Expanding the Chemical Space of Electrophilic ß-Glycosyl ß-Lactams through Photoinduced Diastereoselective Functionalization.

Herein, we present a photoinduced diastereoselective C-3 functionalization of electrophilic ß-glycosyl ß-lactams. The developed protocol is simple, mild, and scalable and explores the use of 3-exomethylene ß-lactams as reaction partners in a Giese type reaction. The key nucleophilic alkyl radical is generated by a photoinduced electron transfer process in the EDA complex formed by NHPI and Hantzsch esters. The diastereoselective hydrogen atom transfer to the ß-lactam radical intermediate enables the synthesis of various N-phenyl ß-glycosyl ß-lactams.

Recent Advances in Photoinduced Modification of Amino Acids, Peptides, and Proteins.

The chemical modification of biopolymers like peptides and proteins is a key technology to access vaccines and pharmaceuticals. Similarly, the tunable derivatization of individual amino acids is important as they are key building blocks of biomolecules, bioactive natural products, synthetic polymers, and innovative materials. The high diversity of functional groups present in amino acid-based molecules represents a significant challenge for their selective derivatization Recently, visible light-mediated transformations have emerged as a powerful strategy for achieving chemoselective biomolecule modification. This technique offers numerous advantages over other methods, including a higher selectivity, mild reaction conditions and high functional-group tolerance. This review provides an overview of the most recent methods covering the photoinduced modification for single amino acids and site-selective functionalization in peptides and proteins under mild and even biocompatible conditions. Future challenges and perspectives are discussed beyond the diverse types of photocatalytic transformations that are currently available.

Side-Selective Solid-Phase Metallaphotoredox N(in)-Arylation of Peptides.

Postsynthetic diversification of peptides through selective modification of endogenous amino acid side chains has enabled significant advances in peptide drug discovery while expanding the biological and medical chemistry space. However, current tools have been focused on the modification of reactive polar and ionizable side chains, whereas the decoration of aromatic systems (e.g., the N(in) of the tryptophan) has been a long-standing challenge. Here, we introduce metallaphotocatalysis in solid-phase peptide synthesis for the on-resin orthogonal N-arylation of relevant tryptophan-containing peptides. The protocol allows the chemoselective introduction of a new C(sp2)-N bond at the N(in) of tryptophan in biologically active protected peptide sequences in the presence of native redox-sensitive side chains. The fusion of metallaphotocatalysis with solid-phase peptide synthesis opens new perspectives in diversifying native amino acid side chains.

Synthesis of non-anomeric C-glycosyl pyrazolidinone derivatives via visible-light photoredox catalysis.

C-Glycosyl compounds have gained considerable attention over the last few decades due to their high chemical stability and promising applications in drug discovery. Herein we disclose an operationally simple, metal-free, photocatalytic approach for the glycosylation of azomethine imines using 4-glycosyl-1,4-dihydropyridines (DHPs) as radical precursors. The protocol features mild reaction conditions, scalability, broad substrate scope, and good functional group tolerance. Moreover, the resulting pyrazolidinone moiety can be easily deprotected, acylated or reduced into a glycosyl ß-alanine analog.

Visible-Light Mediated Carbamoylation of Nitrones under a Continuous Flow Regime.

Herein, we report a rapid and scalable continuous-flow photocatalytic approach for the carbamoylation of nitrones. This protocol makes use of readily available 4-amido-1,4 dihydropyridines as carbamoyl radical precursors. The scope of this transformation exhibits high compatibility with complex structures containing amino acids, peptides, and glycosides. Importantly, the developed method allows a photocatalytic synthetic strategy in combination with flow conditions, maximizing the potential and efficiency for the synthesis of valuable α-(N-hydroxy)amino amides.

Carbamoylation of Azomethine Imines via Visible-Light Photoredox Catalysis.

A versatile and robust photocatalytic methodology to install the amide functional group into azomethine imine ions is described. This protocol is distinguished by its broad scope and mild reaction conditions, which are well suited for the preparation of structurally complex compounds in the form of amino acids, peptides, and small drug-like molecules. Moreover, the generated pyrazolidinone core could be easily converted into ß-alanine analogues.

Recent Advances on Photoinduced Cascade Strategies for the Synthesis of N-Heterocycles.

Over the last decade, visible-light photocatalysis has proved to be a powerful tool for the construction of N-heterocyclic frameworks, important constituents of natural products, insecticides, pharmacologically relevant therapeutic agents and catalysts. This account highlights recent developments and established methods towards the photocatalytic cascades for preparation of different classes of N-heterocycles, giving emphasis on our contribution to the field.

Electrochemical Installation of CFH2 -, CF2 H-, CF3 -, and Perfluoroalkyl Groups into Small Organic Molecules.

Electrosynthesis can be considered a powerful and sustainable methodology for the synthesis of small organic molecules. Due to its intrinsic ability to generate highly reactive species under mild conditions by anodic oxidation or cathodic reduction, electrosynthesis is particularly interesting for otherwise challenging transformations. One such challenge is the installation of fluorinated alkyl groups, which has gained significant attention in medicinal chemistry and material science due to their unique physicochemical features. Unsurprisingly, several electrochemical fluoroalkylation methods have been established. In this review, we survey recent developments and established methods in the field of electrochemical mono-, di-, and trifluoromethylation, and perfluoroalkylation of small organic molecules.

Biocompatible Photoinduced Alkylation of Dehydroalanine for the Synthesis of Unnatural α-Amino Acids.

A site-selective alkylation of dehydroalanine to access protected unnatural amino acids is described. The protocol is characterized by the wide nature of alkyl radicals employed, mild conditions, and functional group compatibility. This protocol is further extended to access peptides, late-stage functionalization of pharmaceuticals, and enantioenriched amino acids.

Post-synthetic functionalization of tryptophan protected peptide sequences through indole (C-2) photocatalytic alkylation.

We report a selective, mild, and efficient C-H functionalization of tryptophan and tryptophan-containing peptides with activated α-bromo-carbonyl compounds under visible-light irradiation. The protocol efficiency is outlined by the wide substrate scope and excellent tolerance of sensitive functional groups present in the amino acid side chains. The method can be successfully extended to access pharmaco-peptide conjugate scaffolds.

Photocatalyzed Intramolecular [2+2] Cycloaddition of N-Alkyl-N-(2-(1-arylvinyl)aryl)cinnamamides.

N-Alkyl-N-(2-(1-arylvinyl)aryl)cinnamamides are converted into natural product inspired scaffolds via iridium photocatalyzed intramolecular [2+2] photocycloaddition. The protocol has a broad substrate scope, whilst operating under mild reaction conditions. Tethering four components forming a trisubstituted cyclobutane core builds rapidly high molecular complexity. Our approach allows the design and synthesis of a variety of tetrahydrocyclobuta[c]quinolin-3(1H)-ones, in yields ranging between 20-99 %, and with excellent regio- and diastereoselectivity. Moreover, it was demonstrated that the intramolecular [2+2]-cycloaddition of 1,7-enynes-after fragmentation of the cyclobutane ring-leads to enyne-metathesis-like products.

Direct access to tetrasubstituted cyclopentenyl scaffolds through a diastereoselective isocyanide-based multicomponent reaction.

An efficient strategy combining the stereocontrol of organocatalysis with the diversity-generating character of multicomponent reactions is described to produce structurally unique, tetrasubstituted cyclopentenyl frameworks. An asymmetric Michael addition-hemiacetalization between α-cyanoketones and α,ß-unsaturated aliphatic aldehydes was performed for constructing cyclic hemiacetals, which were next employed as chiral bifunctional substrates in a new diastereoselective intramolecular isocyanide-based multicomponent reaction. This approach furnished a diversity of structurally complex compounds - including peptidomimetics and natural product hybrids in high stereoselectivity (up to >99% ee and up to >99 : 1 dr) and in moderate to high yields.

Visible-Light-Mediated α-Amino Alkylation of Azomethine Imines: An Approach to N-(ß-Aminoalkyl)pyrazolidinones.

Herein, a mild and robust photocatalytic protocol for the combination of amino and pyrazolidinone functionalities through a radical α-amino alkylation of azomethine iminium ions is demonstrated. This method presents a high functional group tolerance providing direct access to a large family of N-(ß-aminoalkyl)pyrazolidinones in good to excellent yields, including the late-stage incorporation of the pyrazolidinone moiety to pharmaceutical ingredients. We propose a plausible scenario for the C-C bond-forming step which involves radical addition followed by a spin-center-shift event.

Green Approach for Visible-Light-Induced Direct Functionalization of 2-Methylquinolines.

A transition metal- and oxidant-free visible light-photoinduced protocol for direct functionalization of 2-methylquinolines has been developed. This protocol enabled the C-H functionalization of substituted 2-methylquinolines with diacetyl or ethyl pyruvate, under environmentally friendly conditions. A mechanistic investigation based on density functional theory (DFT) calculations provided details about the origins of reactivity and selectivity.

Green asymmetric synthesis of epoxypeptidomimetics and evaluation as human cathepsin K inhibitors.

Cathepsin K (CatK) is a cysteine protease known for its potent collagenolytic activity, being recognized as an important target to the development of therapies for the treatment of bone disorders. Epoxypeptidomimetics have been reported as potent inhibitors of cathepsins, thus in this work we present a green synthesis of new peptidomimetics by using a one-pot asymmetric epoxidation/Ugi multicomponent reaction. The compounds were evaluated against CatK showing selectivity when compared with cathepsin L, with an inhibition profile in the low micromolar IC50 range. Investigation of the mechanism of action carried out for compounds LSPN428 and LSPN694 suggested a mixed inhibition mode and docking studies allowed a better understanding about interactions of inhibitors with the enzyme.

Metal-Free Photoinduced Hydroalkylation Cascade Enabled by an Electron-Donor-Acceptor Complex.

A metal- and photocatalyst-free photoinduced radical cascade hydroalkylation of 1,7-enynes has been disclosed. The process is triggered by a single electron transfer (SET) event involving a photoexcited electron-donor-acceptor complex between an NHPI ester and a Hantzsch ester, which decomposes to afford a tertiary radical that is readily trapped by the enyne. The method provides an operationally simple, robust, and step-economical approach toward the construction of diversely functionalized dihydroquinolinones bearing quaternary centers. A sequential one-pot hydroalkylation-isomerization approach is also offered, giving access to a family of quinolinones. A wide substrate scope and high functional group tolerance were observed in both approaches.

Photoredox Catalysis toward 2-Sulfenylindole Synthesis through a Radical Cascade Process.

A radical cascade process initiated through visible-light induced thiyl radical coupling with ortho-substituted arylisocianides followed by an intramolecular cyclization and subsequent aromatization to access 2-sulfenylindoles is described. The key thiyl radicals are promptly generated via a hydrogen atom transfer event. The redox-neutral protocol features broad substrate scope, excellent functional group tolerance, and mild reaction conditions. Furthermore, the implementation of a continuous flow variant allows smooth scalability with a short residence time through process intensification.

Graphitic Carbon Nitride-Based Materials as Catalysts for the Upgrading of Lignocellulosic Biomass-Derived Molecules.

The use of graphitic carbon nitride (g-C3N4)-based catalysts in the upgrading of lignocellulosic biomass significantly contributes to the greener production of biofuels, polymer precursors, and building blocks. In recent years, several catalysts based on g-C3N4 have been developed and applied in both photocatalyzed and non-photocatalyzed (thermal) reactions. This Review provides an overview on the upgrading of lignocellulosic biomass deploying several compositions of g-C3N4-based catalysts.

One-pot organocatalytic/multicomponent approach for the preparation of novel enantioenriched non-natural selenium-based peptoids and peptide-peptoid conjugates.

A combined organocatalytic and multicomponent synthetic approach was designed for the preparation of selenium-based peptoids and peptide-peptoid conjugates. This single-step synthetic protocol comprises the organocatalytic asymmetric insertion of phenylselenium in the aldehyde moiety followed by the Ugi four-component reaction which results in obtaining the desired compounds in good-to-moderate yields and with good-to-excellent levels of stereoselectivity.

Ugi reaction-derived prolyl peptide catalysts grafted on the renewable polymer polyfurfuryl alcohol for applications in heterogeneous enamine catalysis.

The multicomponent synthesis of prolyl pseudo-peptide catalysts using the Ugi reaction with furfurylamines or isocyanides is described. The incorporation of such a polymerizable furan handle enabled the subsequent polymerization of the peptide catalyst with furfuryl alcohol, thus rendering polyfurfuryl alcohol-supported catalysts for applications in heterogeneous enamine catalysis. The utilization of the polymer-supported catalysts in both batch and continuous-flow organocatalytic procedures proved moderate catalytic efficacy and enantioselectivity, but excellent diastereoselectivity in the asymmetric Michael addition of n-butanal to ß-nitrostyrene that was used as a model reaction. This work supports the potential of multicomponent reactions towards the assembly of catalysts and their simultaneous functionalization for immobilization.