Enantioselective Organocatalytic Intramolecular Aza‐Diels–Alder Reaction

Jarrige, Lucie; Blanchard, Florent; Masson, Géraldine

doi:10.1002/ange.201705746

Cited by 13 publications

(4 citation statements)

References 65 publications

(18 reference statements)

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“…We have previously demonstrated that bulky (S)-2,4,6-triisopropylphenyl 1,1'-bi-2-naphthol phosphoric acid 1 was able to efficiently promote the enantioselectivei ntramolecularP ovarov reactionb etween 2-formylphenyl 3-(4-hydroxyphenyl)acrylate derivatives 2 and 2-aminophenols 3.Awide range of 2-aminophenolsw ith electron-donating and -withdrawing groups were appropriate substrates to afford trans-trans tetrahydrochromeno[4, 3-b]quinolin-6-ones 4 with both high enantio-(98 to > 99 % ee)a nd diastereoselectivities (> 99:1 d.r.) [10] Various substituents on the aromatic ring of phenolic dienophile partners were also well tolerated. At the same time, few substituents on aromatic aldehydes were evaluated in our previous studies and werem ainly limited to bromide, methyl, and methoxy groups.I nt his context, we turned our attention to investigate other substituted salicylaldehydes,w hich possessed synthetic handles for further synthetic elaboration.…”

Section: Resultsmentioning

confidence: 99%

“…In our previous work, we observed that the presenceo ft he 2-hydroxy group on the 2-azadiene played an important role in asymmetric induction. [10] In this context, we were then interested in investigating the influence of using other hydrogenbond donors on enantioselectivity.2 -Aminothiophenol (3b) and tert-butyloxycarbonyl (Boc)-monosubstituted 1,2-diaminobenzene (3c)w ere tested in the intramolecular Povarov reaction with 2a and 5a.S urprisingly,s ubstrate 3b appeared to be unreactiver egardless of the linear partner used, so no desired product wasi solated (4i or 6a), even at higher temperature (50 8C). However,a lthough no reactionw as observed with the linear precursor bearing an ester linker, 2a,b ulky diaminobenzene 3c reacted efficiently with 5a,w hich had an amide linker.…”

Section: Resultsmentioning

confidence: 99%

“…Then, we werei nterested in rationalizing the absence of reactivity of dienophiles with af ree OH group in ortho or meta positions. [10] The above computations were partially reinvestigated and the resultsa re shown in Scheme 4B in black and green, respectively (see the Supporting Information for more details). Unlike the para series, the chiral phosphoric acid could interact with the ortho-substituted substrates through the formationo ft hree hydrogen bonds, leadingt oc omplex M'.S ubsequent displacemento ft he phosphate provides the correspondingc ompound R',w hich is more unstablet han that of the para-substituted analogue R (7.1v s. À11.8 kcal mol À1 ), due to the lack of as econd hydrogenb ond.…”

Section: Resultsmentioning

confidence: 99%

“…To address this limitation, the first example of an asymmetric intramolecular Povarov reactionw ith primary anilinesa st he reaction partners wasr eported by our group in 2017 (Scheme 1D). [10] Under mild conditions, as eries of trisubstitutedt etrahydrochromeno[4, 3-b]quinolin-6-ones and their nitrogen analogues, tetrahydrodibenzo[1,6]naphthyridin-6-ones, were obtained in good to excellent yields with high diastereo-a nd enantioselectivities by using ac hiral phosphoric acid catalyst.R emarkably,n op urification step was required to isolate each cycloadduct in excellent purity. Our previouss tudies showed that the presence of OH groups on both the aniline and dienophile were crucial to reach excellent enantioselectivity.M oreover, para-phenol on the dienophile was found to be criticalf or the success of the intramolecular Povarov reaction because ortho and meta analoguesw ere completely unreactive in this cycloaddition.…”

Section: Introductionmentioning

confidence: 99%

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Enantioselective Synthesis of Complex Fused Heterocycles through Chiral Phosphoric Acid Catalyzed Intramolecular Inverse‐Electron‐Demand Aza‐Diels–Alder Reactions

Jarrige

Gandon

Masson

2020

Chemistry A European J

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As table asymmetrici ntramolecular Povarovr eaction has been established to provide an efficient method to access structurally diverse trans,trans-trisubstituted tetrahydrochromeno[4,3-b]quinolines in high stereoselectivities of up to > 99:1 diastereomeric ratio and 99 %e nantiomeric excess,w ithout any purification step.A dditionally,t of acilitate large-scalea pplication of this method, al ow catalyst loadingp rotocol was employed, 0.2mol %c hiral phosphoric acid, which provided the cycloadducts withouta ny loss in yield and enantioselectivity.T heoretical studies revealed that the reaction occurred throughasequential Mannich reaction and an intramolecular Friedel-Craftsr eaction, wherein the phosphoric acid acted as ab ifunctional catalystt oa ctivate the para-phenolicd ienophile and N-2-hydroxy-2-azadiene simultaneously.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enantioselective Synthesis of Complex Fused Heterocycles through Chiral Phosphoric Acid Catalyzed Intramolecular Inverse‐Electron‐Demand Aza‐Diels–Alder Reactions

Jarrige

Gandon

Masson

2020

Chemistry A European J

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Catalytic Enantioselective Povarov Reactions of Ferrocenecarbaldehyde‐Derived Imines – Brønsted Acid Catalysis at Parts‐Per‐Million Level Loading

et al. 2017

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Despite the broad interest in ferrocene containing compounds, ferrocenyl substrates have been employed in catalytic asymmetric settings only sporadically. Herein, catalytic asymmetric Povarov reactions with ferrocenecarbaldehyde-derived N-aryl imines are presented. This study demonstrates that the stereoelectronic properties of ferrocenyl imines do not preclude their engagement in enantioselective phosphoric acid catalysis: cycloadducts derived from benzyl N-vinylcarbamate were obtained in good yields and nearly enantiopure form using 0.1 mol% of a standard Brønsted acid catalyst. Furthermore, it is shown that specific optimisation with some substrates allowed to lower the catalyst loading up to 10-20 parts-per-million, an unprecedented value for phosphoric acid catalysts. Such low loading protocol could be applied to a preparative scale reaction, and to imines derived from arylaldehydes.

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Catalytic Asymmetric Dearomatization of Indolyl Dihydropyridines through an Enamine Isomerization/Spirocyclization/Transfer Hydrogenation Sequence

et al. 2018

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Ah ighly efficient synthesis of enantioenriched spiroindolines by catalytic asymmetric dearomatization of indolyl dihydropyridines through ac hiral phosphoric acid catalyzede namine isomerization/spirocyclization/transfer hydrogenation sequence has been developed. This reaction proceeds under mild reaction conditions,a ffording novel spiroindolines in good yields (up to 88 %) with excellent enantioselectivity (up to 97 %e e). DFT calculations provide insights into the reaction mechanism as well as the origin of stereochemistry.Synthetic studies of polycyclici ndole derivatives have attracted plenty of research interests due to the widespread occurrence of such structural cores in natural products as well as their biological activities. [1] Pictet-Spengler reactions are widely recognized as one of the most efficient and straightforward methods to afford tetrahydro-b-carbolines. [2] Tr aditionally,t ryptamine derivatives and carbonyl compounds are employed as the substrates of Pictet-Spengler reactions.A s part of our ongoing research on catalytic asymmetric dearomatization (CADA) reactions, [3] we recently developed an efficient asymmetric synthesis of tetrahydro-b-carbolines 2 through chiral phosphoric acid (CPA)-catalyzed sequential enamine isomerization/Pictet-Spengler reaction of indolyl dihydropyridines 1 (Scheme 1a). [4] Spiroindolenine has been generally regarded as ak ey intermediate in Pictet-Spengler reactions.T oc apture and further manipulate the spiroindolenine species would allow unprecedented access to novel polycyclic indole derivatives. [5] In this regard, we envisioned that the analogous reaction of indolyl dihydropyridine 3, which bears aone-methylene prolonged tether, would afford spiroindolenine 4,f rom which an in situ transfer hydrogenation with Hantzsch ester might lead to tetrahydrospiro[indoline-3.1'-quinolizine] 5 (Scheme 1b). Herein, we report the results of the study on this cascade reaction catalyzed by achiral phosphoric acid. [6] Our studies commenced with optimization of the reaction conditions with 3a as the model substrate (Table 1). It was Scheme 1. Reaction design. Table 1: Optimization of the reaction conditions. [a] Entry CHSolvent T [8 8C] t [h] Yield [%] ee [%] [b] 1 C1 H1 Cl(CH 2 ) c] C1 H1 EtOAc 40 36 82 93 [a] Unless otherwise noted, the reaction was performed with 3a (0.1 mmol), C (10 mol %), H (0.2 mmol) in 2.0 mL solvent. [b] Determined by HPLC analysis on achiral stationary phase. [c] 50 mg 3 MS were added and 6mLofEtOAc were used.found that in the presence of 10 mol %o fc hiral phosphoric acid C1 and 2.0 equiv of Hantzsch ester H1,the title reaction proceeded smoothly,d elivering the desired product 5a in 83 %y ield with 81 % ee as asingle diastereoisomer (Table 1, entry 1). Systematic evaluation of aseries of chiral phosphoric acids (C2-C7)r evealed that all of the catalysts tested can promote the reaction, albeit with varied yields and enantioselectivity (entries 2-7). With C1 as the optimal catalyst, the effects of different hydride donors were then examined. The...

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Enantioselective Organocatalytic Intramolecular Aza‐Diels–Alder Reaction

Cited by 13 publications

References 65 publications

Enantioselective Synthesis of Complex Fused Heterocycles through Chiral Phosphoric Acid Catalyzed Intramolecular Inverse‐Electron‐Demand Aza‐Diels–Alder Reactions

Enantioselective Synthesis of Complex Fused Heterocycles through Chiral Phosphoric Acid Catalyzed Intramolecular Inverse‐Electron‐Demand Aza‐Diels–Alder Reactions

Catalytic Enantioselective Povarov Reactions of Ferrocenecarbaldehyde‐Derived Imines – Brønsted Acid Catalysis at Parts‐Per‐Million Level Loading

Catalytic Asymmetric Dearomatization of Indolyl Dihydropyridines through an Enamine Isomerization/Spirocyclization/Transfer Hydrogenation Sequence

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