Angewandte
Communications
Chemie
the unstable crude imine 18. Redissolving the imine in
Acknowledgements
dimethylformamide (DMF) and exposure to pyrrolidine
afforded 7 with the desired S-configured C7 stereochemistry
in low yields, but with no trace of the undesired R-configured
diastereomer 19 or 6-endo-trig regioisomers (Table 1,
entry 5). A substantial increase in reaction yield was observed
when using l-proline as the additive (entry 8). Although the
reaction proceeded without preformation of the imine and
with substoichiometric quantities of the amino acid (entry 9),
lower yields led us to use a full equivalent of the additive. The
reaction also proceeded in the presence of both d-proline
(entry 7) and l-phenylalanine (entry 10), albeit in reduced
yields. The tendency of primary and secondary, but not
tertiary, amines to promote the reaction suggests a mechanism
involving matched enamine catalysis rather than simple
deprotonation of the ketone.
To complete the synthesis of lycopalhine A, the newly
formed pyrrolidine was protected by using di-tert-butyl
dicarbonate to yield dicarbamate 20 before oxidizing the
remaining primary alcohol with 2-iodoxybenzoic acid (IBX).
The potentially biomimetic intramolecular aldol reaction to
form 21 occurred quickly and in excellent yield when using
potassium carbonate in methanol.[14] The diastereoselectivity
of the reaction likely reflects a thermodynamic preference of
21 for a b-hydroxyl group positioned on the concave face of
the molecule, away from the congested inner ring system. A
Lemieux–Johnson oxidative cleavage of the olefin followed
by dual deprotection and acid-catalyzed aminal formation
afforded 1.
The spectroscopic data and optical properties of our
synthetic sample were identical in all respects to those
reported for the natural product.[3a] Indeed, an inseparable
side product (epi-1) purified together with lycopalhine A
directly matched an uncharacterized impurity in the spectra
of Zhaoꢀs isolated sample. Two-dimensional NMR spectros-
copy of the mixture[15] identified the minor product as the C16
epimer of lycopalhine A, which likely exists in equilibrium
with the major isomer through a retro-aldol/aldol-type
mechanism. Deuterium exchange of the protons at C6 and
C15 under basic conditions,[16] as well as the presence of
epimers in both the isolated and synthetic samples, suggests
that lycopalhine A exists as a thermodynamic mixture favor-
ing the closed aldol product and lends further credibility to
a spontaneous cyclization in its biosynthesis.
In summary, we have developed an expedient synthesis of
the complex Lycopodium alkaloid lycopalhine A that relies
on two readily available amino acids for its completion. l-
glutamic acid provides an inexpensive chiral entry point that,
to the best of our knowledge, has not been used previously in
the synthesis of fawcettimine-type alkaloids. l-proline pro-
motes a 5-endo-trig intramolecular Mannich cyclization with
an a-unsubstituted aldehyde under mild conditions. We
anticipate that this organocatalytic approach and the scalable
intermediates encountered in the course of this endeavor will
prove valuable for future studies of complex Lycopodium
alkaloids.
We would like to acknowledge the NaturalSciences and
Engineering Research Council of Canada and SFB 749 for
financial support. We thank Fabio Raith for experimental
assistance, and Felix Hartrampf and Nicolas Armanino for
helpful discussions.
Keywords: aldol reaction · amino acids · Lycopodium alkaloids ·
Mannich reaction · total synthesis
How to cite: Angew. Chem. Int. Ed. 2016, 55, 2191–2194
Angew. Chem. 2016, 128, 2231–2234
[1] Recent reviews on the Lycopodium alkaloids: a) W. A. Ayer,
Alkaloids, Vol. 45 (Eds.: G. A. Cordell, A. Brossi), Academic
Press, New York, 1994, p. 233; c) X. Ma, D. R. Gang, Nat. Prod.
Chem. 2012, 309, 1; e) A. Nakayama, M. Kitajima, H. Takayama,
Synlett 2012, 23, 2014; f) P. Siengalewicz, J. Mulzer, U. Rinner in
the Alkaloids: Chemistry and Biology, Vol. 72 (Ed.: H.-J.
Knçlker), Academic Press, New York, 2013, p. 1; g) R. A.
[2] Selected recent syntheses of fawcettimine-type alkaloids: a) X.
Nakayama, N. Kogure, M. Kitajima, H. Takayama, Angew.
e) N. Shimada, Y. Abe, S. Yokoshima, T. Fukuyama, Angew.
h) H. M. Ge, L.-D. Zhang, R. X. Tan, Z.-J. Yao, J. Am. Chem.
Hong, W. Ai, X. Wang, H. Li, X. Lei, Nat. Commun. 2014, 5,
4614; k) B. Hong, H. Li, J. Wu, J. Zhang, X. Lei, Angew. Chem.
[3] Isolation: a) L.-B. Dong, J. Yang, J. He, H.-R. Luo, X.-D. Wu, X.
48, 9038; b) F.-W. Zhao, Q.-Y. Sun, F.-M. Yang, J.-F. Luo, G.-W.
349; c) F.-W. Zhao, Q.-Y. Sun, F.-M. Yang, G.-W. Hu, J.-F. Luo,
d) Y. Hirasawa, A. Astulla, M. Shiro, H. Morita, Tetrahedron
[6] Aza-Cope Mannich reactions: L. E. Overman, M.-A. Kakimoto,
condensations of aldehydes/ketones and primary amines: S.
following Michael addition to iminoesters: R. Grigg, J. Kemp,
Angew. Chem. Int. Ed. 2016, 55, 2191 –2194
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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