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NHC-Catalyzed Generation of α,β-Unsaturated Acylazoliums for the Enantioselective Synthesis of Heterocycles and Carbocycles.
Acc Chem Res. 2019 02 19; 52(2):425-436.AC

Abstract

This Account is aimed at highlighting the recent developments in the N-heterocyclic carbene (NHC)-catalyzed generation of α,β-unsaturated acylazolium intermediates and their subsequent reactivity with (bis)nucleophiles thereby shedding light on the power of this NHC-bound intermediate in organocatalysis. This key intermediate can be generated by the addition of NHCs to α,β-unsaturated aldehyde or acid derivatives. A wide variety of bisnucleophiles can add across the α,β-unsaturated acylazoliums to form various five and six-membered heterocycles and carbocycles. Moreover, suitably substituted nucleophiles can add to this intermediate and result in valuable products following cascade processes. Employing chiral NHCs in the process can result in the enantioselective synthesis of valuable compounds. In 2013, we developed a unified strategy for the enantioselective synthesis of dihydropyranones and dihydropyridinones by the NHC-catalyzed formal [3 + 3] annulation of 2-bromoenals with readily available 1,3-dicarbonyl compounds or primary vinylogous amides. This reaction takes place under mild conditions with low catalyst loading. Interestingly, employing enolizable aldehydes as the bisnucleophiles in this annulation afforded chiral 4,5-disubstituted dihydropyranones in spite of the competing benzoin/Stetter pathways. Moreover, the use of cyclic 1,3-dicarbonyl compounds such as 4-hydroxy coumarin/pyrazolone afforded the coumarin/pyrazole-fused dihydropyranones. In addition, a [3 + 2] annulation for the synthesis of spiro γ-butyrolactones was demonstrated using 3-hydroxy oxindoles as the bisnucleophile. The interception of α,β-unsaturated acylazolium intermediates with malonic ester derivatives having a γ-benzoyl group resulted in the enantioselective synthesis of functionalized cyclopentenes via a cascade process involving a Michael-intramolecular aldol-β-lactonization-decarboxylation sequence. The use of cyclic β-ketoamides as the coupling partner for catalytically generated α,β-unsaturated acylazoliums resulted in the enantioselective synthesis of spiro-glutarimide and the reaction proceeds in a Michael addition-intramolecular amidation pathway. We have recently demonstrated the enantioselective synthesis of tricyclic δ-lactones with three contiguous stereocenters by the reaction of enals with dinitrotoluene derivatives bearing electron-withdrawing groups, under oxidative conditions. This atom-economic cascade reaction proceeds in a Michael/Michael/lactonization sequence tolerating a range of functional groups. This technique was also used for the N-H functionalization of indoles for the enantioselective synthesis of pyrroloquinolines following the aza-Michael/Michael/lactonization sequence. The use of α-arylidene pyrazolinones as the bisnucleophiles for the tandem generation of dienolate/enolates combined with the NHC-catalyzed generation of α,β-unsaturated acylazoliums resulted in the enantioselective synthesis of pyrazolone-fused spirocyclohexadienones. This formal [3 + 3] annulation proceeds via the vinylogous Michael/spiroannulation/dehydrogenation sequence to afford spirocyclic compounds with an all-carbon quaternary stereocenter. It is reasonable to believe that the chemistry of α,β-unsaturated acylazoliums, catalytically generated through NHCs, will continue to flourish and will lead to amazing results. Future challenges in this area include the applications of this key intermediate in the synthesis of biologically active natural products and drugs.

Authors+Show Affiliations

Organic Chemistry Division , CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road , Pune 411008 , India.Organic Chemistry Division , CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road , Pune 411008 , India.Organic Chemistry Division , CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road , Pune 411008 , India.Department of Organic Chemistry , Indian Institute of Science , Bangalore 560012 , India.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30653296

Citation

Mondal, Santigopal, et al. "NHC-Catalyzed Generation of α,β-Unsaturated Acylazoliums for the Enantioselective Synthesis of Heterocycles and Carbocycles." Accounts of Chemical Research, vol. 52, no. 2, 2019, pp. 425-436.
Mondal S, Yetra SR, Mukherjee S, et al. NHC-Catalyzed Generation of α,β-Unsaturated Acylazoliums for the Enantioselective Synthesis of Heterocycles and Carbocycles. Acc Chem Res. 2019;52(2):425-436.
Mondal, S., Yetra, S. R., Mukherjee, S., & Biju, A. T. (2019). NHC-Catalyzed Generation of α,β-Unsaturated Acylazoliums for the Enantioselective Synthesis of Heterocycles and Carbocycles. Accounts of Chemical Research, 52(2), 425-436. https://doi.org/10.1021/acs.accounts.8b00550
Mondal S, et al. NHC-Catalyzed Generation of α,β-Unsaturated Acylazoliums for the Enantioselective Synthesis of Heterocycles and Carbocycles. Acc Chem Res. 2019 02 19;52(2):425-436. PubMed PMID: 30653296.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NHC-Catalyzed Generation of α,β-Unsaturated Acylazoliums for the Enantioselective Synthesis of Heterocycles and Carbocycles. AU - Mondal,Santigopal, AU - Yetra,Santhivardhana Reddy, AU - Mukherjee,Subrata, AU - Biju,Akkattu T, Y1 - 2019/01/17/ PY - 2019/1/18/pubmed PY - 2019/1/18/medline PY - 2019/1/18/entrez SP - 425 EP - 436 JF - Accounts of chemical research JO - Acc. Chem. Res. VL - 52 IS - 2 N2 - This Account is aimed at highlighting the recent developments in the N-heterocyclic carbene (NHC)-catalyzed generation of α,β-unsaturated acylazolium intermediates and their subsequent reactivity with (bis)nucleophiles thereby shedding light on the power of this NHC-bound intermediate in organocatalysis. This key intermediate can be generated by the addition of NHCs to α,β-unsaturated aldehyde or acid derivatives. A wide variety of bisnucleophiles can add across the α,β-unsaturated acylazoliums to form various five and six-membered heterocycles and carbocycles. Moreover, suitably substituted nucleophiles can add to this intermediate and result in valuable products following cascade processes. Employing chiral NHCs in the process can result in the enantioselective synthesis of valuable compounds. In 2013, we developed a unified strategy for the enantioselective synthesis of dihydropyranones and dihydropyridinones by the NHC-catalyzed formal [3 + 3] annulation of 2-bromoenals with readily available 1,3-dicarbonyl compounds or primary vinylogous amides. This reaction takes place under mild conditions with low catalyst loading. Interestingly, employing enolizable aldehydes as the bisnucleophiles in this annulation afforded chiral 4,5-disubstituted dihydropyranones in spite of the competing benzoin/Stetter pathways. Moreover, the use of cyclic 1,3-dicarbonyl compounds such as 4-hydroxy coumarin/pyrazolone afforded the coumarin/pyrazole-fused dihydropyranones. In addition, a [3 + 2] annulation for the synthesis of spiro γ-butyrolactones was demonstrated using 3-hydroxy oxindoles as the bisnucleophile. The interception of α,β-unsaturated acylazolium intermediates with malonic ester derivatives having a γ-benzoyl group resulted in the enantioselective synthesis of functionalized cyclopentenes via a cascade process involving a Michael-intramolecular aldol-β-lactonization-decarboxylation sequence. The use of cyclic β-ketoamides as the coupling partner for catalytically generated α,β-unsaturated acylazoliums resulted in the enantioselective synthesis of spiro-glutarimide and the reaction proceeds in a Michael addition-intramolecular amidation pathway. We have recently demonstrated the enantioselective synthesis of tricyclic δ-lactones with three contiguous stereocenters by the reaction of enals with dinitrotoluene derivatives bearing electron-withdrawing groups, under oxidative conditions. This atom-economic cascade reaction proceeds in a Michael/Michael/lactonization sequence tolerating a range of functional groups. This technique was also used for the N-H functionalization of indoles for the enantioselective synthesis of pyrroloquinolines following the aza-Michael/Michael/lactonization sequence. The use of α-arylidene pyrazolinones as the bisnucleophiles for the tandem generation of dienolate/enolates combined with the NHC-catalyzed generation of α,β-unsaturated acylazoliums resulted in the enantioselective synthesis of pyrazolone-fused spirocyclohexadienones. This formal [3 + 3] annulation proceeds via the vinylogous Michael/spiroannulation/dehydrogenation sequence to afford spirocyclic compounds with an all-carbon quaternary stereocenter. It is reasonable to believe that the chemistry of α,β-unsaturated acylazoliums, catalytically generated through NHCs, will continue to flourish and will lead to amazing results. Future challenges in this area include the applications of this key intermediate in the synthesis of biologically active natural products and drugs. SN - 1520-4898 UR - https://www.unboundmedicine.com/medline/citation/30653296/NHC_Catalyzed_Generation_of_αβ_Unsaturated_Acylazoliums_for_the_Enantioselective_Synthesis_of_Heterocycles_and_Carbocycles_ L2 - https://dx.doi.org/10.1021/acs.accounts.8b00550 DB - PRIME DP - Unbound Medicine ER -
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