Communications
[9] F. W. Lichtenthaler, E. Cuny, Eur. J. Org. Chem. 2004, 4911 –
4920.
to thermodynamically less stable products either because the
central dioxane ring is forced into a boat conformation (25
and 26) or as unfavorable dipolar interactions are operative
(25, 27). The ease with which the glycosidulose intermediate
spontaneously “folds” into the natural cis,cisoid,trans geom-
etry may even be taken as evidence for such a process to be
operative in non-enzyme-mediated fashion in the biosynthe-
sis of spectinomycin from d-glucose,[23] with an unprotected
form of glycosidulose 22 conceivably being the decisive
intermediate.
In summary, the chemistry detailed herein defines a
concise and general method for the construction of natural
products with a cis,cisoid,trans-interconnected pyran-diox-
ane-cyclohexane framework and has enabled the first syn-
theses of cardiac glycosides with ring A annulated sugars and
an alternate synthesis of the antibiotic spectinomycin. A key
feature of the methodology is the monoglycosylation of the
respective aglycon diols with 4,6-dideoxy-2-ketohexosyl
donors, promoted by an insoluble silver salt, which thereby
substantially extends the utility of the “ulosyl donor
approach”.[7]
[10] a) G. Ekborg, P. J. Garegg, S. Josephson, Carbohydr. Res. 1978,
65, 301 –306; b) M. E. Evans, F. W. Parrish, Methods Carbohydr.
Chem. 1972, 6, 177 –179, M. E. Evans, F. W. Parrish, Methods
Carbohydr. Chem. 1972, 6, 193 –196; c) See ref. [9] (footnote 19
therein).
[11] F. W. Lichtenthaler, A. Löhe, E. Cuny, Liebigs Ann. Chem. 1983,
1973 –1985.
[12] F. W. Lichtenthaler, U. Klꢀres, M. Lergenmüller, S. Schwidetzky,
Synthesis 1992, 179 –184.
[13] The alternative possibility, cyclo-hemiketalization of 13 by
=
OH!C O attack from the upper (equatorial) face would lead
to the sterically and thermodynamically unfavorable trans-
transoid-trans-fused product in which the central dioxane ring
is forced into a boat (or twist-boat) conformation.
[14] Racemic 16, in noncrystalline form, has previously been
prepared through elaboration of the pyranoid portion through
an aldehyde/diene cycloaddition approach: S. Danishefsky, J.
Aubꢁ, M. Bednarski, J. Am. Chem. Soc. 1986, 108, 4145 –4149.
[15] Gomphogenin (17) was prepared from digitoxin by hydrolytic
removal of the sugars and conversion of its aglycon, digitox-
igenin, through a known seven-step procedure: Y. Kamano,
G. R. Pettit, M. Tozawa, J. Chem. Soc. Perkin Trans. 1 1975,
1972 –1976; J. F. Templeton, H. T. A. Cheung, C. R. Sham, T. R.
Watson, J. Chem. Soc. Perkin Trans. 1 1983, 251 –256.
[16] The catalyst was adapted from the Ru/C-mediated hydrogena-
tion of spectinomycin (7), which provided an epimeric mixture
mainly consisting of the (4R)-dihydro analogue 8: W. Rosen-
brook, Jr., R. E. Carney, J. Antibiot. 1975, 28, 953 –959.
[17] T. R. Watson, S. E. Wright, Chem. Ind. London 1954, 1178; T. R.
Watson, S. E. Wright, Aust. J. Chem. 1957, 10, 79 –84.
[18] Natural 2 derived from Asclepias fruticosa was isolated as a
microcrystalline solid as its half-hydrate[3] with m.p. = 250–
2518C, whereas synthetic 2 with m.p. = 189–1918C was found
to crystallize with one mole of CH2Cl2, which accounts for the
comparatively large difference in melting behavior.
[19] T. Suami, S. Nishiyama, H. Ishikawa, H. Okada, T. Kinoshita,
Bull. Chem. Soc. Jpn. 1977, 50, 2754 –2757.
[20] a) C. A. A. van Boeckel, T. Beetz, A. C. Kock-van Dalen, H.
van Bekkum, Recl. Trav. Chim. Pays-Bas 1987, 106, 596 –598;
b) F. W. Lichtenthaler, T. Metz, Eur. J. Org. Chem. 2003, 3081 –
3093.
[21] The less reactive ulosyl bromide (11) gave complex mixtures
under these conditions which contained substantial amounts of
21.
[22] P. M. Herrinton, K. L. Klotz, W. M. Hartley, J. Org. Chem. 1993,
58, 678 –682.
Received: February 4, 2005
Published online: July 6, 2005
Keywords: fused-ring systems · glycosylation · gomphosides ·
.
natural products · spectinomycin
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Angew. Chem. Int. Ed. 2005, 44, 4944 –4948