G
S. Clementson et al.
Account
Synlett
enolate coupling partners24 were surveyed, most of which
necessitated strongly basic conditions and led to deteriora-
tion of the starting material. After considerable optimiza-
tion, we realized that we could modify the base-free, decar-
boxylative -cyanation chemistry developed by the Liu
group25 and translate it to our alkenyl triflate. The formed
nitrile could then be telescoped to target natural product 1,
by adding aqueous HCl in methanol.26
The results summarized in this Account represents our
successful endeavor in the development of a divergent, en-
antioselective synthetic route to the alkenoid family of non-
aromatic Erythrina alkaloids and the first total synthesis of
(+)-DHE (1). Although the generalization of our approach
is yet to be tested, our desire to construct the D-ring at a
late stage and install the quaternary (-tertiary amine) ste-
reocenter at an early stage, was achieved and we aim to ex-
plore this divergency in the synthesis of more Erythrina al-
kaloids.
Tetrahedron Lett. 2001, 42, 8003. (d) Funk, R. L.; Belmar, J. Tetra-
hedron Lett. 2012, 53, 176. (e) Jepsen, T. H.; Glibstrup, E.;
Crestey, F.; Jensen, A. A.; Kristensen, J. L. Beilstein J. Org. Chem.
2017, 13, 988. (f) Jepsen, T. H.; Jensen, A. A.; Lund, M. H.;
Glibstrup, E.; Kristensen, J. L. ACS Med. Chem. Lett. 2014, 5, 766.
(g) Chuang, K. V.; Navarro, R.; Reisman, S. E. Chem. Sci. 2011, 2,
1086. (h) Blackham, E. E.; Booker-Milburn, K. I. Angew. Chem.
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(5) Ocampo, R.; Dolbier, W. R. Jr. Tetrahedron 2004, 60, 9325.
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953.
3 Conclusion
(12) Corey, E. J.; Kang, M.; Desai, M. C.; Ghosh, A. K.; Houpis, I. N.
J. Am. Chem. Soc. 1988, 110, 649.
(13) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H.;
Schrodi, Y. Org. Lett. 2007, 9, 1589.
(14) (a) Gansäuer, A.; Lauterbach, T.; Narayan, S. Angew. Chem. Int.
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(15) McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc. 1974, 96, 4708.
(16) Lo, J. C.; Kim, D.; Pan, C.-M.; Edwards, J. T.; Yabe, Y.; Gui, J.; Qin,
T.; Gutiérrez, S.; Giacoboni, J.; Smith, M. W.; Holland, P. L.;
Baran, P. S. J. Am. Chem. Soc. 2017, 139, 2484.
We have developed a new divergent total synthesis of
(+)-DHE (1) that installs the quaternary stereo center via a
catalytic asymmetric allylic alkylation. A key bicyclic inter-
mediate was accessed via a ring-closing metathesis which
eventually was transformed into the desired natural prod-
uct via a key decarboxylative -cyanation. Several interme-
diates in this sequence will serve as a flexible starting point
for future explorations of the structure–activity relation-
ships of DHE and related Erythrina alkaloids.
(17) Trost, B. M.; Haffner, C. D.; Jebaratnam, D. J.; Krische, M. J.;
Thomas, A. P. J. Am. Chem. Soc. 1999, 121, 6183.
(18) Liu, R.; Winston-McPherson, G. N.; Yang, Z.; Zhou, X.; Song, W.;
Guzei, I. A.; Xu, X.; Tang, W. J. Am. Chem. Soc. 2013, 135, 8201.
(19) Pappo, R.; Allen, D. S.; Lemieux, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478.
Funding Information
We are grateful to the Innovationsfonden (Innovation Fund Denmark,
Grant No. 7038-00149B) for generous support of this project.
I
n
n
o
v
ati
o
nsf
o
n
d
e
n
(7
0
3
8-0
0
1
4
9
B)
(20) (a) Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971, 36,
1379. (b) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1982, 47,
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Acknowledgment
(21) (a) Trost, B. M.; Scḧaffner, B.; Osipov, M.; Wilton, D. A. A. Angew.
Chem. Int. Ed. 2011, 50, 3548. (b) Trost, B. M.; Crawley, M. L.
Chem. Rev. 2003, 103, 2921.
(22) Behera, T. K.; Jarhad, D. B.; Mobin, S. M.; Singh, V. Tetrahedron
2016, 72, 5377.
We would like to gratefully acknowledge Dr. Henrik Pedersen for ana-
lytical assistance throughout this project. We would also like to thank
Emil M̈archer-Rørsted and the Medicinal Chemistry department at H.
Lundbeck A/S for valuable inputs and feedback.
(23) Hoffmann, R. W. Pure Appl. Chem. 1988, 60, 123.
(24) (a) Kuwajima, I.; Urabe, H. J. Am. Chem. Soc. 1982, 104, 6831.
(b) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7996. (c) Carfagna, C.; Musco, A.; Saliese, G. J. Org. Chem. 1991,
56, 261. (d) Jørgensen, M.; Lee, S.; Liu, X.; Wolkowski, J. P.;
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 12557.
References
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