Abstract
l-arginine is often covalently linked to vectors for gene or drug delivery as a means of increasing their transfection activity and reducing toxicity. This strategy relies on the protection of basic nitrogen atoms, for example, by employing the tert-butoxycarbonyl group. Our aim in the present work was to prepare the widely described α N, ω N, ω′ N-tris(tert-butyloxycarbonyl)-l-arginine as a single isomer in high yield and with high levels of purity for use in the esterification of dendrimers with several peripheral hydroxyl groups. Following three reported protocols which assured this goal, we observed the unexpected formation of four additional isomers. Using the first procedure, α N, ω N, ω′ N-tris(tert-butyloxycarbonyl)-l-arginine was never obtained. The second procedure delivered the desired compound as a mixture of geometric isomers (E/Z), while the third protocol led to a single isomer in high yield and purity, but with an unreported symmetrical structure. Since Boc protection is transient, this discovery would seem to be of little interest, but preliminary results from an ongoing investigation of the behavior of each of the isomers obtained in the esterification reactions of interest has shown that their reactivity depends on their structure. Although this research is ongoing, here we report a detailed description of these unexpected results, along with an NMR investigation focusing on the double-bond geometry and position which enabled confirmation of the structures.
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A.A. Reyes, M.L. Purkerson, I. Karl, S. Klahr, Am. J. Kidney Dis. 20, 168 (1999). https://doi.org/10.1016/S0272-6386(12)80546-4
A. Amore, B. Gianoglio, D. Ghigo, L. Peruzzi, M.G. Porcellini, F. Bussolino, C. Costamagna, G. Cacace, G. Picciotto, G. Mazzucco et al., Kidney Int. 47, 1507 (1995). https://doi.org/10.1038/ki.1995.213
I. Nakase, H. Akita, K. Kogure, A. Gräslund, Ü. Langel, H. Harashima, S. Futaki, Acc. Chem. Res. 45, 1132 (2012). https://doi.org/10.1021/ar200256e
I. Nakase, G. Tanaka, S. Futaki, Mol. Biosyst. 9, 855 (2013). https://doi.org/10.1039/c2mb25467k
C. Liu, X. Liu, P. Rocchi, F. Qu, J.L. Iovanna, L. Peng, Bioconjug. Chem. 25, 521 (2014). https://doi.org/10.1021/bc4005156
X. Liu, C. Liu, J. Zhou, C. Chen, F. Qu, J.J. Rossi, P. Rocchi, L. Peng, Nanoscale 7, 3867 (2015). https://doi.org/10.1039/c4nr04759a
J.B. Kim, J.S. Choi, K. Nam, M. Lee, J.S. Park, J.K. Lee, J. Control. Release 114, 110 (2006). https://doi.org/10.1016/j.jconrel.2006.05.011
T. Kim, C.Z. Bai, K. Nam, J. Park, J. Control. Release 136, 132 (2009). https://doi.org/10.1016/j.jconrel.2009.01.028
Q. Peng, J. Zhu, Y. Yu, L. Hoffman, X. Yang, J. Biomater. Sci. Polym. Ed. 26, 1163 (2015). https://doi.org/10.1080/09205063.2015.1080482
S. Alfei, S. Castellaro, G. B. Taptue, Org. Commun. 10, 144 (2017). http://doi.org/10.25135/acg.oc.22.17.07.034
S. Alfei, S. Castellaro, Macromol. Res. 25 (2017). https://doi.org/10.1007/s13233-017-5160-3
H. Konno, K. Kubo, H. Makabe, E. Toshiro, N. Hinoda, K. Nosakaa, K. Akaji, Tetrahedron 63, 9502 (2007). https://doi.org/10.1016/j.tet.2007.06.082
F. Prati, A. Goldman-Pinkovich, F. Lizzi, F. Belluti, R. Koren et al., PLoS ONE 9, 107994 (2014). https://doi.org/10.1371/journal.pone.0107994.g005
M. Shuai, X. Zengping, H. Ge, Z. Lihui, Z. Zhanjuan, G. Jianghong, J. Haiying, L. Tianjun, Eur. J. Med. Chem. 92, 35 (2015). https://doi.org/10.1016/j.ejmech.2014.12.029
J. Izdebski, T. Gers, D. Kunce, P. Markovsky, J. Pept. Sci. 11, 60 (2005). https://doi.org/10.1002/psc.585
M.A. Jones, A.D. Hislop, J.S. Snaith, Org. Biomol. Chem. 4, 3769 (2006). https://doi.org/10.1039/b611170j
O. Keller, W.E. Keller, G. Van Look, G. Wersin, Org. Synth. 63, 160 (1985). https://doi.org/10.15227/orgsyn.063.0160
F. Jahani, M. Tajbakhsh, S. Khaksar, M. Reza, Azizi. Monatsh. Chem. 142, 1035 (2011). https://doi.org/10.1007/s00706-011-0534-2
V.F. Pozdnev, Int. J. Pept. Protein Res. 44, 36 (1994). https://doi.org/10.1111/j.1399-3011.1994.tb00402.x
Ø. Jacobsen, H. Maekawa, N.-H. Ge, C.H. Görbitz, P. Rongved, O.P. Ottersen, M.R. Amiry-Moghaddam, J. Klaveness, J. Org. Chem. 76, 1228 (2011). https://doi.org/10.1021/jo101670a
J. Hlavacek, J. Pıcha, V. Vanek, J. Jiracek, J. Slaninova, V. Fucık, M. Budesınsky, D. Gilner, R.C. Holz, Aminoacid 38, 1155 (2010). https://doi.org/10.1007/s00726-009-0326-8
K. Feichtinger, C. Zapf, H.L. Sings, M. Goodman, J. Org. Chem. 63, 3804 (1998). https://doi.org/10.1021/jo980425s
V.F. Pozdnev, Bioorg. Khim. 12, 1013 (1986)
E. Schnabel, Liebigs Ann. Chem. 702, 188 (1967). https://doi.org/10.1002/jlac.19677020123
X. Fang, J. Mao, R.M. Cory, D.M. McKnightc, K. Schmidt-Rohra, Magn. Reson. Chem. 49, 755 (2011). https://doi.org/10.1002/mrc.2816
S. Fenner, Z.E. Wilson, S.V. Ley, Chem. Eur. J. 22, 15902 (2016). https://doi.org/10.1002/chem.201603157
L. Zservas, M. Winitz, J.P. Greenstein, J. Org. Chem. 22, 1515 (1957). https://doi.org/10.1021/jo01362a052
L. Zservas, T.T. Otani, M. Vinitz, J.P. Greenstein, J. Am. Chem. Soc. 81, 2878 (1959). https://doi.org/10.1021/ja01520a064
A.J. Rosenberg, D.A. Clark, Org. Lett. 14, 4678 (2012). https://doi.org/10.1021/ol3021226
A.N. Chulin, I.L. Rodionov, L.K. Baidakova, L.N. Rodionova, T.A. Balashova, V.T. Ivanov, J. Pept. Sci. 11, 175 (2005). https://doi.org/10.1002/psc.611
R.M. Lanigan, P. Starkov, T.D. Sheppard, J. Org. Chem. 78, 4512 (2013). https://doi.org/10.1021/jo400509n
Acknowledgements
This work was financially supported by University of Genoa (Progetti di Ricerca di Ateneo). The authors wish to thank Dr Gaby Brice Taptue for language assistance and Mr Gagliardo Osvaldo for elemental analysis. A special thanks to Professor Andrea Spallarossa for calculating the energies of the tautomers and rotamers, contributing to the realization of Figs. S27 and S28 in the Online Resource, and providing professional advice.
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Alfei, S., Castellaro, S. N,N,N-Tris(tert-butoxycarbonyl)-l-arginine: five isoforms whose obtainment depends on procedure and scrupulous NMR confirmation of their structures. Res Chem Intermed 44, 1811–1832 (2018). https://doi.org/10.1007/s11164-017-3199-6
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DOI: https://doi.org/10.1007/s11164-017-3199-6