The human tRNA-guanine transglycosylase displays promiscuous nucleobase preference but strict tRNA specificity.

Base-modification can occur throughout a transfer RNA molecule; however, elaboration is particularly prevalent at position 34 of the anticodon loop (the wobble position), where it functions to influence protein translation. Previously, we demonstrated that the queuosine modification at position 34 can be substituted with an artificial analogue via the queuine tRNA ribosyltransferase enzyme to induce disease recovery in an animal model of multiple sclerosis. Here, we demonstrate that the human enzyme can recognize a very broad range of artificial 7-deazaguanine derivatives for transfer RNA incorporation. By contrast, the enzyme displays strict specificity for transfer RNA species decoding the dual synonymous NAU/C codons, determined using a novel enzyme-RNA capture-release method. Our data highlight the broad scope and therapeutic potential of exploiting the queuosine incorporation pathway to intentionally engineer chemical diversity into the transfer RNA anticodon.

De-novo designed ß-lysine derivatives can both augment and diminish the proliferation rates of E. coli through the action of Elongation Factor P.

An investigation into the effect of modified ß-lysines on the growth rates of eubacterial cells is reported. It is shown that the effects observed are due to the post translational modification of Elongation Factor P (EFP) with these compounds catalysed by PoxA. PoxA was found to be remarkably promiscuous, which allowed the activity of a wide range of exogenous ß-lysines to be examined. Two chain-elongated ß-lysine derivatives which differ in aminoalkyl chain length by only 2 carbon units exhibited opposing biological activities - one promoting growth and the other retarding it. Both compounds were shown to operate through modification of EFP.

Catalytic, asymmetric azidations at carbonyls: achiral and meso-anhydride desymmetrisation affords enantioenriched γ-lactams.

An unprecedented organocatalytic process involving the asymmetric addition of azide to meso-anhydrides has been developed, promoted by novel sulfamide-substituted Cinchona alkaloid-based catalysts. Readily available glutaric anhydrides can be smoothly converted to enantioenriched hemi-acyl azides and from there to either γ-amino acids or γ-lactams.

Correction: The kinetic resolution of oxazinones by alcoholysis: access to orthogonally protected ß-amino acids.

Correction for 'The kinetic resolution of oxazinones by alcoholysis: access to orthogonally protected ß-amino acids' by Sarah A. Cronin et al., Org. Biomol. Chem., 2021, 19, 7348-7352, DOI: 10.1039/D1OB01306H.

The kinetic resolution of oxazinones by alcoholysis: access to orthogonally protected ß-amino acids.

The catalytic, alcoholytic kinetic resolution of oxazinones is reported. A novel, stereochemically dense cinchona alkaloid-based catalyst can facilitate the highly enantiodiscriminatory (S up to 101) ring-opening of oxazinones equipped with electrophilic aryl units to generate orthogonally protected ß-amino acids for the first time.

Enantioselective N-heterocyclic carbene-catalysed intermolecular crossed benzoin condensations: improved catalyst design and the role of in situ racemisation.

The enantioselective intermolecular crossed-benzoin condensation mediated by novel chiral N-heterocyclic carbenes derived from pyroglutamic acid has been investigated. A small library of chiral triazolium ions were synthesised. Each possessed a tertiary alcohol H-bond donor and a variable N-aryl substituent. It was found that increasing both the steric requirement and the electron-withdrawing characteristics of the N-aryl ring led to more chemoselective, efficient and enantioselective chemistry, however both quenching the reaction at different times and deuterium incorporation experiments involving the product revealed that this is complicated by product racemisation in situ (except in the case of benzoin itself), which explains the dependence of enantioselectivity on the electrophilicity of the reacting aldehydes common in the literature. Subsequent protocol optimisation, where one reacting partner was an o-substituted benzaldehyde, allowed a range of crossed-benzoins to be synthesised in moderate-good yields with moderate to excellent enantioselectivity.

Base-free enantioselective SN2 alkylation of 2-oxindoles via bifunctional phase-transfer catalysis.

N-Protected oxindole derivatives of unprecedented malleability bearing ester moieties at C-3 have been shown to participate in enantioselective phase-transfer-catalysed alkylations promoted by ad-hoc designed quaternary ammonium salts derived from quinine bearing hydrogen-bond donating substituents. For the first time in such phase-transfer-catalysed enolate alkylations, the reactions were carried out under base-free conditions. It was found that urea-based catalysts outperformed squaramide derivatives, and that the installation of a chlorine atom adjacent to the catalyst's quinoline moiety aided in avoiding selectivity-reducing complications related to the production of HBr in these processes. The influence of steric and electronic factors from both the perspective of the nucleophile and electrophile were investigated and levels of enantiocontrol up to 90% ee obtained. The synthetic utility of the methodology was demonstrated via the concise enantioselective synthesis of a potent CRTH2 receptor antagonist.

Divergent Synthesis of γ-Amino Acid and γ-Lactam Derivatives from meso-Glutaric Anhydrides.

The first divergent synthesis of both γ-amino acid and γ-lactam derivatives from meso-glutaric anhydrides is described. The organocatalytic desymmetrisation with TMSN3 relies on controlled generation of a nucleophilic ammonium azide species mediated by a polystyrene-bound base to promote efficient silylazidation. After Curtius rearrangement of the acyl azide intermediate to access the corresponding isocyanate, hydrolysis/alcoholysis provided uniformly high yields of γ-amino acids and their N-protected counterparts. The same intermediates were shown to undergo an unprecedented decarboxylation-cyclisation cascade in situ to provide synthetically useful yields of γ-lactam derivatives without using any further activating agents. Mechanistic insights invoke the intermediacy of an unconventional γ-N-carboxyanhydride (γ-NCA) in the latter process. Among the examples prepared using this transformation are 8 APIs/molecules of considerable medicinal interest.

Highly Enantio- and Diastereoselective Catalytic Asymmetric Tamura Cycloaddition Reactions.

The first broad-scope catalytic asymmetric Tamura cycloaddition reactions are reported. Under the influence of anion-binding bifunctional catalysis a wide range of α,ß-unsaturated N-trityl imines undergo reactions with enolisable anhydrides to form highly synthetically useful α-tetralone structures with excellent enantio- and -diastereocontrol. In stark contrast to the previous literature benchmarks, doubly activated or highly electron deficient alkenes are not required. A facile two-step, high yielding sequence can convert the cycloadducts to α-haloketones (challenging to generate catalytically by other means) with the net formation of two new C-C bonds and three new contiguous stereocentres with exquisite stereocontrol. A DFT study has provided insight into the catalyst mode of action and the origins of the observed enantiocontrol.

Highly Enantioselective Catalytic Kinetic Resolution of α-Branched Aldehydes through Formal Cycloaddition with Homophthalic Anhydrides.

A new catalytic methodology was developed to promote an efficient one-pot kinetic resolution of racemic aldehydes with selectivity (s*) of up to 91 (99:1 d.r., >99 % ee) in a cycloaddition reaction with enolizable anhydrides to afford dihydroisocoumarin products (a core prevalent in natural products and molecules of medicinal interest) containing three contiguous stereocentres.

Catalytic Asymmetric γ-Lactam Synthesis from Enolisable Anhydrides and Imines.

An anion-binding approach to the problem of preparing enantioenriched γ-lactams from enolisable anhydrides and imines is reported. A simple bisurea catalyst promotes the cycloaddition between α-aryl succinic anhydrides and either PMP- or benzhydryl-protected aldimines to provide γ-lactams with two contiguous stereocentres (one quaternary) with complete diastereocontrol and high to excellent enantioselectivity for the first time. A DFT study has provided insight into the catalyst mode of action and the origins of the observed stereocontrol.

In vivo modification of tRNA with an artificial nucleobase leads to full disease remission in an animal model of multiple sclerosis.

Queuine is a modified pyrrolopyrimidine nucleobase derived exclusively from bacteria. It post-transcriptionally replaces guanine 34 in transfer RNA isoacceptors for Asp, Asn, His and Tyr, in almost all eukaryotic organisms, through the activity of the ancient tRNA guanine transglycosylase (TGT) enzyme. tRNA hypomodification with queuine is a characteristic of rapidly-proliferating, non-differentiated cells. Autoimmune diseases, including multiple sclerosis, are characterised by the rapid expansion of T cells directed to self-antigens. Here, we demonstrate the potential medicinal relevance of targeting the modification of tRNA in the treatment of a chronic multiple sclerosis model­murine experimental autoimmune encephalomyelitis. Administration of a de novo designed eukaryotic TGT substrate (NPPDAG) led to an unprecedented complete reversal of clinical symptoms and a dramatic reduction of markers associated with immune hyperactivation and neuronal damage after five daily doses. TGT is essential for the therapeutic effect, since animals deficient in TGT activity were refractory to therapy. The data suggest that exploitation of the eukaryotic TGT enzyme is a promising approach for the treatment of multiple sclerosis.

Enantioselective Alkylation of 2-Oxindoles Catalyzed by a Bifunctional Phase-Transfer Catalyst: Synthesis of (-)-Debromoflustramine†B.

A new bifunctional phase-transfer catalyst that employs hydrogen bonding as a control element was developed to promote efficient enantioselective SN 2 reactions for the construction all-carbon quaternary stereocenters in high yield and excellent enantioselectivity (up to 97 % ee) utilizing the alkylation of a malleable oxindole substrate. The utility of the methodology was demonstrated through a concise and highly enantioselective synthesis of (-)-debromoflustramine B.

Catalytic Asymmetric Cycloadditions between Aldehydes and Enolizable Anhydrides: cis-Selective Dihydroisocoumarin Formation.

In the presence of a trityl-substituted cinchona alkaloid-based catalyst, homophthalic, aryl succinic, and glutaconic anhydride derivatives reacted with aromatic and aliphatic aldehydes to produce cis-lactones in up to 90:10 dr and 99% ee. A DFT study has shown how the catalyst is uniquely able to bring about the opposite sense of diastereocontrol to that usually observed.

Synthesis of α-alkylated γ-butyrolactones with concomitant anhydride kinetic resolution using a sulfamide-based catalyst.

The Kinetic Resolution (KR) of α-alkylated enolisable disubstituted anhydrides has been shown to be possible for the first time. In the presence of an ad hoc designed novel class of bifunctional sulfamide organocatalyst, a regio-, diastereo- and enantioselective cycloaddition reaction between the enolisable anhydride and benzaldehydes provides densely functionalised γ-butyrolactones in one pot (up to 19 : 1 dr, 94% ee) with control over three contiguous stereocentres. The concomitant resolution of the starting material anhydride, provides access to a range of chiral succinate derivatives with selectivity factors up to S* = 10.5.

Highly chemoselective intermolecular cross-benzoin reactions using an ad hoc designed novel N-heterocyclic carbene catalyst.

The design of a novel N-heterocyclic carbene catalyst incorporating a bulky yet highly electron-deficient N-aryl substituent has allowed the development of an efficient protocol for the first highly chemoselective intermolecular benzoin condensations between two non-identical aromatic aldehydes.

Catalytic asymmetric Tamura cycloadditions involving nitroalkenes.

The first examples of asymmetric Tamura cycloaddition reactions involving singly activated alkenes are reported. Homophthalic anhydride reacts with α-methyl nitrosytrenes in the presence of an alkaloid-based catalyst to generate fused bicyclic aromatic ketone products with three new stereocentres (which are susceptible to subsequent equilibration) in 12-99% ee. An unusual equilibration process which occurs in methanolic medium in the absence of a recognisable base via proton transfer at the α-carbon of an ester was investigated experimentally and computationally.

Catalytic formal cycloadditions between anhydrides and ketones: excellent enantio and diastereocontrol, controllable decarboxylation and the formation of adjacent quaternary stereocentres.

It has been shown for the first time that enolisable anhydrides can participate in highly efficient and diastereo/enantioselective additions to activated ketones. In these reactions the anhydride component formally acts (initially) as the nucleophilic component. These processes are promoted by novel, readily prepared urea-substituted cinchona alkaloid-derived catalysts at low loadings under mild conditions. Three classes of enolisable anhydride and three different types of activated ketone were shown to be compatible with the process - generating a diverse range of structurally distinct and densely functionalised lactone products with the formation of two new stereocentres, one of which is quaternary. In one example, a product incorporating two contiguous quaternary stereocentres (one all carbon) was formed with outstanding enantiocontrol. It has been shown in the case of glutaconic anhydride derivatives that the cycloaddtion process is reversible, and can be accompanied by decarboxylation and olefin isomerisation. Reaction conditions can be modified to give access to three types of product with good-excellent ee.

The first catalytic asymmetric cycloadditions of imines with an enolisable anhydride.

The first catalytic, asymmetric reactions of imines with homophthalic anhydride to form disubstituted 3,4-dihydroisoquinolones are reported. The use of N-mesyl aldimines is key, as more basic imines undergo rapid uncatalysed reactions, while imines possessing larger N-sulphonyl substituents form lactams with lower ee.

A practical aryl unit for azlactone dynamic kinetic resolution: orthogonally protected products and a ligation-inspired coupling process.

The first strategy for bringing about enantioselective azlactone dynamic kinetic resolution to generate orthogonally protected amino acids has been developed. In the presence of a C2-symmetric squaramide-based catalyst, benzyl alcohol reacts with novel yet readily prepared tetrachloroisopropoxycarbonyl-substituted azlactones to generate trapped phthalimide products of significant synthetic interest with excellent enantiocontrol. These materials are masked amino acids which are demonstrably orthogonally protected: cleavage of the phthalimide can be achieved in the presence of the ester and vice versa. This process could be utilized to bring about a highly stereoselective ligation-type coupling of protected serines (at stoichiometric loadings) with racemic azlactones derived from both natural and abiotic amino acids. After deprotection, a subsequent base-mediated O→N acyl transfer occurs to form a dipeptide.