Angewandte
Chemie
Completion of the full carbon skeleton of simaomicin a
required adjustment of the stereochemistry at C7 and
incorporation of the methylene acetal. To this end, a C7
advanced substrate (20) to cyclize to the presence of an
electron-withdrawing carbonyl at C8 (kibdelone C number-
ing). Presumably the ketone deactivates the D-ring such that
it is unable to participate in an electrophilic palladation.
Eventually we solved the problem by introducing an iodide at
C4 and decorating the C3 phenol with a Boc group. A
subsequent Pd-mediated dehydrohalogenative coupling
formed the key biaryl bond and enabled a synthesis of
[
13]
ketone was reduced with Noyoriꢀs catalyst, and the B-ring
silyl and methyl groups were removed. The resulting triol was
alkylated with CH ICl in the presence of Cs CO , forming the
2
2
3
dioxane 2 in good yield. Surprisingly, this transformation
required extensive optimization, with other bases and dihalo-
methanes resulting in substantially lower yields. We speculate
that the reaction involves initial alkylation of the C5 phenol
followed by cyclization by the C7 alcohol. Weaker bases or
poorer electrophiles (for example, CH Br ) led to low
[9]
kibdelone C.
Cognizant of the failure of direct dehydrogenative cou-
pling in the synthesis of kibdelone C, we were intrigued by the
rapid and high-yielding cyclization of simaomicin model
system 22 [Eq. (3)]. Specifically, while the kibdelone model 18
cyclized slowly (ca. 50% conversion after 2 d), the presence of
the methylene acetal in substrate 22 led to complete
2
2
conversion, while reagents with two good leaving groups
for example, CH I ) appeared to promote polymerization.
(
2
2
We next targeted formation of B-D biaryl bond to forge
[
18]
the C-ring and construct the carbon skeleton of simaomicin a.
In the course of our synthetic studies on kibdelone C we had
prepared model system 18 (Scheme 3). Exposure to Pd-
conversion in 12 h. We attribute the improvement offered
by the 1,3-dioxane ring to a conformational bias in which the
rigidity imparted by the extra ring brings C22 and C23
[
19]
(
simaomicin numbering) into closer proximity. With this
result as encouragement, we then examined the reactivity of
the more elaborate substrate 2. Gratifyingly, heating a solu-
tion of the free phenol and Pd(OAc) in DMSO resulted in
2
a dehydrogenative coupling of the B and D-rings to form the
C-ring and the full skeleton of the natural product. Finally,
removal of the benzyl and BOM groups provided optically
active simaomicin a. The latter transformation required care-
fully controlled reaction parameters, with only failure meet-
ing a variety of alternative conditions including hydrogena-
tion, dissolving metal and other Lewis acids. Generally,
removal of the D-ring benzyl group occurred rapidly, but
the remaining ethers showed significant stubbornness. The
optimized conditions featured a large excess of BCl at low
3
temperatures. Ultimately, the natural product was isolated in
1
13
high yield and purity, with H and C NMR spectroscopy and
mass spectrometry data consistent with the reported values.
Only the optical rotation value differed from the isolation
report, as it was similar in magnitude but opposite in sign
(
À759 (synthetic, c = 0.06, DMF) vs. + 836 (natural, c = 0.3,
[20]
DMF)]. We therefore conclude that the natural product is
in fact enantiomeric to the structures shown herein. The
natural enantiomer of simaomicin a should be easily acces-
sible from ent-3, which can be obtained from the same
enzymatic resolution that is used to generate 3, and by using
(S,S)-Ru-9 for hydrogenation.
Simaomicin a is reported to synergize with the DNA-
damaging agent bleomycin at sub-nanomolar concentrations,
and arrest cells in the G1 phase at low nanomolar concen-
[
3]
trations as a single agent. Moreover, it reduced cell
proliferation by 50% (IC ) at concentrations between 0.3
5
0
Scheme 3. Synthesis of simaomicin a via dehydrogenative coupling.
and 19 nm for a range of breast adenocarcinoma, cervical
carcinoma, gastric adenocarcinoma, esophageal carcinoma,
and colon cancer cell lines. Growth inhibition appears to
(
OAc) in DMSO at elevated temperatures effected a direct
2
[4]
dehydrogenative coupling in modest yield, albeit cleanly
result from both G1 arrest and apoptosis. No molecular
target has been identified for simaomicin a or other polycyc-
lic xanthone natural products. In this context, we tested the
cytotoxicity of synthetic ent-simaomicin a against a colon
cancer cell line (HCT116) and two non-small-cell lung cancer
lines (H460, H1819). We found IC50 values of 21, 13, and
87 nm, the first of which is equivalent to the value reported for
[
11]
[
Eq. (1)]. Unfortunately, as is common with model systems,
this one led us astray: we were unable to achieve the
analogous transformation in the context of the entire skeleton
of kibdelone C. In particular, the tetrahydroxanthone 20
II
failed to cyclize under a variety of conditions featuring Pd ,
II
III
III
Cu , Fe , or I [Eq. (2)]. We ascribed the failure of the more
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3
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