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Dendrimeric α,β-dipeptidic conjugates as organocatalysts in the asymmetric Michael addition reaction of isobutyraldehyde to N-phenylmaleimides

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Abstract

A series of polyester dendrimers (1G to 3G generation) based on 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid (bis-MPA) and the core of 1,3-propanediol-2-(hydroxymethyl)-2-methyl (TME) were synthesized and conjugated to the α,β-dipeptide (N-Cbz-Phe-N-Bn-β-Ala-COOH) in convergent fashion. Conventional esterification (DCC, DMAP, DPTS) was used for the above coupling, followed by removal of protecting groups (acetonide and Cbz groups) to provide seven novel organocatalysts exhibiting different sizes and solubilities. The dendritic nature (mono- or di-substituted), ending groups (acetonide or hydroxyl groups) and generation effects of these organocatalysts were evaluated in the Michael addition reaction of isobutyraldehyde to N-phenylmaleimide as benchmark reaction, both in solution and under neat reaction conditions. Reaction yields when using 10 mol% of organocatalyst and NaOH as base varied in the range of good to excellent (neat 96%, aqueous solution 98%, CH2Cl2 solvent 80%), while enantioselectivity as high as 81:19 was achieved. The above enantioselectivity is in line with a positive “dendritic effect”. Regarding the influence of terminal groups, it is appreciated that hydroxyl end-groups afford higher yield relative to analogous acetonide terminal groups. Finally, the scope of the reaction was evaluated with catalysts H2N-Phe-N-Bn-β-Ala-TME-d-2G-A and H2N-Phe-N-Bn-β-Ala-TME-d-2G-OH, which could be recovered and recycled for at least three times without significant loss of catalytic activity.

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Acknowledgements

We thank Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico) for financial support via Grants nos. 220945, 130826 and 60366, and postdoctoral fellowship granted to J.M.L. We also thank M.T. Cortez-Picasso, V.M. González-Díaz, and M.L. Rodríguez-Pérez for NMR spectra, and G. Cuéllar-Rivera for MS-TOF analysis.

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Author notes

  1. José M. Landeros and Lydia Suchy contributed equally.

Authors and Affiliations

  1. Departamento de Química, Centro de Investigación y de Estudios Avanzados, Avenida IPN # 2508, 07360, Ciudad de México, México

    José M. Landeros, Lydia Suchy, Claudia G. Ávila-Ortiz & Eusebio Juaristi

  2. Institut für Organische Chemie, Universität Wien, Währinger Strasse 38, 1090, Vienna, Austria

    Lydia Suchy & Nuno Maulide

  3. El Colegio Nacional, Donceles # 104, Centro Histórico, 06020, Ciudad de México, México

    Eusebio Juaristi

Authors
  1. José M. Landeros
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  2. Lydia Suchy
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  3. Claudia G. Ávila-Ortiz
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  4. Nuno Maulide
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  5. Eusebio Juaristi
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Corresponding author

Correspondence to Eusebio Juaristi.

Additional information

Dedicated fondly and with admiration to Heinz Falk for his important contribution to the development of organic chemistry in Austria, on the occasion of his 80th birthday.

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Landeros, J.M., Suchy, L., Ávila-Ortiz, C.G. et al. Dendrimeric α,β-dipeptidic conjugates as organocatalysts in the asymmetric Michael addition reaction of isobutyraldehyde to N-phenylmaleimides. Monatsh Chem 150, 777–788 (2019). https://doi.org/10.1007/s00706-018-2338-0

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  • DOI: https://doi.org/10.1007/s00706-018-2338-0

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