Organic Letters
Letter
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cytotoxic haouamines. For example, the mechanism of action
of the ecteinascidin34 and anthramycin35 anticancer agents
involves closely related iminium ions that alkylate guanine
residues on DNA.36 We plan to further investigate this
mechanistic hypothesis after completion of the total synthesis
of haouamine A using a slightly modified synthetic end game.
(18) For a similar argumentation in a retrosynthetic approach
toward the [9]paracyclophane pondaplin, see: Leonard, M. S.;
ASSOCIATED CONTENT
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Carroll, P. J.; Joullie, M. M. J. Org. Chem. 2004, 69, 2526.
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(19) Cao, L. Ph.D. dissertation, University of Pittsburgh, 2018.
(20) Bongers, A.; Clavette, C.; Gan, W.; Gorelsky, S. I.; Betit, L.;
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S
* Supporting Information
The Supporting Information is available free of charge on the
Experimental details and H and 13C NMR spectra for
new synthetic intermediates and products (PDF)
1
Accession Codes
(23) Gawley, R. E. Org. React. 1988, 35, 1.
(24) Luh, T. Y.; Chow, H. F.; Leung, W. Y.; Tam, S. W. Tetrahedron
1985, 41, 519.
(25) MacPhillamy, H. B.; Dziemian, R. L.; Lucas, R. A.; Kuehne, M.
E. J. Am. Chem. Soc. 1958, 80, 2172.
(26) Reeves, J. T.; Tan, Z.; Marsini, M. A.; Han, Z. S.; Xu, Y.;
Reeves, D. C.; Lee, H.; Lu, B. Z.; Senanayake, C. H. Adv. Synth. Catal.
2013, 355, 47.
CCDC 1888421 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(27) Nagashima, H. Synlett 2015, 26, 866.
AUTHOR INFORMATION
(28) Ribe, S.; Wipf, P. Chem. Commun. 2001, 299, 299.
(29) Bradshaw, B.; Etxebarria-Jardi, G.; Bonjoch, J. Org. Biomol.
Chem. 2008, 6, 772.
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Corresponding Author
ORCID
(30) In our model system,11 aromatization of the E-ring was
achieved by epoxidation of the cyclohexene moiety, epoxide opening
under mild acidic conditions, oxidation of the allylic alcohol, and
elimination. However, in the current approach toward the complete
polycyclic system of haouamine A, the tertiary amine present in the C-
ring led to the formation of N-oxide and decomposition products
under a variety of conditions. In order to bypass this problem, we
attempted several alternatives, including the epoxidation of the E-ring
cyclohexene with a lactam present in the C-ring, which allowed for a
repeat of the conditions from the model sequence, and successful
aromatization. However, we were subsequently unable to reduce the
amide to the desired allylic amine due to the extreme steric shielding
in the C-ring after formation of the 3-aza[7]paracyclophane.19
(31) Grob, C. A. Angew. Chem., Int. Ed. Engl. 1969, 8, 535.
(32) Liu, X.; Tang, M.; Wang, L.; Chao, R. Rapid Commun. Mass
Spectrom. 2016, 30, 161.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by DOD Award W81XWH-
15-PCRP-IA. We thank D. Crocker (University of Pittsburgh)
for technical assistance in the preparation of the Supporting
Information.
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