D
K. Dong
Letter
Synlett
resulted amino group was further exposed to benzyl chloro-
formate to give the key precursor 1 in 72% yield. Finally, ex-
posure of compound 1 to palladium on carbon and hydro-
gen led to cleavage of benzyl and benzoxycarbonyl simulta-
neously, and the resulted amine could be mesylated to
generate kukoamine B bimesylate through acidification
with methanesulfonic acid quantitively in one pot. Notably,
all the manipulation could be carried out successfully at a
kilogram scale.
In summary, we have developed an efficient strategy to
accomplish the total synthesis of kukoamine B bimethylate
from 1,4-diaminobutane dihydrochloride in 12 steps with a
11.4% overall yield, and all the steps could be carried out at
a kilogram scale.16 The chemoselective protection of the
amino groups and the use of the cyano groups as the pre-
cursor of the amino groups were served as the key reac-
tions to avoid the competitive reaction delicately. The aza-
Michael addition reaction, amidation and hydrogenation of
the cyano group sequence could be streamlined as a general
approach towards the synthesis of polyamine structures.
The kukoamine B bimesylate exhibited better solubility in
water and could be served as a valuable drug candidate. The
further exploration of the pharmacological activities of
kukoamine B bimesylate and its analogues is underway in
our lab.
(3) Hu, X.; Gao, L.; Niu, Y.; Tian, X.; Wang, J.; Meng, W.; Zhang, Q.;
Cui, C.; Han, L.; Zhao, Q. Biochim. Biophys. Acta 2015, 1850, 287.
(4) Hadjipavlou-Litina, D.; Garnelis, T.; Athanassopoulos, C. M.;
Papaioannou, D. J. Enzyme Inhib. Med. Chem. 2009, 24, 1188.
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1529.
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2015, 9, 725.
(7) Hu, X. L.; Guo, L. P.; Song, Q.; Zhang, Q.; Chen, Y.; Wang, J.;
Meng, W. H.; Zhao, Q. C. Neurochem. Int. 2015, 87, 66.
(8) Hu, X. L.; Niu, Y. X.; Zhang, Q.; Tian, X.; Gao, L. Y.; Guo, L. P.;
Meng, W. H.; Zhao, Q. C. Environ. Toxicol. Pharmacol. 2015, 40,
230.
(9) Zheng, X.; Wang, N.; Yang, Y.; Chen, Y.; Liu, X.; Zheng, J. RSC Adv.
2016, 6, 85756.
(10) Chantrapromma, K.; Ganem, B. Tetrahedron Lett. 1985, 22, 23.
(11) Moriwake, T.; Saito, S.; Tamai, H.; Mitsuda, H.; Inaba, M. Hetero-
cycles 1985, 23, 277.
(12) Zhang, Q.; Xu, Y.; Zhang, H.; Zhang, H.; Liu, J.; Zhan, Y.; Yiu, Y.;
Chi, M.; Tian, Y.; Ao, J.; Liu, D. CN105906525, 2016.
(13) Das, S.; Lee, B. H.; Linstadt, R. T. H.; Cunha, K.; Li, Y.; Kaufman,
Y.; Levine, Z.; Lipshutz, A. B. H. R.; Lins, D.; Shea, J.-E.; Heeger, A.
J.; Ahn, B. K. Nano. Lett. 2016, 16, 6709.
(14) Corcé , V.; Morin, E.; Guihé neuf, S.; Renault, E.; Renaud, S.;
Cannie, I.; Tripier, R.; Lima, L. M.; Julienne, P. K.; Gouin, S. G.;
Loré al, O.; Deniaud, D.; Gaboriau, F. Bioconjugate Chem. 2012,
23, 1952.
(15) Gardner, R. A.; Kinkade, R.; Wang, C.; Phanstiel, O. IV. J. Org.
Chem. 2004, 69, 3530.
(16) General Procedure
To a solution of compound 1 (48.2 g, 0.04 mol) in THF (30 mL)
was added methanol (700 mL) and methanesulfonic acid (5.9
mL, 0.09 mol). Then, palladium on carbon (4.8 g) was added to
the mixture carefully. Air in the flask was exhausted, and the
mixture was stirred at ambient temperature for 15 h under
hydrogen atmosphere. TLC showed that all the starting materi-
Acknowledgment
The authors are grateful to the Key Technology R&D Program of
Tianjin (14ZCZDSY00003). We are grateful to Prof. Ying-Chun Cheng,
Sichuan University, for his helpful guidance in the preparation of the
manuscript.
als were consumed (n-BuOH/H2O/HOAc
= 4:1:1, UV), the
mixture was filtered, and the was residue washed with THF. The
filtrate was collected, and the solvent was removed in vacuum
to give kukoamine B bimesylate (16.1 g, 73%) as white solid. 1H
NMR (400 MHz, D2O): δ = 6.84–6.80 (m, 2 H), 6.75 (m, 2 H),
6.67–6.66 (m, 2 H), 3.39–3.34 (m, 2 H), 3.27–3.15 (m, 4 H),
2.91–2.79 (m, 2 H), 2.79 (m, 4 H), 2.79 (s, 6 H), 2.75–2.71 (m, 2
H), 2.66 (m, 2 H), 2.53 (m, 4 H), 1.82 (t, J = 6.8Hz, 2 H), 1.69 (t, J =
6.8 Hz, 2 H), 1.46 (m, 2 H), 1.34 (m, 2 H). 13C NMR (100 MHz,
D2O): δ = 178.5, 178.3, 146.2, 146.1, 144.6, 135.8, 135.6, 135.2,
123.1, 123.0, 118.7, 118.5, 118.4, 49.9, 49.4, 46.8, 44.9, 40.7,
39.1, 39.0, 37.8, 36.3, 33.0, 32.7, 27.8, 27.3, 27.2, 25.1. ESI-
Supporting Information
Supporting information for this article is available online at
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References and Notes
(1) Funayama, S.; Yoshida, K.; Konno, C.; Hikino, H. Tetrahedron Lett.
1980, 21, 1355.
(2) Zhang, Y.; Gao, L.; Cheng, Z.; Cai, J.; Niu, Y.; Meng, W.; Zhao, Q.
Neurotoxic. Res. 2017, 31, 259.
HRMS: m/z calcd for
C28H42N4O6 + H: 531.3183; found:
531.3185.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D