Total synthesis of (±)-δ-rubromycin

Article abstract of DOI:10.1021/ol400864f

Transition-metal-catalyzed spiroketalization cyclization has been performed successfully and has led to the first total synthesis of (±)-δ- rubromycin with a longest linear sequence of 18 steps from commercially available guaiacol in a 2.7% overall yield.

Full text of DOI:10.1021/ol400864f

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Total Synthesis of (()-δ-Rubromycin
Wenjing Wang, Jijun Xue,* Tian Tian, Jie Zhang, Liping Wei, Jidong Shao,
Zhixiang Xie, 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 March 29, 2013
ABSTRACT
Transition-metal-catalyzed spiroketalization cyclization has been performed successfully and has led to the first total synthesis of (()-δ-
rubromycin with a longest linear sequence of 18 steps from commercially available guaiacol in a 2.7% overall yield.
The rubromycin family, although known for more than
50 years,1 has continued to capture the attention of
synthetic chemists because of their range of antitumor
In the past few decades, much effort has been devoted to
the formation of natural products containing a bisbenzan-
nulated 5,6-spiroketal moiety.4 Danishefsky,5 Kita,6 and
Brimble7 have reported the total synthesis of heliquino-
mycinone and γ-rubromycin. However, the 5,6-spiroketal
core was not installed at a late stage, with the fully intact
naphthoquinone and isocoumarin subunits, until 2011 by
Pettus in his convergent total synthesis of γ-rubromycin.8
In spite of this investigation, the most striking problem
surrounding spiroketalization of the fully elaborated core
structure was “Electron Withdrawing Resonance & Induc-
tive Effects.”4e,j The cause principally stems from the
Figure 1. Selected members of the rubromycin family.
(4) (a) Capecchi, T.; de Koning, C. B.; Michael, J. P. Tetrahedron
Lett. 1998, 39, 5429. (b) Capecchi, T.; de Koning, C. B.; Michael, J. P.
J. Chem. Soc., Perkin Trans. 1 2000, 2681. (c) Stevens, J. L.; Welton,
T. D.; Deville, J. P.; Behar, V. Tetrahedron Lett. 2003, 44, 8901. (d)
Tsang, K. Y.; Brimble, M. A.; Bremner, J. B. Org. Lett. 2003, 5, 4425. (e)
Waters, S. P.; Fennie, M. W.; Kozlowski, M. C. Org. Lett. 2006, 8, 3243.
effects2 (see Figure 1). It is the 5,6-spiroketal moiety
that is responsible for the biological activity of these
compounds.3
€
(f) Sorgel, S.; Azap, C.; Reissig, H.-U. Org. Lett. 2006, 8, 4875. (g) Tsang,
K. Y.; Brimble, M. A. Tetrahedron 2007, 63, 6015. (h) Waters, S. P.;
Fennie, M. W.; Kozlowski, M. C. Tetrahedron Lett. 2006, 47, 5409. (i)
Brimble, M. A.; Flowers, C. L.; Trzoss, M.; Tsang, K. Y. Tetrahedron
2006, 62, 5883. (j) Venkatesh, C.; Reissig, H.-U. Synthesis 2008, 3605. (k)
Lowell, A. N.; Fennie, M. W.; Kozlowski, M. C. J. Org. Chem. 2011, 76,
6488. (l) Bandichhor, R.; Lowell, A. N.; Kozlowski, M. C. J. Org. Chem.
2011, 76, 6475.
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Angew. Chem., Int. Ed. 2001, 40, 4709. (b) Siu, T.; Qin, D.; Danishefsky,
S. J. Angew. Chem., Int. Ed. 2001, 40, 4713.
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Harada, S.; Kubo, O.; Morita, N.; Kita, Y. Angew. Chem., Int. Ed. 2007,
46, 7458.
(7) Rathwell, D. C. K.; Yang, S.-H.; Tsang, K. Y.; Brimble, M. A.
Angew. Chem., Int. Ed. 2009, 48, 7996.
(8) Wu, K.-L.; Mercado, E. V.; Pettus, T. R. R. J. Am. Chem. Soc.
(1) (a) Brockmann, H.; Renneberg, K. H. Naturwissenschaften 1953,
40, 59. (b) Brockmann, H.; Lenk, W.; Schwantje, G.; Zeeck, A. Chem.
Ber. 1969, 102, 126. (c) Brockmann, H.; Zeeck, A. Chem. Ber. 1970, 103,
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2000, 729. (b) Ishimi, Y.; Sugiyama, T.; Nakaya, R.; Kanamori, M.;
Kohno, T.; Enomoto, T.; Chino, M. FEBS J. 2009, 276, 3382. (c) Chino,
M.; Nishikawa, K.; Yamada, A.; Ohsono, M.; Sawa, T.; Hanaoka, F.;
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2011, 133, 6114.
r
10.1021/ol400864f
XXXX American Chemical Society

electron-withdrawing nature of the isocoumarin moiety,
which dramatically diminishes the nucleophilicity of the
corresponding phenol moiety. Difficulties in the applica-
tion of the convergent route to the natural product have
been reported by the research groups of Danishefsky,5
Kozlowski,4e and Reissig4j,13a in their respective synthetic
efforts toward heliquinomycinone and purpuromycin.
Therefore, it is an essential goal in the convergent synthesis
of the rubromycin family to find more suitable spiroketa-
lization processes with wider functional group tolerance.
Our investigations into the convergent synthesis of
rubromycins have resulted in several novel and efficient
processes for the construction of spiroketals, including
transition-metal-catalyzed tandem cyclizations,9 hetero-
DielsꢀAlder cycloadditions,10 and hypoiodite-catalyzed
cycloetherifications.11 More recently, a formal synthesis
of γ-rubromycin was achieved using in situ generated
hypoiodite-catalytic cycloetherification as a key step in
our lab.12 However, it could not be performed in a really
convergent way, so further effort was devoted on the
exploration of other more efficient spiroketalization
processes.9a In continuation of our work on transition-
metal-catalyzed cyclizations,9a herein we describe the first
total synthesis of (()-δ-rubromycin through a convergent
route. The process not only is highly efficient and
elegant but also makes great improvements to late stage
spiroketalization with fully intact naphthoquinone and
isocoumarin subunits.
Scheme 2. Synthesis of the Naphthoquinone 5
creating naphthalene rings in a regioselective manner.14
A new strategy was therefore designed for the synthesis
of naphthoquinone 5 (see Scheme 2), from the known
quinone 715 and diene 8.16 Gratifyingly, this reaction in
benzene at rt afforded a mixture of naphthoquinones 10
and 9 in 72% total yield and 2.6:1 ratio. Furthermore,
naphthoquinone 9 could be isolated and converted to
phenol 10 in quantitative yield. The selective reprotection
of phenol 10 with ethoxymethyl chloride (EOMCl) also
provided 11 in almost quantitative yield. The subsequent
ortho-selective iodination of phenol 11 proceeded to give
iodophenol 12, which was then methylated to yield
naphthoquinone 5 in a 74% yield for two steps and a
51% total yield from 7.
Our retrosynthetic analysis is outlined in Scheme 1.
We hypothesized that the entire 5,6-spiroketal moiety of
(()-δ-rubromycin could be prepared from the alkyne 4
through a transition-metal-catalyzed cascade spiroketali-
zation reaction,9a which might avoid the “Electron With-
drawing Resonance & Inductive Effects” and result in
nucleophilic attack of the complete isocoumarins. Obviously,
alkyne 4 could be convergently synthesized from the iso-
coumarin fragment 6 and the naphthalene fragment 5 by a
Sonogashira coupling reaction.
Scheme 3. Synthesis of Isocoumarin Moiety 6b and 21
Naphthoquinone fragment 5 is a highly functionalized
compound, and several research groups have already
Scheme 1. Retrosynthetic Analysis
encountered difficulties in the synthesis of its analogs.4e,13
The DielsꢀAlder reaction is an effective method for
For the isocoumarin alkyne 6b, its synthesis has not been
reported to date. However, there are several reported
(9) (a) Zhang, Y.; Xue, J.; Xin, Z.; Xie, Z.; Li, Y. Synlett 2008, 940. (b)
Xin, Z.; Zhang, Y.; Tao, H.; Xue, J.; Li, Y. Synlett 2011, 1579.
B
Org. Lett., Vol. XX, No. XX, XXXX

methods for the construction of similar isocoumarin
fragments.5,6,17 Accordingly, the synthesis of 6b was
designed as shown in Scheme 3, where a modified
SeyferthꢀGilbert reaction was used to construct the
alkyne, and the isocoumarin ring was synthesized following
Kita’s method.6 From alkene 13, prepared previously by
our group in 7 steps and 40% overall yield from com-
mercially available guaiacol,12 alcohol 14 was synthesized
in a 79% yield through hydroborationꢀoxidation. After
compound 14 was oxidized to the aldehyde 15 with PCC,
15 was treated with 16 in the presence of K2CO3; the
modified SeyferthꢀGilbert homologation proceeded,
and the alkyne 17 was efficiently obtained in a 98%
yield.18 Selective hydrolysis of the aliphatic ester 17 to
the carboxylic acid 18 was completed with 10% aqueous
KOH solution. Then the condensation of 18 and
(triphenylphosphoranylidene)acetonitrile 19 gave 20 in
a moderate yield. It was oxidized by dimethyldioxirane.
The cyclization of the intermediate progressed immedi-
ately, following treatment with potassium tert-butoxide,
to afford isocoumarin 6a in a 78% yield. Final deprotec-
tion with NaHSO4/SiO2 produced 6b. Similarly, alkyne
17 could also be converted to compound 21.
electron-withdrawing mesomeric effect of the isocoumarin
precursor 17 from the advanced alkyne 6a was expected to
increase the nucleophilicity of the phenol.7 With this in
mind, construction of the spiroketal core was attempted
initially using 5 with 17 as a model study. First, a trial
Sonogashira coupling of 5 and 17 was attempted under
various conditions7,19 (Scheme 4). Under strictly anhy-
drous conditions, the alkyne 22 was synthesized in a 72%
yield. After removing the EOM group, compound 23 was
formed and used in the construction of the spiroketal.
To our dismay, the aromatic spiroketal 25 could not be
obtained using our previously reported conditions.9a
Following treatment of PPh3AuCl/AgOTf in CH2Cl2,
benzofuran 24 formed in a high yield. Therefore, attempts
were devoted solely to the conversion of 24 to 25 using
various acids, such as TfOH, TFA, BF3.Et2O, CSA, NIS,
NBS, PPh3AuCl, AgOTf, PdCl2, and CuCl2, which re-
sulted in no conversion at all. These findings were attrib-
uted to impaired nucleophilic attack of the isocoumarin
phenolic oxygen atom. During this process, benzofuran 24
would cyclize in the presence of acid to intermediate
oxonium ion 240. In this intermediate, elimination to the
benzofuran derivative 24 would be much faster than
nucleophilic attack by the isocoumarin precursor hydroxy
function (Scheme 4). Finally, only a trace of the desired
spiroketal 25 was found by treating 24 with catalytic
amounts of AuCl and K2CO3.
Scheme 4. Model Studies for the Spiroketal Scaffold
With the knowledge gained from this prior attempt, it
was clear that nucleophilicity of the isocoumarin precursor
was not the only factor controlling the spiroketalization.
To circumvent formation of the benzofuran before nucleo-
philic attack of the isocoumarin phenolic oxygen atom we
designed a second-generation model study, in which the
construction of benzopyran was prior to the construction
of benzofuran (see Scheme 4). Naphthoquinone portion 5
and isocoumarin precursor 21 provided alkyne 26 via
Sonogashira coupling. Inthe presenceof catalytic amounts
of AuCl and K2CO3, the benzopyran 27 was synthesized
from compound 26 as a 5:1 mixture of Z/E isomers in an
excellent yield. We were pleased that treatment of the
€
(13) (a) Brasholz, M.; Sorgel, S.; Azap, C.; Reissig, H.-U. Eur. J. Org.
Chem. 2007, 3801. (b) Xie, X.; Kozlowski, M. C. Org. Lett. 2001, 3, 2661.
(c) Stevens, J. L.; Welton, T. D.; Deville, J. P.; Behar, V. Tetrahedron
Lett. 2003, 44, 8901. (d) Lowell, A. N.; Fennie, M. W.; Kozlowski, M. C.
€
J. Org. Chem. 2008, 73, 1911. (e) Sorgel, S.; Azap, C.; Reissig, H.-U. Eur.
J. Org. Chem. 2006, 4405.
(14) (a) Savard, J.; Brassard, P. Tetrahedron 1984, 40, 3455. (b) Kelly,
T. R.; Xu, W.; Ma, Z.; Li, Q.; Bhushan, V. J. Am. Chem. Soc. 1993, 115,
5843.
(15) Inman, M.; Moody, C. J. J. Org. Chem. 2010, 75, 6023.
(16) Prepared in two steps and 86% overall yield starting from methyl
acetoacetate: Elban, M. A.; Hecht, S. M. J. Org. Chem. 2008, 73, 785.
(17) (a) Lowell, A. N.; Wall, P. D.; Waters, S. P.; Kozlowski, M. C.
Tetrahedron 2010, 66, 5573. (b) Waters, S. P.; Kozlowski, M. C. Tetra-
hedron Lett. 2001, 42, 3567. (c) Thrash, T. P.; Welton, T. D.; Behar, V.
Tetrahedron Lett. 2000, 41, 29. (d) Brasholz, M.; Reissig, H.-U. Synlett
2004, 2736. (e) Brasholz, M.; Luan, X.; Reissig, H.-U. Synthesis 2005,
3571.
With the “Electron Withdrawing Resonance & Inductive
Effects” taken into consideration, elimination of the
(10) (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. (c) Li, X.; Xue, J.; Huang, C.; Li, Y. Chem.;Asian J. 2012, 7, 903.
(d) Wei, W.; Wang, Y.; Yin, J.; Xue, J.; Li, Y. Org. Lett. 2012, 14, 1158.
(11) Wei, W.; Li, L.; Lin, X.; Li, H.; Xue, J.; Li, Y. Org. Biomol.
Chem. 2012, 10, 3494.
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R. J. K. Tetrahedron 2006, 62, 6673. (b) Gung, B. W.; Dickson, H. Org.
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Lett. 2002, 4, 2517. (c) Roth, G. J.; Liepold, B.; Muller, S. G.; Bestmann,
H. J. Synthesis 2004, 59.
(19) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467. (b) Hiroya, K.; Suzuki, N.; Yasuhara, A.; Egawa, Y.;
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Org. Lett., Vol. XX, No. XX, XXXX
C

benzopyran 27 with 10 mol % AgOTf afforded the desired
spiroketal 25 in 87% yield. Following reduction and
permethylation,20 the spiroketal 25 could perhaps be con-
verted to the natural product (()-δ-rubromycin according
to the procedure reported by Brimble7 and Kita.6
As opposed to the problem seen with “Electron Withdrawing
Resonance & Inductive Effects,” nucleophilic attack of the
phenolic hydroxyl group of isocoumarin proceeded effi-
ciently. The effect of the isocoumarin electron-withdrawing
groups has also been studied by Kozlowski and
co-workers recently.4k Failure to spiroketalize was shown
to be a result of oxidation of a naphthalene subunit to the
naphthaquinone, not the nucleophilicity of the isocou-
marin phenol. Attention was now paid to the conversion
of compound 28 to 29. The conditions that were used to
convert 27 to 25 failed in the transformation of the
benzopyran 28 to the spiroketal 29. Therefore, alternate
conditions for the deprotection and cyclization were
explored. TsOH, PPh3AuCl, PdCl2(PPh3)2, and Pd(OAc)2
did not give any of the desired product. Similar to the removal
of the EOM group of 22, the benzopyran 28 was treated
with NaHSO4/SiO2 in dichloromethane, and the desired
spiroketal 29 formed in 80% yield. Final deprotection with
BBr3 produced 1.8 The spectroscopic data were identical to
those reported in the literature.2a
Scheme 5. Convergent Total Synthesis of (()-δ-Rubromycin
In summary, the first total synthesis of (()-δ-rubromycin
has been achieved through a convergent strategy with a
longest linear sequence of 18 steps from commercially
available guaiacol in a 2.7% overall yield. Palladium,
gold, and silver reagents were screened in the spiroketaliza-
tion of different precursors. A Danishefsky-type Dielsꢀ
Alder reaction was employed to install the requisite highly
functionalized aromatic ring system of the naphthalene
portion 5, in a very short sequence, which makes the total
synthesis of this natural product more efficient and elegant.
This synthesis avoids the “Electron Withdrawing Resonance
& Inductive Effects” and provides a new idea for the
construction of spiroketals, as well as an efficient and
convergent approach to synthesizing rubromycins.
Encouraged by the successful spiroketalization of com-
pound 26 to 25, a more convergent strategy for the first
total synthesis of (()-δ-rubromycin was designed (see
Scheme 5). According to the successful Sonogashira cou-
pling conditions of 5 and 17/21, the benzopyran 28resulted
along with 4b, as a 4:1 mixture of E/Z isomers in a 35%
yield. Unfortunately, transformation of the alkyne 4b to
benzopyran 28 gave no desired product with the AuCl/
K2CO3 catalyst, even over a very long time. With for-
mation of 28 in mind, PdCl2(PPh3)2 was taken into con-
sideration as a possible Sonogashira catalyst. With satis-
faction, compound 28 was obtained by the intramolecular
cyclization of the alkyne 4b catalyzed by PdCl2(PPh3)2.
Acknowledgment. We are grateful for the financial
support provided by the 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.
(20) Kraus, G. A.; Man, T. O. Synth. Commun. 1986, 16, 1037.
The authors declare no competing financial interest.
D
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