Asymmetric Synthesis of Spirobenzazepinones with Atroposelectivity and Spiro‐1,2‐Diazepinones by NHC‐Catalyzed [3+4] Annulation Reactions

Wang, Lei; Li, Sun; Blümel, Marcus; Philipps, Arne R.; Ai, Wang; Puttreddy, Rakesh; Rissanen, Kari; Enders, Dieter

doi:10.1002/anie.201604819

Cited by 173 publications

(59 citation statements)

References 82 publications

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“…Consequently, our calculation results support the experimental finding that the S‐configurational product is the major product. Moreover, the 9.9 kcal/mol energy barrier difference leading to a predicted ee of 99 % which is consistent with the experimental reported er of 99:1 …”

Section: Resultssupporting

confidence: 88%

“…Recently, the Enders's group reported a novel NHC‐catalyzed [3 + 4] cycloaddition reaction furnishing desired spirobenzazepinones. The reaction between an isatin‐derived enal (3C components) and N ‐( ortho ‐chloromethyl)aryl amide (4C components), as shown in Scheme could be effectively catalyzed by using the triazolium‐based NHC and Cs 2 CO 3 as the base.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms and Stereoselectivities of NHC‐Catalyzed [3 + 4] Cycloaddition Reaction between Isatin‐Derived Enal and N‐(ortho‐Chloromethyl)aryl Amide

Zhang

2019

Eur J Org Chem

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Possible mechanisms and origins of stereoselectivity of N‐heterocyclic carbene (NHC) promoted spirobenzazepinone formation from the annulation of an isatin‐derived enal and N‐(ortho‐chloromethyl)aryl amide have been investigated computationally. DFT results (M06–2X) suggest that the preferred mechanism consists of six steps: The nucleophilic coupling of the NHC catalyst and isatin‐derived enal was considered as the first reaction step (step I), followed by generation of the Breslow intermediate through a HCO3– assisted proton transfer event (step II). The next step is the addition of Breslow intermediate to N‐(ortho‐chloromethyl)aryl amide generating the acyl azolium intermediate (step III). Then the reaction proceeds through successive intramolecular cycloaddition (step IV), H2O‐mediated 1,3‐proton transfer (step V) and catalyst elimination (step VI) affording the [3+4] cycloaddition product. Step V plays a pivotal role in determining the stereoselectivity of the reaction and leads to the experimentally observed S‐configuration product. The DFT results account for the experimental observations. Global reactivity index analysis has also been conducted to identify the role of NHC catalyst.

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Section: Resultssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Mechanisms and Stereoselectivities of NHC‐Catalyzed [3 + 4] Cycloaddition Reaction between Isatin‐Derived Enal and N‐(ortho‐Chloromethyl)aryl Amide

Zhang

2019

Eur J Org Chem

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“…[3c, f] In 2016, the Enders group successfully established an NHC-catalyzed asymmetric [3+ +4] cyclization of isatinderived enals with in situ generated aza-o-quinone methides, azoalkenes,and nitrosoalkenes,which proceeds though NHCbased three-carbon homoenolates,l eading to as eries of highly enantioenriched spirooxindoles (Scheme 1a). [4] Since then, an umber of methods have been developed to access 3,3'-spirocyclic oxindole skeletons through NHC-catalyzed [3 + n]annulations of isatin-derived enals [5] by using asimilar concept. [6] Recently,c ooperative catalysis between metals and Nheterocyclic carbenes (NHCs) has greatly enhanced the synthetic repertoire of carbene catalysis.…”

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confidence: 99%

N‐Heterocyclic Carbene/Copper Cooperative Catalysis for the Asymmetric Synthesis of Spirooxindoles

et al. 2019

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Highly enantioselective [3+ +3] and [3+ +4] annulations of isatin-derived enals with ethynylethylene carbonates and ethynyl benzoxazinanones are enabled by NHC/cooper cooperative catalysis,leading to abig library of spirooxindole derivatives in high structural diversity and enantioselectivity (up to 99 %e e). Both reactions represent an icely synergistic integration of NHC and copper catalysis,i nw hichb oth catalysts activate the substrates and the chiral NHC perfectly controls the stereochemistry.The 3,3'-spirocyclicoxindole unit is aprivileged heterocyclic moiety that is prevalent in ag reat number of biologically active natural products and pharmaceutical molecules. [1] Consequently,t he catalytic enantioselective construction of the spirooxindole skeleton with an all-carbon quaternary stereogenic center at the C3-position has received longstanding interest, but still remains asignificant challenge in organic synthesis. [2] In the past two decades,t he chemistry of Nheterocyclic carbenes (NHCs) has witnessed significant development in terms of stereoselective synthesis,a nd now provides apowerful approach to build molecular complexity, primarily through polarity-reversal approaches. [3] In particular, studies on the homoenolate species generated by NHC catalysis have gained widespread popularity in recent years. [3c, f] In 2016, the Enders group successfully established an NHC-catalyzed asymmetric [3+ +4] cyclization of isatinderived enals with in situ generated aza-o-quinone methides, azoalkenes,and nitrosoalkenes,which proceeds though NHCbased three-carbon homoenolates,l eading to as eries of highly enantioenriched spirooxindoles (Scheme 1a). [4] Since then, an umber of methods have been developed to access 3,3'-spirocyclic oxindole skeletons through NHC-catalyzed [3 + n]annulations of isatin-derived enals [5] by using asimilar concept. [6] Recently,c ooperative catalysis between metals and Nheterocyclic carbenes (NHCs) has greatly enhanced the synthetic repertoire of carbene catalysis. [7] Activation modes accessible through cooperative catalysis have resulted in remarkable improvements in reactivity,e fficiency,a nd selectivity for as eries of new enantioselective transformations. NHCs are routinely used as strongly coordinating ligands due to their strong propensity for binding to transition metals with high affinity. [8] As such, the combination of these nucleophilic organocatalysts with transition metals [9] typically leads to the deactivation of either or both of the two catalysts.B yn ow, several groups have figured out solutions to such problems through careful evaluations of catalytic systems,a nd the combination of NHCs with palladium, [10] ruthenium, [11] and copper [12] catalysts has enabled av ariety of unprecedented asymmetric reactions (Scheme 1b). Remarkably,s everal pioneering reports from Scheidt, [10a] Liu, [10b,c] and co-workers have demonstrated synergy between NHC and p-allylpalladium in catalysis.Since then, cooperative catalysis with NHC and palladium, as reported by Glorius and c...

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“…Interestingly, adduct 1 remained unreactive against carbene‐mediated 1,4‐addition (Scheme a) and the starting materials were fully recovered. This lack of reactivity may have been due the need for a more electrophilic Michael acceptor . Some years ago, Wasnaire et al .…”

Section: Introductionmentioning

confidence: 99%

Intermolecular Stetter Reactions on Morita‐Baylis‐Hillman Adducts: an Approach to Highly Functionalized 1,4‐Dicarbonyl Compounds

et al. 2017

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We reported herein an N‐heterocyclic carbene (NHC)‐mediated intermolecular Stetter reaction between oxidized Morita‐Baylis‐Hillman (MBH) adducts and a variety of aldehydes. This protocol allows the synthesis of highly functionalized 1,4‐dicarbonyl compounds. The reaction is an alternative approach to these compounds using commercially available starting materials. This metal‐free process exhibits a wide substrate scope, excellent atom economy, compatibility with functionalized substrates and mild reaction conditions. The 1,4‐dicarbonyl compounds were prepared in two steps via MBH reactions with overall yields up to 99 %. This protocol is easily scalable. The synthetic usefulness of this method was demonstrated in a high yield synthesis of a tri‐substituted pyrrole used as an advanced intermediate in the total synthesis of kinase inhibitors as well as in the synthesis of another heterocycles.

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Asymmetric Synthesis of Spirobenzazepinones with Atroposelectivity and Spiro‐1,2‐Diazepinones by NHC‐Catalyzed [3+4] Annulation Reactions

Cited by 173 publications

References 82 publications

Mechanisms and Stereoselectivities of NHC‐Catalyzed [3 + 4] Cycloaddition Reaction between Isatin‐Derived Enal and N‐(ortho‐Chloromethyl)aryl Amide

Mechanisms and Stereoselectivities of NHC‐Catalyzed [3 + 4] Cycloaddition Reaction between Isatin‐Derived Enal and N‐(ortho‐Chloromethyl)aryl Amide

N‐Heterocyclic Carbene/Copper Cooperative Catalysis for the Asymmetric Synthesis of Spirooxindoles

Intermolecular Stetter Reactions on Morita‐Baylis‐Hillman Adducts: an Approach to Highly Functionalized 1,4‐Dicarbonyl Compounds

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