Thomas Hansen

The stereocontrolled construction of glycosidic linkages from 2-deoxyglycoside donors remains a major challenge in the synthesis of complex oligosaccharides. Herein, we report catalyst-controlled glycosylation protocols that deliver either anomer on demand from the same glycosyl donor, across a broad range of acceptors through simple variation of the chiral Brønsted acid catalyst. Systematic evaluation of a library of readily accessible chiral Brønsted acids reveals how catalyst, donor, and acceptor jointly govern reactivity and stereoselectivity. Mechanistic studies reveal that the stereodivergence originates from distinct reaction pathways promoted by seemingly similar chiral Brønsted acids. This work establishes a general platform for catalyst-controlled anomeric selectivity and expands the synthetic toolbox for stereoselective complex carbohydrate assembly.

While the S _N 1 glycosylation reaction mechanism manifold is dominated by addition reactions to half chair oxocarbenium ions we here reveal that mannosyl oxocarbenium ions react on the bottom face of a boat conformer to avoid steric (Pauli) repulsion.

Influenza neuraminidase (NA) is a critical target for seasonal and pandemic antivirals, including the strains of current concern. Current treatments, such as Zanamivir and Oseltamivir, are limited by noncovalent binding and emerging resistance. We hypothesized that Oseltamivir aziridines would unite transition-state mimicry for tight binding, with aziridine-enabled covalent capture of the catalytic tyrosine, thereby supporting both therapy and activity-based quantification. Here, we present oseltamivir-based aziridines, inspired by cyclophellitol chemistry, that act as covalent inhibitors and activity-based probes via an N -acylaziridine warhead. Free-energy calculations, and NMR observations, indicate a ⁴ H ₅ half-chair preference consistent with the NA transition state, and selected analogues inhibit multiple NA subtypes with low nanomolar binding constants. Diverse evidence establishes covalency: time-dependent inactivation, inhibitor washout, intact-mass shifts, MS/MS identification of a tyrosine adduct, and QM/MM reaction profiles, while cryoEM of N1 aligns with the proposed binding mode, revealing an elimination product. The inhibitors demonstrate formidable activity against diverse viral neuraminidases, including H5N1, and further enable imaging and quantification of active NA. With their dual therapeutic and diagnostic potential, these first-in-class inhibitors indeed benefit from transition state mimicry and covalency, and thus offer a powerful platform for antiviral development and neuraminidase imaging, addressing urgent global health needs in influenza treatment and prevention.

Lewis acids are frequently used as catalysts in glycosylation reactions, however these reagents often suffer from significant limitations such as sensitivity to moisture and poor stereocontrol. Chalcogenonium catalysts have recently emerged as a new class of catalysts with improved Lewis acidity and stability. Here we describe a proof of concept study of the use of 1,2-oxaselenonium salts as effective organocatalysts for the direct and stereoselective dehydrative glycosylation with 1-hydroxy carbohydrates to give deoxyglycosides. The reaction is high yielding, stereoselective and amenable to a wide range of nucleophiles, including primary, secondary and tertiary alcohols and thiols. Experimental and computational mechanistic investigations suggest that the reaction proceeds through a cooperative mechanism involving the hemiacetal donor, acceptor, and catalyst. In this process, the Lewis acidic selenonium catalyst activates the donor, while the incoming alcohol nucleophile engages in a stabilizing hydrogen-bond interaction with the chalcogenonium triflate counterion. DFT calculations suggest a loose S_N2-like transition state with a high degree of oxocarbenium ion character, reminiscent of the mechanism observed for glycosyl-modifying enzymes. The methodology is exemplified on the stereoselective synthesis of a tetrasaccharide in 52% yield.

Bimolecular nucleophilic substitution (S_N2) and base‐induced elimination (E2) generally compete, and it is, therefore, essential to be in control of this competition in synthetic organic chemistry. Herein, we establish guiding principles based on quantitative molecular orbital (MO) theory and the activation strain model to understand and tune the competition between the S_N2 and E2 reactions. We discuss the role of key factors, such as the nature of the Lewis base, leaving group, substrate structure, and the solvent. To this end, we introduce the concepts of characteristic distortivity, transition state acidity, intrinsic nucleophilicity, and apparent nucleophilicity. These intuitive concepts equip chemists with conceptual tools to better understand and design reactions for organic synthesis.

The use of trisubstituted selenonium salts as organocatalysts for the direct and stereoselective synthesis of deoxyglycosides from hemiacetals is described. The reaction conditions are mild and compatible with various functionalities and has a broad substrate scope including examples of 1-hydroxy deoxy-galactoside and glucoside substrates. Mechanistic investigations suggest that the reaction proceeds via a step-wise process involving the he hemiacetal donor, OH acceptor and catalyst, whereby the chalcogen catalysts mediates the key H+ transfer step. This study opens a new avenue for the development of nonmetallic acid/base catalysis for the stereoselective synthesis of complex glycosides.

We report enhanced reaction rates of the Passerini reaction (P-3CR) using 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as a cosolvent. Although alcoholic solvents typically increase the energy barrier of the rate-determining step for the P-3CR, we observed significant rate enhancements even when employing strong hydrogen bond donating (HBD) alcohols as cosolvents. This rate enhancement was observed for most aprotic organic solvents, with the exception of strong hydrogen bond accepting (HBA) solvents such as DMF. Experimental kinetic studies and DFT calculations provided a mechanistic rationale for our observations. An investigation of the substrate scope showed that this rate enhancement generally resulted in a (slight) increase of the overall yield in the P-3CR.

Based on the successful application of a nitroaryl transfer cascade reaction in the total synthesis of various monoterpene indole alkaloids proceeding via fused bicyclic intermediate, we investigated analogous cascade reactions involving spiro, bridged, and alternatively fused bicyclic intermediates. Unfortunately, none of these was found to afford the desired nitroaryl transfer product. DFT studies of the original cascade process revealed that the Truce‐Smiles rearrangement is the rate‐determining step. In addition, we found that the subsequent SO ₂ extrusion is accompanied by retro‐Mannich ring opening, resulting in a stabilized enolate that only recyclizes after activation of the cyclic imine moiety. Computation of the reaction profiles of the proposed alternative cascade reactions showed that the barrier for the Truce‐Smiles rearrangement is unreasonably high for the bridged and alternatively fused systems, but only moderately higher for the five‐membered spiro system. Reasoning that even more electron‐deficient arenesulfonamides should have a lower barrier for the Truce‐Smiles rearrangement, we synthesized the corresponding 2,4‐dinitrobenzenesulfonamide precursor and found that it indeed smoothly undergoes the nitroaryl transfer cascade at room temperature. In this case, however, the cascade reaction produces a cyclic imine product, as the intermediate 2,4‐dinitrophenyl‐substituted enolate is insufficiently nucleophilic to undergo the Mannich cyclization.

We present an Ugi multicomponent approach to explore the chemical space around Aspidosperma‐type monoterpene indole alkaloids. By variation of the isocyanide and carboxylic acid inputs we demonstrate the rapid generation of molecular diversity and the possibility to introduce handles for further modification. The key Ugi three‐component reaction showed full diastereoselectivity towards the cis‐fused ring system, which can be rationalized by DFT calculations that moreover indicate that the reaction proceeds via a Passerini‐type hydrogen bonding mechanism. Several post‐Ugi modifications were also performed, including Pictet‐Spengler cyclization to highly complex nonacyclic natural product hybrid scaffolds.