Use of a Sonogashira - Acetylide Coupling Strategy for the Synthesis of the Aromatic Spiroketal Skeleton of γ-Rubromycin

Article abstract of DOI:10.1021/ol035723c

(Equation presented) The synthesis of the fused aromatic spiroketal core of γ-rubromycin is described via addition of an aryl acetylide fragment to an aryl acetaldehyde fragment. In turn, the aryl acetylene precursor was readily prepared with use of a Sonogashira reaction.

Full text of DOI:10.1021/ol035723c

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4425-4427
Use of a Sonogashira−Acetylide
Coupling Strategy for the Synthesis of
the Aromatic Spiroketal Skeleton of
γ-Rubromycin
,†
Kit Y. Tsang,† Margaret A. Brimble,* and John B. Bremner‡
Department of Chemistry, UniVersity of Auckland, 23 Symonds Street,
Auckland, New Zealand, and Department of Chemistry, UniVersity of Wollongong,
Northfields AVenue, Wollongong, NSW, Australia
m.brimble@auckland.ac.nz
Received September 9, 2003
ABSTRACT
The synthesis of the fused aromatic spiroketal core of γ-rubromycin is described via addition of an aryl acetylide fragment to an aryl acetaldehyde
fragment. In turn, the aryl acetylene precursor was readily prepared with use of a Sonogashira reaction.
While spiroketal ring systems are present as subunits in a
diverse range of bioactive natural products, thereby attracting
considerable attention1 from synthetic chemists, the presence
of spiroketals in which the oxygen atoms are derived from
two aromatic hydroxy groups is less common. The rubro-
mycins 1-3 (Figure 1) are a class of antibiotics isolated from
cultures of Streptomyces2 that exhibit activity against Gram-
positive bacteria. â-Rubromycin 2 and γ-rubromycin 3
exhibit potent inhibition of human telomerase,3 with IC50
values of 3 µM, and are active against the reverse tran-
scriptase of human immunodeficiency virus-1.4 These com-
pounds possess a unique aromatic spiroketal ring system in
which benzannelated furan and pyran rings share one carbon
atom to form a spiroketal system. The fact that R-rubromycin
1, which lacks this aryl spiroketal moiety, exhibits substan-
tially decreased inhibitory potency toward telomerase (IC50
> 200 µM), suggests that this spiroketal system plays an
essential role in the observed inhibition of telomerase.
Structurally related to the rubromycins are purpuromycin 4,5
a potential topical agent for vaginal infections,6 heliquino-
† University of Auckland.
‡ Universtity of Wollongong.
(1) Mead, K. T.; Brewer, B. N. Curr. Org. Chem. 2003, 7, 227-256.
(2) (a) Brockmann, H.; Lenk, W.; Schwantje, G.; Zeeck, A. Tetrahedron
Lett. 1966, 3525. (b) Brockmann, H.; Lenk, W.; Schwantje, G.; Zeeck, A.
Chem. Ber. 1969, 102, 126. (c) Brockmann, H.; Zeeck, A. Chem. Ber. 1970,
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Figure 1.
10.1021/ol035723c CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/21/2003

mycin 5,7 an inhibitor of DNA helicase, and griseorhodins
C 68 and G 7. All of these compounds can act as bioreductive
alkylating agents as postulated by Moore.9
Scheme 2
To date the only synthesis of a naturally occurring
bisbenzannelated spiroketal is the elegant total synthesis of
heliquinomycin 5 reported by Danishefsky et al.10 In this
case the key aromatic 1,6-dioxaspiro[4.5]decane ring system
was assembled via electrophilic spiroketalization of a naph-
thofuran bearing a phenolic hydroxyl group as the nucleo-
philic partner. This particular strategy was complicated by
the limited choice of a suitable electrophile that was
compatible with the highly electron-rich naphthalene ring.
The only other synthesis of a bisbenzannelated spiroketal as
present in γ-rubromycin 3 was reported by de Koning et
al.11 in which a Henry reaction was used to couple two aryl
moieties followed by use of a Nef reaction to liberate the
masked carbonyl group that induces the spiroketalization
step. In this case the Henry condensation and the Nef-type
reaction proceeded in moderate yield. We therefore herein
report the synthesis of several bisbenzannelated spiroketal
analogues of the naturally occurring antibiotic γ-rubromycin
3 (and related compounds) thereby adding to the synthetic
armory for construction of this important structural unit such
that its effect on the inhibition of human telomerase can be
probed.
and 15 (Scheme 2) to the acetylides derived from acetylenes
16 and 17. The versatility of this approach was further
realized by the facile preparation of acetylenes 16 and 17
via Sonogashira reaction12 with an appropriate readily
available aromatic halide (Scheme 3).
As part of our synthetic program directed toward the
synthesis of bioactive spiroketal-containing natural products
we investigated the assembly of the tetracyclic aryl spiro-
ketals 8-10 via disconnection to the methoxymethyl-
protected diphenolic ketones 11-13 (Scheme 1).
Scheme 3
Scheme 1
The aryl acetaldehydes 1411 and 15 were readily prepared
from allyl ethers 18 and 19 (Scheme 2) via Claisen
The strategy for assembly of these spiroketal precursors
11-13 focused on the addition of the aryl acetaldehydes 14
(8) Stroshane, R. M.; Chan, J. A.; Rubalcaba, E. A.; Garetson, A. L.;
Aszalos, A. A.; Roller, P. P. J. Antibiot. 1979, 32, 197.
(9) (a) Moore, H. W. Science 1977, 197, 527. (b) Moore, H. W.; Czerniak,
R. Med. Res. ReV. 1981, 1, 249.
(5) (a) Coronelli, C.; Pagani, H.; Bardone, M. R.; Lancini, G. C. J.
Antibiot. 1974, 27, 161. (b) Bardone, M. R.; Martinelli, E.; Zerilli, L. F.;
Cornelli, C. Tetrahedron 1974, 30, 2747.
(6) Trani, A.; Dallanoce, C.; Pranzone, G.; Ripamonti, F.; Goldstein, B.
P.; Ciabatti, R. J. Med. Chem. 1997, 40, 967.
(7) (a) Chino, M.; Nishikawa, K.; Umekia, M.; Hayashi, C.; Yamazaki,
T.; Tsuchida, T.; Sawa, T.; Hamada, M.; Takeuchi, T. J. Antibiot. 1996,
49, 752. (b) Chino, M.; Nishikawa, K.; Tsuchida, T.; Sawa, R.; Nakamura,
H.; Nakamura, K. T.; Muraoka, Y.; Ikeda, D.; Naganawa, H.; Sawa, T.;
Takeuchi, T. J. Antibiot. 1997, 50, 143.
(10) (a) Qin, D.; Ren, R. X.; Siu, T.; Zheng, C.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2001, 40, 4709. (b) Siu, T.; Qin, D.; Danishefsky, S. J.
Angew. Chem., Int. Ed. 2001, 40, 4713.
(11) (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.
(12) Tykwinski, R. R. Angew. Chem., Int. Ed. 2003, 42, 1566.
(13) Mabic, S.; Vaysse, L.; Benezra, C.; Lepoittevin, J.-P. Synthesis 1999,
1127.
4426
Org. Lett., Vol. 5, No. 23, 2003

rearrangement to phenols 20 and 21, protected as meth-
oxymethyl ethers 22 and 23, followed by either ozonolysis
or oxidative cleavage to aldehydes 14 or 15, respectively.
Sodium periodate cleavage of a diol was required in the latter
case to avoid the undesired formation of quinone byproducts
that were observed when ozonolysis was used.
Scheme 4
The acetylenes 16 and 17 were prepared (Scheme 3) by
Sonogashira coupling12 of methoxymethyl-protected aryl
iodides 26 (prepared from iodophenol 24) and 28 (prepared
from bromophenol 2513 via 2713) with 2-methyl-3-butyn-2-
ol followed by elimination of acetone from the resulting
acetylenes 29 and 30 upon heating with sodium hydroxide
in toluene. This two-step procedure provided a convenient
preparation of the desired acetylenes 16 and 17.
With the aryl acetaldehydes 14,15 and acetylenes 16,17
in hand, attention was directed to their union and subsequent
elaboration to the desired benzannelated spiroketals 8-10
(Scheme 4). Treatment of acetylenes 16 or 17 with n-
butyllithium (1.1 equiv) in THF at -78 °C for 30 min
followed by addition of the appropriate aldehyde 14 or 15
afforded the acetylenic alcohols 31-33 in moderate yield.
Oxidation of the propargylic alcohol proved problematic
hence the acetylenes were subjected to hydrogenation over
palladium on charcoal affording the saturated alcohols 34-
36 in high yield. Subsequent oxidation with tetrapropylam-
monium perruthenate and N-methylmorpholine-N-oxide then
proceeded uneventfully, providing the desired spiroketal
precursors 11-13. The final deprotection and spirocycliza-
tion step necessitated considerable experimentation with our
efforts leading to the use of bromotrimethylsilane as the
optimum reagent to effect deprotection of the methoxymethyl
ether groups and concomitant spirocyclization. Compatibility
of the reagent with the sensitivity of the bisbenzannelated
aryl spiroketals 8-10 thus formed was a key issue in the
present work.
spiroketal. The methodology provides ready access to a range
of benzannelated spiroketals to evaluate their inhibitory
activity against human telomerase.
Acknowledgment. We thank the New Zealand Founda-
tion for Research, Science and Technology for the award of
a Top Achiever Doctoral Scholarship to K.Y.T.
In summary, an efficient method for the construction of
the benzannelated spiroketal core of â-rubromycin 2, γ-ru-
bromycin 3, and related antibiotics has been developed. The
methodology combines the use of a Sonogashira reaction to
prepare an aryl acetylene fragment from, which the derived
acetylide readily adds to an aryl acetaldehyde fragment.
Subsequent oxidation and deprotection of the phenolic groups
under acidic conditions leads to formation of the aryl
Supporting Information Available: Experimental pro-
cedures and MS andNMR data for compounds 8 and 31.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL035723C
Org. Lett., Vol. 5, No. 23, 2003
4427