5+1] cycloaddition of C,N-cyclic N'-acyl azomethine imines with isocyanides

A catalyst-free [5 + 1] cycloaddition reaction between isocyanides and C,N-cyclic N'-acyl azomethine imines as the "isocyanophile" leading to novel heterocycles has been developed. These reactions proceeded quickly and cleanly to afford the corresponding imin-1,3,4-oxadiazin-6-one derivatives in high to excellent yields. A wide range of C,N-cyclic N'-acyl azomethine imines and isocyanides were applicable to this reaction.     

A cascade process toward the synthesis of fused polycyclic dihydropyridines

The synthesis of fused polycyclic dihydropyridines was achieved using a cascade process comprising a Suzuki coupling, a nucleophilic cyclization and a hydrogen migration. Several functional groups are tolerated in this reaction and the methodology could be applied with success to quinoline and isoquinoline derivatives.     

Reactivity and synthesis inspired by the Zincke ring-opening of pyridines

The century-old Zincke process for ring-opening of pyridinium salts produces 5-amino-2,4-pentadienals, a type of donor-acceptor dienes known as Zincke aldehydes. Inspired by this reasonably general and often efficient process for dearomatization, my laboratory has used pyridines as a starting point for heterocycle synthesis, which resulted in unusual syntheses of indoles, pyrrolines, and a formal synthesis of the natural product porothramycin A. Furthermore, our study of the reactivity of Zincke aldehydes has led to accidental discoveries of pericyclic cascade reactions that produce Z-α,β-unsaturated amides or polycyclic lactams, depending upon the identity of the substituents on nitrogen. Finally, a base-mediated formal cycloaddition reaction of tryptamine-derived Zincke aldehydes has served as the key step in concise syntheses of the indole alkaloids norfluorocurarine and strychnine.     

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).     

Amine‐Catalyzed Enantioselective 1,3‐Dipolar Cycloadditions of Aldehydes to C,N‐Cyclic Azomethine Imines

Amine‐catalyzed enantioselective 1,3‐dipolar cycloadditions of aldehydes to C,N‐cyclic azomethine imines were developed. The reactions between diversely substituted C,N‐cyclic azomethine imines and aldehydes proceeded smoothly in the presence of chiral prolinol silyl ether catalyst and gave the C‐1‐substituted tetrahydroisoquinolines in a highly stereoselective manner. These tetrahydroisoquinolines could be efficiently transformed to several other useful polycyclic frameworks.     

Catalytic Aerobic Oxidation and Tandem Enantioselective Cycloaddition in Cascade Multicomponent Synthesis

An efficient multicomponent cascade transformation for the highly diastereo‐ and enantioselective synthesis of complex natural product inspired polycyclic products from simple starting materials is described. The cascade is initiated by copper‐catalyzed aerobic C?H oxidation of cyclopentadiene to cyclopentadienone followed by double catalytic asymmetric 1,3‐dipolar cycloaddition of azomethine ylides. The cascade synthesis efficiently yields structurally complex 5,5,5‐tricyclic products with eight stereocenters with good yields and excellent diastereo‐ and enantiocontrol using one catalyst.     

Bonding analysis and the mechanisms on the ring-opening of alkoxy-bridged bis(silylene) transition-metal complexes toward MeOH

The mechanistic study on the ring-opening of alkoxy-bridged bis(silylene) transition-metal complexes toward MeOH is performed by using density functional theory. Four steps are predicted to be involved in the reaction, formation of hydrogen bonding between R and a MeOH, ring-opening of the Ru-Si1-O1-Si2 four-membered ring, formation of the six-membered ring, and the hydroxyl hydrogen migration to the metal center. It is found that the reaction is favorable thermodynamically and the hydroxyl hydrogen migration is the rate-determining step. Systematic variations of the structural parameters involved in the reaction mechanism are revealed, which revealed the relationship of the bond strength among Ru-Si, Si-O and O-H bonds.     

Total Synthesis of Sculponin U through a Photoinduced Radical Cascade Cyclization

We have accomplished the total synthesis of sculponin U, a polycyclic C-20-oxygenated kaurane diterpenoid featuring a 7,20-lactone-hemiketal bridge, through a radical cascade cyclization triggered by photoinduced electron transfer (PET) of a silyl enolate to form the cyclohexanone-fused bicyclo[3.2.1]octane skeleton. Other key points in our synthetic strategy encompass a Diels–Alder reaction to construct the middle six-membered ring of sculponin U, and an intramolecular radical cyclization induced by iron-catalyzed hydrogen atom transfer to close the western cyclohexane ring. Successful preparation of the enantiopure silyl enolate as the PET precursor enables the asymmetric total synthesis of sculponin U, opening a new avenue for divergent syntheses of structurally related C-20-oxygenated kaurane congeners and pharmaceutical derivatives thereof.     

Base-Selective Five- versus Six-Membered Ring Annulation in Palladium-Catalyzed C–C Coupling Cascade Reactions: New Access to Electron-Poor Polycyclic Aromatic Dicarboximides

Palladium-catalyzed base-selective annulation of dibromonaphthalimide to different aryl boronate esters by combined Suzuki–Miyaura cross-coupling and direct C−H arylation afforded a series of new five- and six-membered ring annulated electron-poor polycyclic aromatic hydrocarbons. Cesium carbonate (Cs₂CO₃) as auxiliary base in these C−C coupling cascade reactions led exclusively to six-membered ring annulation, while the use of organic base diazabicycloundecene (DBU) afforded the corresponding five-membered ring annulated products. This base-dependent selective mode of annulation is attributed to different mechanistic pathways directed by the applied base. The selective annulation was revealed by single crystal X-ray analysis of the respective five- and six-membered ring annulated products. The optical and redox properties of the new polycyclic aromatic dicarboximides were characterized by UV/Vis absorption and fluorescence spectroscopy and cyclic voltammetry.     

Unusually Facile Thermal Homodienyl‐[1,5]‐Hydrogen Shift Reactions in Photochemically Generated Vinyl Aziridines

A range of photochemically generated tri‐ and tetracyclic vinyl aziridines have been found to undergo a general and surprisingly low temperature ring opening through a [1,5]‐hydrogen shift reaction. The rate of the process was found to be highly dependent on the structure and substitution around the azirdine ring and the alkene terminus, with some substrates being observed to undergo ring opening at temperatures as low as 25 °C. The rigid nature of these polycyclic systems precludes a conformational explanation of these rate differences, and an Eyring study confirmed a negligible entropic barrier to the reaction. However, the Eyring plots for two different aziridines systems showed a significant difference in their enthalpies of activation. It is therefore believed that the levels of aziridine ring strain, as well as electronic effects, are the dominant factors in this sequence.     

Oxa bowls: synthesis of new tetraoxa-cages and their C-H.O-mediated solid-state architecture

We have envisioned a new family of oxa-bowls, and a general approach to these entities has been proposed through polycyclic frameworks having two converging olefinic double bonds. Ozonolysis of such molecules was envisaged to give all-cis-tetraaldehyde functionality, which could undergo intramolecular cascade acetalization to oxa-bowls having C(2)(v )()symmetry. Homohypostrophene 16a and its functionalized derivative 16b and hypostrophene 17 on ozonolysis furnished the oxa-cages 22a, 22b, and 23, respectively. Single-crystal X-ray analysis of 22a and 23 showed an interesting network of C-H.O interactions mainly involving the nonacidic cycloalkane hydrogen atoms. The molecule 22a exhibits an interesting tapelike C-H.O hydrogen bonding motif in its crystal structure. On the other hand, the molecule 23 revealed an undulated ribbonlike C-H. O motif. The "chain of rings" pattern of C-H.O interactions in 23 has been observed for the first time in the solid-state structure of oxa-bowls.     

Syntheses of biologically active natural products and leading compounds for new pharmaceuticals employing effective construction of a polycyclic skeleton

Cascade reactions are useful methods for the construction of polycyclic skeletons, which are important cores for biological activities. A variety of cascade reactions carried out under multiple reaction conditions, such as pericyclic, polar, radical, and transition metal-catalyzed reaction conditions, have been investigated. Culmorin, pentalenene, pentalenic acid, deoxypentalenic acid, longiborneol, cedrandiol, 8,14-cedranoxide, atisirene, atisine, and estrane-type steroids were synthesized via the intramolecular double Michael reaction. Aza double Michael reaction was applied to the syntheses of tylophorine, epilupinine, tacamonine, and paroxetine. Furthermore, sequential Michael and aldol reactions were performed in both intramolecular and intermolecular manners, leading to the formation of polycyclic compounds fused to a four-membered ring. Synthesis of paesslerin A utilizing a multicomponent cascade reaction revealed an error in the proposed structure. Unique cascade reactions carried out under radical and transition metal-catalyzed reaction conditions were also investigated. With the combination of several cascade reactions, serofendic acids and methyl 7beta-hydroxykaurenoate, both of which have neuroprotective activity, were synthesized in a selective manner.     

Base‐Selective Five‐ versus Six‐Membered Ring Annulation in Palladium‐Catalyzed C–C Coupling Cascade Reactions: New Access to Electron‐Poor Polycyclic Aromatic Dicarboximides

Palladium‐catalyzed base‐selective annulation of dibromonaphthalimide to different aryl boronate esters by combined Suzuki–Miyaura cross‐coupling and direct C−H arylation afforded a series of new five‐ and six‐membered ring annulated electron‐poor polycyclic aromatic hydrocarbons. Cesium carbonate (Cs₂CO₃) as auxiliary base in these C−C coupling cascade reactions led exclusively to six‐membered ring annulation, while the use of organic base diazabicycloundecene (DBU) afforded the corresponding five‐membered ring annulated products. This base‐dependent selective mode of annulation is attributed to different mechanistic pathways directed by the applied base. The selective annulation was revealed by single crystal X‐ray analysis of the respective five‐ and six‐membered ring annulated products. The optical and redox properties of the new polycyclic aromatic dicarboximides were characterized by UV/Vis absorption and fluorescence spectroscopy and cyclic voltammetry.     

FeCl3‐Mediated Three‐Component Cascade Reaction: An Effective Approach to the Construction of Highly Functionalized Pyrrolo[1,2‐c]quinazolinones

An unexpected FeCl₃‐mediated three‐component cascade reaction has been used to construct structurally diverse pyrrolo[1,2‐c]quinazolinone derivatives with potential biological activities. This method has advantages of mild conditions, simple work‐up, as well as wide substrate scope, which makes it a powerful approach to the synthesis of diverse pyrrolo[1,2‐c]quinazolinones. This cascade reaction involves 1,3‐dipolar cycloaddition between azomethine ylides and allenoates, followed by intramolecular nucleophilic addition in the presence of FeCl₃. The obtained products could be easily transformed into derivatives with the pyrrolo[2,3‐c]quinazoline alkaloid skeleton.     

Polycyclic Indoline‐Benzodiazepines through Electrophilic Additions of α‐Imino Carbenes to Tröger Bases

Polycyclic indoline‐benzodiazepines can be accessed through the intermolecular reaction of Tröger bases with N‐sulfonyl‐1,2,3‐triazoles. Under Rh^II catalysis, α‐imino carbenes are generated and a subsequent cascade of [1,2]‐Stevens, Friedel–Crafts, Grob, and aminal formation reactions yield the polycyclic heterocycles as single isomers (d.r.>49:1, four stereocenters including two bridgehead N atoms). Further ring expansion by insertion of a second α‐imino carbene leads to elaborated polycyclic 9‐membered‐ring triazonanes.     

A facile regioselective 1,3-dipolar cycloaddition protocol for the synthesis of new class of quinolinyl dispiro heterocycles

The 1,3-dipolar cycloaddition reaction of azomethine ylides generated in situ from isatin and secondary amino acids with quinolinyl dipolarophiles in refluxing methanol afforded new class of quinolinyl dispiro heterocycles with multi hetero core units. The regio and stereochemistry of the product was unambiguously assigned by ¹H, ¹³C, 2D NMR techniques and single crystal X-ray analysis. The structures of the compounds are stabilized through the presence of intermolecular hydrogen bonding and intramolecular non-covalent interactions.     

Double C?H Functionalization in Sequential Order: Direct Synthesis of Polycyclic Compounds by a Palladium‐Catalyzed C?H Alkenylation–Arylation Cascade

Palladium‐catalyzed cascade C? H alkenylation and arylation provides convenient access to polycyclic aromatic compounds. Treatment of 3‐bromoaniline derivatives bearing a bromocinnamyl group on the nitrogen atom with a catalytic amount of [Pd(OAc)₂] and PCy₃?HBF₄ in the presence of Cs₂CO₃ in dioxane affords naphthalene‐fused indole derivatives in good yields. This double cyclization reaction is also applicable to heterocyclic substrates, giving fused indoles containing a heteroaromatic ring such as dibenzofuran, dibenzothiophene, carbazole, indole, or benzofuran through heterocyclic C? H arylation. When using a 2,6‐unsubstituted aniline derivative, the first C? H arylation preferentially proceeds at the more hindered position of the aniline ring.     

A Photoredox‐Induced Stereoselective Dearomative Radical (4+2)‐Cyclization/1,4‐Addition Cascade for the Synthesis of Highly Functionalized Hexahydro‐1H‐carbazoles

A stereoselective synthesis of functionalized hexahydrocarbazoles was developed based on an unprecedented photoredox‐induced dearomative radical (4+2)‐cyclization/1,4‐addition cascade between 3‐(2‐iodoethyl)indoles and acceptor‐substituted alkenes. The title reaction simultaneously generates three C−C bonds and one C−H bond, along with three contiguous stereogenic centers. The hexahydro‐1H ‐carbazole products are highly valuable intermediates for the synthesis of novel antibiotics, as well as unnatural ring homologues of polycyclic indoline alkaloids.     

Squaramide‐Catalyzed Asymmetric Reactions

Bifunctional squaramides have emerged as powerful hydrogen‐bonding catalysts for promoting a wide array of useful asymmetric reactions, which provides convenient methods for the construction of complex molecular structures and chiral biologically active compounds. This review highlights the recent advances of our research group in the chiral squaramide‐catalyzed asymmetric reactions, including Michael addition, Mannich reaction, aza‐Henry reaction, Strecker reaction as well as cascade or sequential reactions.     

Inherent Conformational Preferences of Ac‐Gln‐Gln‐NHBn: Sidechain Hydrogen Bonding Supports a β‐Turn in the Gas Phase

Gas‐phase single‐conformation spectroscopy is used to study Ac‐Gln‐Gln‐NHBn in order to probe the interplay between sidechain hydrogen bonding and backbone conformational preferences. This small, amide‐rich peptide offers many possibilities for backbone–backbone, sidechain–backbone, and sidechain–sidechain interactions. The major conformer observed experimentally features a type‐I β‐turn with a canonical 10‐membered ring C=O—H?N hydrogen bond between backbone amide groups. In addition, the C=O group of each Gln sidechain participates in a seven‐membered ring hydrogen bond with the backbone NH of the same residue. Thus, sidechain hydrogen‐bonding potential is satisfied in a manner that is consistent with and stabilizes the β‐turn secondary structure. This turn‐forming propensity may be relevant to pathogenic amyloid formation by polyglutamine segments in human proteins.