Selective Axial-to-Equatorial Epimerization of Carbohydrates

Abstract

Radical-mediated transformations have emerged as powerful methods for the synthesis of rare and unnatural branched, deoxygenated, and isomeric sugars. Here, we describe a radical-mediated axial-to-equatorial alcohol epimerization method to transform abundant glycans into rare isomers. The method delivers highly predictable and selective reaction outcomes that are complementary to other sugar isomerization methods. The synthetic utility of isomer interconversion is showcased through expedient glycan synthesis, including one-step glycodiversification. Mechanistic studies reveal that both site- and diastereoselectivities are achieved by highly selective H atom abstraction of equatorially disposed α-hydroxy C–H bonds.

Site-Selective Modification of (Oligo)Saccharides

“…Moreover, in the absence of the boronate trapping agent, this catalyst system can be used to epimerize axial alcohols into equatorial alcohols, as was shown for galactosides ( Scheme 1 C). 20 Finally, it was recently shown that direct epimerization of 1,2-trans to 1,2-cis diols in partly protected carbohydrates can be achieved with boron-mediated ruthenium-catalyzed hydrogen-borrowing/hydrogen transfer reactions, see the work of W. Tang et al 21 It will not be trivial, if possible at all, to dissect for all these reactions the kinetic and thermodynamic contribution to the observed regio- and stereoselectivity. To give an example, it has been shown by thorough computational studies using relativistic density functional theory that palladium-catalyzed oxidation in pyranoses preferentially takes place at C3 because the ring oxygen impedes the build-up of positive charge at C2 and C4 going to the transition state.…”

“…Interestingly, both the palladium-catalyzed oxidation–sodium borohydride reduction sequence, and the photoredox approach have also been applied directly on α-glucose, so the reducing sugar. 23 Besides epimerization methods, also a number of deoxygenating methods have been developed that can be used to prepare deoxygenated monosaccharides. 24 …”

“… 28 The introduction of an epoxide function in keto glucosides, as well as indium-mediated allylation and propargylation, have also shown to be effective methods to introduce chemical handles. 20 Site-divergent O -propargylation of monosaccharides provides another means to site-selective introduce a bio-orthogonal handle. This latter method has proven to be very versatile, as the alkyne could be used in a later stage for the introduction of biotin and the antiviral agent zidovudine.…”

“…This preference enabled the epimerization of the C4-OH of the galactose residue in raffinose, yielding theanderose ( Scheme 3 C). 45 …”

“…The C3 position in α-glucosides, on the contrary, is not accessible for the decatungstate catalyst and therefore the C2 position is epimerized in these substrates. Moreover, in the absence of the boronate trapping agent, this catalyst system can be used to epimerize axial alcohols into equatorial alcohols, as was shown for galactosides (Scheme C) . Finally, it was recently shown that direct epimerization of 1,2-trans to 1,2-cis diols in partly protected carbohydrates can be achieved with boron-mediated ruthenium-catalyzed hydrogen-borrowing/hydrogen transfer reactions, see the work of W. Tang et al It will not be trivial, if possible at all, to dissect for all these reactions the kinetic and thermodynamic contribution to the observed regio- and stereoselectivity.…”