A Modular Strategy for the Synthesis of Macrocycles and Medium-Sized Rings via Cyclization/Ring Expansion Cascade Reactions.

Macrocycles and medium-sized rings are important in many scientific fields and technologies but are hard to make using current methods, especially on a large scale. Outlined herein is a strategy by which functionalized macrocycles and medium-sized rings can be prepared using cyclization/ring expansion (CRE) cascade reactions, without resorting to high dilution conditions. CRE cascade reactions are designed to operate exclusively via kinetically favorable 5-7-membered ring cyclization steps; this means that the problems typically associated with classical end-to-end macrocyclization reactions are avoided. A modular synthetic approach has been developed to facilitate the simple assembly of the requisite linear precursors, which can then be converted into an extremely broad range of functionalized macrocycles and medium-sized rings using one of nine CRE protocols.

Discovery and mechanism of action studies of 4,6-diphenylpyrimidine-2-carbohydrazides as utrophin modulators for the treatment of Duchenne muscular dystrophy.

Duchenne muscular dystrophy is a fatal disease with no cure, caused by lack of the cytoskeletal protein dystrophin. Upregulation of utrophin, a dystrophin paralogue, offers a potential therapy independent of mutation type. The failure of first-in-class utrophin modulator ezutromid/SMT C1100 in Phase II clinical trials necessitates development of compounds with better efficacy, physicochemical and ADME properties and/or complementary mechanisms. We have discovered and performed a preliminary optimisation of a novel class of utrophin modulators using an improved phenotypic screen, where reporter expression is derived from the full genomic context of the utrophin promoter. We further demonstrate through target deconvolution studies, including expression analysis and chemical proteomics, that this compound series operates via a novel mechanism of action, distinct from that of ezutromid.

Photochemical Methods for Peptide Macrocyclisation.

Photochemical reactions have been the subject of renewed interest over the last two decades, leading to the development of many new, diverse and powerful chemical transformations. More recently, these developments have been expanded to enable the photochemical macrocyclisation of peptides and small proteins. These constructs benefit from increased stability, structural rigidity and biological potency over their linear counterparts, providing opportunities for improved therapeutic agents. In this review, an overview of both the established and emerging methods for photochemical peptide macrocyclisation is presented, highlighting both the limitations and opportunities for further innovation in the field.

Light- and Manganese-Initiated Borylation of Aryl Diazonium Salts: Mechanistic Insight on the Ultrafast Time-Scale Revealed by Time-Resolved Spectroscopic Analysis.

Manganese-mediated borylation of aryl/heteroaryl diazonium salts emerges as a general and versatile synthetic methodology for the synthesis of the corresponding boronate esters. The reaction proved an ideal testing ground for delineating the Mn species responsible for the photochemical reaction processes, that is, involving either Mn radical or Mn cationic species, which is dependent on the presence of a suitably strong oxidant. Our findings are important for a plethora of processes employing Mn-containing carbonyl species as initiators and/or catalysts, which have considerable potential in synthetic applications.

Iridium-Catalyzed Enantioselective Intermolecular Indole C2-Allylation.

The enantioselective intermolecular C2-allylation of 3-substituted indoles is reported for the first time. This directing group-free approach relies on a chiral Ir-(P, olefin) complex and Mg(ClO4 )2 Lewis acid catalyst system to promote allylic substitution, providing the C2-allylated products in typically high yields (40-99 %) and enantioselectivities (83-99 % ee) with excellent regiocontrol. Experimental studies and DFT calculations suggest that the reaction proceeds via direct C2-allylation, rather than C3-allylation followed by in situ migration. Steric congestion at the indole-C3 position and improved π-π stacking interactions have been identified as major contributors to the C2-selectivity.

Radical cyanomethylation via vinyl azide cascade-fragmentation.

Herein, a novel methodology for radical cyanomethylation is described. The process is initiated by radical addition to the vinyl azide reagent 3-azido-2-methylbut-3-en-2-ol which triggers a cascade-fragmentation mechanism driven by the loss of dinitrogen and the stabilised 2-hydroxypropyl radical, ultimately effecting cyanomethylation. Cyanomethyl groups can be efficiently introduced into a range of substrates via trapping of α-carbonyl, heterobenzylic, alkyl, sulfonyl and aryl radicals, generated from a variety of functional groups under both photoredox catalysis and non-catalytic conditions. The value of this approach is exemplified by the late-stage cyanomethylation of pharmaceuticals.

Visible-light-induced intramolecular charge transfer in the radical spirocyclisation of indole-tethered ynones.

Indole-tethered ynones form an intramolecular electron donor-acceptor complex that can undergo visible-light-induced charge transfer to promote thiyl radical generation from thiols. This initiates a novel radical chain sequence, based on dearomatising spirocyclisation with concomitant C-S bond formation. Sulfur-containing spirocycles are formed in high yields using this simple and mild synthetic protocol, in which neither transition metal catalysts nor photocatalysts are required. The proposed mechanism is supported by various mechanistic studies, and the unusual radical initiation mode represents only the second report of the use of an intramolecular electron donor-acceptor complex in synthesis.

Enantioselective Halolactonization Reactions using BINOL-Derived Bifunctional Catalysts: Methodology, Diversification, and Applications.

A general protocol is described for inducing enantioselective halolactonizations of unsaturated carboxylic acids using novel bifunctional organic catalysts derived from a chiral binaphthalene scaffold. Bromo- and iodolactonization reactions of diversely substituted, unsaturated carboxylic acids proceed with high degrees of enantioselectivity, regioselectivity, and diastereoselectivity. Notably, these BINOL-derived catalysts are the first to induce the bromo- and iodolactonizations of 5-alkyl-4( Z)-olefinic acids via 5- exo mode cyclizations to give lactones in which new carbon-halogen bonds are created at a stereogenic center with high diastereo- and enantioselectivities. Iodolactonizations of 6-substituted-5( Z)-olefinic acids also occur via 6- exo cyclizations to provide δ-lactones with excellent enantioselectivities. Several notable applications of this halolactonization methodology were developed for desymmetrization, kinetic resolution, and epoxidation of Z-alkenes. The utility of these reactions is demonstrated by their application to a synthesis of precursors of the F-ring subunit of kibdelone C and to the shortest catalytic, enantioselective synthesis of (+)-disparlure reported to date.

Low-Temperature, Transition-Metal-Free Cross-Dehydrogenative Coupling Protocol for the Synthesis of 3,3-Disubstituted Oxindoles.

A new low-temperature procedure for the synthesis of 3,3-disubstituted 2-oxindoles via cross-dehydrogenative coupling (CDC) is reported. The use of a strong, nonreversible base in these reactions has been found to effect a dramatic drop in reaction temperature (to room temperature) relative to the current state-of-the-art (>100 °C) procedure. When employing iodine as an "oxidant", new evidence suggests that this transformation may occur via a transiently stable iodinated intermediate rather than by direct single-electron oxidation.

Photoredox-catalyzed procedure for carbamoyl radical generation: 3,4-dihydroquinolin-2-one and quinolin-2-one synthesis.

A reductive approach for carbamoyl radical generation from N-hydroxyphthalimido oxamides under photoredox catalysis is outlined. This strategy was applied to the synthesis of 3,4-dihydroquinolin-2-ones via the intermolecular addition/cyclization of carbamoyl radicals with electron deficient olefins in a mild, redox-neutral manner. Under a general set of reaction conditions, diversely substituted 3,4-dihydroquinolin-2-ones, including spirocyclic systems can be prepared. By using chlorine-substituted olefins, aromatic quinolin-2-ones can also be accessed.

Ring-Expansion Reactions in the Synthesis of Macrocycles and Medium-Sized Rings.

Functionalised macrocycles and medium-sized rings have applications in a number of scientific fields, ranging from medicinal chemistry and supramolecular chemistry, to catalysis and nanotechnology. However, their value in these areas can be undermined by a simple, but important limitation: large ring systems are very often difficult to make. Traditional end-to-end cyclisation reactions of long linear precursors are typically unpredictable and impractical processes, mainly due to unfavourable enthalpic and entropic factors. Most published methods to make large rings focus on minimising the damage inflicted by performing the difficult cyclisation step; in contrast, ring-expansion reactions enable it to be avoided altogether. In this Review article, it is highlighted how "growing" rings from existing cyclic systems via ring expansion can expedite the efficient, practical and scalable synthesis of macrocycles and medium-sized rings.

Photoredox-Catalyzed Reductive Carbamoyl Radical Generation: A Redox-Neutral Intermolecular Addition-Cyclization Approach to Functionalized 3,4-Dihydroquinolin-2-ones.

The first reductive generation of carbamoyl radicals using photoredox catalysis for their formation is reported. This approach facilitated the development of a redox-neutral synthesis of functionalized 3,4-dihydroquinolin-2-ones via the novel intermolecular addition-cyclization of carbamoyl radicals across electron-deficient alkenes. To illustrate the versatility of this reaction, a diverse collection of 3,4-dihydroquinolin-2-ones, including fused cyclic and spirocyclic systems inspired by natural products, has been prepared.

Bifunctional catalyst promotes highly enantioselective bromolactonizations to generate stereogenic C-Br bonds.

A novel bifunctional catalyst derived from BINOL has been developed that promotes the highly enantioselective bromolactonizations of a number of structurally distinct unsaturated acids. Like some known catalysts, this catalyst promotes highly enantioselective bromolactonizations of 4- and 5-aryl-4-pentenoic acids, but it also catalyzes the highly enantioselective bromolactonizations of 5-alkyl-4(Z)-pentenoic acids. These reactions represent the first catalytic bromolactonizations of alkyl-substituted olefinic acids that proceed via 5-exo mode cyclizations to give lactones in which new carbon-bromine bonds are formed at a stereogenic center with high enantioselectivity. We also disclose the first catalytic desymmetrization of a prochiral dienoic acid by enantioselective bromolactonization.

APPLICATIONS OF MULTICOMPONENT ASSEMBLY PROCESSES TO THE FACILE SYNTHESES OF DIVERSELY FUNCTIONALIZED NITROGEN HETEROCYCLES.

Several multicomponent assembly processes have been developed for the synthesis of intermediates that may be elaborated by a variety of cyclizations to generate a diverse array of highly functionalized heterocycles from readily-available starting materials. The overall approach enables the efficient preparation of libraries of small molecules derived from fused, privileged scaffolds.

Application of a sequential multicomponent assembly process/huisgen cycloaddition strategy to the preparation of libraries of 1,2,3-triazole-fused 1,4-benzodiazepines.

A strategy featuring a multicomponent assembly process followed by an intramolecular azide-alkyne dipolar (Huisgen) cycloaddition was implemented for the facile synthesis of three different 1,2,3-triazolo-1,4-benzodiazepine scaffolds. A diverse library of 170 compounds derived from these scaffolds was then created through N-functionalizations, palladium-catalyzed cross-coupling reactions, and several applications of α-aminonitrile chemistry.

Synthesis and diversification of 1,2,3-triazole-fused 1,4-benzodiazepine scaffolds.

A substituted heterocyclic scaffold comprising a 1,4-benzodiazepine fused with a 1,2,3-triazole ring has been synthesized and diversified via a variety of refunctionalizations. The strategy features the rapid assembly of the scaffold by combining 3-4 reactants in an efficient multicomponent assembly process, followed by an intramolecular Huisgen cycloaddition.