Aza-Ortho-Quinone Methides as Reactive Intermediates: Generation and Utility in Contemporary Asymmetric Synthesis

The aza-ortho-quinone methide (aza-o-QM) chemistry has overwhelmingly progressed in the past few decades. This review aims to integrate various transition metal-catalyzed and organocatalytic strategies in taming aza-o-QM intermediates, including the aza-ortho-vinylidene quinone methide (aza-o-VQM), aza-ortho-alkynyl quinone methide (aza-o-AQM), aza-para-quinone methide (aza-p-QM), and indole-based aza-o-QM analog. These transient species are often utilized for the direct and enantioselective synthesis of complex (hetero)polycyclic or fused-ring molecular scaffolds such as tetrahydroquinoline and indoline, among others, which are abundant in many natural products, bioactive compounds, and pharmaceuticals.     

An ortho-Quinone Methide Mediates Disulfide Migration in the Biosynthesis of Epidithiodiketopiperazines

The transannular disulfide functions as a key structural element imparting diverse biological activities to epidithiodiketopiperazines (ETPs). Although mechanisms were proposed in previous studies, α,β′-disulfide formation in ETPs is not well-determined owing to the failure to identify the hypothetical intermediate. Herein, we characterize the key ortho-quinone methide (o-QM) intermediate and prove its involvement in the carbon-sulfur migration from an α,α′- to an α,β′-disulfide by elucidating pretrichodermamide A biosynthesis, which is catalyzed by a FAD-dependent thioredoxin oxygenase TdaE harboring a noncanonical CXXQ motif. Biochemical investigations of recombinant TdaE and mutants demonstrated that the construction of the α,β′-disulfide was initiated by Gln140 triggering proton abstraction for generation of the essential o-QM intermediate, accompanied by β′-acetoxy elimination. Subsequent attack on the α,α′-disulfide by Cys137 led to disulfide migration and spirofuran formation. This study expands the biocatalytic toolbox for transannular disulfide formation and sets the stage for the targeted discovery of bioactive ETPs.     

Discovery and Biomimetic Synthesis of a Phloroglucinol-Terpene Adduct Collection from Baeckea frutescens and Its Biogenetic Origin Insight

A phloroglucinol-terpene adduct (PTA) collection consisting of twenty-four molecules featuring three skeletons was discovered from Baeckea frutescens. Inspired by its biosynthetic hypothesis, we synthesized this PTA collection by reductive activation of stable phloroglucinol precursors into highly reactive ortho-quinone methide (o-QM) intermediates and subsequently Diels–Alder cycloaddition. We also demonstrated, for the first time, the generation process of the active o-QM by performing dynamic NMR and HPLC-MS monitoring experiments. Moreover, the PTA collection showed significant antifeedant effect toward the Plutella xylostella larvae.     

Ortho-Quinone Methide Driven Synthesis of New O,N- or N,N-Heterocycles

To synthesize functionalized Mannich bases that can serve two different types of ortho-quinone methide (o-QM) intermediates, 2-naphthol and 6-hydroxyquinoline were reacted with salicylic aldehyde in the presence of morpholine. The Mannich bases that can form o-QM and aza-o-QM were also synthesized by mixing 2-naphthol, 2-nitrobenzaldehyde, and morpholine followed by reduction of the nitro group. The highly functionalized aminonaphthol derivatives were then tested in [4+2] cycloaddition with different cyclic imines. The reaction proved to be both regio- and diastereoselective. In all cases, only one reaction product was obtained. Detailed structural analyses of the new polyheterocycles as well as conformational studies including DFT modelling were performed. The relative stability of o-QMs/aza-o-QM were also calculated, and the regioselectivity of the reactions could be explained only when the cycloaddition started from aminodiol 4 . It was summarized that starting from diaminonaphthol 25 , the regioselectivity of the reaction is driven by the higher nucleophilicity of the amino group compared with the hydroxy group. 12H-benzo[a]xanthen-12-one ( 11 ), formed via o-QM formation, was isolated as a side product. The proton NMR spectrum of 11 proved to be very unique from NMR point of view. The reason for the extreme low-field position of proton H-1 could be accounted for by theoretical calculation of structure and spatial magnetic properties of the compound in combination of ring current effects of the aromatic moieties and steric compression within the heavily hindered H(1)-C(1)-C(12b)-C(12a)-C(12)=O structural fragment.     

o-Quinone methide with overcrowded olefin component as a dehydridation catalyst under aerobic photoirradiation conditions

An o-quinone methide (o-QM) featuring an overcrowded olefinic framework is introduced, which exhibits dehydridation activity owing to its enhanced zwitterionic character, particularly through photoexcitation. The characteristics of this o-QM enable the operation of dehydridative catalysis in the oxidation of benzylic secondary alcohols under aerobic photoirradiation conditions. An experimental analysis and density functional theory calculations provide mechanistic insights; the ground-state zwitterionic intermediate abstracts a hydride and proton simultaneously, and the active oxygen species facilitate catalyst regeneration.

An o-quinone methide (o-QM) featuring an overcrowded olefinic framework is introduced, which exhibits dehydridation activity owing to its enhanced zwitterionic character, particularly through photoexcitation.     

Photolysis of <Emphasis Type="Italic">o</Emphasis>-iodo- and <Emphasis Type="Italic">o</Emphasis>-bromophenols in aqueous solution of sodium sulfite and organic solvents

The photochemical reaction of o-iodo- and o-bromophenol in an aqueous sodium sulfite solution proceeds via both nonchain and chain mechanisms. The formation of the intermediate product, aromatic radical anion, was observed. The quantum yield of the photochemical reaction of o-iodophenol increases, when the electron donor diphenylamine is irradiated. In the photolysis of o-halophenols in organic solvents, free iodine is evolved in addition to aromatic products. The products of the photolysis of o-iodophenol in ethanol and carbon tetrachloride were identified by gas chromatography-mass spectrometry. These are phenol in the case of ethanol and a mixture of o-chlorophenol and hydroxychloro-substituted biphenyls in the case of carbon tetrachloride. The quantum yields were determined for all photochemical reactions studied.     

Elucidation of Pseurotin Biosynthetic Pathway Points to Trans‐Acting C‐Methyltransferase: Generation of Chemical Diversity

Pseurotins comprise a family of structurally related Aspergillal natural products having interesting bioactivity. However, little is known about the biosynthetic steps involved in the formation of their complex chemical features. Systematic deletion of the pseurotin biosynthetic genes in A. fumigatus and in vivo and in vitro characterization of the tailoring enzymes to determine the biosynthetic intermediates, and the gene products responsible for the formation of each intermediate, are described. Thus, the main biosynthetic steps leading to the formation of pseurotin A from the predominant precursor, azaspirene, were elucidated. The study revealed the combinatorial nature of the biosynthesis of the pseurotin family of compounds and the intermediates. Most interestingly, we report the first identification of an epoxidase C‐methyltransferase bifunctional fusion protein PsoF which appears to methylate the nascent polyketide backbone carbon atom in trans.     

Catalytic deoxygenation of organic compounds by carbon monoxide: III. The reaction under pressure of aromatic nitro compounds in the presence of o-phthalaldehyde

The reaction of o-phthalaldehyde with several aromatic nitro compounds in the presence of carbon monoxide and catalytic quantities of hexarhodium-hexadecacarbonyl eventuated in the formation of the corresponding N-substituted isoindolinone as the major product. A reaction mechanism has been suggested incorporating deoxygenation of the nitro compound by carbon monoxide to a nitrene intermediate and the subsequent interception of the latter by o-phthalaldehyde.     

(±)-Diinsininone: made nature's way

We report the synthesis of diinsininone (33), the aglycone of (±)-diinsinin (2). Thereby, we complete the first construction of a proanthocyanidin (PA) type-A compound incorporating a [3.3.1]-bicyclic ketal as its characteristic core. Our strategy utilizes a coupling between a benzopyrilium salt and a flavanone that proves applicable to other PA type-A compounds. During this undertaking, treatment of naringenin (9) with 2-iodoxybenzoic acid (IBX) followed by reductive work-up affords eriodictyol (10). This reactivity mirrors that of catechol hydroxylase (F3H) found in the flavonoid pathway. Other interesting transformations include the formation of flavonoids through an ortho-quinone methide (o-QM) cycloaddition-oxidation sequence and regioselective β-glycosidations of several unprotected flavanones suggesting a likely synthesis of 2 from the aglycone 33.     

Total Synthesis of Illisimonin A and Merrilactone A

Illicium sesquiterpenes are a large family of biologically active secondary metabolites isolated from Illicium species of plants and are well-known for their activity of neurite outgrowth in cultured neurons. Herein, we propose a comprehensive biosynthetic pathway for illicium sesquiterpenes and report a synthetic route to illisimonin A and merrilactone A based on it. We think that the carbon scaffolds of most of the illicium sesquiterpenes could be synthesized from a dicarbonyl derivative of allo-cedrane through retro-Dieckmann condensation, oxidative cleavage and aldol reaction at suitable oxidation states in Nature. The common intermediate for illisimonin A and merrilactone A similar to the dicarbonyl derivative of allo-cedrane was assembled with up to 82 % ee by an asymmetric intramolecular desymmetrizing reductive Heck reaction by the use of a new type of chiral phosphine ligand. The syntheses of illisimonin A and merrilactone A supported the key transformations of the proposed biosynthetic pathway.     

Crystallization of bisphenol-A polycarbonate induced by organic salts: Chemical modification of the polymer. I. Model reactions

The chemical modifications induced in diphenyl carbonate (DPC) by sodium arylcarboxylates between 200 and 250°C were studied to model the behavior of bisphenol-A polycarbonate – salt systems. Reaction between the salt and DPC produces sodium phenoxide, the phenyl arylcarboxylate corresponding to the salt, and carbon dioxide. The two latter compounds probably result from the decarboxylation of an unstable intermediate compound, viz., a mixed carboxylic carbonic anhydride. CO₂ and sodium phenoxide act as catalysts transforming DPC into phenyl salicylate via the formation of a small amount of sodium salicylate. Electrophilic acylation of sodium phenoxide by DPC is another possible but minor source of phenyl salicylate. Above 250°C, phenyl salicylate becomes unstable and pyrolyzes into o-phenoxybenzoic acid, which is immedicately esterified in the presence of DPC into phenyl o-phenoxybenzoate. In DPC + sodium o-chlorobenzoate systems, reaction between phenyl o-chlorobenzoate and sodium phenoxide is another source of phenyl o-phenoxybenzoate.     

Naphtho[1′,2′:5,6]pyrano[2,3–6][1,5]benzodiazepine Derivatives

The reaction of 3-(dimethylamino)-1-oxo-1H-naphtho[2,1-b]pyran-2-carbaldehyde (Ia) with o-phenylenediamines or N-monosubstituted o-phenylenediamines in refluxing glacial acetic acid afforded the corresponding naphtho[1′,2′:5,6]pyrano[2,3-b][1,5]benzodiazepin-15-(8H)ones V in very good yields. A similar result was achieved when the reaction was carried out in refluxing pyridine, using N-monosubstituted o-phenylenediamine hydrochlorides. The isolation of a significant intermediate as well as the synthesis through a different univocal pathway confirmed the structure of the compounds V. Moreover the reaction of Ia with N-monosubstituted o-phenylenediamines in refluxing pyridine generally afforded only low yields of compounds V, sometimes together with naphtho[1′,2′:5,6]pyrano[2,3-b][1,5]benzodiazepin-15-(13H)ones VII, isomers of V.     

Design and Synthesis of New Withaferin A Inspired Hedgehog Pathway Inhibitors

Withanolides constitute a well-known family of plant-based alkaloids characterised by widespread biological properties, including the ability of interfering with Hedgehog (Hh) signalling pathway. Following our interest in natural products and in anticancer compounds, we report here the synthesis of a new class of Hh signalling pathway inhibitors, inspired by withaferin A, the first isolated member of withanolides. The decoration of our scaffolds was rationally supported by in silico studies, while functional evaluation revealed promising candidates, confirming once again the importance of natural products as inspiration source for the discovery of novel bioactive compounds. A stereoselective approach, based on Brown chemistry, allowed the obtainment and the functional evaluation of the enantiopure hit compounds.     

An Efficient,One‐Pot,Green Synthesis of Tetracyclic Imidazo[2,1‐b]Thiazoles via Electrochemically Induced Tandem Heteroannulation Reactions

A series of novel catechol‐fused tetracyclic compounds, with an imidazo[2,1‐b]thiazole central core, were successfully synthesized through the anodic oxidation of catechols in the presence of 2‐mercaptobenzimidazole in aqueous solution. The cyclic voltammetric results indicate that a one‐pot four‐step sequential reaction occurs between 2‐mercaptobenzimidazole and the electrochemically derived o‐benzoquinones affording fused polyheterocyclic compounds. The mechanism of this catalyst‐free, domino reaction is proved as an ECEC pathway using controlled‐potential coulometry. In addition, the electrosyntheses of fused compounds have been successfully performed in ambient conditions in an undivided cell using an environmentally friendly method with high atom economy. The structures of products were characterized by FT‐IR, ¹H NMR, ¹³C NMR, and HRMS spectrometric methods.     

Asymmetric Synthesis of 1,4‐Dicarbonyl Compounds from Aldehydes by Hydrogen Atom Transfer Photocatalysis and Chiral Lewis Acid Catalysis

Enantioenriched 1,4‐dicarbonyl compounds are versatile synthons in natural product and pharmaceutical drug synthesis. We herein report a mild pathway for the efficient enantioselective synthesis of these compounds directly from aldehydes through synergistic cooperation between a neutral eosin Y hydrogen atom transfer photocatalyst and a chiral rhodium Lewis acid catalyst. This method is distinguished by its operational simplicity, abundant feedstocks, atom economy, and ability to generate products in high yields (up to 99 %) and high enantioselectivity (up to 99 % ee).     

Organocatalyzed Asymmetric Friedel‐Crafts Reactions: An Update

The Friedel‐Crafts alkylation (F‐CA) reaction is a special kind of carbon?carbon bond formations, which is frequently being used for the formation of such bond in some aromatic rings in organic synthesis. Its asymmetric variant gives enantiorich products. Commonly, an in situ organocatalyzed asymmetric Friedel‐Crafts alkylation (AF‐CA) proceeds via generation of an enamine as an intermediate. The organocatalyzed‐AF‐CA was discovered and established in the mid‐1980s and reviewed comprehensively in 2010. In this report, we are trying to update the applications of novel organocatalysts in the AF‐CA as a versatile synthetic strategy, which is frequently used in the effective asymmetric synthesis of complex molecules, pharmaceutically important compounds and most importantly in the total synthesis of biologically active natural products.     

Gold(I)‐Catalyzed Cycloisomerizations and Alkoxycyclizations of ortho‐(Alkynyl)styrenes

Indenes and related polycyclic structures have been efficiently synthesized by gold(I)‐catalyzed cycloisomerizations of appropriate ortho‐(alkynyl)styrenes. Disubstitution at the terminal position of the olefin was demonstrated to be essential to obtain products originating from a formal 5‐endo‐dig cyclization. Interestingly, a complete switch in the selectivity of the cyclization of o‐(alkynyl)‐α‐methylstyrenes from 6‐endo to 5‐endo was observed by adding an alcohol to the reaction media. This allowed the synthesis of interesting indenes bearing an all‐carbon quaternary center at C1. Moreover, dihydrobenzo[a]fluorenes can be obtained from substrates bearing a secondary alkyl group at the β‐position of the styrene moiety by a tandem cycloisomerization/1,2‐hydride migration process. In addition, diverse polycyclic compounds were obtained by an intramolecular gold‐catalyzed alkoxycyclization of o‐(alkynyl)styrenes bearing a nucleophile in their structure. Finally, the use of a chiral gold complex allowed access to elusive chiral 1H‐indenes in good enantioselectivities.     

Mechanistic Studies on the Photogenerated Dienol with α-Phenyl-N-tert-Butylnitrones

The mechanism for the photochemical reactions of o-methyl-benzaldehyde ( 1 ), o-methyl-acetophenone ( 2 ) and o-methyl-benzophenone ( 3 ) in the presence of α-phenyl-N-tert-butylnitrone (PBN) to the formation of stable nitroxyl radicals 4–6 is studied. The nitroxyl radical product 6 can also be obtained by the thermolysis of benzocyclobutenol with PBN. Thus, the radical products were derived from a novel and regioselective 4+2 cycloaddition of the photogenerated dienol intermediate with PBN.     

Secologanin,a Biogenetic Key Compound—Synthesis and Biogenesis of the Iridoid and Secoiridoid Glycosides

The monoterpene glycoside secologanin is a key intermediate in the biosynthesis of most indole, cinchona, ipecacuanha, and pyrroloquinoline alkaloids, as well as of simple monoterpene alkaloids. More than a thousand alkaloids are formed from secologanin in vivo; this represents almost a quarter of this large group of natural products. It is also the parent compound of the secoiridoids. Many of the compounds derived from secologanin display a high degree of biological activity and are employed as pharmaceuticals, e.g., the dimeric indole alkaloid leurocristine (vincristine) which is used very successfully in the treatment of acute leukemia. A knowledge of the biosynthesis and biological reactions of secologanin provides a sound basis for the biosynthesis-orientated classification of numerous natural products and the taxonomy of many plants. Secologanin and structurally related substances can be synthesized in a few steps by stereocontrolled photochemical and thermal cycloadditions. Its biomimetic reaction with amines and amino acids yields other natural products and compounds of pharmacological interest.     

Synthesis of New 1‐Hydroxyindole‐2‐Carboxylates and Mechanistic Studies on Reaction Pathways

Synthesis of new 1‐hydroxyindole‐2‐carboxylates 1 and mechanistic studies on the reaction pathways were described. The substrates 2 , prepared through two‐step synthetic sequences, were treated with nucleophiles in the presence of SnCl₂ · 2H₂O to obtain compounds 1 . In particular, the mechanistic studies led to a significant finding that reactions with thiol nucleophiles occur through a newly proposed pathway (path B: 1,4‐addition followed by reduction/condensation) rather than through a previously assumed pathway (path A: reduction/condensation followed by 1,5‐addition). Further mechanistic investigations revealed steric effects of o‐substituents in 2 governing the ratio of products ( 1i / 7 ).