Exoselective 1,3-Dipolar [3 + 6] Cycloaddition of Azomethine Ylides with 2-Acylcycloheptatrienes: Stereoselectivity and Mechanistic Insight

He, Zhao‐Lin; Sheong, Fu Kit; Li, Qinghua; Lin, Zhenyang; Wang, Chun‐Jiang

doi:10.1021/acs.orglett.5b00011

Cited by 46 publications

(15 citation statements)

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“…In 2015, we developed the Cu(I)-catalyzed (3+6) cycloaddition of azomethine ylides with 2-acyl cycloheptatriene using ( S , R p )- L3b as the chiral ligand, affording 58 in good yields with exclusive exo- selectivity and high enantioselectivities (Scheme ). A stepwise mechanism leading to exo -selectivity was proposed based on DFT calculations.…”

Section: Catalytic Asymmetric 13-dipolar Cycloaddition Of N-metallate...mentioning

confidence: 99%

Catalytic Asymmetric Reactions with N-Metallated Azomethine Ylides

2020

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Conspectus Optically active nitrogen-containing compounds have attracted substantial attention due to their ubiquity in the cores of natural products and bioactive molecules. Among the various synthetic approaches to nitrogenous frameworks, catalytic asymmetric 1,3-dipolar cycloadditions are one of the most attractive methods because of their powerful ability to rapidly construct various chiral N-heterocycles. In particular, N-metallated azomethine ylides, common and readily available 1,3-dipoles, have been extensively applied in dipolar cycloaddition reactions. Despite the fact that asymmetric transformations of azomethine ylides have been investigated for decades, most of the efforts have been directed toward the preparation of pyrrolidines using glycinate-derived α-unsubstituted aldimine esters as the precursors of the azomethine ylides. While α-substituted azomethine ylides derived from amino esters other than glycinate have seldom been harnessed, the construction of non-five-membered chiral N-heterocycles via 1,3-dipolar cycloadditions remains underexplored. In addition, the asymmetric α-functionalization of aldimine esters to prepare acyclic nitrogenous compounds such as α-amino acids, in which an in situ-generated N-metallated azomethine ylide serves as the nucleophile, has not been sufficiently described. In this Account, we mainly discuss the achievements we have made in the past decade toward broadening the applications of N-metallated azomethine ylides for the preparation of nitrogen-containing compounds. We began our investigation with the design and synthesis of a new type of chiral ligand, TF-BiphamPhos, which not only coordinates with Lewis acids to activate dipolar species but also serves as an H-bond donor to increase the reactivity of dipolarophiles with significantly enhanced stereochemical control. Using the Cu(I) or Ag(I)/TF-BiphamPhos complex as the catalyst, we achieved highly stereoselective (3+2) cycloadditions of glycinate and non-glycinate-derived azomethine ylides with diverse dipolarophiles, producing a variety of enantioenriched pyrrolidines with multiple stereocenters in a single step. To further expand the synthetic utility of N-metallated azomethine ylides, we successfully developed higher order cycloadditions with fulvenes, tropone, 2-acyl cycloheptatrienes, and pyrazolidinium ylides serving as the reaction partner, and this reaction provides straightforward access to enantioenriched fused piperidines, bridged azabicyclic frameworks, and triazines via (3+6)- and (3+3)-type cycloadditions. Using N-metallated azomethine ylides as the nucleophile, we realized Cu(I)-catalyzed asymmetric 1,4-Michael additions with α,β-unsaturated bisphosphates/Morita–Baylis–Hillman products, furnishing an array of structurally diverse unnatural α-amino acids. Based on the strategy of synergistic activation, we achieved highly efficient dual Cu/Pd and Cu/Ir catalysis for the α-functionalization of aldimine esters via the asymmetric allylic/allenylic alkylation of N-metallated azomethine ylides. No...

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Section: Catalytic Asymmetric 13-dipolar Cycloaddition Of N-metallate...mentioning

confidence: 99%

Catalytic Asymmetric Reactions with N-Metallated Azomethine Ylides

2020

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“… 5 Recent developments in enantioselective higher order (3 + 3) cycloaddition further extended the synthetic applicability of AMYs to approach six-membered N-heterocycles including piperidines and 1,4,5-triazines. 6 In contrast, assembling important skeletons other than five-/six-membered rings, for instance, seven-membered N-heterocycles, via 1,3-dipolar (3 + 4) cycloaddition of AMYs is extremely difficult owing to the disfavored entropic factors and transannular interactions 7 and the challenge in stereocontrol of multiple stereogenic centers. 4 In 2014, we reported an Et 3 N-catalyzed formal (3 + 4) annulation of aldimine esters with methyl coumalate for the preparation of functionalized racemic azepine derivatives.…”

Section: Introductionmentioning

confidence: 99%

Stereodivergent synthesis of enantioenriched azepino[3,4,5-cd]-indoles via cooperative Cu/Ir-catalyzed asymmetric allylic alkylation and intramolecular Friedel–Crafts reaction

Lü

Fan

et al. 2022

Chem. Sci.

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“…Few methods for the synthesis of these scaffolds are shown in Figure . These protocols have employed [3 + 2]- [6 + 3]- [4 + 4 + 1]- and [4 + 3 + 2]- cycloaddition reactions as well as macrocyclizations . In addition, elegant contributions using Ugi–Heck, Ugi-ring opening metathesis, and Ugi-intramolecular arylation to access medium-sized ring systems were reported .…”

Section: Introductionmentioning

confidence: 99%

Divergent Strategy for Diastereocontrolled Synthesis of Small- and Medium-Ring Architectures

et al. 2020

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Nitrogen and oxygen medium rings, in particular nine-membered rings, epitomize a unique area of chemical space that occurs in many natural products and biologically appealing compounds. The scarcity of 8- to 12-membered rings among clinically approved drugs is indicative of the difficulties associated with their synthesis, principally owing to the unfavorable entropy and transannular strain. We report here a scandium triflate-catalyzed reaction that allows for a modular access to a diverse collection of nine-membered ring heterocycles in a one-pot cascade and with complete diastereocontrol. This cascade features an intramolecular addition of an acyl group-derived enol to a α,β-unsaturated carbonyl moiety, leading to N- and O-derived medium-ring systems. Computational studies using the density functional theory support the proposed mechanism. Additionally, a one-pot cascade leading to hexacyclic chromeno[3′,4′:2,3]indolizino[8,7-b]indole architectures, with six fused rings and four contiguous chiral centers, is reported. This novel cascade features many concerted events, including the formation of two azomethine ylides, [3 + 2]-cycloaddition, 1,3-sigmatropic rearrangement, Michael addition, and Pictet–Spengler reaction among others. Phenotypic screening of the resulting oxazonine collection identified chemical probes that regulate mitochondrial membrane potential, adenosine 5′-triphosphate contents, and reactive oxygen species levels in hepatoma cells (Hepa1-6), a promising approach for targeting cancer and metabolic disorders.

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Exoselective 1,3-Dipolar [3 + 6] Cycloaddition of Azomethine Ylides with 2-Acylcycloheptatrienes: Stereoselectivity and Mechanistic Insight

Cited by 46 publications

References 50 publications

Catalytic Asymmetric Reactions with N-Metallated Azomethine Ylides

Catalytic Asymmetric Reactions with N-Metallated Azomethine Ylides

Stereodivergent synthesis of enantioenriched azepino[3,4,5-cd]-indoles via cooperative Cu/Ir-catalyzed asymmetric allylic alkylation and intramolecular Friedel–Crafts reaction

Divergent Strategy for Diastereocontrolled Synthesis of Small- and Medium-Ring Architectures

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