Iterative benzyne-furan cycloaddition reactions: Studies toward the total synthesis of ent-Sch 47554 and ent-Sch 47555

Article abstract of DOI:10.1021/ol061007+

7-Fluoro-5,8-dimethoxy-1-naphthol, prepared from the lithiation and benzyne formation from 1,4-difluoro-2,5-dimethoxybenzene and Diels-Alder cycloaddition with furan, was sequentially C-glycosidated under Suzuki conditions and O-glycosidated using di-O-ac

Full text of DOI:10.1021/ol061007+

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2859-2861
Iterative Benzyne−Furan Cycloaddition
Reactions: Studies toward the Total
Synthesis of ent-Sch 47554 and ent-Sch
47555
Gillian E. Morton and Anthony G. M. Barrett*
Department of Chemistry, Imperial College London, South Kensington,
London SW7 2AZ, England
agmb@imperial.ac.uk
Received April 27, 2006
ABSTRACT
7-Fluoro-5,8-dimethoxy-1-naphthol, prepared from the lithiation and benzyne formation from 1,4-difluoro-2,5-dimethoxybenzene and Diels
Alder cycloaddition with furan, was sequentially C-glycosidated under Suzuki conditions and O-glycosidated using di-O-acetyl- -rhamnal to
provide the corresponding -naphthyl C,O-disaccharide. Further lithiation, benzyne formation, and cycloaddition with furan gave an oxa-
bridged 1,4-dihydroanthracenyl C,O-disaccharide, a model compound relevant to the total synthesis of Sch 47555.
−
L
â
Sch 47554 (1) and Sch 47555 (2) (Figure 1) are two
angucycline antibiotics1 that were isolated at Schering-Plough
from the fermentation broths of a strain of Streptomyces sp.
(SCC-2136), originally isolated from a Canadian soil sample.2
Both compounds showed antifungal activities against a
variety of yeasts and dermatophytes including Candida
albicans, Candida tropicalis, Candida stellatoidea, Tricho-
phyton mentagrophytes, Trichophyton rubrum, Trichophyton
tonsurans, and Microsporum canis with the greater activity
shown by Sch 47554 (1).2 As part of our ongoing interest in
diverse biologically active benz[a]anthracene antibiotics,3 we
wished to explore the use of 1,4-difluoro-2,5-dimethoxy-
benzene (7), an equivalent of the double benzyne 1,4-
dimethoxycyclohexa-1,2,3-trien-5-yne,4 in the synthesis of
model anthraquinones structurally related to the ring ABC
unit of Sch 47554 (1).
(1) Rohr, J.; Thiericke, R. Nat. Prod. Rep. 1992, 9, 103.
(2) Chu, M.; Yarborough, R.; Schwartz, J.; Patel, M. G.; Horan, A. C.;
Gullo, V. P.; Das, P. R.; Puar, M. S. J. Antibiot. 1993, 46, 861.
(3) Thomson, R. H. Naturally Occurring Quinones III; Chapman and
Hall: New York, 1987.
Figure 1. Sch 47554 (1) and Sch 47555 (2).
10.1021/ol061007+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/02/2006

To construct the A-C ring unit of Sch 47554 (1), we
sought to utilize O-glycosidation of naphthol 6, O to C trans-
glycosidation, and subsequent further glycosidation via a
Ferrier-type rearrangement25 using glycal 4. We have previ-
ously reported the synthesis of naphthol 6 from 1,4-difluoro-
2,5-dimethoxybenzene (7) via a benzyne-furan Diels-Alder
reaction (Scheme 1).4 However, the O to C trans-glycosi-
dation does pose several potential problems. It is known that
the rearrangement of a naphthol with a halide substituent at
C-3 is inefficient and only provides C-glycosides in very
poor yields (<5%).11,26,27 These results likely arise through
perturbation by the halide substituent reducing electron
density at the position ortho to the naphthol. Nonetheless,
Suzuki has described the use of a catalytic quantity of
scandium triflate16 or excess hafnocene dichloride and silver
perchlorate21 to mediate the rearrangement of halo-substituted
O-glycosides to provide C-glycosides in good to excellent
yields. As convenient model studies, we sought to prepare
the naphthyl disaccharide 8 (Figure 8) and related compounds
Scheme 1. Retrosynthesis of Sch 47554 (1)
The synthesis of C-aryl glycosides from the Lewis acid
catalyzed rearrangement of the corresponding O-glycosides
is well documented as a powerful method for their construc-
tion from simple precursors in a regio- and stereocontrolled
manner when the glycoside is ortho to a phenol or naphthol
unit.5-8 Lewis acids including boron trifluoride etherate,9-14
tin tetrachloride,15 scandium triflate,16 trimethylsilyl tri-
flate,17,18 and Cp2MCl2-AgClO4 (M ) Zr, Hf)19-24 have been
used to catalyze the reaction. In this rearrangement, the
choice of Lewis acid is critical to the yield and the
stereoselectivity of the transformation.
Figure 2. Target model disaccharide 8.
corresponding to the enantiomers of the A-C ring units of
the natural products 1 and 2.
(4) Morton, G. E.; Barrett, A. G. M. J. Org. Chem. 2005, 70, 3525.
(5) Du, Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998, 54, 9913.
(6) Bililign, T.; Griffith, B. R.; Thorson, J. S. Nat. Prod. Rep. 2005, 22,
742.
(7) Jaramillo, C.; Knapp, S. Synthesis 1994, 1.
(8) Postema, M. H. D. Tetrahedron 1992, 48, 8545.
(9) Matsumoto, T.; Katsuki, M.; Suzuki, K. Tetrahedron Lett. 1988, 29,
6935.
(10) Kometani, T.; Kondo, H.; Fujimori, Y. Synthesis 1988, 1005.
(11) Brimble, M. A.; Davey, R. M.; McLeod, M. D.; Murphy, M. Aust.
J. Chem. 2003, 56, 787.
(12) Kumazawa, T.; Onda, K.; Okuyama, H.; Matsuba, S.; Sato, S.;
Onodera, J. Carbohydr. Res. 2002, 337, 1007.
(13) Andrews, F. L.; Larsen, D. S.; Larsen, L. Aust. J. Chem. 2000, 53,
15.
(14) Andrews, F. L.; Larsen, D. S. Tetrahedron Lett. 1994, 35, 8693.
(15) Matsumoto, T.; Hosoya, T.; Suzuki, K. Tetrahedron Lett. 1990, 31,
4629.
(16) Ben, A.; Yamauchi, T.; Matsumoto, T.; Suzuki, K. Synlett 2004,
225.
(17) Mahling, J.-A.; Schmidt, R. R. Synthesis 1993, 325.
(18) Toshima, K.; Matsuo, G.; Ishizuka, T.; Ushiki, Y.; Nakata, M.;
Matsumura, S. J. Org. Chem. 1998, 63, 2307.
(19) Matsumoto, T.; Maeta, H.; Suzuki, K.; Tsuchihashi, G. Tetrahedron
Lett. 1988, 29, 3567.
(20) Suzuki, K. Pure Appl. Chem. 1994, 66, 2175.
(21) Matsumoto, T.; Yamaguchi, H.; Suzuki, K. Tetrahedron 1997, 53,
16533.
The glycosyl donor ent-5 was synthesized from di-O-
acetyl-L-rhamnal (4)28 following reaction with water at 80
°C11 to provide the trans-alkene 9,29 which was directly
hydrogenated at ambient pressure to provide the lactol 1030
(Scheme 2). Subsequent acetylation gave the diacetate ent-
5. Scandium triflate or hafnocene dichloride and silver
perchlorate promoted condensation of the aryl fluoride 6 and
acetate ent-5 gave the desired equatorial C-aryl glycoside
11 (44% or 59% respectively) as a single diastereoisomer
(Scheme 2). O-Methylation proceeded smoothly to provide
naphthalene 12, which was saponified using methanolic
potassium carbonate to give alcohol 13. Ferrier-type rear-
rangement of di-O-acetyl-D-rhamnal31 (ent-4) in the presence
of alcohol 13 promoted by indium trichloride32 gave acetate
(25) Ferrier, R. J.; Prasad, N. J. Chem. Soc. C 1969, 570.
(26) Brimble, M. A.; Brenstrum, T. J. Tetrahedron Lett. 2000, 41, 1107.
(27) Brimble, M. A.; Brenstrum, T. J. J. Chem. Soc., Perkin Trans. 1
2001, 1612.
(28) Renneberg, B.; Li, Y.; Laatsch, H.; Fiebig, H. Carbohydr. Res.
2000, 329, 861.
(29) Lau, J.; Pedersen, E. B.; Nielsen, C. M. Acta Chem. Scand. 1991,
45, 616.
(30) Oberthu¨r, M.; Leimkuhler, C.; Kahne, D. Org. Lett. 2004, 6, 2873.
(31) Torii, S.; Inokuchi, T.; Masatsugu, Y. Bull. Chem. Soc. Jpn. 1985,
58, 3629.
(22) Matsumoto, T.; Katsuki, M.; Jona, H.; Suzuki, K. J. Am. Chem.
Soc. 1991, 113, 6982.
(23) Hosoya, T.; Ohashi, Y.; Matsumoto, T.; Suzuki, K. Tetrahedron
Lett. 1996, 37, 663.
(24) Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem.
Soc. 1994, 116, 1004.
2860
Org. Lett., Vol. 8, No. 13, 2006

Scheme 2. Synthesis of Disaccharide 16
Scheme 3. Synthesis of the Ring A-C Unit 8 and
Cycloaddition with Furan
In summary, we have successfully prepared enantiomeric
model ring A-C disaccharide units 16 and 8 for Sch 47554
(1) and Sch 47555 (2) from difluoride 7 using O to C trans-
glycosidation and a Ferrier-type O-glycosidation. In addition,
the fluoride 8 was converted into the corresponding benzyne,
which was trapped with furan in a Diels-Alder reaction.
Further investigations into the total synthesis of Sch 47554
(1) and Sch 47555 (2) will be reported in due course.
14 (78%). The full structure and relative stereochemistry of
C-glycoside 14 was confirmed by X-ray crystallographic
structure determination. Subsequently enone 16 was prepared
in two steps (69%) by hydrolysis of acetate 14 using
potassium carbonate in methanol followed by immediate
oxidation of the unstable alcohol 15 using manganese
dioxide.
Acknowledgment. We thank GlaxoSmithKline for the
generous endowment (to A.G.M.B.), the Royal Society and
the Wolfson Foundation for a Royal Society Wolfson
Research Merit Award (to A.G.M.B.), the Wolfson Founda-
tion for establishing the Wolfson Centre for Organic
Chemistry in Medical Sciences at Imperial College, and the
Engineering and Physical Sciences Research Council for
generous support of our studies. We additionally thank Dr.
Andrew P. White (Imperial College) for X-ray crystal
structure determinations and Peter R. Haycock and Richard
N. Sheppard (both at Imperial College) for high-resolution
NMR spectroscopy.
Hydrogenation of alkene 14 and subsequent saponification
gave the ring A-C unit of ent-Sch 47555 18 (90%). In
contrast saponification of 14 followed by hydrogenation
resulted in extensive decomposition. To examine benzyne
formation, alcohol 18 was protected as the benzyl ether 8
(83%) and allowed to react with n-butyllithium and furan.
This gave the cycloadduct 19 (85%) as a 1:1 mixture of
diastereoisomers (Scheme 3). Cycloadduct 19 was allowed
to react with acetic acid in tetrahydrofuran at reflux to give
the C-aryl glycoside 20 (66%). Clearly, the disaccharide unit
proved to be more prone to cleavage than the oxa-bridged
1,4-dihydroanthracenyl unit under acidic conditions.
Supporting Information Available: Experimental pro-
cedures and structural data for all new compounds; X-ray
1
crystallographic structure for 14 (CIF); copies of H NMR,
13C NMR, and NOESY NMR spectra for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(32) Babu, B. S.; Balasubramanian, K. K. Tetrahedron Lett. 2000, 41,
1271.
OL061007+
Org. Lett., Vol. 8, No. 13, 2006
2861