Approaches to Polycyclic 1,4-Dioxygenated Xanthones. Application to Total Synthesis of the Aglycone of IB-00208

Article abstract of DOI:10.1021/ol503336t

(Chemical Equation Presented). Hexacyclic xanthone natural products such as IB-00208 present a formidable challenge in organic synthesis. A new approach to polycyclic 1,4-dioxygenated xanthones from benzocyclobutenones has been developed and applied to the first total synthesis of the aglycone of IB-00208. The 22-step synthesis features an acetylide stitching process that joins an aryl aldehyde with an angularly fused benzocyclobutenone, which was prepared by a ring-closing metathesis reaction. The resulting acetylenic benzocyclobutenone diol underwent a Moore rearrangement to give an intermediate that was further elaborated to the aglycone of IB-00208 as a mixture of hydroquinone-quinone tautomers.

Full text of DOI:10.1021/ol503336t

Letter
pubs.acs.org/OrgLett
Approaches to Polycyclic 1,4-Dioxygenated Xanthones. Application
to Total Synthesis of the Aglycone of IB-00208
†
‡
§
Jingyue Yang, Daniel Knueppel, Bo Cheng, Douglas Mans, and Stephen F. Martin*
Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
*
S Supporting Information
ABSTRACT: Hexacyclic xanthone natural products such as IB-00208 present a formidable challenge in organic synthesis. A new
approach to polycyclic 1,4-dioxygenated xanthones from benzocyclobutenones has been developed and applied to the first total
synthesis of the aglycone of IB-00208. The 22-step synthesis features an acetylide stitching process that joins an aryl aldehyde
with an angularly fused benzocyclobutenone, which was prepared by a ring-closing metathesis reaction. The resulting acetylenic
benzocyclobutenone diol underwent a Moore rearrangement to give an intermediate that was further elaborated to the aglycone
of IB-00208 as a mixture of hydroquinone−quinone tautomers.
he polycyclic, xanthone antibiotic IB-00208 (1) (Figure 1)
T
was isolated by Romero and co-workers in 2003 from the
1
culture broth of Actinomadura sp. This novel compound
exhibits potent cytotoxic activity (MIC = 1 nM) against several
tumor cell lines including P388D1, A-549, HT-29, and SK-
MEL-28, as well as strong antibiotic activity against several
Gram-positive bacteria. The hexacyclic core of IB-00208
contains a 1,4-dioxygenated xanthone subunit and is structur-
2
3
ally related to citreamicin α (2), kibdelone A (3), and
4
cervinomycin A (4), all of which exhibit significant biological
2
activities (Figure 1). The relative stereochemistry of the sugar
moiety in IB-00208 (1) was established by analysis of spin−
spin coupling constants and supported by NOESY experiments;
however, the absolute stereochemistry at C(3) of 1 is not
known.
Owing to the complex polycyclic structures and potent
biological activities of 1−4, there has been considerable interest
in the total synthesis of these and other polycyclic
Figure 1. IB-00208 and related polycyclic, 1,4-dioxygenated xanthone-
derived natural products.
5
−7
xanthones,
but neither IB-00208 nor citreamicin α has yet
quinone formation, deprotection, and stereo- and regioselective
glycosylation of the sterically less encumbered phenolic group.
In our original plan, we had envisioned that electrocyclic ring
opening of 7 would generate the acetylenic vinyl ketene 6 in
succumbed to total synthesis. A key structural subunit
embedded in many of these natural products is a 1,4-
dioxygenated xanthone, which itself presents significant
8
challenges to synthesis. In the context of our interest in
9
accord with the findings of Moore. Simple analogs of 6 can
these and other polycyclic xanthone natural products, we
recently developed a concise route to 1,4-dioxygenated
xanthones that features a novel extension of the Moore
cyclize via a radical pathway, a reaction manifold that our group
11
leveraged in a concise total synthesis of cribrostatin 6, but
compound 6 is also suitably substituted to undergo cyclization
via an ionic pathway to give 5 in a process inspired by a related
9
,10
cyclization,
and we now report the application of this
general entry to xanthones to the first total synthesis of the
aglycone of IB-00208.
12
transformation reported by Fuganti. Intermediate 7 would be
Our approach to IB-00208 (1) is outlined in a retrosynthetic
format in Scheme 1. We reasoned that the late stage
intermediate 5 could be converted into 1 via benzylic oxidation,
Received: November 17, 2014
©
XXXX American Chemical Society
A
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Scheme 1. Overview of Retrosynthetic Analysis of IB-00208
Scheme 2. Synthesis of Cyclobutenone 9
non-nucleophilic base bromomagnesium 2,2,6,6-tetramethyl-
piperidide (TMPMgBr) generated a dianion that was coupled
accessed by union of the aldehyde 8 and the key intermediate
fused-cyclobutenone 9 by an acetylide stitching sequence.
When we initiated this project, angular, polycyclic cyclobutene-
dione derivatives such as 9 were unknown, but we reasoned 9
might be accessible from coupling of 10 and the known vinyl
squarate 11, followed by ring closing metathesis (RCM) to
form the benzene ring in 9.
19
with aldehyde 8, which was prepared via silylation of the
20
corresponding known phenol, to deliver 20 in 80% yield.
Scheme 3. Preparation of 20 by Acetylide Stitching
1
3
Toward preparing the fused cyclobutenedione 9, commer-
cially available 2-bromo-1,4-dimethoxybenzene (12) was
treated with n-BuLi, and the resulting aryllithium reagent was
allowed to react with propylene oxide to yield the racemic
14
secondary alcohol 13 (Scheme 2). Although the absolute
stereochemistry at C(3) of 1 is unknown, both enantiomers of
propylene oxide are commercially available, so it is possible to
prepare either enantiomer of 13, and hence of the aglycone of
1
, via this approach. Regioselective bromination of 13 by NBS
in the presence of a catalytic amount of ammonium nitrate
1
5
(NH NO ), followed by installation of a MOM group, which
4 3
served the dual roles of being a protecting group and the source
of a carbon atom in the A-ring, gave 14 in excellent yield. The
hydroquinone protecting groups were easily removed by a
redox process, and a TMSOTf-induced oxa-Pictet−Spengler
At this juncture, the key sequence of electrocyclic ring
opening and subsequent cyclizations was at hand. In model
studies with an analog of 20 lacking the A-ring, we were unable
to selectively oxidize the acetylenic-benzylic alcohol moiety to
give a ketone. In view of this unfavorable precedent, the ketal
group in 20 was removed to deliver 21 (Scheme 4), which
upon heating in DMSO (0.005 M) at 100 °C gave 22 in 54%
overall yield from 20. No hexacyclic product related to 5 that
would have arisen from cyclization of a putative acetylenic vinyl
16
cyclization generated the dihydropyran ring of 15. A Duff
17
reaction of 15 with hexamethylenetetramine (HMTA) gave
6 in 58% overall yield from 14. Protection of the
1
hydroquinone moiety in 16 as its bis-MOM ether, followed
by Wittig olefination, furnished 10 in 73% overall yield. The
aryllithium reagent derived from 10 by metal−halogen
exchange was then coupled with vinyl squarate 11 following a
13
18
12
procedure reported by Moore to give 18 in 64% yield.
ketene as expected from the work of Fuganti was observed
RCM of 18 in the presence of Grubbs II catalyst afforded
cyclobutenone 9 in 81% yield.
The next stage of the synthesis involved an acetylide stitching
process to assemble a compound related to 7. Accordingly, 9
was converted into propargyl alcohol 19 in 88% yield (Scheme
under any of the conditions examined. Rather, 21 simply
underwent a Moore rearrangement to give exclusively
9
,10
benzoquinone 22.
Completing the synthesis of IB-00208 (1) from 22 required
selective oxidations of the secondary alcohol at C(15) and the
methylene group at C(1) as well as cyclization to form the
3). Double deprotonation of 19 using an excess of the strong,
B
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Scheme 4. Sequential Rearrangement and Cyclizations of 21
Scheme 5. Synthesis of the Aglycone of IB-00208 (1)
because the redox potentials of the B- and D-rings would be
predicted to be similar, so 29a and 29b should be of
comparable stability. Unfortunately, the tautomers 29a and
2
9b were somewhat prone to decomposition, so we were not
able to separate or purify either of them for further
characterization and elaboration.
In summary, we completed the first total synthesis of racemic
9a, the aglycone of IB-00208 (1), together with its
2
hydroquinone−quinone tautomer 29b. The longest linear
sequence in the synthesis required 22 steps from commercially
available starting materials. Preparation of key intermediate 9
via an RCM reaction represented a potentially general route to
polycyclic benzocyclobutenedione derivatives, and an acetylide
stitching process was exploited to couple 9 with an aryl
aldehyde leading to ketone 21. Our initial plan to form the
hexacyclic framework of IB-00208 by a one-pot, electrocyclic
ring-opening/cyclization cascade from 21 could not be
implemented, but an alternative approach was adopted
successfully that led to 28, the monoprotected aglycone of
IB-00208. Deprotection of 28 gave a mixture of the tautomeric
aglycones 29a and 29b.
pyranone E-ring. In the event, benzylic oxidation at C(1) of 22
21
proceeded selectively with DDQ in the presence of MeOH to
produce the acetal 23 in 85% yield (Scheme 4). Oxidation of
the alcohol at C(15) using IBX gave 24, and subsequent
fluoride-ion induced removal of the TBS group gave spirocycle
2
5 via spontaneous cyclization of the intermediate phenoxide.
The regiochemical outcome of this cyclization to form a
spirocyclic ring system rather than the desired 1,4-dioxygenated
xanthone is consistent with previous observations from our
laboratory that the substitution pattern on the F-ring of 24
10
governs the regioselectivity. Hydrolysis of the C(1) acetal
followed by oxidation of the intermediate hemiacetal with
pyridinium dichromate (PDC) in the presence of 3 Å molecular
22
sieves gave lactone 26 in 81% overall yield from 25.
We have shown that simpler spirocyclic ketones related to 26
ASSOCIATED CONTENT
Supporting Information
■
*
S
10
undergo rearrangement to give xanthones, so we were
gratified to discover that heating 26 at 180 °C in a microwave
reactor gave a mixture of hydroquinone 27 and quinone 28,
both of which lacked the phenolic MOM protecting group at
C(17) (Scheme 5). Although oxidation of 27 to 28 occurred
slowly upon exposure of 27 to air under ambient conditions,
continued heating of a mixture of 27 and 28 in the presence of
oxygen led to the exclusive formation of 28 in 79% yield from
Complete experimental procedures, full characterization of new
1
13
compounds, and copies of H and C NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sfmartin@mail.utexas.edu.
Present Addresses
2
6. Initial attempts to remove the C(5) phenolic MOM
protecting group of 28 under acidic conditions gave complex
mixtures. However, reaction of 28 with freshly distilled
†
2
3
Dow AgroSciences LLC, 9330 Zionsville Road, Indianapolis,
TMSBr, followed by workup and partial purification by
fractional precipitation, furnished a mixture (∼2:1) of
IN 46268
‡
1
California Institute for Biomedical Research, 11119 North
compounds for which the LC-HRMS and H NMR spectral
Torrey Pines Road, Suite 100, La Jolla, CA 92037.
data (see Supporting Information) are consistent with those
expected for 29a, the aglycone of 1, and its isomer 29b, which
is produced by tautomerization of the initially formed 29a. It
was perhaps not unexpected that the hydroquinone−quinone
tautomers 29a and 29b were obtained upon deprotection of 28,
§
GSK, 709 Swedeland Road, UMW2810, King of Prussia, PA
1
9406.
Notes
The authors declare no competing financial interest.
C
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Letter
(
14) Adapted from procedure to prepare enantiomerically pure (S)-
ACKNOWLEDGMENTS
■
1
3; see: Wagner, J. M.; McElhinny, C. J.; Lewin, A. H.; Carroll, F. I.
Tetrahedron: Asymmetry 2003, 14, 2119−2125.
15) Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi, K.;
We thank the National Institutes of Health (GM31077) and
the Robert A. Welch Foundation (F-0652) for support. J.Y.
thanks the Cancer Prevention Research Institute of Texas for
support as postdoctoral trainee, D.K. thanks the National
Science Foundation for a graduate research fellowship, and
D.M. thanks the NIH for a postdoctoral fellowship. We also
thank Dr. Richard Pederson (Materia, Inc.) for catalyst support,
Mr. Shawn Blumberg (The University of Texas at Austin) for
technical assistance, and Dr. Ian Riddington (The University of
Texas at Austin) for helpful discussions of MS data.
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