Angewandte
Chemie
DOI: 10.1002/anie.201305331
Natural Products Chemistry
Synthesis and Biological Evaluation of Paleo-Soraphens**
Hai-Hua Lu, Aruna Raja, Raimo Franke, Dirk Landsberg, Florenz Sasse, and Markus Kalesse*
Natural products are exploited as a rich source of biologically
active compounds and can be isolated as metabolites from
plants, fungi, animals, and microorganisms. In particular,
polyketides from fungi and bacteria have been the focus of
chemical and biological investigations. Since the biosynthesis
of modular polyketides follows a linear assembly, genetic
analysis can be used to rationalize the biosynthesis of
polyketides and even to predict the stereochemical out-
come.[1] Consequently, these genetic analyses have been used
to define the stereochemistry of natural products and thus
guide their total synthesis.[2] So far in natural product
synthesis the structures of isolated natural products have
served as targets. However, if one compares modular
polyketide synthases to the isolated natural products, it
becomes apparent that in a large variety of polyketides at
least one enzymatic activity is nonproductive. Whether this is
the consequence of an evolutionary process or a chemical
consequence of the substrate is still unknown. Nevertheless,
we were interested in natural products that exhibit the
structure predicted by the intact polyketide synthases to see if
and how their biological behavior would change as a conse-
quence of the altered structure.
Here, we present the synthesis and biological activity of
two soraphen derivatives that contain the structure derived
from its polyketide synthases. Soraphen[3] inhibits the eukary-
otic acetyl-coenzyme A carboxylase (ACC)[4] and conse-
quently was considered a potential antifungal and antitumor
compound.[5] Its biosynthetic origin was described by Ligon
et al.,[6] and Mꢀller and Flosset et al.[7] and they identified two
positions of the isolated natural product that differed from the
genetically expected outcome.
secondary alcohol was not produced either. Meanwhile, there
is still a double bond between C9 and C10. The presence of
this double bond can be rationalized by an isomerization of
the preceding a,b-unsaturated ester to the deconjugated b,g-
enoate. Ligon et al. proposed that this double bond is
a consequence of postketide transformations. In any case
the presence and position of this double bond is believed not
to be the direct consequence of the polyketide synthase
(Scheme 1).
The synthesis of soraphen A was completed independ-
ently by research groups led by Giese[8] and Trost,[9] and with
partial syntheses put forward by Sinnes and others.[10] Based
on reported difficulties in using the internal double bond as
a handle for a convergent synthesis, we decided to use
a macrolactonization and a Nozaki–Hiyama–Kishi reaction in
the endgame of our syntheses (Scheme 2). As depicted in
Scheme 3, our synthesis of the western segment 6 features
a strategic olefin cross-metathesis.[11]
Starting from the known chiral diol 1,[12] which in our case
was conveniently obtained by proline-catalyzed a-oxida-
tion[13] of 4-pentenal,[14] selective protection of the primary
hydroxy group and etherification of the remaining secondary
alcohol afforded alkene 2 (Scheme 3). This set the stage for
the cross-metathesis with the known (S)-1-phenyl-3-buten-1-
ol (3).[15] In the presence of 1.5 mol% of the Grubbs II
catalyst, the cross-metathesis reaction smoothly provided the
desired product in good yield. Subsequent reduction of the
double bond by either imide reduction[16] or heterogeneous
hydrogenation afforded chiral alcohol 4, which was then
protected as a PMB ether (5). Finally, TBS removal with CSA
and IBX-mediated oxidation[17] of the resulting primary
alcohol afforded the desired western segment 6. For the
synthesis of the eastern segment (Scheme 4), we envision that
the combination of syn-Evans aldol reaction[18] and anti-
Marshall reaction[19] with commercially available (R)-Roche
ester will greatly enhance the efficiency for constructing the
five contiguous stereocenters.
Ligon et al. pointed out that the expected trisubstituted
double bond (C2–C3), which should be established by
module 8, is missing due to the inactivity of the dehydratase
activity within that domain.[6] Additionally, the ketoreductase
must have been nonfunctional as well since the expected
Thus, syn-Evans aldol reaction of 7 with aldehyde 8[20]
afforded the corresponding adduct 9. Subsequent TBS
protection of the secondary hydroxy group and reductive
removal of the chiral auxiliary afforded alcohol 10, which was
transformed to the corresponding aldehyde 11.[21] Finally, an
anti-Marshall reaction generated two additional desired chiral
centers and the vinyl iodide segment 13 was completed
through a hydrozirconation–iodination sequence.
With both segments in hand, we began the endgame of the
synthesis with the Nozaki–Hiyama–Kishi coupling
(Scheme 5).[22] The two segments were joined to form the
desired adduct, albeit as a 2:1 mixture of the allylic alcohol
[*] Dr. H.-H. Lu, Dr. D. Landsberg, Prof. Dr. M. Kalesse
Institut fꢀr Organische Chemie und Biomolekulares
Wirkstoffzentrum (BMWZ), Leibniz Universitꢁt Hannover
Schneiderberg 1B, 30167 Hannover (Germany)
and
Helmholtz Centre for Infection Research (HZI)
Inhoffenstrasse 7, Braunschweig (Germany)
E-mail: Markus.Kalesse@oci.uni-hannover.de
A. Raja, Dr. R. Franke, Dr. F. Sasse
Department of Chemical Biology
Helmholtz-Zentrum fꢀr Infektionsforschung (HZI)
Inhoffenstrasse 7, Braunschweig (Germany)
[**] We thank the Alexander von Humboldt Foundation for a fellowship
to H.-H.L.
diastereoisomers. Hence, a sequence of oxidation and chela-
[23]
tion-controlled reduction with Zn(BH4)2
at low temper-
Supporting information for this article is available on the WWW
ature provided the desired alcohol 15 in excellent yield and
Angew. Chem. Int. Ed. 2013, 52, 13549 –13552
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
13549
Lu, Hai-Hua
