The influence of C2 [OH  F] substitution on the stereochemical course of chemical glycosylation was interrogated in both D-glucose and its C4 epimer D-galactose. Molecular editing at C2 and configurational inversion at C4 were simultaneously investigated by variable-temperature glycosylation studies of both systems. Extrapolation of the differences in enthalpic (ΔΔH_βα^‡) and entropic (ΔΔS_βα^‡) contributions that discriminate these closely similar systems revealed that deoxofluorination at the C2 position induces an enthalpic bias that augments β-stereoselection. Intriguingly, the enhanced stereoselectivity of the C4 epimer D-galactose was found to be entropic in nature. Given the prominence of these scaffolds in chemical biology, delineating the factors that underpin selectivity will be critical in developing novel glycosylation methods and in rationalizing differences with the natural systems post facto.

Die moderne Organokatalyse hat sich zu einem essenziellen Bestandteil der gegenwärtigen organischen Synthese entwickelt. Einer der markantesten Aspekte organokatalytischer Prozesse ist die biomimetische Weise, in welcher der Katalysator das Substrat bindet, wobei oftmals kovalent gebundene Intermediate in einer Art gebildet werden, die an enzymatische Katalyse erinnert. In der Tat geht der Prozess der Intermolekularisierung oft mit Konformationsänderungen des Katalysatorgerüsts einher, was die Analogie zu biologischen Systemen weiter verstärkt. Die Isolierung und Untersuchung dieser Katalyse-Intermediate vereinfachen die rasche Erstellung von Konformations- und Reaktivitätsprofilen, welche die Entwicklung organokatalytischer Reaktionen erleichtern und/oder Reaktionsresultate erklären können. Die Dekonstruktion von kovalent gebundenen Organokatalyse-Intermediaten als Designstrategie gewinnt an Bedeutung, motiviert durch die Fortschritte aus der Untersuchung von Reaktionsintermediaten in der mechanistischen metallorganischen und Enzymkatalyse.

Modern organocatalysis has rapidly evolved into an essential component of contemporary organic synthesis. One of the most distinctive aspects of organocatalytic processes is the biomimetic nature in which the catalyst engages the substrate, often forming covalently bound intermediates in a manner reminiscent of enzyme catalysis. Indeed, the process of intramolecularization is often accompanied by a conformational change of the catalyst scaffold, further accentuating this analogy with biological systems. The isolation and study of these catalytic intermediates facilitate the rapid generation of conformation and reactivity profiles to assist in organocatalytic reaction development and/or clarify reaction outcomes. Emulating the formative advances that have derived from studying reaction intermediates in mechanistic organometallic and enzymatic catalysis, the deconstruction of covalently bound organocatalysis intermediates is gaining momentum as a design strategy.

Substituting N-methylpyrrole for N-methyindole in secondary-amine-catalysed Friedel–Crafts reactions leads to a curious erosion of enantioselectivity. In extreme cases, this substrate dependence can lead to an inversion in the sense of enantioinduction. Indeed, these closely similar transformations require two structurally distinct catalysts to obtain comparable selectivities. Herein a focussed molecular editing study is disclosed to illuminate the structural features responsible for this disparity, and thus identify lead catalyst structures to further exploit this selectivity reversal. Key to effective catalyst re-engineering was delineating the non-covalent interactions that manifest themselves in conformation. Herein we disclose preliminary validation that intermolecular aromatic (CH–π and cation–π) interactions between the incipient iminium cation and the indole ring system is key to rationalising selectivity reversal. This is absent in the N-methylpyrrole alkylation, thus forming the basis of two competing enantio-induction pathways. A simple L-valine catalyst has been developed that significantly augments this interaction.

Invited for the cover of this issue is the group of Ryan Gilmour at the Westfälische Wilhelms-Universität Münster. The image depicts how the modes of stereoinduction differ for­ N-methylpyrrole to­ N-methylindole. Read the full text of the article at 10.1002/chem.201500270.

Herein we report the first application of infrared multiple-photon dissociation (IRMPD) spectroscopy to study noncovalent interactions in organocatalysis. Phenylalanine-derived iminium ions, central to numerous organocatalytic processes, display dynamic conformational behavior as a consequence of stabilizing noncovalent interactions (e.g., CH–π, π–π). Electronic modulation of the aryl ring causes notable variation in the conformation; this can be detected spectroscopically and correlated with enantioselectivity. Given that these interactions, which orchestrate stereoinduction, encode for specific conformers (I, II, or III), a diagnostic IRMPD spectrum is generated: the C=O stretching frequency of the imidazole carbonyl group serves as a diagnostic marker. The calculated conformers and their respective spectra can be compared with experimental data. Consequently, valuable insight into the ubiquitous noncovalent interactions associated with MacMillan-catalyst-derived α,β-unsaturated iminium ions can be obtained in the absence of solvent or counterion effects. A preliminary structure–catalysis correlation is disclosed, thus demonstrating the potential of this approach for studying reactive intermediates and facilitating catalyst design.

Acyclic conformational control often relies on destabilising noncovalent interactions to give rise to predictable conformer populations. Pertinent examples of such strategies include allylic strain (A^1,2 and A^1,3) and syn-pentane interactions. However, the incorporation of fluorine vicinal to an electron-withdrawing group (F–C_β–C_α–X) can lead to predictable conformations as a consequence of stabilising hyperconjugative and/or electrostatic interactions. Herein, we describe the application of a fluorine gauche effect to predictably control torsional rotation in a class of fluorinated 4-(dimethylamino)pyridine (DMAP) analogues. Intramolecularisation, such as protonation or acylation, generates an electropositive nitrogen centre vicinal to the fluorine atom at a molecular hinge (F–C_β–C_α–N⁺); this is the only rotatable sp³–sp³ bond. In so doing, this “substrate binding” triggers a conformational change akin to the induced fit process inherent to enzymatic systems. Herein, we validate this design approach to control molecular space. A number of X-ray structures are documented that display this gauche preference (φ_NCCF ≈ 60°). Preliminary catalysis experiments are disclosed together with a kinetic and reactivity analysis.

The enantioselective, organocatalytic aziridination of small, medium and macro-cyclic enals is reported using (S)-2-(fluorodiphenyl methyl)-pyrrolidine. Central to the reaction design is the reversible formation of a β-fluoroiminium ion intermediate, which is pre-organised on account of the fluorine-iminium ion gauche effect. This conformational effect positions the fluorine substituent synclinal-endo to the electropositive nitrogen centre thus benefiting from favourable stereoelectronic and electrostatic interactions (σ_C−Hσ_C−F*; F^δ−…N⁺). Consequently, one of the shielding groups on the fluorine-bearing carbon atom is positioned above the π-system, forming the basis of an enantioinduction strategy. Treatment of this intermediate with a “nitrene” source furnished a series of novel, optically active aziridines (e.r. up to 99.5:0.5). Further derivatisation of the product aziridines gives facile access to various amino acid derivatives, including β-fluoroamino acids. Crystallographic analyses of both the aziridines and their derivatives are disclosed.