Multicomponent Reactions in Ligation and Bioconjugation Chemistry

Abstract

Multicomponent reactions (MCRs) encompass an exciting class of chemical transformations that have proven success in almost all fields of synthetic organic chemistry. These convergent procedures incorporate three or more reactants into a final product in one pot, thus combining high levels of complexity and diversity generation with low synthetic cost. Striking applications of these processes are found in heterocycle, peptidomimetic, and natural product syntheses. However, their potential in the preparation of large macro- and biomolecular constructs has been realized just recently. This Account describes the most relevant results of our group in the utilization of MCRs for ligation/conjugation of biomolecules along with significant contributions from other laboratories that validate the utility of this special class of bioconjugation process. Thus, MCRs have proven to be efficient in the ligation of lipids to peptides and oligosaccharides as well as the ligation of steroids, carbohydrates, and fluorescent and affinity tags to peptides and proteins. In the field of glycolipids, we highlight the power of isocyanide-based MCRs with the one-pot double lipidation of glycan fragments functionalized as either the carboxylic acid or amine. In peptide chemistry, the versatility of the multicomponent ligation strategy is demonstrated in both solution-phase lipidation protocols and solid-phase procedures enabling the simultaneous lipidation and biotinylation of peptides. In addition, we show that MCRs are powerful methods for synchronized lipidation/labeling and macrocyclization of peptides, thus accomplishing in one step what usually requires long sequences. In the realm of protein bioconjugation, MCRs have also proven to be effective in labeling, site-selective modification, immobilization, and glycoconjugation processes. For example, we illustrate a successful application of multicomponent polysaccharide-protein conjugation with the preparation of multivalent glycoconjugate vaccine candidates by the ligation of two antigenic capsular polysaccharides of a pathogenic bacterium to carrier proteins. By highlighting the ability to join several biomolecules in only one synthetic operation, we hope to encourage the biomolecular chemistry community to apply this powerful chemistry to novel biomedicinal challenges.

Visible Light‐Induced Sulfonylation/Arylation of Styrenes in a Double Radical Three‐Component Photoredox Reaction

“…As several bonds are formed in a single operation, MCRs grant fast and easy access to products of elaborate molecular complexity . They have thus become a key tool in drug discovery, natural product synthesis, heterocyclic chemistry, and bioconjugation . Advantages of MCRs over traditional stepwise synthesis include a lower step count, the reduction of resource usage and chemical waste.…”

A Peptide Backbone Stapling Strategy Enabled by the Multicomponent Incorporation of Amide N‐Substituents

“…As shown in Scheme , the goal was to implement the whole route on solid‐phase, including the incorporation of the olefin‐containing N‐substitutions and the final macrocyclization step. For this, the key step is the efficient implementation of the on‐resin Ugi multicomponent reaction that simultaneously incorporates an Fmoc‐AA and an olefin‐functionalized isocyanide, along with the oxo‐component . Although the Ugi reaction can be undertaken with many different carbonyls, its poor stereoselectivity favors the use of formaldehyde—or symmetric ketones like acetone leading to Aib—to avoid formation of complex diastereomeric mixtures.…”

“…For this, the keys tep is the efficient implementation of the on-resinU gi multicomponent reactiont hat simultaneously incorporates an Fmoc-AAa nd an olefin-functionalized isocyanide, along with the oxo-component. [15] Althought he Ugi reaction can be undertaken with many different carbonyls, [16] its poor stereoselectivity favors the use of formaldehyde-or symmetric ketones like acetonel eadingt o Aib-to avoid formation of complexd iastereomeric mixtures. In this regard, we have recently developed av ersatile aminocatalysis-mediated on-resin Ugi reaction procedure [17] that ensures full conversion in the multicompoment incorporation of the Fmoc-AA-OH (carboxylic acid) and the isocyanide component.…”

Diversification of Peptidomimetics and Oligopeptides through Microwave‐Assisted Rhodium(III)‐Catalyzed Intramolecular Annulation

“…The Ugi four-component reaction (Ugi-4CR) is regarded as one of the most attractive reactions for synthesizing multifunctional compounds, [1] especially for the generation of polymorphous peptidomimetics and peptides. [2] Moreover it also provides an opportunity for various post-transformations with diverse functional groups to synthesize pharmacologically important heterocyclic scaffolds, mostly in two operational steps. [3] Furthermore, microwave-assisted organic synthesis (MAOS) has been proven to be a powerful strategy in organic chemistry.…”