Synthesis of (±)-γ-rubromycin via a new hypoiodite-catalytic oxidative cycloetherification

Article abstract of DOI:10.1021/ol3024874

A new synthesis of γ-rubromycin is presented through a new oxidative, bisbenzannulated spiroketalization as a key step which is catalyzed by an in situ generated hypoiodite species, developed previously by our group. This key transformation has high efficiency and convenient conditions. This is a new and efficient catalytic application for organohypoiodine reagents.

Full text of DOI:10.1021/ol3024874

ORGANIC
LETTERS
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Vol. XX, No. XX
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Synthesis of (()-γ-Rubromycin via a New
Hypoiodite-Catalytic Oxidative
Cycloetherification
Liping Wei, Jijun Xue,* Hongbiao Liu, Wenjing Wang, and Ying Li*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, Gansu, P. R. China
xuejj@lzu.edu.cn; liying@lzu.edu.cn
Received September 10, 2012
ABSTRACT
A new synthesis of γ-rubromycin is presented through a new oxidative, bisbenzannulated spiroketalization as a key step which is catalyzed by an
in situ generated hypoiodite species, developed previously by our group. This key transformation has high efficiency and convenient conditions.
This is a new and efficient catalytic application for organohypoiodine reagents.
One of the challenges currently facing synthetic chemists
is the development of efficient and elegant chemical pro-
cesses that allow for the rapid synthesis of functional,
diverse, and molecularly complex bioactive compounds
from simple starting materials.1 Recently, organohyperva-
lent iodine reagents have attracted significant attention as
versatile and environmentally benign oxidants, as well as for
their strong potential use in many applications in organic
synthesis.2 The most impressive recent achievements in the
field have included the development of new hypervalent
iodine reagents and reagent systems and the discovery of
catalytic applications for organohypoiodite compounds.2,3
Some of these applications include the hypervalent iodine
catalytic R-oxyacetylation and R-oxyalkylation4 of carbonyl
compounds. Additionally, intramolecular R-oxyphenyla-
tion of carbonyl compounds has proven to be useful in the
construction of oxa-benzocycles, but there are few reports
on their application in natural product synthesis.
Rubromycins (Figure 1), isolated by Brockmann and
co-workers, are a class of antibiotics with a wide spectrum
of biological activity, which contain highly functionalized,
multiple fused-cyclic scaffolds with bisbenzannulated
spiroketal cores.5 As the typical example, γ-rubromycin
(1), traces of which can be isolated from Streptomyces
cultures, displays potent activity against human telomerase
(IC50 = 3 μM)6 and inhibits mammalian DNA-polymerase
(1) (a) Reetz, M. T. Angew. Chem., Int. Ed. 2001, 40, 284. (b) Wu,
C. Y.; Chang, C. F.; Szu, J.; Chen, Y.; Wong, C. H.; Lin, C. H. Angew.
Chem., Int. Ed. 2003, 42, 4661. (c) Kodadek, T. Chem. Commun. 2011,
(4) (a) Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamoto,
K. J. Am. Chem. Soc. 2005, 127, 12244. (b) Dohi, T.; Maruyama, A.;
Yoshimura, M.; Morimoto, K.; Tohma, H.; Kita, Y. Angew. Chem., Int.
Ed. 2005, 44, 6193. (c) Uyanik, M.; Suzuki, D.; Yasui, T.; Ishihara, K.
Tetrahedron 2010, 66, 5841. (d) Uyanik, M.; Okamoto, H.; Yasui, T.;
Ishihara, K. Science 2010, 328, 1376. (e) Uyanik, M.; Suzuki, D.; Yasui,
T.; Ishihara, K. Angew. Chem., Int. Ed 2011, 50, 5331.
(5) (a) Brockmann, H.; Lenk, W.; Schwantje, G.; Zeeck, A. Tetra-
hedron Lett. 1966, 7, 3525. (b) Brockmann, H.; Lenk, W.; Schwantje, G.;
Zeeck, A. Chem. Ber. 1969, 102, 126. (c) Brockmann, H.; Zeeck, A.
Chem. Ber. 1970, 103, 1709.
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47, 9757. (d) Duart, M. J.; Anton-Fos, G. M.; Aleman, P. A.; Gay-Roig,
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J. Med. Chem. 2005, 48, 1260.
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Angew. Chem., Int. Ed. 2009, 48, 4605. (b) Dohi, T.; Maruyama, A.;
Takenaga, N.; Senami, K.; Minamitsuji, Y.; Fujioka, H.; Caemmerer,
S. B.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 3787. (c) Uyanik, M.;
Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed. 2010, 49, 2175.
(d) Richardson, R. D.; Wirth, T. Angew. Chem., Int. Ed. 2006, 45,
4402. (e) Zhdankin, V. V; Stang, P. J. Chem. Rev. 2008, 108, 5299.
(f) Dohi, T.; Kita, Y. Chem. Commun. 2009, 16, 2073. (g) Uyanik, M.;
Ishihara, K. Chem. Commun. 2009, 16, 2086.
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A.; Goto, Y.; Mizushina, Y.; Sakaguchi, K.; Hayashi, H. Biochemistry
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M. S.; Nemykin, V. N.; Zhdankin, V. V. Tetrahedron 2010, 66, 5745.
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10.1021/ol3024874
XXXX American Chemical Society

and HIV-1 reverse transcriptase.7 Heliquinomycin (2) is a
selective inhibitor of a cellular DNA helicase that inhibits
the growth of tumor cell lines,8 and purpuromycin9 (3a) has
been considered for use as a topical agent for vaginal
infections.10
methods have included transition-metal catalyzed spiro-
ketalizations,16 hetero-DielsÀAlder reactions,17 and
hypoiodite-catalyzed R-oxyphenylation.18 Among them, a
new organohypervalent iodine system,18 generated in situ
from the irradiative aerobic oxidation of tetrabutylammo-
nium iodide (TBAI), or the oxidation of peroxy acid, has
proved highly useful. In continuation of our investigations
into organohypervalent iodine and the total synthesis of
natural products, our new catalytic hyperiodite system has
been employed in the total synthesis of the rubromycins. In
this respect, an efficient synthesis of a key known precursor
of γ-rubromycin is described herein.
Scheme 1. Retrosynthetic Analysis
The important biological properties and interesting
structures of members of the rubromycin family have made
them attractive synthetic targets. In past decades, much
effort has been devoted to the formation of natural products
on a bisbenzannulated scaffold. Danishefsky,11 Kita,12
Brimble,13 Kozlowski,14 and Pettus15 have reported the
total synthesis of heliquinomycinone and (()-γ-rubromycin
and the formal synthesis of purpuromycin. In these studies,
compound 4 was the key intermediate for γ-rubromycin.
In past years, our investigations into the construction of
spiroketals has resulted in several new and efficient spir-
oketalizations that are convenient to use in the construc-
tion of natural product spiroketal scaffolds. Some of these
Figure 1. Selected members of the rubromycin family.
The retrosynthetic analysis outlined in Scheme 1 proceeds
from the hypoiodite-catalyzed spiroketalization onward
toward the synthesis of γ-rubromycin (1). The literature
reports that compound 4 is the key intermediate in the
synthesis of γ-rubromycin.12,13 Based on our previous
experience in the synthesis of bisbenzannulated spiroke-
tal cores, we hypothesized that the [5,6]-spiroketal inter-
mediate 4 could be synthesized by intramolecular
cyclization of the phenolic hydroxyl with the R-oxyphe-
nylation of carbonyl compound 5, catalyzed by TBAI in
the presence of m-chlorobenzoic acid (mCPBA) and
tetrabutylammonium fluoride (TBAF). Compound 5
could be obtained from naphthofuran 8 and isocoumar-
in precursor 7 through an aldol reaction followed by a
reduction.
(8) (a) Ishimi, Y.; Sugiyama, T.; Nakaya, R.; Kanamori, M.; Kohno,
T.; Enomoto, T.; Chino, M. FEBS J. 2009, 276, 3382. (b) Chino, M.;
Nishikawa, K.; Yamada, A.; Ohsono, M.; Sawa, T.; Hanaoka, F.;
Ishizuka, M.; Takeuchi, T. J. Antibiot. 1998, 51, 480.
(9) Bardone, M. R.; Martinelli, E.; Zerilli, L. F.; Coronelli, C.
Tetrahedron 1974, 30, 2747.
(10) (a) Waters, S. P.; Kozlowski, M. C. Tetrahedron Lett. 2001, 42,
3567. (b) Trani, A.; Dallanoce, C.; Panzone, G.; Ripamonti, F.; Goldstein,
B. P.; Ciabatti, R. J. Med. Chem. 1997, 40, 967.
(11) Siu, T.; Qin, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001,
40, 4713.
(12) Akai, S.; Kakiguchi, K.; Nakamura, Y.; Kuriwaki, I.; Dohi, T.;
Harada, S.; Kubo, O.; Morita, N.; Kita, Y. Angew. Chem., Int. Ed. 2007,
46, 7458.
(13) Rathwell, D. C. K.; Yang, S. H.; Tsang, K. Y.; Brimble, M. A.
Angew. Chem., Int. Ed. 2009, 48, 7996.
(14) (a) Lowell, A. N.; Fennie, M. W.; Kozlowski, M. C. J. Org.
Chem. 2011, 76, 6488. (b) Bandichhor, R.; Lowell, A. N.; Kozlowski,
M. C. J. Org. Chem. 2011, 76, 6475.
(15) Wu, K. L.; Mercado, E. V.; Pettus, T. R. R. J. Am. Chem. Soc.
2011, 133, 6114.
The synthesis of isocoumarin precursor 7 began from
phenol 9, which was prepared in five steps from commer-
cially available guaiacol according to Brimble’s protocol
(Scheme 2).13 Allylation of phenol 9afforded 10 in an almost
quantitative yield. A Claisen rearrangement of 10 in N,
N-diethylaniline gave rise to product 11 in 95% yield, which
was protected as an ethoxymethyl ether under standard
conditions. Cleavage of the double bond by ozonolysis in
anhydrous MeOH at À78 °C provided aldehyde 7 in 92%
yield.
(16) Zhang, Y.; Xue, J.; Xin, Z.; Xie, Z.; Li, Y. Synlett 2008, 2008,
940.
(17) (a) Zhou, G.; Zheng, D.; Da, S.; Xie, Z.; Li, Y. Tetrahedron Lett.
2006, 47, 3349. (b) Zhou, G.; Zhu, J.; Xie, Z.; Li, Y. Org. Lett. 2008, 10,
721.
(18) Wei, W.; Li, L.; Lin, X.; Li, H.; Xue, J.; Li, Y. Org. Biomol.
Chem. 2012, 10, 3494.
(19) Lowell, A. N.; Fennie, M. W.; Kozlowski, M. C. J. Org. Chem.
2008, 73, 1911.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Synthesis of Isocoumarin Precursor 7
Scheme 4. Model Synthesis of the Scaffold
Due to its highly functionalized structure, the synthesis
of precursor 8 remained a challenge. Our synthetic route to
8 utilized the Dieckmann condensation as a key step and
began from readily prepared Kozlowski’s ortho-quinone
13(Scheme 3).19 First, 13was reduced underthe conditions
described by Kozlowski,19 and the formed naphthodiol
was reacted with methyl bromoacetate in the presence of
potassium bicarbonate and DMF, to generate 14 in
82% yield. Methylation of 14 and hydrolysis using 10%
aqueous potassium hydroxide formed the diacid 16. A
Dieckmann condensation of 16, carried out in the presence
of acetic anhydride, fused sodium acetate, and boiling
acetic acid, gave 17 in 85% yield.20 Subsequent conversion
to ketone 8 was accomplished by boiling 17 in 1 N aqueous
HCl in MeOH.
tert-butyldimethylsilyl (TBDMS) protecting group with
TBAF in tetrahydrofuran (THF), the key precursor 21was
formed in 96% yield. Using our previously reported
conditions,18 compound 21 was treated with TBAI and
mCPBA, in the presence of TBAF, to produce the desired
spiroketal 22 in 82% yield.
The final phase of our formal synthesis involved the
synthesis of compound 4 (Scheme 5). The synthesis of 6
revealed that the condensations of 7 with 17 and of 7 with 8
were efficient. In the presence of lithium diisopropylamide
(LDA), the aldol condensation of 7 and 17 provided 6 in
85% yield. By using lithium hexamethyldisilylamide
(LHMDS) instead of LDA as a base, the reaction of 7
and 8 produced 6 in 82% yield. Removal of the hydroxyl
group was attempted under various conditions, including
acid-promoted dehydration, Al2O3-mediated elimination,
mesylationÀreduction, and so on.21 Finally, dehydration
succeeded with methanesulfonyl chloride and triethyla-
mine; it produced olefin 23 with high efficiency in 86%
yield. Olefin 23 was then hydrogenated to afford 24 in
almost quantitative yield. After removal of the ethoxy-
methyl (EOM) group with trifluoroacetic acid, compound
5 was formed, allowing the key spirocylization step to be
attempted. Effective cyclization of 5 was accomplished
with TBAI as the catalyst, mCPBA as the oxidant, TBAF
as the additive, and THF as the solvent. At room tempera-
ture, bisbenzannulated spiroketal 25 was generated in 88%
yield after 1 h. The last step was reduction of the ketone. In
the presence of sodium borohydride, spiroketal 25 was first
reduced to the alcohol 26, which was further reduced with
trifluoroacetic acid and triethylsilane at 50 °C, forming the
known advanced intermediate 4 in 81% yield. Compound
4 can be converted to the target natural product easily
according to Kita’s12 and Brimble’s13 procedure. It will be
noted that the structures of intermediates 5, 6, 25, and 26
are related to those of heliquinomycin (2) and griseorhodin
(3b). Therefore, they are potentially useful in the total
synthesis of these natural products.
Scheme 3. Synthesis of Naphthofuran Ketone 8
With the two key precursors in hand, a trial condensa-
tion and cyclization was tried using compound 8 and 18 as
substrates (Scheme 4). Under neutral Al2O3 conditions, 8
condensed with 18 and formed 19 in 62% yield. This was
followed by PdÀC catalyzed hydrogenation that yielded
compound 20 quantitively. After the removal of the
In summary, a formal synthesis of γ-rubromycin has
been achieved with a longest linear sequence of only 12
(20) (a) Maya, Y.; Ono, M.; Watanabe, H.; Haratake, M.; Saji, H.;
Nakayama, M. Bioconjugate Chem. 2008, 20, 95. (b) Venkatesan, A. M.;
Dos Santos, O.; Ellingboe, J.; Evrard, D. A.; Harrison, B. L.; Smith,
D. L.; Scerni, R.; Hornby, G. A.; Schechter, L. E.; Andree, T. H. Bioorg.
Med. Chem. Lett. 2010, 20, 824.
(21) In both acid-promoted dehydration and Al2O3-mediated elim-
ination, the substrates failed to dehydrate, which instead resulted in
complex mixtures. MsCl (1.2 equiv) and pyridine at 0 °C for 2 h afforded
compound 23 in a low yield.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 5. Completion of Advanced Spiroketal Intermediate 4
steps and 24% overall yield, using in situ generated
hypoiodite-catalytic cycloetherification as a key step. The
synthesis gave a good overall yield, and all the reactions
were not overly difficult to execute. This work presents a
novel catalytic application of hypoiodite reagents, which
represents a substantial achievement in the field of orga-
nohypervalent iodine chemistry. These results provide a
new and efficient approach to synthesizing γ-rubromycin,
as well as possible intermediates for other natural pro-
ducts. Further investigations in this field are underway.
Acknowledgment. We are grateful for the financial
support provided by Natural Science Foundation of China
(NSFC Nos. 21072084 and 21272099).
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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