Carbohydrates (CHO) are the formal adducts of carbon (atoms) to water with a repeating unit that structurally resembles H-C̈-OH (hydroxymethylene). Although hydroxymethylene has been suggested as a building block for sugar formation, it is a reactive species that had escaped detection until recently. Here we demonstrate that formaldehyde reacts with its isomer hydroxymethylene to give glycolaldehyde in a nearly barrierless reaction. This carbonyl-ene-type transformation operates in the absence of base and solvent at cryogenic temperatures similar to those found in extraterrestrial environments or interstellar clouds. Hydroxymethylene acts as a building block for an iterative sugar synthesis, as we demonstrate through the formation of the triose glyceraldehyde. The thermodynamically preferred ketose dihydroxyacetone does not form, and the formation of further branched sugars in the iterative synthesis presented here is unlikely. The results therefore provide a link between the well-known formose (Butlerow) reaction and sugar formation under non-aqueous conditions.

The evolution of organocatalysis led to various valuable approaches, such as multicomponent as well as domino and tandem reactions. Recently, organomulticatalysis, i.e., the modular combination of distinct organocatalysts enabling consecutive reactions to be performed in one pot, has become a powerful tool in organic synthesis. It allows the construction of complex molecules from simple and readily available starting materials, thereby maximizing reaction efficiency and sustainability. A logical extension of conventional multicatalysis is a multicatalyst, i.e., a catalyst backbone equipped with independent, orthogonally reactive catalytic moieties. Herein we highlight the impressive advantages of asymmetric organomulticatalysis, examine its development, and present detailed reactions based on the catalyst classes employed, ranging from the very beginnings to the latest multicatalyst systems. R. C. Wende was born inRosenberg (Olesno), Poland, in 1984. He studied chemistry at the Justus-Liebig University, Giessen, where he obtained his B. Sc. degree in 2008 and his M. Sc. degree in 2010. Currently he is working on his PhD under the supervision of P. R. Schreiner. His research focuses on the development of novel synthetic oligopeptide and thiourea organocatalysts for multicatalysis reactions.

Inspired by the extraordinary selectivities of acylases, we envisioned the use of lipophilic oligopeptidic organocatalysts for the acylative kinetic resolution/desymmetrization of rac- and meso-cycloalkane-1,2-diols. Here we describe in a full account the discovery and development process from the theoretical concept to the final catalyst, including scope and limitations. Competition experiments with various alcohols and electrophiles show the full potential of the employed oligopeptides. Additionally, we utilized NMR and IR-spectroscopic methods as well as computations to shed light on the factors responsible for the selectivity. The catalyst system can be readily modified to a multicatalyst by adding other catalytically active amino acids to the peptide backbone, enabling the stereoselective one-pot synthesis of complex molecules from simple starting materials.

We report on a detailed NMR spectroscopic study of the catalyst-substrate interaction of a highly enantioselective oligopeptide catalyst that is used for the kinetic resolution of trans-cycloalkane-1,2-diols via monoacylation. The extraordinary selectivity has been rationalized by molecular dynamics as well as density functional theory (DFT) computations. Herein we describe the conformational analysis of the organocatalyst studied by a combination of nuclear Overhauser effect (NOE) and residual dipolar coupling (RDC)-based methods that resulted in an ensemble of four final conformers. To corroborate the proposed mechanism, we also investigated the catalyst in mixtures with both trans-cyclohexane-1,2-diol enantiomers separately, using advanced NMR methods such as T relaxation time and diffusion-ordered spectroscopy (DOSY) measurements to probe molecular aggregation. We determined intramolecular distance changes within the catalyst after diol addition from quantitative NOE data. Finally, we developed a pure shift EASY ROESY experiment using PSYCHE homodecoupling to directly observe intermolecular NOE contacts between the trans-1,2-diol and the cyclohexyl moiety of the catalyst hidden by spectral overlap in conventional spectra. All experimental NMR data support the results proposed by earlier computations including the proposed key role of dispersion interaction.

Multicatalysts consisting of non-natural oligopeptides with distinctly different catalytic moieties create molecular complexity in a multistep one-pot sequence starting from simple alkenes yielding highly enantiomerically enriched trans-diols.