Total synthesis and absolute stereochemical assignment of kibdelone C

Article abstract of DOI:10.1021/ja203642n

Kibdelones are hexacyclic tetrahydroxanthones and potent anticancer agents isolated from an Australian microbe. Herein, we describe the synthesis of a chiral, nonracemic iodocyclohexene carboxylate EF ring fragment of the kibdelones employing an intramolecular iodo halo-Michael aldol reaction and its merger with an ABCD ring fragment to afford the congener kibdelone C.

Full text of DOI:10.1021/ja203642n

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Total Synthesis and Absolute Stereochemical Assignment of
Kibdelone C
David L. Sloman,† Jeffrey W. Bacon,‡ and John A. Porco, Jr.*,†
†Center for Chemical Methodology and Library Development (CMLD-BU) and ‡Chemical Instrumentation Center (CIC-BU),
Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, United States
S Supporting Information
b
ABSTRACT: Kibdelones are hexacyclic tetrahydro-
xanthones and potent anticancer agents isolated from an
Australian microbe. Herein, we describe the synthesis of a
chiral, nonracemic iodocyclohexene carboxylate EF ring
fragment of the kibdelones employing an intramolecular
iodo halo-Michael aldol reaction and its merger with an
ABCD ring fragment to afford the congener kibdelone C.
olycyclic xanthone natural products are a diverse family of
polyketides characterized by their highly oxygenated hexacyclic
P
frameworks. Kibdelones AꢀC (1ꢀ3, Figure 1) are hexacyclic
tetrahydroxanthone1b natural products isolated by Capon and co-
workers from the rare Australian microbe Kibdelosporangium sp. along
with isomeric metabolites including isokibdelone A (4, Figure 1).1a
During their isolation, it was found that methanol solutions of 2and 3
equilibrated to a mixture of 1ꢀ3,1b likely through keto/enol tauto-
merizations followed by quinone/hydroquinone redox reactions. The
kibdelones also display potent nanomolar activity in a variety of
human tumor cell lines. For example, 3 has a GI50 of <1 nm against
both an SR (leukemia) tumor cell line and SN12C (renal) cell
carcinoma. There are numerous related hexacyclic xanthone natural
products (cf. 5ꢀ9, Figure 1).2 Overall, the class of molecules exhibits
a diverse range of biological activities, including potent antimalarial,
antibiotic, anticoccidial, and anticancer properties.2
Figure 1. Kibdelones and related hexacyclic xanthone natural products.
Despite extensive synthetic efforts toward polycyclic xanthones
such as the cervinomycins 5,3cꢀg there have been limited reports on
synthetic efforts3a,b,h toward hexacyclic tetrahydroxanthone natural
products, in part due to the challenge in constructing the polyhy-
droxylated F-ring moiety. In our retrosynthetic analysis, we envi-
sioned that the congener kibdelone C (3) may be obtained from
merger of ABCD fragment 124 and 2-iodo-1-cyclohexenecarbox-
ylate fragment 13 (Figure 2). To access the tetrahydroxanthone ring
system, we envisioned use of an oxa-Michael/retro-Michael5 Friedelꢀ
Crafts annulation sequence. This approach has been utilized in
the literature for the synthesis of xanthones from biaryl ethers3d,6
but has not previously been used to access tetrahydroxanthone
ring systems. Fragment 12 may be derived from Pt(IV)-
catalyzed arylation of quinone monoketal 10 and hydroxystyrene
11.4 We envisioned that the chiral EF-ring fragment 13 may be
obtained from diastereoselective, intramolecular halo-Michael aldol
reaction of aldehyde ynoate 14, the latter derived from protected
diol 15. Numerous literature reports describe intermolecular reac-
tions of preformed β-iodoallenoates reacting with aldehydes,7
including a recent report by Frontier and co-workers on an
intramolecular variant with an alkynone substrate.8
Figure 2. Retrosynthetic analysis for kibdelone C.
The synthesis of EF-ring fragment 13 began with DessꢀMartin
periodinane oxidation of the commercially available, enantiopure
alcohol 15.9 Zinc acetylide chelation-controlled addition to aldehyde
16, followed by benzylation with NaH in THF and desilylation with
TBAF, provided the 1,3-anti-protected propargylic alcohol 17 (60%,
three steps, Scheme 1).10 17 was oxidized to a carboxylic acid in a
two-step sequence using IBX in ethyl acetate11 followed by Pinnick
oxidation. Further treatment with H2SO4 in MeOH provided both
the derived methyl ester and deprotected propargylic diol 18 (73%,
Received: April 20, 2011
Published: June 07, 2011
r
2011 American Chemical Society
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Scheme 1. Synthesis of the EF-Ring Fragment
Scheme 2. Fragment Coupling
it is possible that the relative thermodynamic stability of 20 and 21
may be reflected in the product ratio if epimerization by a retro-halo-
Michael aldol process15 can occur under the reaction conditions.
Initial attempts at fragment coupling of 12 with benzyl-protected
iodoacrylate 20 proved to be unsuccessful under a variety of basic
palladium- and copper-catalyzed conditions.16 We therefore decided
to target the benzyl-deprotected acetonide 13 (Scheme 2) as
reaction partner with the expectation that an unprotected, allylic
hydroxyl should impart greater reactivity in oxa-Michael reactions.5b
Numerous conditions for debenzylation of 20 were attempted,
including hydrogenolysis and various Lewis acids (e.g., AlCl3, ZrCl4,
and TMSI).13 Most conditions led to either degradation or forma-
tion of complex aggregates and emulsions upon aqueous workup.
However, treatment of 20 with BCl317 effected smooth conversion to
a triol which was reprotected by treatment with 2,2-dimethoxypro-
pane under acidic conditions to afford 13 (87%, two steps).
Initial base-catalyzed oxa-Michael reactions of ABCD-ring frag-
ment 12 and iodocyclohexene carboxylate 13 included evaluation of
NaH, K2CO3, Cs2CO3, (n-Bu)4NOH, and KOtBu as base in either
CH3CN or DMF at temperatures from 25 to 100 °C. However,
these conditions failed to produce any detectable coupling products.
We next evaluated a variety of copper- and palladium-catalyzed
methods, including conditions reported by Buchwald and co-work-
ers for CꢀO bond formation using Cu(I), picolinic acid, and K3PO4
as base in DMSO (Scheme 2).16c In light of the latter precedent for
coupling of sterically hindered and electron-rich nucleophiles, we
believed that this would be an effective condition for fragment
coupling of 12 and 13. Further experimentation revealed that Cu(I)
was not required for the transformation. DMSO proved to be an
optimal solvent, presumably due to its ability to dissolve phenolate-
(s) derived from dihydrophenanthrene 12 at reduced temperatures.
The base was also found to be important, as little or no conversion was
observed with NaH, K2CO3, Cs2CO3, and KOtBu. Moreover, the
workup procedure was found to be crucial due to acid sensitivity of
vinylogous carbonate 23. Careful workup at 0 °C with 0.5 N KHSO4
(pH 2) was found to be optimal for protonation of the phenolates
and to minimize degradation of the newly formed vinylogous carbo-
nate linkage. 1H NMR comparison of the phenol chemical shifts of
dihydrophenanthrene 12 and vinylogous carbonate 23 strongly
supported the desired connectivity of the oxa-Michael product.13
Initially we believed that the lack of reactivity seen in iodoacrylate
20 versus 13 may be due to the steric bulk imparted by the allylic,
benzyl ether moiety. Conformer searches of both 13 and 20 were
performed using Spartan ’08, calculated at a semiempirical level of
theory using an AM1 basis set. In the low-energy conformer of
Figure 3. Proposed mechanisms for formation of 20 and 21.
three steps). Selective benzylation of the secondary alcohol of 18
was achieved through benzylidene formation with benzaldehyde
dimethylacetal and p-TsOH in toluene followed by reduction with
sodium cyanoborohydride and TMSCl in CH3CN to provide bis-
benzyl ether 19 (76%, two steps).12 Primary alcohol 19 was finally
oxidized with IBX to afford the ynoate aldehyde 14 (90%).11
We next evaluated the intramolecular halo-Michael aldol reaction.
Treatment of 14 with of magnesium iodide7f,g (2 equiv) at ꢀ20 °C
in CH2Cl2 afforded 2-iodo-1-cyclohexenecarboxylate 20 in 78%
yield (19% overall yield from 15) on a multigram scale along with
minor diastereomer 21 (9%). The stereochemistry of the major
diastereomer was confirmed by X-ray crystal structure analysis of the
derived p-bromobenzoate 22.13 A proposed mechanism for the trans-
formation is shown in Figure 3. We envision reversible7f formation of
β-iodoallenoate diastereomers A and B; the former may undergo
cyclization through transition state C to give 20, and the latter may
react through assembly D to afford 21. The preference for C vs D
leading to major diastereomer 20 may be due to stabilizing chelation
of the R-benzyl ether and aldehyde with MgI2.7a,b,d,g,14 Alternatively,
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Figure 5. Proposed mechanism for xanthone formation.
Figure 4. AM1 low-energy conformers for 20 and 13.
Scheme 3. Xanthone Formation and Elaboration to 3
Figure 6. X-ray crystal structure of kibdelone C methyl ether 25.
two molecules in the asymmetric unit, confirming the hexacyclic
tetrahydroxanthone framework (Figure 6).13 Due to the known
instability of kibdelone B (2),1b we envisioned an oxidative
demethylation/in situ reduction sequence to access kibdelone
C (3).24 Attempted oxidations using ceric ammonium nitrate
(CAN) were found to be both pH and temperature sensitive.
Reaction of 25 with 2.0 equiv of CAN in pH 7.0 buffer afforded
mixtures of B- and D-ring-oxidized products, as well as a com-
pound showing a mass for both B- and D-ring hydroquinones.
Reaction of 25 with CAN in water led to a 3:2 mixture of B- vs
D-ring-oxidized products. Treatment of 25 with CAN (2.2 equiv)
and 10 equiv of AcOH at room temperature for 2 min, followed by a
reductive quench with excess sodium dithionite, provided a ∼5:1
mixture of 3 and a doubly demethylated product. In this case, we
believe that protonation of the xanthone carbonyl with acetic acid
may produce a DE-ring benzopyrylium species13,25 which should
reduce the propensity for oxidation of the D ring. Alternatively, it is
possible that the more selective oxidant cerium(IV) acetate may be
formed under the reaction conditions.26 1H and 13C NMR and UV/
dibenzyl ether 20, the allylic ether substituent appears to be in an
axial orientation. In contrast, in the low-energy conformer of
successful substrate 13, the hydroxyl moiety resides in an equatorial
orientation (Figure 4). The lone pair of the benzyl ether may raise
the LUMO of the acrylate system by a σꢀπ* interaction which may
also contribute to the low reactivity observed for 20.18
The acid lability of 23 proved to be disappointing, as in our initial
plan for formation of the tetrahydroxanthone ring system we en-
visioned treatment of ester 23 with sulfuric acid,19a Eaton’sreagent,19b
or polyphosphoric acid,19c known reagents for intramolecular
FriedelꢀCrafts annulation of esters. A report describing a mild,
intramolecular FriedelꢀCrafts cyclization using cyanuric chloride
and AlCl3 led us to target the carboxylic acid derived from ester 23.20
We were able to saponify 23 by treatment with LiOH in dioxane. In
this reaction, some cleavage of the vinylogous carbonate linkage to
afford 12 was observed (LC/MS). We carried the crude acid mixture
(containing ∼10% of 12) directly into cyclization via treatment with
cyanuric chloride and pyridine in DCE (75 °C) to afford tetrahy-
droxanthone 24 (39%, two steps, Scheme 3).20 The fact that AlCl3
was not required for the transformation led us to propose the mecha-
nism shown in Figure 5. Activation of the carboxylic acid may afford
an intermediate such as E which can further react to form the highly
reactive R-oxo-ketene21,22 intermediate F; the latter may further
undergo 6π-electrocyclization and re-aromatization to form 24. As
the reaction was conducted with excess pyridine, it is conceivable that
intermediate E is an acyl pyridinium23 rather than an acid chloride.
In the final stages of the synthesis, we found that 24 was a poor
substrate for oxidative demethylation.13 The acetonide was
removed via treatment with 3 N HCl in THF to provide triol
25 in 95% yield (Scheme 3). X-ray crystal analysis of 25 showed
23
vis spectra and optical rotation ([R]D = þ48° synthetic, þ49°
natural (c = 0.5, CHCl3)) for synthetic 3 were identical in
all aspects to those of the natural product.1 The absolute stereo-
chemical assignment of natural kibdelone C was thus assigned as
10R,11S,13S as shown in structure 3 (Figure 1).
In summary, a convergent total synthesis of kibdelone C has
been achieved. A diastereoselective halo-Michael/aldol reac-
tion sequence was used to construct the highly functionalized
2-iodo-1-cyclohexenecarboxylate EF-ring fragment 13. The
ABCD dihydrophenanthrene fragment 12 was reacted through
a site-selective oxa-Michael reaction to afford a sensitive vinylo-
gous carbonate precursor 22. The acid lability of 22 was
overcome utilizing cyanuric chloride to mildly activate a derived
carboxylic acid to afford the tetrahydroxanthone ring system. A
precursor to kibdelone C, methyl ether 24, was synthesized and
found to be very stable in relation to the highly oxidizable 3.
Further studies concerning the synthesis and biological evalua-
tion of additional kibdelone congeners and additional tetrahy-
droxanthone natural products are currently in progress and will
be reported in due course.
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’ ASSOCIATED CONTENT
4-hydroxycyclohexenone, see: (b) Nising, C. F.; Ohnem€uller, U. K.; Br€ase,
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Supporting Information. Experimental procedures and
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b
characterization data for all new compounds described herein,
including CIF files for 22 and 25. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
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Corresponding Author
porco@bu.edu
’ ACKNOWLEDGMENT
We thank the National Institutes of Health (R01 CA137270)
and Merck Research Laboratories for research support, Drs. Emil
Lobkovsky (Cornell) and Bruce Noll (Bruker) for X-ray crystal
structure analyses and refinement assistance, and Dr. Paul Ralifo
(Boston University) for NMR assistance. We thank Andrew Little,
Stephen Scully, and Dr. Branko Mitasev (Boston University) for
extremely helpful and stimulating discussions. We also thank Prof.
Robert J. Capon(University of Queensland) for kindly providing a
natural sample and 1H and 13C NMR spectra for kibdelone C and
Prof. Joseph Ready (University of Texas Southwestern Medical
Center) for sharing details of their synthesis prior to publication.
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