Hydrogen‐Bond‐Induced Chiral Axis Construction: Theoretical Study of Cinchonine–Thiourea‐Catalyzed Enantioselective Intramolecular Cycloaddition

Theoretical calculations were performed to investigate the mechanism and enantioselectivity of cinchonine–thiourea‐catalyzed intramolecular hetero‐Diels–Alder cycloaddition of ethynylphenol derivatives to afford axial chirality naphthalenylpyran products via a vinylidene ortho‐quinone methide (VQM) intermediate. The results show that this transformation occurs through a reaction pathway involving the deprotonation of the naphthol moiety by the quinuclidine base, intramolecular proton transfer in ammonium naphthalenolate, and [4+2] cycloaddition. It is found that the axial chirality of the VQM intermediate is generated by the protonation step, which affects the enantioselectivity of the reaction. The enantioselectivity for the generation of the VQM intermediate is controlled by steric repulsion with the cinchonine framework, which provides an R‐axial chirality VQM as the major intermediate. Moreover, the enantioselectivity for the axial chirality of the naphthopyran product is controlled by the cycloaddition step, in which an extra hydrogen bond between the naphthalenol and cinchonine moieties leads to a favorable configuration for the generation of the S‐axial chirality naphthopyran product. The calculated enantioselectivity and enantiomeric excesses coincide with experimental observations.     

Synthesis of Functionalized Pyrazoles via 1,3‐Dipolar Cycloaddition of α‐Diazo‐β‐ketophosphonates,Sufones and Esters with Electron‐Deficient Alkenes

1,3‐Dipolar cycloaddition of diazo compounds with olefinic substrates is a promising atom‐economic strategy for the construction of functionalized pyrazoles. Over the last few years, our group has been engaged in the synthesis of phosphonyl/sulfonylpyrazoles and pyrazole esters by employing Bestmann‐Ohira Reagent (BOR) and its sulfur and ester analogs as 1,3‐dipole precursors with various dipolarophiles. This account describes the novel synthetic methods developed in our laboratory, in the perspective of closely related work by others, for the synthesis of phosphonyl/sulfonylpyrazoles, pyrazole esters and the total synthesis of Withasomnine, a natural product, by using 1,3‐dipolar cycloaddition as the key step.     

Gold‐Catalyzed [2+2+1] Cycloaddition of 1,6‐Diyne Carbonates and Esters with Aldehydes to 4‐(Cyclohexa‐1,3‐dienyl)‐1,3‐dioxolanes

A synthetic method to stereoselectively prepare 4‐(cyclohexa‐1,3‐dienyl)‐1,3‐dioxolanes in good to excellent yields by gold(I)‐catalyzed [2+2+1] cycloaddition of 1,6‐diyne carbonates and esters with aldehydes is described. The cascade process involves 1,2‐acyloxy migration followed by cyclopropenation and cycloreversion. This leads to an unprecedented [2+2+1] cycloaddition of the resulting alkenylgold carbenoid species, examples of which are extremely rare, with two aldehyde molecules at catalyst loadings as low as 1 mol %. The usefulness of this cycloisomerization chemistry was further demonstrated by the transformation of one example to the corresponding phenol.     

Cobalt‐Catalyzed Formal [4+2] Cycloaddition of α,α′‐Dichloro‐ortho‐Xylenes with Alkynes

A formal [4+2] cycloaddition of α,α′‐dichloro‐ortho‐xylenes with various alkynes has been developed using a low‐valent cobalt catalyst. The transformation has a wide substrate scope and high functional‐group tolerance and led to 1,4‐dihydronaphthalenes. The formed cycloadducts were easily aromatized with MnO₂ under air. A mechanistic investigation suggests that the transformation proceeds through a benzyl cobaltation of alkyne, not the classical Diels–Alder reaction of ortho‐quinodimethanes. This methodology provides a straightforward and streamlined access to linearly expanded π‐conjugated aromatics.     

Control of the Stereochemical Course of [4+2] Cycloaddition during trans‐Decalin Formation by Fsa2‐Family Enzymes

Enzyme‐catalyzed [4+2] cycloaddition has been proposed to be a key transformation process in various natural product biosynthetic pathways. Recently Fsa2 was found to be involved in stereospecific trans‐decalin formation during the biosynthesis of equisetin, a potent HIV‐1 integrase inhibitor. To understand the mechanisms by which fsa2 determines the stereochemistry of reaction products, we sought an fsa2 homologue that is involved in trans‐decalin formation in the biosynthetic pathway of an enantiomerically opposite analogue, and we found phm7, which is involved in the biosynthesis of phomasetin. A decalin skeleton with an unnatural configuration was successfully constructed by gene replacement of phm7 with fsa2, thus demonstrating enzymatic control of all stereochemistry in the [4+2] cycloaddition. Our findings highlight enzyme‐catalyzed [4+2] cycloaddition as a stereochemically divergent step in natural product biosynthetic pathways and open new avenues for generating derivatives with different stereochemistry.     

Short Synthesis of Enantiopure Thieno[2,3‐f]triazolo[1,5‐a][1,4]diazepines and Thieno[2,3‐f][1,4]diazepin‐5‐ones

Starting from 2‐carboxy‐3‐thenylazide 1 and enantiopure amines 2 as the chiral building blocks, we developed a two‐step synthesis of the title compounds involving an intramolecular azide cycloaddition as the key step.     

Protecting‐Group‐Free One‐Pot Synthesis of Glycoconjugates Directly from Reducing Sugars

The conversion of sugars into glycomimetics typically involves multiple protecting‐group manipulations. The development of methodology allowing the direct aqueous conversion of free sugars into glycosides, and mimics of oligosaccharides and glycoconjugates in a high‐yielding and stereoselective process is highly desirable. The combined use of 2‐azido‐1,3‐dimethylimidazolinium hexafluorophosphate and the Cu‐catalyzed Huisgen cycloaddition allowed the synthesis of a range of glycoconjugates in a one‐step reaction directly from reducing sugars under aqueous conditions. The reaction, which is completely stereoselective, may be applied to the convergent synthesis of triazole‐linked glycosides, oligosaccharides, and glycopeptides. The procedure provides a method for the one‐pot aqueous ligation of oligosaccharides and peptides bearing alkyne side chains.     

Stereoselective Ag‐Catalyzed 1,3‐Dipolar Cycloaddition of Activated Trifluoromethyl‐Substituted Azomethine Ylides

A silver‐catalyzed 1,3‐dipolar cycloaddition of fluorinated azomethine ylides and activated olefins is reported. The reaction offers a straightforward and atom‐economical procedure for the preparation of fluorinated pyrrolidines. Broad scope and high levels of diastereoselectivity have been achieved simply by using AgOAc/PPh₃ as the catalyst system. The high efficiency of the cycloaddition relies on the presence of a metal‐coordinating group on the imine moiety, such as an ester or heteroaryl group. The asymmetric version of the cycloaddition has been developed by using Taniaphos as a chiral ligand.     

Diastereoselective [3+2] Annulation of Aromatic/Vinylic Amides with Bicyclic Alkenes through Cobalt‐Catalyzed C−H Activation and Intramolecular Nucleophilic Addition

A highly diastereoselective method for the synthesis of dihydroepoxybenzofluorenone derivatives from aromatic/vinylic amides and bicyclic alkenes is described. This new transformation proceeds through cobalt‐catalyzed C?H activation and intramolecular nucleophilic addition to the amide functional group. Transition‐metal‐catalyzed C?H activation reactions of secondary amides with alkenes usually lead to [4+2] or [4+1] annulation; to the best of our knowledge, this is the first time that a [3+2] cycloaddition is described in this context. The reaction proceeds under mild conditions and tolerates a wide range of functional groups. Mechanistic studies imply that the C?H bond cleavage may be the rate‐limiting step.     

Synthesis of Chiral Pyrazoles: A 1,3‐Dipolar Cycloaddition/[1,5] Sigmatropic Rearrangement with Stereoretentive Migration of a Stereogenic Group

The reactions between terminal alkynes and α‐chiral tosylhydrazones lead to the obtention of chiral pyrazoles with a stereogenic group directly attached at a nitrogen atom. The cascade reaction includes decomposition of the hydrazone into a diazocompound, 1,3‐dipolar cycloaddition of the diazo compound with the alkyne, and [1,5] sigmatropic rearrangement with migration of the stereogenic group. This strategy has been successfully applied to the synthesis of structurally diverse chiral pyrazoles through α‐chiral tosylhydrazones, obtained from α‐phenylpropionic acid, α‐amino acids, and 2‐methoxycyclohexanone. Notably, the stereoretention of the [1,5] sigmatropic rearrangements represent very rare examples of this stereospecific transformation.     

Rhodium(II)‐Catalyzed Cycloaddition Reactions of Non‐classical 1,5‐Dipoles for the Formation of Eight‐Membered Heterocycles

A new type of intermolecular rhodium(II)‐catalyzed [5+3] cycloaddition has been developed. This higher‐order cycloaddition between pyridinium zwitterion 1,5‐dipole equivalents and enol diazoacetates enables the formation of eight‐membered heterocyclic skeletons, which are otherwise difficult to construct. The optimized cycloaddition occurs efficiently under mild conditions with a wide range of pyridinium zwitterions and with high functional‐group tolerance.     

One‐Pot Stereoselective Synthesis of 2‐Acylaziridines and 2‐Acylpyrrolidines from N‐(Propargylic)hydroxylamines

The stereoselective direct transformation of N‐(propargylic)hydroxylamines into cis‐2‐acylaziridines was achieved by the combined use of AgBF₄ and CuCl. Copper salts were found to promote the transformation of the intermediary 4‐isoxazolines into 2‐acylaziridines and both 3‐aryl‐ and 3‐alkyl‐substituted 2‐acylaziridines could be prepared by using this method. Furthermore, subsequent 1,3‐dipolar cycloaddition of azomethine ylides that were generated in situ from the intermediary 2‐acylaziridines with maleimides was achieved in a stereoselective one‐pot procedure to afford the corresponding 2‐acylpyrrolidines, which consisted of an octahydropyrrolo[3,4‐c]pyrrole skeleton.     

Synthesis of Novel 5,6‐Dihydropyrrolo[2,1‐a]isoquinolines via Grob Reaction between (E)‐1,1,1‐Trifluoro‐3‐nitro‐2‐butene and 3,4‐Dihydroisoquinolines

Uncatalyzed cycloaddition of 3,4‐dihydroisoquinolines to (E)‐1,1,1‐trifluoro‐3‐nitro‐2‐butene via Grob reaction provide a simple one‐step route to the 5,6‐dihydropyrrolo[2,1‐a]isoquinolines, which represent the basic structural framework of the antitumor active alkaloid crispine.     

Synthesis of 3′,4′‐Diaryl‐4′H‐spiro[indoline‐3,5′‐[1′,2′,4′]oxadiazol]‐2‐ones via DMAP‐catalyzed Domino Reactions and Their Antibacterial Activity

A convenient and metal‐free DMAP‐catalyzed domino reaction of isatins, arylamines and hydroximoyl chlorides has been developed to achieve 1,3‐dipolar cycloaddition of imines into aryl nitrile oxides at ambient temperature. In this one‐pot transformation, a 1,2,4‐oxadiazole skeleton was efficiently formed. This methodology needs no extra additives and features wide substrate scope, good functional group tolerance and mild reaction conditions. A plausible mechanism for this process was proposed. Moreover, the antibacterial activities of the products were evaluated towards Staphylococcus epidermidis, Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae using the Broth microdilution method.     

Dipolar Cycloaddition Reactions of Azomethine Ylides Generated by endocyclic‐exocyclic 1,3‐dipole Rearrangement

Dipolar cycloaddition of polycyclic azomethine ylides, in which the central nitrogen atom is part of a pyrrolidine ring and bears a methoxycarbonyl group with norbornenes has been shown to produce two main types of products featuring pyrrolizidine rings. In conjuction with results of quantum chemical calculations (B3LYP), mechanistic rationale was postulated. The key reaction step is unprecedented endocyclic to exocyclic azomethine ylide rearrangement by an intermolecular prototropic migration (formal [1,3] H‐shift).     

Catalyst‐Free Regioselective [3+2] Cycloadditions of α,β‐unsaturated N‐arylnitrones with Alkenes to Access Functionalized Isoxazolidines: A DFT Study

The catalyst‐free regioselective [3+2]‐cycloaddition of α,β‐unsaturated N‐arylnitrones with alkenes are developed. The series of synthetically important functionalized isoxazolidines are prepared in good to excellent yields by step economic pathway under ligand and transition‐metal‐free conditions. The regioselective cycloaddition pathway supported by control experiment and computational study.     

Total Synthesis of Potent Antitumor Agent (−)‐Lasonolide A: A Cycloaddition‐Based Strategy

A detailed account of the enantioselective total synthesis of (?)‐lasonolide A is described. Our initial synthetic route to the top tetrahydropyran ring involved Evans asymmetric alkylation as the key step. Initially, we relied on the diastereoselective alkylation of an α‐alkoxyacetimide derivative containing an α′ stereogenic center and investigated such an asymmetric alkylation reaction. Although alkylation proceeded in good yield, the lack of diastereoselectivity prompted us to explore alternative routes. Our subsequent successful synthetic strategies involved highly diastereoselective cycloaddition routes to both tetrahydropyran rings of lasonolide A. The top tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3‐dipolar cycloaddition reaction. The overall process constructed a bicyclic isoxazoline, which was later unravelled to a functionalized tetrahydropyran ring as well as a quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a Jacobsen catalytic asymmetric hetero‐Diels–Alder reaction as the key step. The synthesis also features a Lewis acid catalyzed epoxide opening to form a substituted ether stereoselectively.     

Synthesis of (3‐N‐substituted‐piperidin‐4‐ylidene)acetic Acid Ethyl Esters

A convenient preparation of skeletons 2A and 2B (cyclic γ,δ‐diamino‐α,β‐unsaturated esters) is reported by a three‐step synthetic route based on a sequence of NBS‐mediated one‐pot α‐bromination/Wittig olefination of piperidin‐4‐one 3 , nucleophilic addition with NaN₃, and followed by PPh₃‐promoted Staudinger reduction/substitution or CuI‐catalyzed Huisgen 1,3‐dipolar cycloaddition.     

Two‐step Synthesis of Multi‐Substituted Amines by Using an N‐Methoxy Group as a Reactivity Control Element

The development of a two‐step synthesis of multi‐substituted N‐methoxyamines from N‐methoxyamides is reported. Utilization of the N‐methoxy group as a reactivity control element was the key to success in this two‐step synthesis. The first reaction involves a N‐methoxyamide/aldehyde coupling reaction. Whereas ordinary amides cannot condense with aldehydes intermolecularly due to the poor nucleophilicity of the amide nitrogen, the N‐methoxy group enhances the nucleophilicity of the nitrogen, enabling the direct coupling reaction. The second reaction in the two‐step process was nucleophilic addition to the N‐methoxyamides. Incorporation of the N‐methoxy group into the amides increased the electrophilicity of the amide carbonyls and promoted the chelation effect. This nucleophilic addition enabled quick diversification of the products derived from the first step. The developed strategy was applicable to a variety of substrates, resulting in the elaboration of multi‐substituted piperidines and acyclic amines, as well as a substructure of a complex natural alkaloid.     

CuAAC Click Reactions in the Gas Phase: Unveiling the Reactivity of Bis‐Copper Intermediates

Copper‐catalysed azide alkyne cycloaddition (CuAAC) has been considered a breakthrough transformation over the last 15 years. Its debated mechanism arouses continuously growing interest. By means of a mass spectrometer modified ad hoc, the entire catalytic cycle of CuAAC reaction has been investigated in the gas phase. Ion‐molecule reactions were performed inside the mass spectrometer to reproduce step‐by‐step, at a molecular level, the complete catalytic cycle of the click reaction. We successfully challenged the reactivity of elusive mono‐ and bis‐copper intermediates by ion‐molecule reactions leading to the production of mass‐characterized triazole products, paving the way for detailed energetic studies to be performed in the gas phase. The structures of the relevant species, calculated at a DFT level, helped rationalise our experimental results.