Synthetic studies directed toward the assembly of the C-glycoside fragment of the telomerase inhibitor D8646-2-6

Article abstract of DOI:10.1021/ol034873k

(Matrix presented) Construction and characterization of the C-glycosidic moiety of telomerase inhibitor D8646-2-6 (1) are described. This is the first example of the C-glycosylation using electron-poor aromatics, 4-hydroxypyrone, as a glycosyl acceptor. T

Full text of DOI:10.1021/ol034873k

ORGANIC
LETTERS
2003
Vol. 5, No. 16
2837-2839
Synthetic Studies Directed toward the
Assembly of the C-Glycoside Fragment
of the Telomerase Inhibitor D8646-2-6
Akira Kanai,†,‡ Tomoyuki Kamino,†,‡ Kouji Kuramochi,‡ and
,†,‡
Susumu Kobayashi*
Frontier Research Center for Genomic Drug DiscoVery and Faculty of
Pharmaceutical Sciences, Tokyo UniVersity of Science, 2641 Yamazaki,
Nodashi, Chiba 278-8510, Japan
kobayash@rs.noda.tus.ac.jp
Received May 19, 2003
ABSTRACT
Construction and characterization of the C-glycosidic moiety of telomerase inhibitor D8646-2-6 (1) are described. This is the first example of
the C-glycosylation using electron-poor aromatics, 4-hydroxypyrone, as a glycosyl acceptor. The glycosylation reaction and base-promoted
isomerization affords desired â-C-glycoside in a 61% overall yield.
D8646-2-6 (1) was isolated as an inhibitor of telomerase from
the culture broth of Epicoccum purpurascens by the Mit-
subishi Pharma Corporation group.1 It has a unique C3-py-
ranosyl 4-hydroxypyrone structure with a conjugated hep-
taene side chain. The relative and absolute stereochemistry
of 1 have not been determined. Analysis of the reported 1H
NMR data of 1 strongly suggests a C3-â-galactopyranosyl-
4-hydroxypyrone structure, although the chirality of the two
centers in the side chain is not known. The galactopyranosyl-
4-hydroxypyrone structure is quite interesting when com-
pared to C-glycosides containing phenol or naphthol deriva-
tives as aryl units.2 There are some examples of 4-hydroxypy-
rones connected to a 4-deoxyglucose as sugar moiety, and
most of them have antifungal activity.3 The most challenging
step in the synthesis of 1 involves the construction of the
pyranosyl 4-hydroxypyrone moiety. The R-pyrone moieties
of meroterpenoids (mixed polyketide-terpenoid metabolites)
are usually constructed by the cyclization of the correspond-
ing â,δ-diketo esters.4 A similar strategy involving the
cyclization of R-C-pyranosyl â,δ-diketo ester, which could
(2) For reviews on aryl C-glycosides, see: (a) Jaramillo, C.; Knapp, S.
Synthesis 1994, 1. (b) Hacksell, U.; Davis, G. D., Jr. Prog. Med. Chem.
1985, 22, 1. (c) Suzuki, K.; Matsumoto, T. In Recent Progress in the
Chemical Synthesis of Antibiotics and Related Microbial Products; Lukacs,
G., Ed.; Springer: Berlin, 1993; Vol. 2, p 353. For isolation and structure
determination of C-glycosides, see: (a) Ayer, W. A.; Kawahara, N.
Tetrahedron Lett. 1995, 36, 7953. (b) Hochlowski, J. E.; Whittern, D. N.;
Buko, A.; Alder, L.; McAlpine, J. B. J. Antibiot. 1995, 48, 614. (c) Saijo,
R.; Nonaka, G.; Nishioka, I.; Chen, I.-S.; Hwang, T.-H. Chem. Pharm. Bull.
1989, 37, 2940. (d) Imamura, N.; Kakinuma, K.; Ikekawa, N.; Tanaka, H.;
Omura, S. J. Antibiot. 1981, 34, 1517. (e) Traxler, P.; Fritz, H.; Fuhrer, H.;
Richter, W. J. J. Antibiot. 1980, 33, 967.
(3) (a) Namikoshi, M.; Kobayashi, H.; Yoshimoto, T.; Meguro, S.;
Akano, K. Chem. Pharm. Bull. 2000, 48, 1452. (b) Evidente, A.; Conti, L.;
Altomare, C.; Bottalico, A.; Sindona, G.; Segre, A. L.; Logrieco, A. Nat.
Toxins 1994, 2, 4. (c) Xaio, J.-Z.; Kumazawa, S.; Yoshikawa, N.; Mikawa,
T.; Sato, Y. J. Antibiot. 1993, 46, 48.
† Faculty of Pharmaceutical Sciences.
(4) (a) Hagiwara, H.; Kobayashi, K.; Miya, S.; Hoshi, T.; Suzuki, T.;
Ando, M.; Okamoto, T.; Kobayashi, M.; Yamamoto, I.; Ohtsubo, S.; Kato,
M.; Uda, H. J. Org. Chem. 2002, 67, 5969. (b) Zhang, F.; Danishefsky, S.
J. Angew. Chem., Int. Ed. 2002, 41, 1434.
‡ Frontier Research Center for Genomic Drug Discovery.
(1) Kimura, J.; Furui, M.; Kanda, M.; Sugiyama, M. Jpn. Kokai Tokkyo
Koho 2002, 8 (in Japanese).
10.1021/ol034873k CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/08/2003

tempted an OfC glycosyl rearrangement10 of 5 by treatment
with Lewis acid. Despite varying the reaction conditions
(TMSOTf in CH2Cl2, BF3‚OEt2 in CH2Cl2, AgClO4 in
CH2Cl2, etc.), none of the desired C-glycoside was obtained
and, in most cases, almost all of the starting material 5 was
recovered. The low reactivity of the OfC rearrangement
could be due to electron-withdrawing acetoxy group at C-2
in 5. This led us to employ an O-benzyl-protected galactose
derivative as the glycosyl donor. After a systematic survey
of glycosyl acceptors (4-OBn pyrone, 4-OMe pyrone,
4-OTMS pyrone), Lewis acids, and solvents (TMSOTf in
CH2Cl2/CH3CN, BF3‚OEt2 in CH2Cl2/CH3CN, SnCl4 in
CH2Cl2, AlCl3 in CH2Cl2), we obtained a mixture of both
C-glycosides (7 and 8) and O-glycosides (9 and 10) by
treatment of tetra-O-benzyl-D-galactopyranosyl fluoride 611
with 4-hydroxy-6-methylpyrone 3 in the presence of BF3‚OEt2
in CH2Cl2 (Table 1, entry 1). The structures of the C-gly-
Figure 1. Structure of D8646-2-6 and some examples that
contained deoxyglucose as a sugar moiety.
be readily prepared by C-glycosylation of â-ketoester or
malonate,5 might seem like an obvious synthetic route.
However, a direct coupling of 4-hydroxypyrone to the sugar
moiety is desirable for establishing a convergent and efficient
methodology. Despite extensive studies into the C-glycosy-
lation of electron-rich aromatics,6 there have been no reports
concerning C-glycosylation of 4-hydroxypyrone. During the
course of our investigations into the synthesis of 1, we
studied the reaction of 4-hydroxypyrone and galactose
derivatives. The results of these experiments are described
in this paper.
Table 1. Glycosylation Reaction between the Galactosyl
Fluoride 6 and Pyrones 3 and 4
We examined coupling of O-(2,3,4,6-tetra-O-acetyl-â-D-
galactopyranosyl)trichloracetimidate 27 to 4-hydroxy-6-
methylpyrone 3 or its TMS ether 48 (Scheme 1). In both
Scheme 1. Glycosylation Reaction between the
Trichloroacetimidate 2 and Pyrones 3 and 4
pyrone BF3‚OEt2
entry (equiv) (equiv)
solvent
yield (%)
9, 10 (15)
1
2
3
4
5
6
7
8
9
3 (1)
3 (3)
3 (5)
3 (10)
3 (5)
3 (10)
3 (10)
4 (5)
1
1
1
1
1
3
3
1
1
CH2Cl2 7 (15) 8 (8)
CH2Cl2 7 (47) 8 (1)
CH2Cl2 7 (56) 8 (5)
CH2Cl2 7 (54) 8 (4)
CH3CN 7 (9) 8 (14)
CH3CN 7 (21) 8 (16)
CH2Cl2 7 (36) 8 (7)
CH2Cl2 7 (40) 8 (3)
9, 10 (7)
9, 10 (20)
9, 10 (21)
9, 10 (2)
9, 10 (8)
9, 10 (37)
9, 10 (38)
cases O-glycosylation proceeded smoothly in the presence
of TMSOTf in CH2Cl2 affording â-O-glycoside 59 in high
yield (90% for 3 and 87% for 4), but we could not detect
the formation of the desired C-glycoside. With an excellent
methodology developed by Suzuki in mind, we also at-
4 (10)
CH2Cl2 7 (32) 8 (trace) 9, 10 (46)
cosides 7 and 8 were established by 1H NMR analysis. The
anomeric proton of the minor glycoside 8 appeared at δ 4.71
with J ) 9.4 Hz allowing us to determine the â-C-glycoside
structure. The R-C-glycoside structure of the major isomer
7 could not be unambiguously determined from the chemical
shift and the coupling constant of the anomeric proton (δ
5.25 as a singlet). However, the strong NOE (7%) between
(5) (a) Gervay, J.; Hadd, M. J. J. Org. Chem. 1997, 62, 6961. (b) Allevi,
P.; Anastasia, M.; Ciuffreda, P.; Fiecchi, A.; Scala, A. J. Chem. Soc., Perkin
Trans. 1 1989, 1275. (c) Stewart, A. O.; Williams, R. M. J. Am. Chem.
Soc. 1985, 107, 4289. (d) Hanessian, S.; Pernet, A. G. Can. J. Chem. 1974,
52, 1266.
(6) (a) Kometani, T.; Kondo, H.; Fujimori, Y. Synthesis 1988, 1005. (b)
Rasolojaona, L.; Mastagli, P. Carbohydr. Res. 1985, 143, 246-248. (c)
Schmidt, R. R.; Hoffmann, M. Tetrahedron Lett. 1982, 23, 409-412. (d)
Eade, R. A.; Pham, H.-P. Aust. J. Chem. 1979, 32, 2483.
(7) (a) Upreti, M.; Ruhela, D.; Vishwakarma, R. A. Tetrahedron 2000,
56, 6577. (b) Kluge, M.; Schneider, B.; Sicker, D. Carbohydr. Res. 1997,
298, 147.
(10) (a) Suzuki, K. Pure Appl. Chem. 1994, 66, 2175. (b) Matsumoto,
T.; Katsuki, M.; Jona, H.; Suzuki, K. J. Am. Chem. Soc. 1991, 113, 6982.
(c) Matsumoto, T.; Hosoya, T.; Suzuki, K. Tetrahedron Lett. 1990, 31, 4629.
(d) Matsumoto, T.; Katsuki, M.; Jona, H.; Suzuki, K. Tetrahedron Lett.
1989, 30, 6185. (e) Matsumoto, T.; Katsuki, M.; Suzuki, K. Tetrahedron
Lett. 1988, 29, 6935.
(8) (a) Bonsignore, L.; Cabiddu, S.; Loy, G.; Secci, D. Heterocycles 1989,
29, 913. (b) Ziegler, T.; Layh, M.; Effenberger, F. Chem. Ber. 1987, 120,
1347. (c) Effenberger, F.; Ziegler, T.; Scho¨nwa¨elder, K.-H.; Kesmarszky,
T.; Bauer, B. Chem. Ber. 1986, 119, 3394.
(11) (a) Kanie, O.; Ito, Y.; Ogawa, T. Tetrahedron Lett. 1996, 37, 4551.
(b) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. 2001, 40, 1576.
(9) Anomeric proton of 5 appeared at δ 5.20 with J ) 7.9 Hz.
2838
Org. Lett., Vol. 5, No. 16, 2003

H-1′ and H-2′ and the NOE (8%) between H-1′ and H-6′
promoted ring-opening followed by recyclization, giving the
unambiguously established the stereochemistry, which in-
dicates that the R-C-glycoside 7 adopts the C4 confor-
thermodynamically more stable â-isomer (Scheme 3).
1
mation with the equatorially oriented pyrone moiety. The
yield of C-glycoside was improved by using an excess
amount of pyrone 3 (Table 1, entry 1-4). In acetonitrile,
C-glycosylation did not proceed well, but the desired â-C-
glycoside was obtained in higher yield than in CH2Cl2. We
think that this selectivity is due to the nitrile effect.12 When
TMS-protected pyrone 4 was used, a considerable amount
of O-glycosylation products were formed (Table 1, entry
8-9).
Scheme 3. Isomerization of 7 to 8
To determine whether C-glycoside was formed via O-gly-
coside, 9 and 10 were separately treated with BF3‚OEt2 in
CH2Cl2 (Scheme 2). Interestingly, both 9 and 10 afforded
Finally, it was necessary to deprotect 8. Hydrogenolysis
of 8 with Pd(OH)2-H2 in THF provided 11 in 65% yield
(Scheme 4). The 1H NMR and 13C NMR spectral data of 11
Scheme 2. Attempted OfC Glycosyl Rearrangement
Scheme 4. Hydrogenolysis of the C-Glycoside 8
in CD3OD were in good accordance with those of 1 except
for the differences due to the conjugated side chain moiety.
In summary, glycosylation of 4-hydroxypyrone 3 and
galactopyranosyl fluoride 6 provides the first reported
synthetic route to C3-pyranosyl-4-hydroxypyrone. We also
observed the base-promoted isomerization of R-C-glycoside
into the desired â-C-glycoside 8. This two-step process
affords 8 in a 61% overall yield. Furthermore, the present
investigation supports the proposed C3-â-galactopyranosyl-
4-hydroxypyrone core structure of 1.
only a trace amount of C-glycoside. Therefore, C-glycosy-
lation and O-glycosylation compete in the case of 4-hy-
droxypyrone. These results are quite different from glyco-
sylation reactions involving electron-rich aromatics.
The results also show that the Fries-type rearrangement,
which proceeded during acylation of 4-hydroxypyrone, did
not occur.13
Although the desired â-C-glycoside was produced as a
minor isomer, we found that the R-C-glycoside 7 underwent
ready and quantitative isomerization5a,14 with DBU in re-
fluxing THF. Isomerization probably proceeds via base-
Application of this method to the total synthesis of 1 is
currently in progress.
Acknowledgment. We thank Dr. Tamotsu P. Niki (Gen-
com Corporation) for helpful discussions and Mitsubishi
Pharma Corporation for providing the NMR spectra of
D8646-2-6.
Supporting Information Available: Detail experimental
procedure, full characterization, and copies of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) (a) Hashimoto, S.; Hayashi, M.; Noyori, R. Tetrahedron Lett. 1984,
25, 1379. (b) Andersson, F.; Fu¨gedi, P.; Garegg, P. J.; Nashed, M.
Tetrahedron Lett. 1986, 27, 3919. (c) Ito, Y.; Ogawa, T. Tetrahedron Lett.
1987, 28, 4701.
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Tanaka, H.; Harigaya, Y.; Omura, S.; Smith, A. B., III. J. Org. Chem. 1995,
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OL034873K
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