2012)

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