Angewandte
Chemie
DOI: 10.1002/anie.201411618
Total Synthesis
trans-Hydrogenation: Application to a Concise and Scalable Synthesis
of Brefeldin A**
Michael Fuchs and Alois Fꢀrstner*
Abstract: The important biochemical probe molecule brefel-
din A (1) has served as an inspirational target in the past, but
none of the many routes has actually delivered more than just
a few milligrams of product, where documented. The approach
described herein is clearly more efficient; it hinges upon the
first implementation of ruthenium-catalyzed trans-hydrogena-
tion in natural products total synthesis. Because this unortho-
dox reaction is selective for the triple bond and does not touch
the transannular alkene or the lactone site of the cycloalkyne, it
outperforms the classical Birch-type reduction that could not
be applied at such a late stage. Other key steps en route to
1 comprise an iron-catalyzed reductive formation of a non-
terminal alkyne, an asymmetric propiolate carbonyl addition
mediated by a bulky amino alcohol, and a macrocyclization by
ring-closing alkyne metathesis catalyzed by a molybdenum
alkylidyne.
constituents into the endoplasmatic reticulum. This massive
but reversible morphological change is caused by binding of
1 to a protein complex consisting of a catalytic guanine
exchange factor (GEF) and the small G protein adenosine
ribosylation factor 1 (ARF1), which exerts key regulatory
functions for vesicle budding and transport.[3,4] Two inde-
pendent crystal structures showed that 1 inserts in a wedge-
like manner at the interface of these proteins and thereby
brings the GDP/GTP exchange critical for the proper
functioning of the ARF1 GTPase to a halt.[5]
Equally rich is the synthetic record of brefeldin. More
than 40 different strategies in pursuit of 1 or its less potent
sibling 2 have been described over the past four decades.[6–12]
Although many original solutions were found, several recur-
ring themes can also be noticed in this impressive body of
work. The most obvious one is the enduring dominance of
macrolactonization for the formation of the 13-membered
ꢀ
F
ew natural products have as illustrious a pedigree as
ring. Only a few macrocyclizations through C C bond
brefeldin A (1), which had originally been isolated from
Penicillium decumbens but was later
formation have been pursued with varying success,[8] with
ring-closing olefin metathesis (RCM)[13] at the D10,11 bond
being the only catalytic method applied to date.[9] Since the
current state of the art does not allow E-selectivity to be
imposed on RCM by catalyst control,[14] the observed isomer
ratios were case dependent and typically unfavorable.
also found in other fungal strains.[1]
This macrolide is endowed with
antifungal, antiviral, nematocidal,
and antimitotic activity and had
been selected by the National
Cancer Institute for detailed preclin-
ical survey for its ability to drive
Other groups chose to set the embedded E-olefins more
concisely, for instance through the trans-reduction of an
appropriate alkyne precursor. With one exception, where
a two-step protocol of trans-hydrosilylation/proto-desilylation
was pursued to form the enoate motif of 1,[10] they all resorted
to the use of alkali metals in liquid ammonia.[11] Because of
the harsh conditions, this methodology necessitates consid-
erable oxidation state and protecting group management
en route to the final product and therefore needs to be
carefully timed. We felt that the procedure for direct alkyne
trans-hydrogenation recently disclosed by our group provides
a larger window of opportunity and should qualify for
applications to polyfunctional compounds where Birch
reduction has no bearing.[15,16] Since this emerging method-
ology is as yet hardly understood and has never been applied
to natural product chemistry, a late-stage implementation into
a route to 1 might help in scouting the strategic assets of this
method, as well as any possible pitfalls.
Finally, a literature survey showed that the amounts of
brefeldin A (1) formed de novo in the numerous campaigns of
the last four decades were minute and mostly in the single-
digit milligram range, where documented.[6,17,18] Although 1 is
accessible by fermentation,[19] this status quo is deemed
inadequate by todayꢀs standards in the field of target-oriented
synthesis.[20] Therefore we felt encouraged to pursue this
prominent target once again, hoping that a new route based
various human cancer cell lines into
apoptosis.[2] Although this profile did
not translate into a clinical success,
1 gained prominence in chemical
biology and biomedical research for
its stunning effects on intracellular
protein trafficking. Upon incubation with 1, eukaryotic cells
rapidly disassemble the Golgi apparatus and redistribute its
[*] Dr. M. Fuchs, Prof. A. Fꢀrstner
Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim/Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
[**] Generous financial support by the Austrian Science Fund (Erwin
Schrçdinger fellowship to M.F., J3466 N28) and by the MPG is
gratefully acknowledged. We thank J. Rust and Prof. C. W. Lehmann
for solving the X-ray structures.
Supporting information for this article is available on the WWW
ꢁ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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