Synthesis of 2,3-Dialkyl-5-hydroxybenzofurans via a One-pot, Three-step Reaction Sequence of 2-Monosubstituted 1,3-Diketones and 1,4-Benzoquinones.

An economical one-pot, three-step reaction sequence of readily available 2-monosubstituted 1,3-diketones and 1,4-benzoquinones has been explored for the facile access of 2,3-dialkyl-5-hydroxybenzofurans. By using cheap K2CO3 and conc. HCl as the reaction promoters, the reaction occurs smoothly via sequential Michael addition, aromatization, retro-Claisen, deacylation, hemiketalization, and dehydration processes under mild conditions in a practical manner. Additionally, an interesting phenomenon was observed during the derivatization studies, where the dihydroquinoline was converted into tetrahydroquinoline and quinoline products, respectively, via a disproportionation process.

Organocatalytic Enantioselective Functionalization of Cyclic α-Hydroxyamides: Access to Chiral Cyclic Imides and Azapolycyclic Compounds.

A highly efficient enantioselective enamine-catalyzed asymmetric conjugate addition has been developed to directly convert unfunctionalized cyclic α-hydroxyamides into chiral cyclic α-hydroxyamides by reacting with vinyl sulfones, which could be used as versatile azacyclic synthons in the following sequences: (1) as the precursors of cyclic N-acyliminium ions to prepare natural productlike chiral azapolycyclic compounds under acidic conditions and (2) to construct chiral cyclic imides bearing unilateral substituents via oxidation reaction-induced formal desymmetrization.

Brønsted-Acid-Catalyzed In Situ Formation of Acyclic Tertiary Enamides and Its Application to the Preparation of Diverse Nitrogen-Containing Heterocyclic Compounds.

A Brønsted acid-catalyzed cascade process, involving in situ formation of acyclic tertiary enamides and intramolecular Michael reaction, is developed for the synthesis of functionalized cyclic tertiary enamides. Based on the dual reactivities of the enamide moiety, several reaction sequences were realized by using rationally designed substrates, leading to biologically relevant nitrogen-containing heterocyclic compounds with diverse structural skeletons in a concise and diastereocontrolled manner.

Asymmetric iminium ion-catalyzed conjugate addition of 2-hydroxycinnamaldehydes and 2-oxocarboxylic esters: synthesis of chiral polysubstituted bridged bicyclic ketals.

A highly regio-, chemo-, and stereoselective cascade process initiated by enantioselective iminium-catalyzed conjugate addition of 2-hydroxycinnamaldehydes and 2-oxocarboxylic esters is presented. Normal cinnamaldehydes are not reactive under the same reaction conditions. Bridged bicyclic ketals rather than acetals bearing stereocenters on both the bridge carbon and bridgehead ketal carbon are synthesized.

Triethylamine-Promoted Henry Reaction/Elimination of HNO2/Cyclization Sequence of Functionalized Nitroalkanes and 2-Oxoaldehydes: Diversity-Oriented Synthesis of Oxacycles.

The triethylamine-promoted cascade Henry reaction/elimination of HNO2/cyclization reaction of 2-oxoaldehydes with nitroalkanes bearing various remote functionalities is described. Both chiral and achiral nitroalkanes were applicable to this protocol, leading to a variety of oxacycles, such as chromenes, chromanes, cyclic hemiacetals, and polycyclic acetals. An unexpected regioselective photooxygenation occurred without sensitizer during derivatization to convert a derived diene product into a dioxetane by reaction with singlet oxygen, which provided chromen-2-one and benzaldehyde after fragmentation.

Asymmetric Retro-Claisen Reaction Catalyzed by Chiral Aza-Bisoxazoline-Zn(II) Complex: Enantioselective Synthesis of α-Arylated Ketones.

An asymmetric retro-Claisen reaction of α-monosubstituted ß-diketones and quinones (or quinone imine) has been developed under the catalysis of a chiral aza-bisoxazoline-Zn(II) complex. The reaction proceeds via a sequence of conjugate addition, arylation, hemiketal anion-initiated C-C bond cleavage, and enantioselective protonation of enolate to provide various functionalized α-arylated ketones bearing a tertiary stereogenic center with high enantioselectivities. Notably, biologically important benzofuran and γ-butyrolactone derivatives could be synthesized by application of the developed protocol.

Enantioselective Michael Addition/Cyclization/Desymmetrization Sequence of Prochiral Cyclic Hemiacetals and Nitroolefins: Synthesis of Chiral Oxygen-Bridged Bicyclic Compounds.

The organocatalytic enantioselective Michael addition of functionalized prochiral cyclic hemiacetals and nitroolefins has been developed under cooperative enamine and hydrogen bond catalysis. The obtained chiral hemiacetal intermediates could be used in the subsequent diastereocontrolled cyclization/desymmetrization divergent process to access (1) 9-oxabicyclo[3.3.1]nonane or 8-oxabicyclo[3.2.1]octane frameworks via oxocarbenium ion-mediated Friedel-Crafts cyclization, and (2) 2,9-dioxabicyclo[3.3.1]nonane frameworks via intramolecular nucleophilic cyclization. Experimental results suggest that there is neighboring group participation controlling the diastereoselectivities of the desymmetrization process.

Asymmetric Organocatalytic Access to Spiro-fused Heterocyclic Compounds: E1cB Elimination Mediates Formal [4 + 2] Annulation.

Based on the intramolecular E1cB elimination, a novel [4 + 2] cyclization was designed and successfully applied to the asymmetric synthesis of polycyclic compounds which contained both chromane and spirooxindole moieties. In the reaction, regardless of the competitive pathways resulting from multireactive sites of starting materials, products could be obtained in good yields (up to 84%) and with excellent enantioselectivities (most 98 to >99% ee) under the catalysis of a chiral bifunctional thiourea-tertiary amine (1-5 mol %).

Synthesis of Chiral Polycyclic Tetrahydrocarbazoles by Enantioselective Aminocatalytic Double Activation of 2-Hydroxycinnamaldehydes with Dienals.

An efficient aminocatalytic enantioselective double-activation strategy has been developed that combines several different aminocatalytic modes in a cascade process, such as iminium ion, vinylogous iminium ion, trienamine, and dienamine activations. By using this strategy, 2-hydroxycinnamaldehydes worked well with various dienals via [4 + 2] cycloaddition and the oxa-Michael reaction-initiated cascade, respectively, leading to chiral polycyclic tetrahydrocarbazole and chromane derivatives with excellent diastereo- and enantioselectivities.

Asymmetric organocatalytic vinylogous Michael addition triggered triple-cascade reactions of 2-hydroxycinnamaldehydes and vinylogous nucleophiles: construction of benzofused oxabicyclo[3.3.1]nonane scaffolds.

An organocatalytic vinylogous Michael addition triggered triple-cascade reaction has been developed. 2-Hydroxycinnamaldehydes worked under iminium activation with either acyclic or cyclic ketone-derived α,α-dicyanoalkenes, yielding the benzofused oxabicyclo[3.3.1]nonanes bearing one quaternary stereocenter with excellent stereoselectivities.

Asymmetric organocatalytic multicomponent reactions for efficient construction of bicyclic compounds bearing bisacetal and isoxazolidine moieties.

An organocatalytic multicomponent reaction of N-protected hydroxylamines, acrylaldehyde and acetal-containing enones was developed. Bisacetal-containing bicyclic isoxazolidine derivatives bearing four continuous stereocenters were formed with excellent stereoselectivities. A plausible reaction pathway was proposed based on 18O-labeling control experiments.

Expanding the Boxmi Ligand Family: Synthesis and Application of NON and NSN Ligands.

Two synthetic strategies for a new family of neutral NON ligands featuring a "bis(oxazolinylmethylidene)isobenzofuran" framework (boxman) are reported. A Pd-mediated cyclization reaction forming the isobenzofuran core constitutes the key reaction in the eight-step synthetic route to the nonbackbone-methylated target compound H,Rboxman. In contrast, the introduction of two additional methyl groups provides stereochemical control during backbone construction and thereby access to the methylated derivative Me,Rboxman, which was synthesized in five steps and improved yields. In addition, the synthetic sequence was transferred to the thio analogue, providing access to the NSN ligand H,Rboxmene. Subsequent complexation experiments with iron and cobalt chloride precursors afforded the four-coordinated chlorido complexes Me,RboxmanMCl2 (R = Ph, iPr; M = Fe, Co) and established the boxman family as trans-chelating, bidentate bis(oxazoline) ligands. Application of the latter in the nickel(II)- and zinc(II)-catalyzed α-fluorination of ß-ketoesters and oxindoles (up to 98% yield and 94% ee) demonstrated their suitability for enantioselective catalysis.

Application of E1cB Elimination in Asymmetric Organocatalytic Cascade Reactions To Construct Polyheterocyclic Compounds.

By introducing a carbon functionality at 2-position of chromane, the formal asymmetric functionalization of the 3-position of 2-substituted chromane has been realized via a highly chemo-, regio-, and stereoselective organocatalytic cascade reaction in a sequential one-pot manner involving an E1cB mechanism governed ring-opening process. Critical to our success was the design of a chiral dipeptide-based bifunctional acid-base organocatalyst, which exhibited high catalytic activity at low catalyst loading (1-0.1 mol %), leading to biologically interesting polyheterocyclic compounds.

The Quinary Catalyst-Substrate Complex Induced Construction of Spiro-Bridged or Cagelike Polyheterocyclic Compounds via a Substrate-Controlled Cascade Process.

The asymmetric organocatalytic cascade reaction of cyclic ß-oxo aldehydes to 2-hydroxycinnamaldehydes is developed. The bifunctional tertiary amine-thiourea catalyst was used in a rationally designed multiple catalysis where the asymmetric iminium catalysis and thiourea anion-binding catalysis were combined by carboxylate anion as a ternary catalytic system to form a quinary catalyst-substrate complex, providing an efficient protocol for the construction of enantioenriched spiro-bridged or cagelike polyheterocyclic compounds. The reuse of catalysts was also successfully realized.

Asymmetric Organocatalyzed Reaction Sequence To Synthesize Chiral Bridged and Spiro-Bridged Benzofused Aminals via Divergent Pathways.

A highly efficient asymmetric organocatalysis-triggered reaction sequence is developed. 2-Hydroxy cinnamaldehydes and cyclic N-sulfonyl ketimines were both used as multisite substrates (more than two reactive sites) to access structurally diverse chiral bridged and spiro-bridged benzofused aminal derivatives, where an inseparable equilibrating mixture of isomers can be regioselectively converted into bridged benzofused aminals with different ring connectivities via divergent pathways. Several stereoselective transformations of the resulted bridged aminals are presented.

Aspergiolides A and B: Core Structural Establishment and Synthesis of Structural Analogues.

The core structure of marine natural products aspergiolides A (1a) and B (1b) was achieved via a concise, two-step procedure with satisfactory yield. Based on this protocol, a natural products mimic library containing 25 structural simplified analogues of 1a was then constructed. Several prepared analogues showed potential cytotoxic activity against five different tumor cell lines, and compound 7bb, in particular, exhibited cytotoxicity comparable to that of 1a.

Two Competitive but Switchable Organocatalytic Cascade Reaction Pathways: The Diversified Synthesis of Chiral Acetal-Containing Bridged Cyclic Compounds.

The organocatalytic enantioselective synthesis of methanobenzodioxepine derivatives bearing a 6,6,5-bridged ring system is presented. The m-CPBA-triggered in situ α-oxidation of ß-oxoesters to provide the required but unstable α-hydroxy-ß-dicarbonyl substrates is the key to this three-step sequence, providing the desired cyclic acetals with excellent stereoselectivities containing two bridgehead and one fully substituted stereocenters. It is noteworthy that the absence of m-CPBA furnished the acetal products bearing a 6,6,6-bridged ring system with similar good results from the same starting materials.

Organocatalytic Asymmetric Synthesis of Spiro-Bridged and Spiro-Fused Heterocyclic Compounds Containing Chromane, Indole, and Oxindole Moieties.

Following the reactivity inversion strategy, two different two-step sequences were designed and successfully applied to the asymmetric synthesis of spiro-bridged and spiro-fused heterocyclic compounds, which combined chromane, indole, and oxindole, three potential pharmacophores, in one molecule. The power of these two organocatalytic pathways is underscored by mild reaction conditions and high efficiency in the production of synthetically challenging, but biologically important heterocyclic products, which could be transformed into more biologically interesting heterocyclic structures.

Different hybridized oxygen atoms controlled chemoselective formation of oxocarbenium ions: synthesis of chiral heterocyclic compounds.

Based on the electronic properties of different hybridized oxygen atoms (sp3versus sp2) in the structure of O,O-acetals containing an enol ether moiety, the chemoselective formation of oxocarbenium ions was realized to furnish diversified chiral heterocyclic compounds with excellent stereoselectivities by reacting with different types of nucleophiles. Additionally, an unexpected intramolecular oxocarbenium ion transfer was also reported to form polycyclic products containing the O,O-acetal functional group.

Asymmetric Organocatalytic Sequential Reaction of Structurally Complex Cyclic Hemiacetals and Functionalized Nitro-olefins To Synthesize Diverse Heterocycles.

Structurally complex cyclic hemiacetals bearing a racemic tetrasubstituted stereocenter have been prepared in a concise manner and were successfully used in an organocatalytic enantioselective sequence to react with functionalized nitro-olefins, providing bicyclic acetal-containing compounds as two separable epimers with excellent stereoselectivity. The reaction showed broad substrate scope, with respect to the starting hemiacetals. Moreover, this protocol allows the synthetic transformation of the products to various interesting heterocyclic compounds with substantial structural diversity and broad functionality.