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. 2018 Nov 9;3(11):15182-15192.
doi: 10.1021/acsomega.8b01752. eCollection 2018 Nov 30.

Versatile Synthetic Approach for Selective Diversification of Bicyclic Aza-Diketopiperazines

Florent Péron  1 , Stéphanie Riché  1 , Brigitte Lesur  2 , Marcel Hibert  1 , Philippe Breton  2 , Jean-Marie Fourquez  2 , Nicolas Girard  1 , Dominique Bonnet  1
Affiliations

Versatile Synthetic Approach for Selective Diversification of Bicyclic Aza-Diketopiperazines

Florent Péron et al. ACS Omega. .

Abstract

Herein, we report a convenient synthesis of unprecedented aza-diketopiperazines (aza-DKPs). The strategy is based on selective diversification of bicyclic aza-DKP scaffolds by click reaction, N-acylation, and/or N-alkylation. These scaffolds containing either azido or amino groups were obtained by a key Rh(I)-catalyzed hydroformylative cyclohydrocarbonylation reaction of allyl-substituted aza-DKP. The methodology is readily amenable to the parallel synthesis of original aza-DKPs to enlarge the chemical diversity of aza-heterocycles.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
General structure of novel bicyclic aza-DKPs and selected examples of known biologically active 2,5-DKPs.
Figure 2
Figure 2
Design of aza-DKP scaffolds 5 and 8 ready to functionalize.
Scheme 1
Scheme 1. Preparation of Aza-DKP Scaffolds 5 and 8
Scheme 2
Scheme 2. Synthesis of Dehydroalanine-Containing Aza-DKP 9 from Aza-DKP 5 and 6
Scheme 3
Scheme 3. Functionalization of Aza-DKP Scaffold 8
Scheme 4
Scheme 4. Access to Disubstituted Aza-DKPs by N-Alkylation of Scaffold 11a
See this image and copyright information in PMC

References

    1. Stockwell B. R. Exploring biology with small organic molecules. Nature 2004, 432, 846–854. 10.1038/nature03196. - DOI - PMC - PubMed
    1. Lovering F.; Bikker J.; Humblet C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 2009, 52, 6752–6756. 10.1021/jm901241e. - DOI - PubMed
    1. Borthwick A. D. 2,5-Diketopiperazines: synthesis, reactions, medicinal chemistry, and bioactive natural products. Chem. Rev. 2012, 112, 3641–3716. 10.1021/cr200398y. - DOI - PubMed
    1. Hoffman R. V.; Nayyar N. Reaction of hydrazines with.alpha.-lactams for the preparation of 1,2,4-triazine-3,6-diones and aza-urea peptide mimetics. J. Org. Chem. 1995, 60, 5992–5994. 10.1021/jo00123a048. - DOI
    2. Hoffman R. V.; Reddy M. M.; Klumas C. M.; Cervantes-Lee F. The reactions of hydrazines with α-lactams. Regiochemistry of hydrazine addition and subsequent ring closure to N-aminohydantoins or 1,2,4-triazine-3,6-diones. J. Org. Chem. 1998, 63, 9128–9130. 10.1021/jo981650c. - DOI
    1. Obreza A.; Urleb U. A two-step synthesis of hexahydropyrrolo-[1,2-d][1,2,4]triazine-1,4-dione and related compounds. Synth. Commun. 2003, 33, 1011–1018. 10.1081/SCC-120016366. - DOI