A new route to C-aryl glycosides

Article abstract of DOI:10.1021/ol025549c

(equation presented) A six-step route for de novo synthesis of C-aryl glycosides based on cycloaddition of an aryl nitrile oxide with 4-pentyn-2-ol has been developed.

Full text of DOI:10.1021/ol025549c

ORGANIC
LETTERS
2002
Vol. 4, No. 6
977-978
A New Route to C-Aryl Glycosides
Frank M. Hauser* and Xingding Hu
Department of Chemistry, State UniVersity of New York at Albany,
Albany, New York 12222
fh473@sarah.albany.edu
Received January 12, 2002
ABSTRACT
A six-step route for de novo synthesis of C-aryl glycosides based on cycloaddition of an aryl nitrile oxide with 4-pentyn-2-ol has been developed.
There are a large number of naturally occurring C-aryl
1
glycosides, of which vineomycinone B2 (Figure 1) is an
Scheme 1
Figure 1. Vineomycinone B2.
example. Since many of these substances have significant
anticancer activity, there has been strong interest in the
development of routes for synthesis of C-aryl glycosides.2
While most of these approaches have employed coupling of
an aryl group with a sugar derivative, a few have involved
construction of the sugar fragment from nonsaccharide
precursors.3
Our interest in total synthesis of naturally occurring C-aryl
glycosides has led us to develop a new and brief route for
de novo construction of C-aryl glycosides. In establishing
the potential of the plan, racemic syntheses were performed.
in 78% yield. Hydrogenolysis of 3 (H2, Raney Ni) followed
by acid treatment to effect cyclization of the diketone
intermediate afforded the arylpyranone 4a. Reaction of 4a
5
with Mn(OAc)3 gave a 4.4:1 ratio of diastereoisomeric
acetoxy pyranones from which the trans-isomer 4b was
isolated in 65% yield. Hydrogenation of 4b furnished the
pure C-arylpyranose (()-5 as the sole product in 93% yield.
Although the stereochemistry of 5 could be obtained directly
1
from the coupling constants in the H NMR spectrum, 2D-
NMR, NOE, and NOSEY were performed to confirm the
assignment.
Having established the viability of the plan with a simple
aromatic group, we next tested the potential of the route using
a more complex aromatic system; this is shown in Scheme
2. Cycloaddition of the nitrile oxide derived from the
As shown in Scheme 1, the nitrile oxide derived from
reaction of the oxime 1 with NCS4 underwent cycloaddition
with the racemic acetylene 2 to afford the isoxazole (()-3
(1) Imaura, N.; Kakinuma, K.; Ikekawa, N.; Tanaka, H.; Omura, S. J.
Antibiot. 1981, 34, 1517.
10.1021/ol025549c CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/16/2002

the pyranone 8a through sequential hydrogenolysis of the
N-O bond of the isoxazole followed by acid-catalyzed
intramolecular cyclization. Manganic acetate oxidation of 8a
afforded a 64% yield of the trans-acetoxy compound 8b
along with 21% of the cis-diastereoisomer, which were
readily separated through silica chromatography. Surpris-
ingly, catalytic hydrogenation of 8b did not result in the
expected regio- and stereoselective reduction of the enone
moiety in the pyranose ring but instead proceeded with
concurrent reduction of both the pyranone and the terminal
aromatic ring!
Scheme 2
Ultimately we were able to effect selective reduction of
the enone moiety in 9 through use of a procedure reported
by Tius et al.6 in a similar system. A high yield (92%) one-
pot procedure involving catalytic reduction of 8b with in
situ methylation afforded 9.7 Treatment of 9 with NaBH3-
CN at pH 4 in methanol gave 10 as the sole product. Here
again, determination of the stereochemistry was straightfor-
1
wardly achieved through H-1H decoupling. Protection of
the alcohol group in 10 as the acetate and oxidation with
CAN provided the quinone (()-11.
There are a number of inherent advantages to use of this
route for C-aryl glycoside synthesis. Principal among these
is that minimal protection steps are required, and neither low
temperature nor anhydrous conditions are required for any
of the steps. Furthermore, since hydroxyl functionality is
introduced in protected form, manipulation of individual
hydroxyl groups should be possible.
In future work we will explore use of the plan for optically
active total synthesis of C-aryl glycosides and application
of the methodology to total synthesis of naturally occurring
C-aryl glycosides.
Acknowledgment. We thank Marcus Tius for helpful
discussions. This work was generously supported by the
National Cancer Institute of the National Institutes of Health
(CA 18141).
Supporting Information Available: Experimental details
for 3, 4a, 4b, 5, 7, 8a, 8b, and 9-11 are available. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL025549C
(2) For a review see: (a) The Chemistry of C-Glycosides; Levy, D. E.,
Tang, C., Eds.; Elsevier Science Ltd.: Oxford, U.K. (b) Fuganti, C.; Serra,
S. Synlett 1999, 1241.
(3) Danishefsky, S. J.; Uang, B. J.; Quallich, G. J. Am Chem. Soc. 1985,
107, 1285. Berich, M. D.; Cambie, R. C.; Rutledge, P. S. Aust. J. Chem.
1999, 52, 303. Schmidt, B. Org. Lett. 2000, 2, 791.
(4) Liu, K.-C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45,
3916.
(5) Demir, A. S.; Jeganathan, A.; Watt, D. S. J. Org. Chem. 1989, 54,
4020.
(6) Tius, M. A.; Gomez-Galeno, J.; Gu, X-q.; Zaidi, J. H. J. Am. Chem.
Soc. 1991, 113, 5775.
(7) Catalytic hydrogenation of 9 also resulted in concurrent reduction
of both the pyranone and terminal aromatic ring.
anthraquinone oxime 6 with the acetylene 2 gave the
isoxazole (()-7, which was straightforwardly converted to
978
Org. Lett., Vol. 4, No. 6, 2002