A method for the synthesis of 2-aroyl-5-aryl-pyrroles using phenacyl azide and α,β-unsaturated aldehyde at room temperature has been developed. High yield, atom economy and requirement of economic substrates, reagents and organocatalyst as well as non-involvement of cryogenic or very high temperature and inert or anhydrous conditions make this protocol a sustainable synthetic approach towards the synthesis of 2-aroyl-5-aroyl-pyrroles.

Abstract

Structurally diverse pyrroles were synthesized by direct coupling of α, β-unsaturated aldehydes and phenacyl azides. The scope of the synthetic method was successfully demonstrated by synthesizing 28 different phenyl(5-phenyl-1H-pyrrol-2-yl)methanones in high yields (87–95 %). Derivatization of a few synthesized pyrroles was demonstrated which shows the potential application of the developed protocol in new functional materials. To get a mechanistic insight of the reaction, a typical reaction was performed in a deuterated solvent and the progress of the reaction was monitored by recording its ¹H NMR at regular time intervals.

Lactams by Ring Transformation: δ-Butyrolactams with an exocyclic ester moiety in the δ-position were accessed by reduction of cyclic α-azido-β-oxocyclopentane carboxylates with Zn−AcOH. The ring transformation proceeded readily under the conditions of the reduction which is an unprecedented process.

Abstract

δ-Butyrolactams with an exocyclic ester moiety in the δ-position were accessed by reduction of 1-azido-2-cyclopentanone carboxylates with PBu₃ or Zn−AcOH. The ring transformation proceeded readily under the conditions of this reduction which is an unprecedented process. Primary amines formed by catalytic hydrogenation of α-azido-β-oxoesters with larger ring sizes or with benzannulation do not show this rearrangement under the conditions of the azide reduction. In these cases, the ring transformation to respective lactams was achieved by treatment of the α-amino-β-oxoesters with a stoichiometric amount of lithium diisopropylamide.

This study outlines the development of novel boronic acids as catalysts for the direct synthesis of amides from carboxylic acids and amines. The Lewis acidity of the boronic acids was estimated by means of computational techniques, and the observed increase in catalytic activity was corroborated by kinetic data derived from a model reaction. Our investigations led to the discovery of a set of ortho-(sulfonyloxy)benzeneboronic acids that compared favorably with the established state-of-the-art. These newly developed catalysts demonstrated efficacy in the coupling of aliphatic, aromatic, and heteroaromatic acids, as well as primary and secondary amines.

Herein, a convenient and operationally simple protocol for the ex-situ generation of bis(trifluoromethyl)disulfide from the readily available and commercial Langlois reagent is reported. The one-step synthesis of the toxic and volatile CF3SSCF3 is performed in a two-chamber reactor with simple PPh3 and N-bromosuccinimide as the activator, allowing for the safe handling and tandem utilization in direct trifluoromethylthiolation reactions. The versatility of the ex-situ generated CF3SSCF3 is demonstrated in known electrophilic, nucleophilic, and a radical trifluoromethylthiolation reactions. Furthermore, the application of the CF3SSCF3 in a copper-catalyzed cross-coupling with boronic acids is disclosed, showing good to excellent yields of trifluoromethyl-substituted aryl products, including pharmaceutically relevant molecules.

In search of EVH1 domain inhibitors as potential anti-metastasis drugs, we have developed an efficient and scalable liquid-phase synthesis of pseudo-peptidic ligands composed of conformationally defined proline-derived modules (ProMs).

Abstract

In the search for efficient inhibitors for the enabled/vasodilator-stimulated phosphoprotein homology 1 (EVH1) domain to reduce cell motility in metastatic cancer, we previously developed a toolkit of proline-derived modules (ProMs), which mimic the PPII helix found in the natural −FPPPP− binding motif of EVH1. In this work, we describe the modular assembly of these ProM-based pentapeptidic EVH1 ligands through liquid phase peptide synthesis. We initially used pentafluorophenyl (Pfp) active esters for amide bond formation and built up the growing peptide chain from the C- to the N-terminus. Switching to HATU/DIPEA coupling conditions and changing the directionality of the synthesis from the N- to the C-terminus afforded the target ligands with improved overall yields and purity. Employing a Fmoc-protected (instead of the N-acetylated) phenylalanine derivative as N-terminal building block significantly reduced epimerization. In contrast to the originally used solid phase peptide synthesis (SPPS), the developed solution phase method allowed for a facile alteration of the C-terminal ProM unit and the production of various pentapeptidic ligands in an efficient fashion even on a multigram scale.

Is it possible to build up molecular complexity without the help of a catalyst? Yes, it is! With the suitable starting-materials, a domino or multicomponent reaction can be initiated just turning on the right light.

Abstract

Achieving high molecular complexity can be not trivial, but the exploitation of domino reactions provides an atom- and step-economical method to reach this target. Over the past decades, a lot of efforts have been put on the development of photocatalytic cascades employing both metal-based and purely organic catalysts. Despite the effectiveness of these protocols, catalyst- and additive-free light-induced domino reactions are gaining momentum thank to their efficiency, operational simplicity and sustainability. The increasing number of papers published on this field in the last years is a proof of the appeal of these transformations. In this Review, we discuss domino and multicomponent reactions mediated by light with a focus on photocatalyst- and additive-free processes. The most recent advances in the synthesis of complex nitrogen-, oxygen-, sulphur- and selenium-heterocycles together with multicomponent cascades are analysed with an emphasis on both experimental and mechanistic studies.

In this Concept, the bio-derived signal transduction machineries utilised for protocell communication are reviewed and categorised into enzyme cascades, DNA strand displacement, and gene-mediated systems. Future opportunities for synthetic chemists to develop new bio-inspired and fully synthetic alternatives to these bio-derived machineries in the form of synthetic enzymes or “synzymes” are highlighted.

Abstract

The bottom-up fabrication of synthetic cells (protocells) from molecules and materials, is a major challenge of modern chemistry. A significant breakthrough has been the engineering of protocells capable of chemical communication using bio-derived molecules and ex situ stabilised cell machineries. These, however, suffer from short shelf-lives, high costs, and require mild aqueous conditions. In this Concept Article we analyse the chemistry at the heart of protocell communication to highlight new opportunities for synthetic chemists in protocell engineering. Specifically, we (i) categorise the main bio-derived chemical communication machineries in enzyme cascades, DNA strand displacement, and gene-mediated communication; (ii) review the chemistries of these signal transduction machineries; and (iii) introduce new types of bio-inspired, fully synthetic artificial enzymes to replace their natural counterparts. Developing protocells that incorporate synthetic analogues of bio-derived signal transduction machineries will improve the robustness, stability, and versatility of protocells, and broaden their applications to highly strategic fields such as photocatalysis and fine chemicals production.

N-hydroxy-γ-lactams are produced through an enzymatic sequence combining a lipase-catalyzed hydroxylamidation with an oxidase/peroxidase-induced ene-type cyclization. This methodology provides a mild and scalable access to N-heterocyclic building blocks from basic γ,δ-unsaturated esters and aqueous hydroxylamine, and its utility is illustrated by the formal total synthesis of the tetracyclic alkaloid cephalotaxine.

Abstract

The assembly of enzymatic cascades and multi-step reaction sequences represents an attractive alternative to traditional synthetic-organic approaches. The biocatalytic reaction mediators offer not only mild conditions and permit the use of environmentally benign reagents, but the high compatibility of different enzymes promises more streamlined reaction setups. In this study, a triple-enzymatic strategy was developed that enables the direct conversion of γ,δ-unsaturated esters to N-hydroxy-γ-lactam building blocks. Hereby, a lipase-catalyzed hydroxylaminolysis generates hydroxamic acid intermediates that are subsequently aerobically activated by horseradish peroxidase and glucose oxidase to cyclize in an intramolecular nitroso ene reaction. Utilizing the hydroxylaminolysis/ene-cyclization sequence for the preparation of an aza-spirocyclic lactam, the multi-enzymatic methodology was successfully employed in the synthesis of key intermediates en route to alkaloids of the Cephalotaxus family.

An asymmetric protocol for the synthesis of novel benzofused ϵ-lactones starting from quinone methides and activated acetic acid esters using chiral isothiourea Lewis base catalysts has been developed.

Abstract

We herein report a two-step protocol for the asymmetric synthesis of novel chiral benzofused ϵ-lactones starting from O-protected hydroxymethyl-para-quinone methides and activated aryl esters. By using chiral isothiourea Lewis base catalysts a broad variety of differently substituted products could be obtained in yields of around 50 % over both steps with high levels of enantioselectivities, albeit low diastereoselectivities only.

Described herein are the total syntheses of salinosporamides via a strategy involving rapid construction of the pyrrolidinone core of the natural products from the simple amino acid serine. The key to the success of this synthesis was the stereoselective installation of three contiguous stereocenters on the pyrrolidinone core via a single aldol cyclization step, which employed the principles of ′memory of chirality” and dynamic kinetic resolution.

Abstract

The first total synthesis of (−)-salinosporamide D was achieved using d-serine as the sole chiral source. This approach stands out for its application of the principles of memory of chirality and dynamic kinetic resolution in the intramolecular aldol reaction of serine-derived oxazolidines. These strategies enabled the rapid construction of a pyrrolidinone core and installation of contiguous stereocenters. The key intermediate was readily obtained, culminating the asymmetric total synthesis of salinosporamide D. The total synthesis of salinosporamides A and I was also achieved using the same chemistry.