Carbohydrates are involved in nearly all aspects of biochemistry, but their complex chemical structures present long-standing practical challenges to their synthesis. In particular, stereochemical outcomes in glycosylation reactions are highly dependent on the steric and electronic properties of coupling partners, and thus, carbohydrate synthesis is not easily predictable. Here, we report the discovery of a macrocyclic bis-thiourea derivative that catalyzes stereospecific invertive substitution pathways of glycosyl chlorides. The utility of the catalyst is demonstrated in the synthesis of 1,2-trans-, 1,2-cis-, and 2-deoxy-β-glycosides. Mechanistic studies are consistent with a cooperative mechanism in which an electrophile and a nucleophile are simultaneously activated to effect a stereospecific substitution reaction.

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Polarization transfer is demonstrated as a sensitive technique for the measurement of isotopic fractionation of protonated carbons at natural abundance. This method allows kinetic isotope effects (KIEs) to be determined with substantially less material or shorter acquisition time compared with traditional experiments. Computations quantitatively reproduce the KIEs in a Diels–Alder reaction and a catalytic glycosylation. The glycosylation is shown to occur by an effectively concerted mechanism.

We describe the rational design of a linked, bis-thiourea catalyst with enhanced activity relative to monomeric analogs in a representative enantioselective anion-abstraction reaction. Mechanistic insights guide development of this linking strategy to favor substrate activation though the intramolecular cooperation of two thiourea subunits while avoiding nonproductive aggregation. The resulting catalyst platform overcomes many of the practical limitations that have plagued hydrogen-bond donor catalysis and enables use of catalyst loadings as low as 0.05 mol %. Computational analyses of possible anion-binding modes provide detailed insight into the precise mechanism of anion-abstraction catalysis with this pseudo-dimeric thiourea.

A convergent route to the synthesis of manassantins A and B, potent inhibitors of HIF-1, is described. Central to the synthesis is a stereoselective addition of an organozinc reagent to a 2-benzenesulfonyl cyclic ether to achieve the 2,3-cis-3,4-trans-4,5-cis-tetrahydrofuran of the natural products. Preliminary structure—activity relationships suggested that the (R)-configuration at C-7 and C-7″′ is not critical for HIF-1 inhibition. In addition, the hydroxyl group at C-7 and C-7″′ can be replaced with carbonyl group without loss of activity.