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. 2016 Aug 31;21(9):1140.
doi: 10.3390/molecules21091140.

Practical and Efficient Synthesis of α-Aminophosphonic Acids Containing 1,2,3,4-Tetrahydroquinoline or 1,2,3,4-Tetrahydroisoquinoline Heterocycles

Mario Ordóñez  1 , Alicia Arizpe  2 , Fracisco J Sayago  3 , Ana I Jiménez  4 , Carlos Cativiela  5
Affiliations

Practical and Efficient Synthesis of α-Aminophosphonic Acids Containing 1,2,3,4-Tetrahydroquinoline or 1,2,3,4-Tetrahydroisoquinoline Heterocycles

Mario Ordóñez et al. Molecules. .

Abstract

We report here a practical and efficient synthesis of α-aminophosphonic acid incorporated into 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline heterocycles, which could be considered to be conformationally constrained analogues of pipecolic acid. The principal contribution of this synthesis is the introduction of the phosphonate group in the N-acyliminium ion intermediates, obtained from activation of the quinoline and isoquinoline heterocycles or from the appropriate δ-lactam with benzyl chloroformate. Finally, the hydrolysis of phosphonate moiety with simultaneous cleavage of the carbamate afforded the target compounds.

Keywords: N-acyliminium ions; conformationally constrained; α-aminophosphonic acids.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
α-Amino acids characterized by a tetrahydroquinoline or tetrahydroisoquinoline heterocyles and their α-amino phosphonic analogues.
Scheme 1
Scheme 1
Synthesis of 1,2,3,4-tetrahydroquinoline-2-phosphonic acid 4 from lactam 7.
Scheme 2
Scheme 2
Synthesis of 1,2,3,4-tetrahydroquinoline-2-phosphonic acid 4 from quinoline.
Scheme 3
Scheme 3
First attempt to synthetize 1,2,3,4-tetrahydroisoquinoline-1-phosphonic acids derivatives.
Scheme 4
Scheme 4
Synthesis of 1,2,3,4-tetrahydroisoquinoline-1-phosphonic acid 5 from isoquinoline.
Scheme 5
Scheme 5
Synthesis of 1,2,3,4-tetrahydroisoquinoline-3-phosphonic acid, TicP 6.
See this image and copyright information in PMC

References

    1. Ko E., Liu J., Perez L.M., Lu G., Schaefer A., Burgess K. Universal peptidomimetics. J. Am. Chem. Soc. 2011;133:462–477. doi: 10.1021/ja1071916. - DOI - PMC - PubMed
    1. Hruby V.J. Designing peptide receptor agonists and antagonists. Nat. Rev. Drug. Discov. 2002;1:847–858. doi: 10.1038/nrd939. - DOI - PubMed
    1. Brindisi M., Butini S., Franceschini S., Brogi S., Trotta F., Ros S., Cagnotto A., Salmona M., Casagni A., Andreassi M., et al. Targeting Dopamine D3 and Serotonin 5-HT1A and 5-HT2A Receptors for developing effective antipsychotics: Synthesis, biological characterization, and behavioral studies. J. Med. Chem. 2014;57:9578–9597. doi: 10.1021/jm501119j. - DOI - PubMed
    1. Mitsunaga S., Ohbayashi T., Sugiyama S., Saitou T., Tadokoro M., Satoh T. Asymmetric synthesis of cyclic α-amino acid derivatives by the intramolecular reaction of magnesium carbenoid with an N-magnesio arylamine. Tetrahedron: Asymmetry. 2009;20:1697–1708. doi: 10.1016/j.tetasy.2009.06.024. - DOI
    1. Kurata K., Inoue K., Nishimura K., Hoshiya N., Kawai N., Uenishi J. Synthesis of optically pure (R)- and (S)-tetrahydroisoquinoline-1- and -3-carboxylic acids. Synthesis. 2015;47:1238–1244.

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