E and those in the “carbohydrate sector,” we sought a
glycosylation method that would efficiently interface with
our synthetic route to scalemic aglycon.
Scheme 2. Installation of the Epipodophyllotoxin C4-Sulfide,
Sulfoxide, or Sulfone
Though Koenigs-Knorr glycosylation was originally used
to make podophyllotoxin conjugates,10,11 most current ap-
proaches rely upon a “reverse glycosylation” approach due
to Kuhn and von Wartburg, wherein the aglycon serves as
the “reverse glycosyl donor” and the sugar as “reverse
glycosyl acceptor.”12 The reaction is normally run at -20
to 0 °C, under F3B-Et2O promotion. An important modi-
fication by Allevi, wherein a silyl sugar is employed,
facilitates control of the anomeric stereochemistry.13
Our approach to the aglycon employs a C4-O-SEM
protecting group. Fortuitously, we observed that, under the
SEM deprotection conditions of Kim,14 a significant amount
of C4-thioether may be formed. More recently, we have found
that substitution of F3B-OEt2 for Br2Mg-OEt2 improves
conversion to the thioether (Scheme 1).
controlled oxidation provided either the corresponding sul-
foxide(s) (12) or sulfone (13). A 10:1 ratio of readily
separable diastereomeric sulfoxides was obtained. The pure
major diastereomer was carried on for lignan conjugate
synthesis.
Whereas initial attempts to activate 11 with NBS, SnCl4,
or Hg(CN)2 led largely to decomposition products, activation
with AgOTf or MeOTf was quite successful (Scheme 3).
Scheme 1. Removal of the C4-O-SEM Protecting Group with
Direct Thioether Installation
Scheme 3. Use of an Epipodophyllotoxin C4-Thioether for
Lignan Conjugation
This synthetic move would serve as a simultaneous SEM
deprotection/aglycon activation procedure, were it possible
to develop a sulfur-based reverse glycosylation method here.
Toward this end, we chose the natural product as our model
system. C4′-O-Cbz-protected epipodophyllotoxin 10 was
efficiently converted to the thioether, as for 7. Subsequent
With cyclohexanol as intercepting nucleophile, the lignan
conjugate 14 was obtained in good yields and with complete
control of stereochemistry (exclusively C4-S). The stereo-
chemical outcome is certainly suggestive of an SN1-like
process, though in both cases, effective conversion requires
warming to room temperature.
(5) Utsugi, T.; Shibata, J.; Sugimoto, Y.; Aoyagi, K.; Wierzba, K.;
Kobunai, T.; Terada, T.; Oh-hara, T.; Tsuruo, T.; Yamada, Y. Cancer Res.
1996, 56, 2809-2814.
(6) Zhang, Y.-L.; Tropsha, A.; McPhail, A. T.; Lee, K.-H. J. Med. Chem.
1994, 37, 1460-1464.
(7) Huang, T.-S.; Lee, C.-C.; Chao, Y.; Shu, C.-H.; Chen, L.-T.; Chen,
L.-L.; Chen, M.-H.; Yuan, C.-C.; Whang-Peng, J. Pharm. Res. 1999, 16,
997-1002.
These observations provided the first evidence that a
sulfur-based reverse glycosylation strategy would be feasible
in the epopodophyllotoxin family. We next turned our
attention to sulfoxide 12, anticipating that activation might
be more efficiently achieved in this system. After all, 12
may be viewed as a doubly vinylogous analogue of an
anomeric sulfoxide. And Kahne has nicely demonstrated that
highly reactive glycosyl donors are obtained upon treatment
of anomeric sulfoxides with triflic anhydride.15,16 More
recently, Gin has shown that placement of the sulfoxide
functionality in solution, can also lead to a reactive glyco-
sylating species, in the presence of an unprotected anomeric
hydroxyl or a glycal, upon addition of triflic anhydride.17
We present here, to our knowledge, the first example of
the third logical variant of the Kahne-type activation
(8) Berkowitz, D. B.; Choi, S.; Maeng, J.-H. J. Org. Chem. 2000, 65,
847-860.
(9) (a) Loike, J. D.; Horwitz, S. B. Biochemistry 1976, 15, 5443-5448.
(b) Long, B. H.; Musial, S. T.; Brattain, M. G. Biochemistry 1984, 23,
1183-1188.
(10) Kuhn, M.; von Wartburg, A. HelV. Chim. Acta 1968, 51, 163-168.
(11) For an alternative glycosylation of (epi)podophyllotoxin, in which
a glucosyl phosphinimidate or phosphate serves as glycosyl donor, see:
Hashimoto, S.; Honda, T.; Ikegami, S. Tetrahedron Lett. 1991, 32, 1653-
1654.
(12) (a) Kuhn, M.; von Wartburg, A. HelV. Chim. Acta 1968, 51, 1631-
1640. (b) Kolar, C.; Moldenhauer, H.; Kneissl, G. J. Carbohydr. Chem.
1990, 571-583. (c) Allevi, P.; Anastasia, M.; Ciuffreda, P.; Sanvito, A.
M.; Macdonald, P. Tetrahedron Lett. 1992, 33, 4831-4834.
(13) (a) Allevi, P.; Anastasia, M.; Ciuffreda, P.; Bigatti, E.; Macdonald,
P. J. Org. Chem. 1993, 58, 4175-4178. (b) Vogel, K.; Sterling, J.; Herzig,
Y.; Nudelman, A. Tetrahedron 1996, 52, 3049-3056. (c) Daley, L.;
Guminski, Y.; Demerseman, P.; Kruczynski, A.; Etievant, C.; Imbert, T.;
Hill, B. T.; Monneret, C. J. Med. Chem. 1998, 41, 4475-4485.
(14) Kim, S.; Kee, I. S.; Park, Y. H.; Park, J. H. Synlett 1991, 183-184.
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