Concise three-component synthesis of defucogilvocarcin M

Article abstract of DOI:10.1021/ol049261u

(Matrix Presented) Concise synthesis of defucogilvocarcin M was achieved via the [2 + 2 + 2] approach to β-phenylnaphthalene structure.

Full text of DOI:10.1021/ol049261u

ORGANIC
LETTERS
2004
Vol. 6, No. 15
2503-2505
Concise Three-Component Synthesis of
Defucogilvocarcin M
Isao Takemura, Koreaki Imura, Takashi Matsumoto, and Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, and CREST,
Japan Science and Technology (JST) Agency, 2-12-1, O-okayama, Meguro-ku,
Tokyo 152-8551, Japan
ksuzuki@chem.titech.ac.jp
Received April 22, 2004
ABSTRACT
Concise synthesis of defucogilvocarcin M was achieved via the [2 + 2 + 2] approach to â-phenylnaphthalene structure.
We report herein a new, efficient synthetic route to de-
fucogilvocarcin M (1a), representing the chromophore of the
gilvocarcin-class antibiotics (Figure 1).1-3 The necessity of
developing a new process emerged during our first synthesis
of ravidomycin (1d), an amino sugar congener of this class
of antibiotics. Although the synthesis was achieved by
adopting the scheme that had been effective for the neutral
sugar congeners 1b and 1c, several problems arose as a result
of the presence of a dimethylamino group in 1d. More steps
were required, and some transformations were capricious due
to the deactivation of Lewis acids or transition metal
catalysts.4
(1) For a review on the gilvocarcin-class antibiotics, see: Hua, H. H.;
Saha, S. Recl. TraV. Chim. Pays-Bas 1995, 144, 341-355.
(2) For isolation and structure determination of the gilvocarcin-
ravidomycin class antibiotics, see the following. (a) Gilvocarcin V and M:
Horii, S.; Fukase, H.; Mizuta, E.; Hatano, K.; Mizuno, K. Chem. Pharm.
Bull. 1980, 28, 3601-3611. Takahashi, K.; Yoshida, M.; Tomita, F.;
Shibahara, K. J. Antibiot. 1981, 34, 271-275. Hirayama, N.; Takahashi,
K.; Shibahara, K.; Ohashi, Y.; Sasade, Y. Bull. Chem. Soc. Jpn. 1981, 54,
1338-1342. (b) Ravidomycin: Findlay, J. A.; Liu, J.-S.; Radics, L.; Rakhit,
S. Can. J. Chem. 1981, 59, 3018-3020. (c) Deacetylravidomycin M: Arai,
M.; Tomoda, H.; Matsumoto, A.; Takahashi, Y.; Woodruff, B. H.; Ishiguro,
N.; Kobayashi, S.; Omura, S. J. Antibiot. 2001, 54, 554-561. (d)
Defucogilvocarcin V: Misra, R.; Tritch, H. R., III; Pandey, R. C. J. Antibiot.
1985, 38, 1280-1283. (e) Defucogilvocarcin M (Mer-1020dE): Nakashima,
T.; Fujii, T.; Sakai, K.; Sameshima, T.; Kumagai, H.; Yoshioka, T. PCT
Patent Appl. WO98/22612 A1, 1998.
(3) For the synthesis of defucogilvocarcins, see: (a) Patten, A. D.;
Nguyen, N. H.; Danishefsky, S. J. J. Org. Chem. 1988, 53, 1528. (b) McGee,
R. L.; Confalone, P. N. J. Org. Chem. 1988, 53, 3695-3701. (c) Jung, M.
E.; Jung, Y. H. Tetrahedron Lett. 1988, 29, 2517-2520. (d) McKenzie, T.
C.; Hassen, W.; Macdonald, S. J. F. Tetrahedron Lett. 1987, 28, 5435-
5436. (e) Hart, D. J.; Merriman, G. H. Tetrhedron Lett. 1989, 30, 5093-
5096. (f) Deshpande, P. P.; Martin, O. R. Tetrahedron Lett. 1990, 31, 6313-
6316. (g) James, C. A.; Snieckus, V. Tetrahedron Lett. 1997, 38, 8149-
8152.
Figure 1. Gilvocarcin-class antibiotics (M and V represent the
C(8) substituent (R) methyl and vinyl, respectively).
10.1021/ol049261u CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/29/2004

Thus, we decided to pursue synthetic routes that would
be viable in the presence of such basic functionality. Our
idea was to exploit molecular strain in several pericyclic
processes to avoid the use of catalysts or promoters.
As the prelude to a second-generation total synthesis of
ravidomycin (1d), we now describe a flexible, efficient access
to its chromophore, using a [2 + 2 + 2] cycloaddition/
pericyclic cyclization approach (Scheme 1). A three-step
cyclobuten(di)one derivatives with varying oxidation patterns,
including the ones that possess C-glycoside motifs (Figure
2).
We reasoned that benzocyclobutenone 2, among others,
would be best suited for the present purpose; this could be
readily prepared as reported (Scheme 2).5e Importantly, the
Scheme 2. Preparation of Benzocyclobutenone 2
Scheme 1. [2 + 2 + 2] Route to â-Phenylnaphthalene Cores
strained carbonyl group in 2 would serve as an effective
platform for the facile introduction of a styryl unit. Concern-
ing the subsequent ring expansion step (see step 3 in Scheme
1), we had positive data accumulated for the related but
simpler substrates.6,7
process was envisioned that identified the â-phenylnaphtha-
lene as a key structural motif: The first stage would involve
[2 + 2] cycloaddition of the benzyne I to the olefin II to
give the benzocyclobutene III. The second step would
introduce an additional two carbons in the form of a styryl
unit to give IV, and finally, sequential pericyclic reactions
would form the dihydronaphthalene VI. Through the release
of molecular strain in the whole process, spontaneous
conversion would hopefully occur to furnish the requisite
â-phenylnaphthalene structure.
Scheme 3 shows how the styryl bromide 6 was prepared;
it is the building block needed for introducing the styryl
Scheme 3. Preparation of Styryl Bromide 6
Our plan was predicated upon the known regioselective
[2 + 2] cycloaddition of R-alkoxybenzynes with ketene silyl
acetals,5 which provides a generous repertoire of benzo-
moiety. Triflate 38 was subjected to Sonogashira reaction9
with trimethylsilylacetylene to give, after desilylation, acet-
ylene 4. Selective addition of hydrogen bromide to the triple
(4) For the total synthesis of ravidomycin, see: (a) Futagami, S.; Ohashi,
Y.; Imura, K.; Ohmori, K.; Matsumoto, T.; Suzuki, K. Tetrahedron Lett.
2000, 41, 1063-1066. For the total synthesis of gilvocarcin M and V, see:
(b) Matsumoto, T.; Hosoya, T.; Suzuki, K. J. Am. Chem. Soc. 1992, 114,
3568-3570. Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am.
Chem. Soc. 1994, 116, 1004-1015.
Figure 2. Various benzocyclobutenones available.
2504
Org. Lett., Vol. 6, No. 15, 2004

bond was then effected by using Et4N+(HBr2)-,10 giving
the vinyl bromide 5 in excellent yield. Conversion of
ester 5 into 1,3-dioxane acetal 6 was effected by reduc-
tion of the ester moiety with LiAlH4, oxidation of the
resulting benzyl alcohol, and acetalization of the aldehyde
so formed.
Scheme 4. Total Synthesis of Defucogilvocarcin M
Scheme 4 shows a short synthesis of defucogilvocarcin
M (1a). Benzocyclobutenone 25e was coupled with the
vinyllithium species generated from vinyl bromide 6, giving
adduct 7 in quantitative yield (THF, -78 °C, 5 min), ready
for the key ring enlargement. We were pleased to find that,
upon thermolysis of 7 in refluxing toluene for 8.5 h,
naphthalene 8 was obtained in 95% yield after acetylation
of the crude products.11 Note that the product was fully
aromatized by the in situ elimination of a mole of methanol.
Hydrolysis of the acetal moiety in 8 with 80% acetic acid
(room temperature, 4 h) gave the corresponding aldehyde
in 98% yield, which was oxidized with NaClO2 (NaH2PO4,
2-methyl-2-butene, H2O, acetone, room temperature, 15 min)
and converted to lactone 9 in 98% yield by methanolysis of
the acetate followed by acidification. Final debenzylation was
cleanly effected by hydrogenolysis on 10% Pd-C in a THF/
DMF solvent mixture (12/1, v/v), giving defucogilvocarcin
(5) For the [2 + 2] cycloaddition of benzynes and ketene silyl acetals,
see: (a) Hosoya, T.; Hasegawa, T.; Kuriyama, Y.; Matsumoto, T.; Suzuki,
K. Synlett 1995, 177-179. (b) Hosoya, T.; Hasegawa, T.; Kuriyama, Y.;
Suzuki, K. Tetrahedron Lett. 1995, 36, 3377-3380. (c) Hosoya, T.; Hamura,
T.; Kurayama, Y.; Miyamoto, M.; Matsumoto, T.; Suzuki, K. Synlett 2000,
520-522. (d) Matsumoto, T.; Yamaguchi, H.; Hamura, T.; Tanabe, M.;
Kuriyama, Y.; Suzuki, K. Tetrahedron Lett. 2000, 41, 8383-8387. (e)
Hamura, T.; Hosoya, T.; Yamaguchi, H.; Kuriyama, Y.; Tanabe, M.;
Miyamoto, M.; Yasui, Y.; Matsumoto, T.; Suzuki, K. HelV. Chim. Acta
2002, 85, 3589-3604.
(6) For our contribution in this area, see: Matsumoto, T.; Hamura, T.;
Miyamoto, M.; Suzuki, K. Tetrahedron Lett. 1998, 39, 4853-4856. Hamura,
T.; Miyamoto, M.; Matsumoto, T.; Suzuki, K. Org. Lett. 2002, 4, 229-
232. Hamura, T.; Miyamoto, M.; Imura, K.; Matsumoto, T.; Suzuki, K.
Org. Lett. 2002, 4, 1675-1678. Hamura, T.; Tsuji, S.; Matsumoto, T.;
Suzuki, K. Chem. Lett. 2002, 280-281.
(7) (a) For reviews on related reactions, see: Moore, H. W.; Yerxa, B.
R. Chemtracts 1992, 5, 273-313. Liebeskind, L. S. Tetrahedron 1989, 45,
3053-3060. (b) For leading references, see: Jackson, D. K.; Narasimhan,
L.; Swenton, J. S. J. Am. Chem. Soc. 1979, 101, 3989-3990. Liebeskind,
L. S.; Iyer, S.; Jewell, C. F., Jr. J. Org. Chem. 1986, 51, 3067-3068.
Hickman, D. N.; Wallace, T. W.; Wardleworth, J. M. Tetrahedron Lett.
1991, 32, 819-822. Perri, S. T.; Foland, L. D.; Decker, O. H. W.; Moore,
H. W. J. Org. Chem. 1986, 51, 3067-3068.
M (1a) in 85% yield. All spectroscopic data of the synthetic
material was fully consistent with the literature data.12
In conclusion, we have reported a short total synthesis of
defucogilvocarcin M that now provides efficient access to
the core skeleton of the gilvocarcin-ravidomycin class of
antibiotics. Simplicity and efficiency of the overall process
should contribute to the future realization of a new synthesis
of ravidomycin and its congeners. Further studies along these
lines are now in progress in our laboratories.
Acknowledgment. Partial financial support by 21st
Century COE Program is gratefully acknowledged.
Supporting Information Available: Spectroscopic and
analytical data of the compounds in Schemes 3 and 4 and
the synthetic sample of defucogilvocarcin M (1a). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(8) Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. Tetrahedron
Lett. 1994, 35, 4591-4594. Hosoya, T.; Takashiro, E.; Yamamoto, Y.;
Matsumoto, T.; Suzuki, K. Heterocycles 1996, 42, 397-414.
(9) Cousseau, J. Synthesis 1980, 805-806.
(10) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467-4470.
(11) Protection of the phenol was necessary, because further conversion
otherwise did not work. Upon hydrolysis of the acetal without protection
of the phenol, spontaneous cyclization occurred to give the corresponding
lactol, which failed to undergo oxidation to the desired lactone 9 under a
variety of conditions, giving only the corresponding quinone instead.
OL049261U
(12) We thank Drs. Isshiki and Nakashima, Mercian Co., for authentic
1H and 13C NMR spectra of 1a.
Org. Lett., Vol. 6, No. 15, 2004
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