Total synthesis of gelsemiol

Article abstract of DOI:10.1002/chem.201203746

Let it grow! The neuritogenic iridoid gelsemiol has been prepared in synthetic form by a radical cascade and skeletal rearrangement. This compound accelerates the differentiation of neurons and growth of neuritis (see scheme). Copyright

Full text of DOI:10.1002/chem.201203746

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DOI: 10.1002/chem.201203746
Total Synthesis of Gelsemiol
Patrick Burch,[a] Massimo Binaghi,[a] Manuel Scherer,[a] Corinna Wentzel,[b]
David Bossert,[a] Luc Eberhardt,[a] Markus Neuburger,[a] Peter Scheiffele,[b] and
Karl Gademann*[a]
The power of natural products in controlling biological
processes on a molecular level renders them ideal starting
points for the discovery of new mechanisms of actions, as
can be exemplified by the successful drugs vancomycin, qui-
nine, and artemisinin.[1] To this end, identifying natural
products that generate a desired phenotype in cell-based
assays and understanding their structure/activity relationship
is essential. In the therapeutic area related to neurodegener-
ative diseases, several natural products inducing (neurito-
genic) or enhancing (neuritotrophic) neurite outgrowth have
been studied for which the mechanism of action remains un-
clear.[2]
of gelsemiol (1) combined with its striking biological activi-
ty, we embarked on a research program directed towards
this natural product target. Herein, we report the first enan-
tioselective total synthesis of gelsemiol (1) and its biological
evaluation.
Although there have been several interesting approaches
reported for the synthesis of related iridoids (e.g., by Grieco
et al.,[6] Mangion and MacMillan,[7] Robertson et al.,[8]
Makama,[9] and Zanoni, Vidari and co-workers[10]), we were
intrigued by the radical cascade/skeletal rearrangement of
Markꢀ et al. on the oxabicycloACHTNUGRTNEUNG
[3.3.0]octanone skeleton.[11]
Modification of the starting materials and elaboration of the
skeleton should result in a straightforward access to gelse-
miol (1). The synthesis started out with a trans-selective hy-
drozirconation of alkyne 2 by using Schwartzꢁs reagent and
PhSeBr to give rise to the stable vinylselenide
3
(Scheme 1).[12–14] Separate preparation of the Schwartzꢁs re-
Interesting biological activity, generally unidentified
mechanisms of action combined with structural complexity
render natural products ideal targets for organic synthesis
combined with biological studies. In the context of our pro-
gram on the synthesis and biological evaluation of neurito-
genic natural products,[3] we became interested in gelsemiol
(1), a C(6), C(11)-oxidized iridoid first isolated from Gelse-
mium sempervirens (Gentianales).[4] A subsequent publica-
tion by Ohizumi and co-workers reported the isolation of 1
from Verbena littoralis (Lamiales) and demonstrated its neu-
ritotrophic properties in the PC-12D cell line in the pres-
ence of nerve-growth factor (NGF).[5] Attracted by the ster-
eochemically complex, densely functionalized architecture
[a] P. Burch,+ M. Binaghi,+ M. Scherer, D. Bossert, Dr. L. Eberhardt,
Dr. M. Neuburger, Prof. Dr. K. Gademann
Department of Chemistry
University of Basel, St. Johanns-Ring 19
4056 Basel (Switzerland)
E-mail: karl.gademann@unibas.ch
[b] C. Wentzel, Prof. Dr. P. Scheiffele
Biozentrum, University of Basel
Klingelbergstrasse 50/70, 4056 Basel (Switzerland)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203746.
Scheme 1. Preparation of intermediate acid 7.
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agent resulted in better yields and stereoselectivity com-
pared with a in situ preparation procedure.[15] The prepara-
tion of bicyclic intermediate 5 proved to be more challeng-
ing than anticipated. We initially attempted to realize the in-
verse electron-demand Diels–Alder reaction (IEDDA) at
ambient pressure and in the presence of a catalytic amount
of the in situ formed CuII–tert-BuBox (Box = bis-oxazoline)
complex, but mostly undesired byproducts were obtained.
Interestingly, conducting the IEEDA reaction under reduced
pressure and under neat conditions led to the bicyclic com-
pound 5 in high yield and with a high enantioselectivity of
92:8 e.r. With 5 in hand, we were able to obtain the rear-
ranged bicyclic lactone 6 in good yield via the radical reac-
tion/skeletal rearrangement sequence developed by Markꢀ
et al.[11]
Figure 1. Assignment of the configuration of compound 7 by X-ray crys-
tal-structure analysis.
the product mixture of 1 and 8 to Raney nickel in the ab-
sence of H2, it was observed that lactol 8 could be oxidized
to lactone 1. We were able to confirm this result by separat-
ing lactol 8 from lactone 1 and by demonstrating that the
lactol 8 itself can be oxidized to gelsemiol (1) by using
Raney nickel in the absence of H2 in EtOH (Scheme 2).
Raney nickel has been frequently utilized in transfer-hydro-
genation reactions,[19] and oxidations of secondary alcohols
to ketones by using Raney nickel are known.[20] To the best
of our knowledge, this example represents the first Raney
nickel mediated oxidation of an activated lactol at room
temperature. The scope and limitations of this method are
currently under investigation. Iridoid 1 can also be obtained
without the formation of the lactol 8 by activation of the
Preparation of bicyclic iodoacid 7 was realized from olefin
6 without purification or isolation of the different intermedi-
ates in a one-pot procedure (Scheme 2). Addition of the bi-
[21]
acid 7 by using the Vilsmeier salt, followed by NaBH4 re-
duction and Raney nickel reduction by using H2. The struc-
ture of 1 was confirmed by comparison of its spectral data
with those reported in the literature.[4,5] Two chemical shift
assignments were corrected, because C(4) and C(9) were
mistakenly assigned. In addition, X-ray diffraction analysis
of the synthetic sample of gelsemiol (1) confirmed its as-
signed structure.
Scheme 2. Two different synthetic approaches to access gelsemiol (1)
from acid 7.
After finding a synthetic route to the natural product se-
cured, we wanted to profile its biological activity in a neu-
rite outgrowth assay by using rat pheochromocytoma
cells.[5,22] In addition, derivatives obtained along the synthe-
sis were subjected to biological evaluation to profile the
pharmacophore. Although for gelsemiol (1) the neuritotro-
phic activity described in the literature could be confirmed
(Figure 2), none of the compounds obtained did induce the
desired phenotype. After reproduction of the reported neu-
ritotrophic activity by using PC-12 cells and NGF as was
shown above, we attempted to find a similar morphological
response by using primary granule cells from mice pups in
combination with brain-derived neurotrophic factor
(BDNF).[23] However, no activity could be observed.
In summary, the first total synthesis of gelsemiol (1) was
accomplished in nine steps and an overall yield of 14%.
Key features of the synthesis involve: 1) a stereoselective in-
verse electron-demand Diels–Alder reaction catalyzed by a
chiral Cu Lewis acid; 2) a radical reaction/skeletal rear-
rangement cascade; and 3) a mild alkylation/iodolactoniza-
tion procedure. A lactol oxidation by Raney nickel was en-
cyclic lactone 6 and trimethylchlorosilane to a solution of in
situ prepared methyl cuprate led the alkylation and opening
of the lactone.[16] Saponification of the mono-ester malonate
moiety under basic conditions was followed by mild pH ad-
justment of the mixture with solid CO2, thereby preventing
decarboxylation of the malonic acid under acid conditions.
In situ iodolactonization[16,17] gave the desired iodocarboxy-
late 7 in 56% yield over three steps. The configuration of
this bicyclic intermediate was confirmed by X-ray crystal-
structure analysis (Figure 1).
Finding an efficient way to reduce the acid 7 became the
most time-consuming part of the synthesis. After screening
multiple reduction reagents, the best yields were obtained
by making a detour via the lactol 8. First, acid 7 was reduced
with an excess of BH3·DMS. After a solvent change from
THF to EtOH, Raney nickel was added, and a hydrogen at-
mosphere applied to remove the benzyl group[18] and the
iodo group,[10] which led to the desired natural product 1
and the lactol 8 in a 4:6 mixture. Interestingly, by exposing
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Chem. Eur. J. 2013, 19, 2589 – 2591

Total Synthesis of Gelsemiol
COMMUNICATION
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Acknowledgements
K.G. is a European Young Investigator (EURYI). We gratefully acknowl-
edge the Swiss National Science Foundation (200021-144028 and PE0022-
117136) and the Latsis foundation for financial support. We thank York
Schramm (Univ. of Basel) for technical assistance with HPLC measure-
ments.
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Keywords: natural products · PC-12 cells · rearrangement ·
synthetic methods · total synthesis
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Received: October 19, 2012
Published online: January 10, 2013
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