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. 2022 Sep 23;24(37):6711-6715.
doi: 10.1021/acs.orglett.2c02433. Epub 2022 Sep 12.

Organocatalytic Enantioselective γ-Position-Selective Mannich Reactions of β-Ketocarbonyl Derivatives

Venkati Bethi  1 , Fujie Tanaka  1
Affiliations

Organocatalytic Enantioselective γ-Position-Selective Mannich Reactions of β-Ketocarbonyl Derivatives

Venkati Bethi et al. Org Lett. .

Abstract

Catalytic asymmetric Mannich reactions of β-ketocarbonyl derivatives (such as β-ketoesters and (2-oxopropyl)phosphonate), resulting in the formation of a C-C bond at the γ-position of the β-ketocarbonyl derivatives with high enantioselectivities, are reported. The bond formation at the α-position of the β-ketoester was reversible, and the γ-position-reacted product δ-amino β-ketoester derivative was kinetically formed and was stable. The dynamic kinetic process was key for the direct access to the γ-position-reacted products from β-ketocarbonyls under catalytic conditions.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Mannich Reactions of β-Ketocarbonyls
E = electrophiles; for simplicity, changes in charge or protonation are not shown.
Scheme 2
Scheme 2. Treatment of 4aa under the Catalytic Conditions with Amine C and Oxalic Acid
Scheme 3
Scheme 3. Reactions of 4aa under the Catalytic Conditions with Amine C and Oxalic Acid
Scheme 4
Scheme 4. Transformations of the γ-Position Reaction Products
See this image and copyright information in PMC

References

    1. Govender T.; Arvidsson P. I.; Maguire G. E. M.; Kruger H. G.; Naicker T. Enantioselective Organocatalyzed Transformations of β-Ketoesters. Chem. Rev. 2016, 116, 9375–9437. 10.1021/acs.chemrev.6b00156. - DOI - PubMed
    1. Wasa M.; Liu R. Y.; Roche S. P.; Jacobsen E. N. Asymmetric Mannich Synthesis of α-Amino Esters by Anion-Binding Catalysis. J. Am. Chem. Soc. 2014, 136, 12872–12875. 10.1021/ja5075163. - DOI - PMC - PubMed
    2. You Y.; Luo S. Catalytic Asymmetric Mannich Type Reaction with Tri-/Difluoro- orTrichloroacetaldimine Precursors. Org. Lett. 2018, 20, 7137–7140. 10.1021/acs.orglett.8b03083. - DOI - PubMed
    3. Xu H.; Nazli A.; Zou C.; Wang Z.-P.; He Y. Bench-stable Imine Surrogates for the One-pot and Catalytic Asymmetric Synthesis of α-Amino Esters/Ketones. Chem. Commun. 2020, 56, 14243–14246. 10.1039/D0CC06055K. - DOI - PubMed
    4. You Y.; Zhang L.; Cui L.; Mi X.; Luo S. Catalytic Asymmetric Mannich Reaction with N-Carbamoyl Imine Surrogates of Formaldehyde and Glyoxylate. Angew. Chem., Int. Ed. 2017, 56, 13814–13818. 10.1002/anie.201707005. - DOI - PubMed
    5. Hatano M.; Horibe T.; Ishihara K. Chiral Lithium (I) Binaphtholate Salts for the Enantioselective Direct Mannich-Type Reaction with a Change of Syn/Anti and Absolute Stereochemistry. J. Am. Chem. Soc. 2010, 132, 56–57. 10.1021/ja909874b. - DOI - PubMed
    6. Song J.; Wang Y.; Deng L. The Mannich Reaction of Malonates with Simple Imines Catalyzed by Bifunctional Cinchona Alkaloids: Enantioselective Synthesis of β-Amino Acids. J. Am. Chem. Soc. 2006, 128, 6048–6049. 10.1021/ja060716f. - DOI - PMC - PubMed
    7. Lou S.; Taoka B. M.; Ting A.; Schaus S. E. Asymmetric Mannich Reactions of β-Keto Esters with Acyl Imines Catalyzed by Cinchona Alkaloids. J. Am. Chem. Soc. 2005, 127, 11256–11257. 10.1021/ja0537373. - DOI - PubMed
    8. Hamashima Y.; Sasamoto N.; Hotta D.; Somei H.; Umebayashi N.; Sodeoka M. Catalytic Asymmetric Addition of β-Ketoesters to Various Imines by Using Chiral Palladium Complexes. Anew. Chem., Int. Ed. 2005, 44, 1525–1529. 10.1002/anie.200462202. - DOI - PubMed
    1. Cai M.; Xu K.; Li Y.; Nie Z.; Zhang L.; Luo S. Chiral Primary Amine/Ketone Cooperative Catalysis for Asymmetric α-Hydroxylation with Hydrogen Peroxide. J. Am. Chem. Soc. 2021, 143, 1078–1087. 10.1021/jacs.0c11787. - DOI - PubMed
    2. Zhu Y.; Zhang L.; Luo S. Asymmetric α-Photoalkylation of β-Ketocarbonyls by Primary Amine Catalysis: Facile Access to Acyclic All-Carbon Quaternary Stereocenters. J. Am. Chem. Soc. 2014, 136, 14642–14645. 10.1021/ja508605a. - DOI - PubMed
    3. Malerich J. P.; Hagihara K.; Rawal V. H. Chiral Squaramide Derivatives are Excellent Hydrogen Bond Donor Catalysts. J. Am. Chem. Soc. 2008, 130, 14416–14417. 10.1021/ja805693p. - DOI - PMC - PubMed
    1. Griggs S. D.; Thompson N.; Tape D. T.; Fabre M.; Clarke P. A. A Two-Step Synthesis of 2-Spiropiperidines. Chem. Eur. J. 2017, 23, 9262–9265. 10.1002/chem.201702467. - DOI - PubMed
    2. Ghorai M. K.; Kumar A.; Halder S. Regioselective Addition of 1,3-Dicarbonyl Dianion to N-Sulfonyl Aldimines: an Expedient Route to N-Sulfonyl Piperidines and N-Sulfonyl Azetidines. Tetrahedron 2007, 63, 4779–4787. 10.1016/j.tet.2007.03.081. - DOI
    1. Denmark S. E.; Heemstra J. R.; Beutner G. L. Catalytic, Enantioselective, Vinylogous Aldol Reactions. Angew. Chem,. Int. Ed. 2005, 44, 4682–4698. 10.1002/anie.200462338. - DOI - PubMed
    2. Wang Q.; Gemmeren M.; List B. Asymmetric Disulfonimide-Catalyzed Synthesis of δ-Amino-β-Ketoester Derivatives by Vinylogous Mukaiyama–Mannich Reactions. Angew. Chem., Int. Ed. 2014, 53, 13592–13595. 10.1002/anie.201407532. - DOI - PubMed
    3. Wang Q.; List B. Disulfonimide-Catalyzed Asymmetric Synthesis of δ-Amino-β-Keto Esters. Synlett 2015, 26, 807–809. 10.1055/s-0034-1379999. - DOI
    4. Singer R. A.; Carreira E. M. Catalytic, Enantioselective Dienolate Additions to Aldehydes: Preparation of Optically Active Acetoacetate Aldol Adducts. J. Am. Chem. Soc. 1995, 117, 12360–12361. 10.1021/ja00154a049. - DOI