Exploration of the Copper-Catalyzed Sydnone and Sydnonimine-Alkyne Cycloaddition Reactions by High-Throughput Experimentation.

The reactivity of sydnones and sydnonimines toward terminal alkynes under copper catalysis has been explored using High-Throughput-Experimentation. A large panel of ligands and reaction conditions have been tested to optimize the copper-catalyzed sydnone click reaction discovered by our group ten years ago. This screening approach led to the identification of new ligands, which boosted the catalytic properties of copper and allowed the discovery of a new copper-catalyzed click-and-release reaction involving sydnonimines. This reaction allowed chemoselective ligation of terminal alkynes with sydnonimines and, simultaneously, the release of an isocyanate fragment molecule that can be used for further transformations.

A General Copper-based Photoredox Catalyst for Organic Synthesis: Scope, Application in Natural Product Synthesis and Mechanistic Insights.

Organic transformations can broadly be classified into four categories including cationic, anionic, pericyclic and radical reactions. While the last category has been known for decades to provide remarkably efficient synthetic pathways, it has long been hampered by the need for toxic reagents, which considerably limited its impact on chemical synthesis. This situation has come to an end with the introduction of new concepts for the generation of radical species, photoredox catalysis - which simply relies on the use of a catalyst that can be activated upon visible light irradiation - certainly being the most efficient one. The state-of-the-art catalysts mostly rely on the use of ruthenium and iridium complexes and organic dyes, which still considerably limits their broad implementation in chemical processes: alternative readily available catalysts based on inexpensive, environmentally benign base metals are therefore strongly needed. Furthermore, expanding the toolbox of methods based on photoredox catalysis will facilitate the discovery of new light-mediated transformations. This article details the use of a simple copper complex which, upon activation with blue light, can initiate a broad range of radical reactions.

Base-Mediated Generation of Ketenimines from Ynamides: Direct Access to Azetidinimines by an Imino-Staudinger Synthesis.

Ynamides were used as precursors for the in situ generation of highly reactive ketenimines that could be trapped with imines in a [2+2] cycloaddition. This imino-Staudinger synthesis led to a variety of imino-analogs of ß-lactams, namely azetidinimines (20 examples), that could be further functionalized through a broad range of transformations.

Self-Organization Ability of Chiral Nα-Substituted, Nß-Boc Protected α-Hydrazinoacetamides in the Crystal and Solution States.

The limitations of peptides have severely hampered their use in pharmacology, thus prompting the design of new peptidomimetic foldamers. This requires precise knowledge of the secondary structure of new compounds and the ability to predict their folding. Conformational studies of the basic units of these foldamers can be of invaluable assistance in designing new bioactive compounds. To this end, we investigated the conformation of three chiral Nα-substituted, Nß-Boc protected α-hydrazinoacetamide model compounds containing various side chains both on the Nα- and Cα-atoms in both the crystal and solution states. On the basis of IR absorption spectroscopy, NMR, molecular dynamics calculations and X-ray diffraction experiments, we demonstrated that these three models adopt conformational preferences, relying on eight-, six- or five-membered H-bonded pseudocycles (C8, C6 or C5), depending on the steric bulk of both Nα- or Cα-side chains. This study sheds light onto the versatile folding ability of the specific class of α-Nα-hydrazinopeptides and emphasizes the key role of the Cα-side chain on the conformational preference of the folding.

Spontaneous Self-Assembly of Fully Protected Ester 1:1 [α/α-Nα-Bn-hydrazino] Pseudodipeptides into a Twisted Parallel ß-Sheet in the Crystal State.

Previous studies have demonstrated that amidic α/ß-pseudodipeptides, 1:1 [α/α-Nα-Bn-hydrazino], have the ability to fold via a succession of γ-turn (C7 pseudocycle) and hydrazinoturn in CDCl3 solution, their amide terminals enabling the formation of an intramolecular H-bond network. Despite their lack of a primary amide terminals allowing the formation of the hydrazinoturn, their ester counterparts 1-4 were proven to self-assemble into C6 and C7 pseudocycles by intramolecular H-bonds in solution state and into an uncommon twisted parallel ß-sheet through intermolecular H-bonding in the crystal state to form a supramolecular helix, with eight molecules needed to complete a full 360° rotation. Such self-organization (with eight molecules) has only been observed in a specific α/α-pseudodipeptide, depsipeptide (Boc-Leu-Lac-OEt). Relying on IR absorption, NMR, X-ray diffraction, and CD analyses, the aim of this study was to demonstrate that stereoisomers of ester 1:1 [α/α-Nα-Bn-hydrazino] pseudodipeptides 1-4 are able to self-assemble into this ß-helical structure. The absolute configuration of the asymmetric Cα-atom of the α-amino acid residue influences the left- or right-handed twist without changing the pitch of the formed helix.

Evidence of nanotubular self-organization in solution and solid states of heterochiral cyclo 1:1 [α/α-N(α)-Bn-hydrazino]mers series.

The cyclization of heterochiral 1:1 [α/α-N(α)-Bn-hydrazino]mers leads to the corresponding cyclotetramer and cyclohexamer 3 and 4. X-ray crystallographic analysis of 3 unveils its ability to self-assemble into nanotubular structures. Further experiments conducted in the solid state through SEM analyses demonstrate the capability of 3 and 4 to form aerogels consisting of a network of nontwisted fibers, thus confirming the presence of self-organization within this series of mixed-hydrazinopeptides. Subsequent FTIR and NMR studies demonstrate the presence of an equilibrium between monomeric (intramolecular H-bonds) and nanotubular (intermolecular H-bonds) forms in solution. This equilibrium can be modified by varying the solvent.

A practical and sustainable two-component Minisci alkylation via photo-induced EDA-complex activation.

An operationally simple, open-air, and efficient light-mediated Minisci C-H alkylation method is described, based on the formation of an electron donor-acceptor (EDA) complex between nitrogen-containing heterocycles and redox-active esters. In contrast to previously reported protocols, this method does not require a photocatalyst, an external single electron transfer agent, or an oxidant additive. Achieved under mildly acidic and open-air conditions, the reaction incorporates primary-, secondary-, and tertiary radicals, including bicyclo[1.1.1]pentyl (BCP) radicals, along with various heterocycles to generate Minisci alkylation products in moderate to good yields. Additionally, the method is exploited to generate a stereo-enriched, hetereoaryl-substituted carbohydrate.

A general synthesis of azetidines by copper-catalysed photoinduced anti-Baldwin radical cyclization of ynamides.

A general anti-Baldwin radical 4-exo-dig cyclization from nitrogen-substituted alkynes is reported. Upon reaction with a heteroleptic copper complex in the presence of an amine and under visible light irradiation, a range of ynamides were shown to smoothly cyclize to the corresponding azetidines, useful building blocks in natural product synthesis and medicinal chemistry, with full control of the regioselectivity of the cyclization resulting from a unique and underrated radical 4-exo-dig pathway.

Azetidinimines as a novel series of non-covalent broad-spectrum inhibitors of ß-lactamases with submicromolar activities against carbapenemases KPC-2 (class A), NDM-1 (class B) and OXA-48 (class D).

The occurrence of resistances in Gram negative bacteria is steadily increasing to reach extremely worrying levels and one of the main causes of resistance is the massive spread of very efficient ß-lactamases which render most ß-lactam antibiotics useless. Herein, we report the development of a series of imino-analogues of ß-lactams (namely azetidinimines) as efficient non-covalent inhibitors of ß-lactamases. Despite the structural and mechanistic differences between serine-ß-lactamases KPC-2 and OXA-48 and metallo-ß-lactamase NDM-1, all three enzymes can be inhibited at a submicromolar level by compound 7dfm, which can also repotentiate imipenem against a resistant strain of Escherichia coli expressing NDM-1. We show that 7dfm can efficiently inhibit not only the three main clinically-relevant carbapenemases of Ambler classes A (KPC-2), B (NDM-1) and D (OXA-48) with Ki's below 0.3 µM, but also the cephalosporinase CMY-2 (class C, 86% inhibition at 10 µM). Our results pave the way for the development of a new structurally original family of non-covalent broad-spectrum inhibitors of ß-lactamases.

Regioselective Single-Electron Tsuji-Trost Reaction of Allylic Alcohols: A Photoredox/Nickel Dual Catalytic Approach.

A radical-mediated functionalization of allyl alcohol derived partners with a variety of alkyl 1,4-dihydropyridines via photoredox/nickel dual catalysis is described. This transformation transpires with high linear and E-selectivity, avoiding the requirement of harsh conditions (e.g., strong base, elevated temperature). Additionally, using aryl sulfinate salts as radical precursors, allyl sulfones can also be obtained. Kinetic isotope effect experiments implicated oxidative addition of the nickel catalyst to the allylic electrophile as the turnover-limiting step, supporting previous computational studies.

Synthesis of various secosteroidal macrocycles by ring-closing metathesis.

We set out to describe an efficient and versatile method for preparing secosteroidal macrocycles from cholic acid, via an oxidative ring-expansion/ring-opening sequence and a ring-closing metathesis reaction as the key steps. The characteristic ¹H and ¹³C NMR spectroscopic features of the synthesized compounds are reported.

Synthesis and characterization of (±)-13-hydroxy-3,11-diaza steroids.

An efficient strategy for introducing a nitrogen atom in positions 3 and 11 of the steroidal skeleton, which are key positions for biological purposes, is described. This procedure involves an intramolecular Diels-Alder cycloaddition of o-quinodimethanes which are generated from a 3-azabicyclo[4.2.0]octa-1,3,5-trien-7-one. The characteristic (1)H and (13)C NMR spectroscopic features of the synthesized compounds are reported.

Stereoselective synthesis of pentacyclic steroids functionalized at C-11.

We set out to describe an efficient and versatile method for preparing pentacyclic steroids diversely substituted at C-11 from cholic acid, via a stereoselective epoxidation and the epoxide opening as the key steps. The characteristic (1)H and (13)C NMR spectroscopic features of the synthesized compounds are reported.