Communications
doi.org/10.1002/ejoc.202100160
[7] P. M. S. D. Cal, J. B. Vicente, E. Pires, A. V. Coelho, L. F. Veiros, C. Cordeiro,
their versatile conjugation to virtually any type of protein
ligands (e.g. small organic molecules, peptides and peptidomi-
metics), aiming at the reversible-covalent engagement of Lys ɛ-
amino groups on the targeted protein.
1
2
3
4
5
6
7
8
9
[8] G. Akçay, M. A. Belmonte, B. Aquila, C. Chuaqui, A. W. Hird, M. L. Lamb,
[9] Figure 1B: Protein: BIR domain of melanoma inhibitor of apoptosis (ML–
IAP), Protein Data Bank (PDB): 3F7G, see: a) F. Cohen, B. Alicke, L. O.
Elliott, J. A. Flygare, T. Goncharov, S. F. Keteltas, M. C. Franklin, S.
Frankovitz, J. P. Stephan, V. Tsui, D. Vucic, H. Wong, W. J. Fairbrother, J.
1 L5G, see: b) J.-P. Xiong, T. Stehle, R. Zhang, A. Joachimiak, M. Frech,
Protein: type 1 interleukin-1 receptor, PDB: 1G0Y, see: c) G. P. Vigers,
36927–36933; Figure 1E: Protein: Histone-binding protein RBBP4, PDB:
6ZRD, see: d) P. Hart, P. Hommen, A. Noisier, A. Krzyzanowski, D. Schüler,
A. T. Porfetye, M. Akbarzadeh, I. R. Vetter, H. Adihou, H. Waldmann,
Experimental Section
The synthetic procedures for the preparation of compounds 1–4
1
are reported in the Supporting Information, along with the H- and
13C-NMR spectra, and MS spectrometry data.
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Acknowledgements
[10] A. Dal Corso, M. Catalano, A. Schmid, J. Scheuermann, D. Neri, Angew.
17428. This work includes a comparative analysis of the reactivity of
different benzaldehyde derivatives (including 2-formyl-phenylboronic
acid and 2HB) towards imine bond formation with Nα-acetyl-lysine in
aqueous buffer at pH 7.4. 1H NMR spectra were recorded to quantify
the percentage of hydration product and/or imine formation, leading to
the calculation of dissociation constants and to a final ranking of the
intrinsic aldehyde reactivity.
[11] The 2HB fragment is also installed in the drug voxelotor (Oxbryta™,
recently approved for the treatment of sickle cell disease), which
prevents the polymerization of mutant hemoglobin (HbS) by forming
an imine bond between 2HB and the amino group of an N-terminal
valine residue, see: B. Metcalf, C. Chuang, K. Dufu, M. P. Patel, A. Silva-
Garcia, C. Johnson, Q. Lu, J. R. Partridge, L. Patskovska, Y. Patskovsky,
S. C. Almo, M. P. Jacobson, L. Hua, Q. Xu, S. L. Gwaltney, C. Yee, J. Harris,
B. P. Morgan, J. James, D. Xu, A. Hutchaleelaha, K. Paulvannan, D.
[12] a) E. C. Dreaden, S. C. Mwakwari, Q. H. Sodji, A. K. Oyelere, M. A. El-
[14] T. V. Hansen, L. Skattebøl, Org. Synth. 2005, 82, 64–68.
[15] While the terminal alkyne group is mainly used in copper-catalyzed
Huisgen cycloadditions (see: E. Lallana, R. Riguera, E. Fernandez, Angew.
Chem. Int. Ed. 2011, 50, 8794–8804; Angew. Chem. 2011, 123, 8956–
Giovanni Sacco thanks the University of Milan for a PhD fellow-
ship, Simon Stammwitz (Leibniz Universität Hannover, DE) thanks
the European Union for an Erasmus+ fellowship. We also
gratefully acknowledge Ministero dell’Università e della Ricerca
(PRIN 2015 project 20157WW5EH) for financial support.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Aldehydes · Conjugation · Regioselectivity · Schiff
bases · Skattebøl formylation
[2] a) V. Bandlow, S. Liese, D. Lauster, K. Ludwig, R. R. Netz, A. Herrmann, O.
Dal Corso, D. Arosio, L. Belvisi, M. Paolillo, L. Pignataro, C. Gennari, Org.
Arosio, L. Belvisi, L. Pignataro, M. Caruso, C. Gennari, Chem. Eur. J. 2017,
23, 14410–14415; d) A. Pina, M. Kadri, D. Arosio, A. Dal Corso, J. Coll, C.
13421; Angew. Chem. 2016, 128, 13606–13619.
8966), azides have been exploited for
a wider range of ligation
protocols, see: a) B. L. Oliveira, Z. Guo, G. J. L. Bernardes, Chem. Soc. Rev.
[16] Y. Aeschi, S. Drayss-Orth, M. Valášek, F. Raps, D. Häussinger, M. Mayor,
Eur. J. Org. Chem. 2017, 28, 4091–4103.
[17] A. P. Crew, K. Raina, H. Dong, Y. Qian, J. Wang, D. Vigil, Y. V. Serebrenik,
B. D. Hamman, A. Morgan, C. Ferraro, K. Siu, T. K. Neklesa, J. D. Winkler,
[18] The formation of stable imine bonds with 2HB derivatives has been
used for polymer design, see: J. Huang, H. Zhu, H. Liang, J. Lu, Polym.
[19] Semipreparative RP-HPLC with water/acetonitrile mixtures in the
presence of TFA also failed to afford the monomeric product 4. After
liophilization of the eluted fraction, the oligomer 17 was obtained
instead.
[6] a) S. R. Adusumalli, D. G. Rawale, U. Singh, P. Tripathi, R. Paul, N. Kalra,
b) S. R. Adusumalli, D. G. Rawale, K. Thakur, L. Purushottam, N. C. Reddy,
Cossar, L. M. Levy, S. Hristeva, T. Genski, T. Hoffmann, L. Brunsveld, D.
K. V. Gothelf, Angew. Chem. Int. Ed. 2021, 60, 6539–6544; Angew. Chem.
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Manuscript received: February 9, 2021
Revised manuscript received: February 25, 2021
Accepted manuscript online: February 26, 2021
Eur. J. Org. Chem. 2021, 1763–1767
1767
© 2021 Wiley-VCH GmbH