General strategies for the synthesis of the major classes of C-aryl glycosides

Full text of DOI:10.1021/ja0108640

J. Am. Chem. Soc. 2001, 123, 6937-6938
6937
dihydronaphthols was known.6,7 However, sugars had never been
used in such constructions, and the feasibility of oxidizing the
intermediate, electron-rich dihydronaphthols efficiently to the
corresponding naphthols without accompanying dehydration was
clearly uncertain. To establish the underlying viability of this new
approach to C-aryl glycosides we embarked on a series of model
studies, some of which are summarized in Schemes 2-6. Our
first initiative was to determine whether a 2-glycosyl furan would
undergo a Diels-Alder reaction with benzynes. To address this
question, 4 was prepared (R:â 1:9) by the reaction of furan with
the glycosyl acetate 3 (Scheme 2).8 After some preliminary
experimentation using various bases and temperatures, we dis-
covered that 5 could be efficiently deprotonated ortho to the chloro
group using sec-BuLi at -95 °C. After furan 4 was added, the
mixture was allowed to warm slowly to room temperature during
which time benzyne generation and cycloaddition ensued to give
6.9 Acid-catalyzed rearrangement of 6 then delivered the Group
I C-aryl glycoside representative 7 as a single diastereomer in
excellent overall yield.
General Strategies for the Synthesis of the Major
Classes of C-Aryl Glycosides
David E. Kaelin, Jr., Omar D. Lopez, and Stephen F. Martin*
Department of Chemistry and Biochemistry
The UniVersity of Texas, Austin, Texas 78712
ReceiVed April 3, 2001
The C-aryl glycoside antibiotics, as exemplified by kidamycin
(1), constitute an important class of biologically active natural
products.1 While kidamycin represents a member of one subgroup
of this family, there are four common structural types of C-aryl
glycosides (Groups I-IV), which have been classified on the basis
of the substitution pattern of the sugar residue(s) and the hydroxyl
group(s) on the aromatic ring.2 Hence, one of the significant
challenges presented by these complex antibiotics lies in the
design and development of a unified strategy for the synthesis of
the four major subgroups of this family.3,4
Scheme 1
Scheme 2
Similarly, we found that the 3-glycosyl furan 9, which was
prepared by application of known procedures,10,11 reacted with
1,4-dimethoxybenzyne to give 10 in 91% yield (Scheme 3). The
acid-catalyzed rearrangement of 10 furnished a readily separable
mixture (10:1) of the Group II C-aryl glycoside model 11, which
was obtained as a single diastereomer, and the isomeric m-
substituted product. Oxidation of 11 with PhI(OAc)2 and reduction
of the quinone thus produced with Na2S2O4 gave the Group IV
C-aryl glycoside 12 in 70% overall yield.
Having demonstrated that representative C-aryl glycosides of
Groups I (i.e., 7), II (i.e., 11), and IV (i.e., 12) were accessible
via Path A of Scheme 1, it remained to prepare a model of the
more challenging Group III C-aryl glycosides. The key interme-
diate 2,4-diglycosyl furan 16 was first prepared by sequential
additions of metalated furans derived from 1312 to the glucose-
derived lactones 813 and 1514 followed by hydride reduction of
After considering a number of novel approaches to C-aryl
glycosides, we were attracted to the two pathways that are
summarized in Scheme 1. The acid-catalyzed rearrangement of
compounds related to 2, which are formed by cycloadditions of
furans and benzynes, was well-known to give naphthols (Path
A).5 However, C-furyl glycosides have never been employed as
dienes in such processes. As a precedent for the introduction of
a second sugar residue via Path B, it is relevant that opening of
oxabicyclic compounds 2 via an SN2′ reaction with carbanions
and via a palladium-catalyzed reaction with aryl iodides to give
(1) Hansen, M. R.; Hurley, L. H. Acc. Chem. Res. 1996, 29, 249 and
references therein.
(2) Parker, K. A. Pure Appl. Chem. 1994, 66, 2135.
(3) For reviews of C-glycoside synthesis, see: (a) Jaramillo, C.; Knapp,
S. Synthesis 1993, 1. (b) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides;
Elsevier Science: Tarrytown, NY, 1995. (c) Postema, M. H. D. In C-Glycoside
Synthesis; Rees, C. W., Ed.; CRC Press: Boca Raton, FL, 1995. (d) Nicotra,
F. Top. Curr. Chem. 1997, 187, 44. (e) Du, Y.; Linhardt, R. J. Tetrahedron
1998, 54, 9913.
(4) For selected approaches to C-aryl glycosides, see: (a) Parker, K. A.;
Koh, Y. H. J. Am. Chem. Soc. 1994, 116, 11149. (b) Hosoya, T.; Takashiro,
E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116, 1004. (c) Pulley,
S. R.; Carey, J. P. J. Org. Chem. 1998, 63, 5275. (d) McDonald, F. E.; Zhu,
H. Y. H. Tetrahedron 1997, 53, 11061. (e) Toshima, K.; Matsuo, G.; Ishizuka,
T.; Ushiki, Y.; Nakata, M.; Matsumura, S. J. Org. Chem. 1998, 63, 2307. (f)
Fuganti, C.; Serra, S. Synlett 1999, 1241. (g) Brimble, M. A.; Brenstrum, T.
J. Tetrahedron Lett. 2000, 41, 2991. (h) Matsumoto, T.; Yamaguchi, H.;
Tanabe, M.; Yasui, Y.; Suzuki, K. Tetrahedron Lett. 2000, 41, 8393. (i) Parker,
K. A.; Georges, A. T. Org. Lett. 2000, 2, 497.
(6) For reviews, see: (a) Chiu, P.; Lautens, M. Top. Curr. Chem. 1997,
190, 3. (b) Woo, S.; Keay, B, A. Synthesis 1996, 669.
(7) (a) Duan, J.-P.; Cheng, C.-H. Tetrahedron Lett. 1993, 34, 4019. (b)
Moinet, C.; Fiaud, J.-C. Tetrahedron Lett. 1995, 36, 2051. (c) Duan, J.-P.;
Cheng, C.-H.; Organometallics 1995, 14, 1608. (d) Feng, C.-C.; Nandi, M.;
Sambaiah,; Cheng, C.-H. J. Org. Chem. 1999, 64, 3538.
(8) Grynkiewicz, G.; BeMiller, J. N. Carbohydr. Res. 1984, 131, 273.
(9) All new compounds were purified (>95%) by flash chromatography
1
and were characterized by H and 13C NMR, IR, and HRMS. Cycloadducts
6, 10, and 17 were obtained as mixtures (ca 1:1) of diastereomers. Only the
â-anomers of 7, 11, 12, 18, 22, and 24 were observed (determined by 1H
NMR); the anomeric proton was a dd or a br d with one large (ax-ax, 10.9-
11.4 Hz) and one small (ax-eq, 1.9-2.1 Hz) coupling constant.
(10) Czernecki, S.; Ville, G. J. Org. Chem. 1989, 54, 610.
(11) Boyd, V. A.; Drake, B. E.; Sulikowski, G. A. J. Org. Chem. 1993,
58, 3191.
(5) For examples, see: (a) Giles, R. G. F.; Sargent, M. V.; Sianipar, H. J.
Chem. Soc., Perkin Trans. 1 1991, 1571. (b) Batt, D. G.; Jones, D. G.; La
Greca, S. J. J. Org. Chem. 1991, 56, 6704.
10.1021/ja0108640 CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/22/2001

6938 J. Am. Chem. Soc., Vol. 123, No. 28, 2001
Communications to the Editor
Scheme 3
Scheme 5
Scheme 4
Scheme 6
derived from dehydration, we eventually found that use of
recrystallized DDQ as the oxidant gave the naphthol 21. Reduction
of 21 by catalytic hydrogenation then delivered the Group II
C-aryl glycoside 22 as a single diastereomer.
Similarly, we found that the sugar-substituted cycloadduct 6
underwent ring opening, albeit under more forcing conditions,
with 19 to give intermediate dihydronaphthols that underwent
oxidation in situ to give 23 in 68% overall yield (Scheme 6).
Reduction of the glycal by catalytic hydrogenation then provided
the Group III C-aryl glycoside model 24.
We have thus developed general protocols for C-aryl glycoside
synthesis that may be applied to the efficient preparation of the
four major classes of C-aryl glycoside antibiotics. The first
approach showcases the cycloadditions of glycosyl furans with
benzynes followed by acid-catalyzed rearrangement of the
intermediate cycloadduct, whereas the second features the pal-
ladium-catalyzed, SN2′-like opening of furan-benzyne cycload-
ducts with iodo glycals. The application of regioselective variants
of these novel routes to the syntheses of naturally occurring C-aryl
glycoside antibiotics is the subject of several active investigations,
the results of which will be disclosed in due course.
the intermediate lactols (Scheme 4). Gratifyingly, when 1,4-
dimethoxybenzyne was generated in the presence of 16, smooth
cycloaddition ensued to deliver 17, which underwent facile acid-
catalyzed rearrangement to provide the Group III C-aryl glycoside
model 18 as a single diastereomer.
Even though we had convincingly established the general
applicability of the approach to C-aryl glycosides outlined in Path
A of Scheme 1, we were intrigued by the alternative approach of
Path B as it might possess some advantage in certain circum-
stances. In the event, we conducted a number of preliminary
experiments to determine whether glycosyl carbanions might
induce the SN2′ opening of 20. However, significant quantities
of ring-opened products could not be isolated. While the pos-
sibility remains that such reactions might prove useful, we were
attracted instead to the possibilities afforded by the palladium-
catalyzed reaction of iodo glycals such as 1915 with 20 according
to the precedent of Cheng and others.7 Indeed, we discovered
that the reaction of 19 with 20 proceeded readily under the
conditions optimized by Cheng to give a mixture (1:1) of the
diastereomeric cis-dihydronaphthol precursors of 21 (Scheme 5).
Although the oxidation of these dihydronaphthols to 21 under
numerous conditions gave substantial quantities of the naphthalene
Acknowledgment. We thank the Robert A. Welch Foundation, the
National Institutes of Health, Pfizer Inc., and Merck Research Laboratories
for their generous support of this research. We also thank Dr. Matthew
A. Marx for helpful suggestions.
Supporting Information Available: Experimental procedures for
compounds 7, 21, and 23, complete characterization (1H and 13C NMR,
IR, and mass spectral data) for 7, 11, 12, 18, 21, 22, 23, and 24, and
copies of 1H NMR spectra for all new compounds (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) Johanson, G.; Sundquist, S.; Nordvall, G.; Nilsson, B. M.; Brisander,
M. J. Med. Chem. 1997, 40, 3804.
(13) Pocker, Y.; Green, E. J. Am. Chem. Soc. 1974, 96, 166.
(14) Rollin, P.; Sinay¨, P. Carbohydr. Res. 1981, 98, 139.
(15) Friesen, R. W.; Loo, R. W.; Sturino, C. F. Can. J. Chem. 1994, 72,
1262.
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