Asymmetric aerobic oxidative NHC-catalysed synthesis of dihydropyranones utilising a system of electron transfer mediators

Axelsson, Anton; Hammarvid, Emmelie; Ta, Linda; Sundén, Henrik

doi:10.1039/c6cc06060a

Cited by 40 publications

(31 citation statements)

References 56 publications

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“…Treatment with equimolar amounts of NHC precatalyst 4 and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) in methanol yielded the ringopened diketoester 3 in 95 % yield, as previously reported. 39 However, usage of slightly higher loadings of DBU (15 mol%) in absence of 4 yielded compound 2 in 89% isolated yield. A stochiometric amount of methyl acetate was also detected in the crude reaction mixture by 1 H NMR, suggesting that 2 is formed via a retro-Claisen fragmentation of the 1,3-diketone of compound 3.…”

Section: Results and Discussion Reaction Optimization And Scopementioning

confidence: 99%

“…For instance, both Smith et al and our group have observed facile ring-opening with methanol when using Brønsted bases (Scheme 2 A). 39,46 Huang et al have shown that it is possible to extend this type of reaction by treating the acyclic ester with either hydrazine or hydroxylamine, yielding pyrazoles or isoxazoles respectively. 41 A diastereoselective epoxidation of the enol double bond using m-CPBA with only slight erosion of enantiopurity was developed by Chi and coworkers (Scheme 2 B).…”

Section: Scheme 2 Reactivity Of Dihydropyranonesmentioning

confidence: 99%

“…By relying on our aerobic oxidative protocol for synthesis of dihydropyranones, (S)-1 could be obtained in good yield and 94% ee on gram scale. 39 Treatment of (S)-1 with DBU under standard conditions gave (S)-2 in satisfying 85% yield and 92% ee (Scheme 5). Chiral aminoalcohols are also viable reaction partners and and (S)-prolinol, (S)-valinol, (S)-tryptophanol and (S)-isoleucinol could be used to synthesize the corresponding 5-oxo-hexanamides in 87-96% yield.…”

Section: Difficult Nucleophilementioning

confidence: 99%

“…[34][35][36][37][38] Lately, several strategies that uses oxygen as oxidant has been reported. [38][39][40][41] The latter approaches represents an important step towards making 3,4-dihydropyranones valuable starting material for further functionaliszation. [42][43][44]…”

Section: Introductionmentioning

confidence: 99%

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Formal Addition of Acetone to Unactivated Michael Acceptors via Ring-Opening and Retro-Claisen Fragmentation of Dihydropyranones

Axelsson¹,

Hammarvid²,

Rahm³

et al. 2019

Preprint

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<div><div><div><p>We present a general protocol for the formal Michael addition of acetone to a,b-unsaturated esters and amides, a transformation difficult to perform using current methods. The protocol comprises of an amidine catalyzed relay ring-opening and fragmentation of 3,4-dihydropyranones. The reaction proceeds under mild conditions, has a broad substrate scope and the products can be isolated in good to excellent yields (30 examples, with up to 97 % yield). The method can be applied to homochiral substrates with total preservation of chiral information, generating products in high optical purity. Kinetic experiments upported by quantum chemical modeling indicates that the reaction is of second order with respect to the catalyst. The kinetic isotope effect has been determined to be 2.3, which supports a mechanism in which the catalyst takes a bifunctional role, acting both as a Brønsted base and as a hydrogen bond donor. The findings presented here enables a rapid entry to compounds previously considered difficult to access and highlights the dual functionality of amidine superbases as catalysts.</p></div></div></div>

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Section: Results and Discussion Reaction Optimization And Scopementioning

confidence: 99%

Section: Scheme 2 Reactivity Of Dihydropyranonesmentioning

confidence: 99%

Section: Difficult Nucleophilementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Formal Addition of Acetone to Unactivated Michael Acceptors via Ring-Opening and Retro-Claisen Fragmentation of Dihydropyranones

Axelsson¹,

Hammarvid²,

Rahm³

et al. 2019

Preprint

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“…Furthermore, the authors considered that the possible oxygenative path of the investigated mechanism occurs in the minority of cases. Sundén and co-workers reported the aerobic NHC-catalyzed synthesis of dihydropyranones via multistep electron transfer in 2016 ( Figure 11) [53]. The assumption of this work is the oxidation of ETM first, by oxygen from air.…”

Section: Oxidative Nhc Catalysismentioning

confidence: 89%

N-Heterocyclic Carbene Catalysis under Oxidizing Conditions

Dzieszkowski

Rafiński

2018

Catalysts

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N-heterocyclic carbene organocatalysis under oxidizing conditions provides a vast range of various synthetic procedures via diverse mechanisms. The available catalysts, bases, oxidants, and oxidizing methods afford numerous opportunities for developing this branch of organocatalysis. Furthermore, implementation of tandem reactions and cooperative catalysis in the described methodology significantly expands the possibilities of modern organic chemistry. This approach allows the synthesis of different structurally complex and often enantiomerically enriched substances, which can be interesting in terms of biological activity and natural product synthesis. Many esters, amides, thioesters, lactams, lactones, and other cyclic compounds obtained in oxidative or oxygenative reactions promoted by N-heterocyclic carbenes can be interesting precursors in advanced organic synthesis. Sophistication and broad applicability prove that the described synthetic approaches are exceptionally worthy of further development.

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