Catalytic Asymmetric Cycloaddition Research Articles

Construction of Spiro[pyrrolidine-azlactone] via [2 + 3] Cycloaddition of Alkylidene Azlactone with Trifluoromethylated Imine.

A Ag-catalyzed [2 + 3] cycloaddition of alkylidene azlactones with trifluoromethylated imines has been documented, providing spiro[pyrrolidine-azlactones] bearing four adjacent stereogenic centers with good yields and excellent diastereoselectivities. Catalytic asymmetric cycloaddition has also been developed with good yields and excellent enantioselectivities. Further gram-scale preparation and synthetic transformation to pyrrolidine derivative showed the good practicality and applicability of this reaction.

Catalytic Asymmetric Cycloadditions of Cyclic Sulfamidate Imines: Straightforward Access to Chiral N‐Heterocycles

AbstractChiral N‐heterocyclic compounds are key structures in natural compounds and pharmaceuticals, and they serve as essential building blocks of functional materials. Catalytic asymmetric cycloaddition reactions represent one of the most efficient synthetic strategies for constructing optically active heterocycles. Cyclic sulfamidate imines have recently come to be extensively studied and widely utilized in both organocatalytic and transition metal‐catalyzed asymmetric cycloadditions, where they have been shown to provide various N‐fused‐heterocycles and spiro‐cycles exhibiting high efficiencies with excellent stereoselectivities. This review highlights recent advancements in catalytic asymmetric cycloadditions of cyclic sulfamidate imines for the stereoselective synthesis of biologically active sulfamidate‐containing heterocycles since 2012 while focusing on the diverse reactivities of cyclic sulfamidate imines and the mechanisms of chiral induction in catalysis.

Zinc-Catalyzed Enantioselective Formal (3+2) Cycloadditions of Bicyclobutanes with Imines: Catalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes.

The cycloaddition reaction involving bicyclo[1.1.0]butanes (BCBs) offers a versatile and efficient synthetic platform for producing C(sp3)-rich rigid bridged ring scaffolds, which act as phenyl bioisosteres. However, there is a scarcity of catalytic asymmetric cycloadditions of BCBs to fulfill the need for enantioenriched saturated bicycles in drug design and development. In this study, an efficient synthesis of valuable azabicyclo[2.1.1]hexanes (aza-BCHs) by an enantioselective zinc-catalyzed (3+2) cycloadditions of BCBs with imines is reported. The reaction proceeds effectively with a novel type of BCB that incorporates a 2-acyl imidazole group and a diverse array of alkynyl- and aryl-substituted imines. The target aza-BCHs, which consist of α-chiral amine fragments and two quaternary carbon centers, are efficiently synthesized with up to 94% yield and 96.5:3.5 er under mild conditions. Experimental and computational studies reveal that the reaction follows a concerted nucleophilic ring-opening mechanism of BCBs with imines. This mechanism is distinct from previous studies on Lewis acid-catalyzed cycloadditions of BCBs.

Zinc‐Catalyzed Enantioselective Formal (3+2) Cycloadditions of Bicyclobutanes with Imines: Catalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes

The cycloaddition reaction involving bicyclo[1.1.0]butanes (BCBs) offers a versatile and efficient synthetic platform for producing C(sp3)‐rich rigid bridged ring scaffolds, which act as phenyl bioisosteres. However, there is a scarcity of catalytic asymmetric cycloadditions of BCBs to fulfill the need for enantioenriched saturated bicycles in drug design and development. In this study, an efficient synthesis of valuable azabicyclo[2.1.1]hexanes (aza‐BCHs) by an enantioselective zinc‐catalyzed (3+2) cycloadditions of BCBs with imines is reported. The reaction proceeds effectively with a novel type of BCB that incorporates a 2‐acyl imidazole group and a diverse array of alkynyl‐ and aryl‐substituted imines. The target aza‐BCHs, which consist of α‐chiral amine fragments and two quaternary carbon centers, are efficiently synthesized with up to 94% yield and 96.5:3.5 er under mild conditions. Experimental and computational studies reveal that the reaction follows a concerted nucleophilic ring‐opening mechanism of BCBs with imines. This mechanism is distinct from previous studies on Lewis acid‐catalyzed cycloadditions of BCBs.

Catalytic asymmetric (3 + 3) cycloaddition between different 2-indolylmethanols

Catalytic asymmetric (3 + 3) cycloaddition between different 2-indolylmethanols

Palladium-Catalyzed Ligand-Controlled Switchable Hetero-(5 + 3)/Enantioselective [2σ+2σ] Cycloadditions of Bicyclobutanes with Vinyl Oxiranes.

For nearly 60 years, significant research efforts have been focused on developing strategies for the cycloaddition of bicyclobutanes (BCBs). However, higher-order cycloaddition and catalytic asymmetric cycloaddition of BCBs have been long-standing formidable challenges. Here, we report Pd-catalyzed ligand-controlled, tunable cycloadditions for the divergent synthesis of bridged bicyclic frameworks. The dppb ligand facilitates the formal (5+3) cycloaddition of BCBs and vinyl oxiranes, yielding valuable eight-membered ethers with bridged bicyclic scaffolds in 100% regioselectivity. The Cy-DPEphos ligand promotes selective hetero-[2σ+2σ] cycloadditions to access pharmacologically important 2-oxabicyclo[3.1.1]heptane (O-BCHeps). Furthermore, the corresponding catalytic asymmetric synthesis of O-BCHeps with 94-99% ee has been achieved using chiral (S)-DTBM-Segphos, representing the first catalytic asymmetric cross-dimerization of two strained rings. The obtained O-BCHeps are promising bioisosteres for ortho-substituted benzenes.

Palladium-catalyzed enantioselective decarboxylation of vinyl cyclic carbamates: Generation of amide-based aza-1,3-dipoles and application to asymmetric 1,3-dipolar cycloaddition

The catalytic asymmetric dipolar cycloaddition reaction is efficient for the construction of various chiral valuable carbo- and heterocycles. Thus, the design and exploration of new dipoles and the subsequent control of their reactivity for various stereoselective cycloadditions are significant aspects of modern organic synthesis. Herein, we have developed a series of vinyl cyclic carbamates containing an oxazolidine-2,4‑dione fragment and used them as reactive precursors for in situ generation of amide-based aza-π-allylpalladium 1,3-dipoles, which could be applied to asymmetric decarboxylative 1,3-dipolar cycloaddition with different types of dipolarophiles containing C=C, C=N, and C=O double bonds. This strategy provides an opportunity for the synthesis of previously unusual structures, such as highly functionalized optically pure pyrrolidin-2-ones, imidazolidin-4-ones, and oxazolidin-4-ones. This protocol also has significant features including wide substrate scope, mild reaction conditions, simple operation, and good to excellent results (70 examples, up to 99 % yield, >20:1 dr and 99 % ee). This unique method significantly expands the reaction range of the amide-based aza-π-allylpalladium 1,3-dipoles compared to the precedents.

Asymmetric (4+n) Cycloadditions of Indolyldimethanols for the Synthesis of Enantioenriched Indole‐Fused Rings

AbstractCatalytic asymmetric construction of chiral indole‐fused rings has become an important issue in the chemical community because of the significance of such scaffolds. In this work, we have accomplished the first catalytic asymmetric (4+2) and (4+3) cycloadditions of 2,3‐indolyldimethanols by using indoles and 2‐naphthols as suitable reaction partners under the catalysis of chiral phosphoric acids, constructing enantioenriched indole‐fused six‐membered and seven‐membered rings in high yields with excellent enantioselectivities. In addition, this approach is used to realize the first enantioselective construction of challenging tetrahydroindolocarbazole scaffolds, which are found to show promising anticancer activity. More importantly, theoretical calculations of the reaction pathways and activation mode offer an in‐depth understanding of this class of indolylmethanols. This work not only settles the challenges in realizing catalytic asymmetric cycloadditions of indolyldimethanols but also provides a powerful strategy for the construction of enantioenriched indole‐fused rings.

Asymmetric (4+n) Cycloadditions of Indolyldimethanols for the Synthesis of Enantioenriched Indole-Fused Rings.

Catalytic asymmetric construction of chiral indole-fused rings has become an important issue in the chemical community because of the significance of such scaffolds. In this work, we have accomplished the first catalytic asymmetric (4+2) and (4+3) cycloadditions of 2,3-indolyldimethanols by using indoles and 2-naphthols as suitable reaction partners under the catalysis of chiral phosphoric acids, constructing enantioenriched indole-fused six-membered and seven-membered rings in high yields with excellent enantioselectivities. In addition, this approach is used to realize the first enantioselective construction of challenging tetrahydroindolocarbazole scaffolds, which are found to show promising anticancer activity. More importantly, theoretical calculations of the reaction pathways and activation mode offer an in-depth understanding of this class of indolylmethanols. This work not only settles the challenges in realizing catalytic asymmetric cycloadditions of indolyldimethanols but also provides a powerful strategy for the construction of enantioenriched indole-fused rings.

Design and Organocatalytic Asymmetric Synthesis of Indolyl-Pyrroloindoles Bearing Both Axial and Central Chirality.

An axially chiral indolyl-pyrroloindole scaffold, a new member of axially chiral indole-based scaffolds, has been designed, and the catalytic asymmetric construction of this scaffold has been established by the strategy of organocatalytic asymmetric (2 + 3) cycloaddition of 3,3'-bisindoles with isoindolinone-based propargylic alcohols. By this approach, a series of indolyl-pyrroloindole derivatives bearing both axial chirality and central chirality were synthesized in high yields with excellent diastereo- and enantioselectivities (up to 95% yield, 91:9 dr, 99% ee). This reaction not only realizes the first catalytic asymmetric (2 + n) cycloaddition of 3,3'-bisindoles as 1,2-dinucleophiles but also provides a new strategy for atroposelective construction of axially chiral indole-based scaffolds bearing five-five-membered rings, thus solving the challenges in constructing this class of axially chiral indole-based scaffolds.

PC-Phos Enabled Catalytic Palladium-heteroallyl Asymmetric Cycloaddition.

Asymmetric cycloaddition reactions are the most powerful tool to the expeditious construction of enantioenriched cyclic motifs in organic chemistry. In sharp contrast to well-developed cycloaddition reactions via the palladium-trimethylenemethane (Pd-TMM) intermediate, hetero (3 + 2) cycloadditions of the heteroallyl cations remain rare, largely due to their thermally forbidden nature. To the best of our knowledge, there is no example of asymmetric version leading to enantioenriched heterocycles reported so far. Herein we enabled the first example of catalytic asymmetric (3 + 2) cycloaddition of electrophilic palladium-heteroallyl zwitterion intermediate (Pd-OTMM or Pd-NTMM) with cyclic or acyclic 1,3-dienes via a pathway terminated with C-N or C-O bond formation, delivering the highly substituted or fused pyrrolidine and tetrahydrofuran rings in high yields with excellent regio-, diastereo-, and enantioselectivity. Engineering the PC-Phos, one of the chiral sulfinamide phosphine (Sadphos) type ligands, by introducing the di-tert-butyl or/and 3,5-difluorophenyl group is a vital component in achieving excellent catalytic reactivity and enantioselectivity.

Asymmetric Total Synthesis of Shizukaol J, Trichloranoid C and Trishizukaol A.

The asymmetric total synthesis of three lindenane sesquiterpenoid oligomers, shizukaol J, trichloranoid C and trishizukaol A, has been accomplished concisely in 15, 16 and 18 longest linear steps, respectively. The expeditious construction of molecular architectures was facilitated by Nelson's catalytic asymmetric ketene-aldehyde cycloaddition, a sequence of allylic alkylation/reduction/acidic cyclization to forge a lactone, and a double aldol condensation cascade to construct the 5/6 bicyclic system. Diastereoselective nucleophilic substitution promoted by a phase transfer catalyst constructed the C11 quaternary stereogenic center, thus prompting synthetic efficacy toward shizukaol J. The synthesis of trichloranoid C and trishizukaol A was achieved after a cascade involving furanyl diene formation and a Diels-Alder reaction, as well as a one-pot sequence involving furan oxidation and global deprotection. Furthermore, our biological evaluation revealed that two compounds exhibited unexpected toxicity against tumor cell lines.

Organocatalytic Asymmetric [2 + 4] Cycloadditions of 3-Vinylindoles with ortho-Quinone Methides.

Catalytic asymmetric [2 + 4] cycloadditions of 3-vinylindoles with ortho-quinone methides and their precursors were carried out in the presence of chiral phosphoric acid to afford a series of indole-containing chroman derivatives with structural diversity in overall high yields (up to 98%), good diastereoselectivities (up to 93:7 dr) and moderate to excellent enantioselectivities (up to 98% ee). This approach not only enriches the chemistry of catalytic asymmetric cycloadditions involving 3-vinylindoles but is also useful for synthesizing chiral chroman derivatives.

Catalytic Asymmetric (3 + 3) Cycloaddition of Oxyallyl Zwitterions with α-Diazomethylphosphonates.

The unique structure of oxyallyls represents a significant challenge for their catalytic asymmetric applications. Herein, an unprecedented chiral imidodiphosphoric acid-catalytic enantioselective (3 + 3) cycloaddition between oxyallyl zwitterions generated in situ from α-haloketones and α-diazomethylphosphonates was developed. Pharmaceutically interesting chiral pyridazine-4(1H)-ones were obtained in up to 98% yields with excellent stereoselectivities (up to 99% ee, > 99:1 dr).

Application of 3-Alkyl-2-vinylindoles in Catalytic Asymmetric Dearomative (2+3) Cycloadditions.

The first application of 3-alkyl-2-vinylindoles in catalytic asymmetric dearomative cycloadditions was established by chiral phosphoric acid (CPA)-catalyzed (2+3) cycloaddition with azoalkenes, leading to the generation of chiral pyrroloindolines bearing two tetrasubstituted stereogenic centers in good yields (61-96%) and excellent stereoselectivities (all >95:5 dr, 86-99% ee). This reaction has realized the first enantioselective dearomative cycloaddition of 3-alkyl-2-vinylindoles, which brings a new reactivity to this class of vinylindoles and will enrich the chemistry of 3-alkyl-2-vinylindoles. In addition, this approach has provided a useful strategy for the construction of enantioenriched pyrroloindoline skeletons bearing two tetrasubstituted stereogenic centers. More importantly, the bioassay of these chiral pyrroloindolines has revealed that some compounds exhibit strong anti-cancer activity against Hela and MCF-7 cell lines, which will be helpful for discovering anti-cancer drug candidates.

Au(I)/(R)-BINOL-Ti(IV) Concerted Catalyzed Asymmetric Cascade Cycloaddition Reaction of Arylalkynols.

An efficient catalytic asymmetric cascade cycloaddition reaction of arylalkynols with dioxopyrrolidines was developed. This reaction was achieved using Au(I) and (R)-BINOL-Ti(IV) bimetallic catalysts and exclusively delivered a series of chiral oxo-bridged bicyclic benzooxacine compounds in up to 86% yield with 96% ee as well as >33:1 dr. Meanwhile, three new σ bonds and three new stereogenic centers were formed in a one-pot process.

Development of Dipolarophiles for Catalytic Asymmetric Cycloadditions through Pd-π-Allyl Zwitterions.

The development of new and efficient methodology for the construction of optically active molecules is of great interest in both synthetic organic and medicinal chemistry fields. To this end, the personal account summarizes our studies on the development of electron-deficient alkenes, allenes, and alkynes containing single activator as new dipolarophiles for Pd-catalyzed asymmetric cycloaddition reactions. These new dipolarophiles can participate in Pd-catalyzed asymmetric [3+2] and [4+2] cycloadditions through Pd-π-allyl 1,3- and 1,4-zwitterions in-situ generated by the reaction of Pd(0) catalyst with vinyl aziridines, vinyl epoxides, vinyl cyclopropanes, 4-vinyl-1,3-dioxan-2-ones, and vinyl benzoxazinanones. These [3+2] and [4+2] cycloadditions provide efficient approaches to a wide range of enantiomerically enriched five- and six-membered ring compounds containing contiguous chiral centers with high to excellent chemo-, diastereo-, and enantioselectivities. The utilities of these protocols are demonstrated by transformation of the cycloadducts into other useful chiral building blocks. DFT calculations reveal the dissimilar reactivity of different electron deficient alkenes and rationalize the mechanism and stereo-control of the reaction. A Pd-catalyzed inverse [3+2] cycloaddition is disclosed.

Enantioselective Copper-Catalyzed [3 + 3] Cycloaddition of Tertiary Propargylic Esters with 1H-Pyrazol-5(4H)-ones toward Optically Active Spirooxindoles.

A copper-catalyzed enantioselective [3 + 3] cycloaddition of 3-ethynyl-2-oxoindolin-3-yl acetates with 1H-pyrazol-5(4H)-ones for the construction of optically active spirooxindoles bearing a spiro all-carbon quaternary stereocenter has been realized. With a combination of Cu(OTf)2 and chiral tridentate ketimine P,N,N-ligand as the catalyst, the reaction displayed broad substrate scopes, good yields, and high enantioselectivities. This represents the first catalytic asymmetric propargylic cycloaddition with tertiary propargylic esters as the bis-electrophiles for access to chiral spirocyclic frameworks.

Inverse-Electron-Demand Palladium-Catalyzed Asymmetric [4+2] Cycloadditions Enabled by Chiral P,S-Ligand and Hydrogen Bonding.

Catalytic asymmetric cycloadditions of ambident Pd-containing dipolar species with nucleophilic dipolarophiles, namely, inverse-electron-demand cycloadditions, are challenging and underdeveloped. Possibly, the inherent linear selectivity of Pd-catalyzed intermolecular allylations and the lack of efficient chiral ligands are responsible for this limitation. Herein, two cycloadditions of such intermediates with deconjugated butenolides and azlactones were accomplished by using a novel chiral hybrid P,S-ligand and hydrogen bonding. By doing so, highly functionalized, optically active dihydroquinol-2-ones were produced with generally high reaction efficiencies and selectivities. Preliminary DFT calculations were performed to explain the high enantio- and diastereoselectivities.

Synergetic iridium and amine catalysis enables asymmetric [4+2] cycloadditions of vinyl aminoalcohols with carbonyls

Catalytic asymmetric cycloadditions via transition-metal-containing dipolar intermediates are a powerful tool for synthesizing chiral heterocycles. However, within the field of palladium catalysis, compared with the well-developed normal electron-demand cycloadditions with electrophilic dipolarophiles, a general strategy for inverse electron-demand ones with nucleophilic dipolarophiles remains elusive, due to the inherent linear selectivity in the key palladium-catalyzed intermolecular allylations. Herein, based on the switched regioselectivity of iridium-catalyzed allylations, we achieved two asymmetric [4+2] cycloadditions of vinyl aminoalcohols with aldehydes and β,γ-unsaturated ketones through synergetic iridium and amine catalysis. The activation of vinyl aminoalcohols by iridium catalysts and carbonyls by amine catalysts provide a foundation for the subsequent asymmetric [4+2] cycloadditions of the resulting iridium-containing 1,4-dipoles and (di)enamine dipolarophiles. The former provides a straightforward route to a diverse set of enantio-enriched hydroquinolines bearing chiral quaternary stereocenters, and the later represent an enantio- and diastereodivergent synthesis of chiral hydroquinolines.