ORGANIC
LETTERS
2011
Vol. 13, No. 20
5584–5587
Short and Efficient Synthetic Route to
Methyl r-Trioxacarcinoside B and
Anomerically Activated Derivatives
Thomas Magauer and Andrew G. Myers*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge,
Massachusetts 02138, United States
Received August 25, 2011
ABSTRACT
A 9-step synthetic route to the complex carbohydrate methyl R-trioxacarcinoside B from 2-acetylfuran is described. Anomerically activated forms,
including 1-phenylthio, 1-O-(40-pentenyl), 1-fluoro, and 1-O-acetyl derivatives are also prepared.
The eight-carbon 2-deoxysugar trioxacarcinose B (1) is a
constituent of both trioxacarcins and quinocyclines, struc-
turally distinct classes of bacterial fermentation products
with antiproliferative and antibiotic effects.1 Trioxacarcin
A (2) and quinocycline B (3), depicted in Figure 1, are
representative members of each structural class; in both
cases, the trioxacarcinose B sugar residue is found in R-
glycosidic linkage with the aglycon core. Members of both
natural product series have also been identified that con-
tain an R-linked 7-(S)-dihydrotrioxacarcinose B (4) resi-
due. To date, one route for the synthesis of trioxacarcinose
B and two routes to 7-(S)-dihydrotrioxacarcinose B have
beenreported. Paulsen and Sinnwellfirstdescribeda 7-step
sequence to methyl R-7-(S)-dihydrotrioxacarcinoside B
using L-rhamnal diacetate as starting material (2.2%
yield).2 Suami and co-workers later developed an 11-step
route to methyl R-trioxacarcinoside B from the same pre-
cursor (4.3% yield).3 More recently, Koert and co-workers
reported a 15-step route to methyl R-7-(S)-dihydrotrioxa-
carcinoside B (6.4% yield) by de novo construction of the
carbohydrate residue, using a lipase to resolve an early
intermediate.4
Here we describe a short and practical sequence for
the synthesis of trioxacarcinose B and anomerically acti-
vated forms using 2-acetylfuran as starting material
(Scheme 1). Reduction of 2-acetylfuran by Noyori’s pro-
tocol (dihydrogen, 50 bar, trans-RuCl2-[(R)-xylbinap][(R)-
daipen], 0.005 mol %, purification by distillation) afforded
the (S)-alcohol 6 (94 g) in 77% yield and g99% ee.5,6 This
versatile building block is also commercially available.
Oxidative ring expansion7 of furan 6 with bromine
in methanol, also a known transformation,8 provided
an anomeric mixture (R:β ≈ 1.2:1) of methyl acetals
from which the pure R-anomer 7 could be obtained by
medium pressure liquid chromatography (5.3 g, 20%).
Conjugate reduction of 7 (5.2 g) with lithium tri-
sec-butylborohydride (1.2 equiv) in tetrahydrofuran at
ꢀ78 °C and trapping of the resulting enolate with
Comins’ reagent9 (1.1 equiv) afforded the vinyl triflate
(5) Noyori, R.; Ohkuma, T.; Koizumi, M.; Yoshida, M.; Noyori, R.
Org. Lett. 2000, 2, 1749–1751.
(1) (a) Matern, U.; Grisebach, H. Eur. J. Biochem. 1972, 29, 1–4. (b)
Shirahata, K.; Iida, T.; Hirayama, N. Tennen Yuki Kagobutsu Toronkai
Koen Yoshishu 1981, 24, 199–206.
(6) [R]D25 = ꢀ20.2 (c = 1.06, CHCl3), ref 4 [R]D24 = ꢀ20.1 (c = 1.00,
CHCl3).
(2) Paulsen, H.; Sinnwell, V. Chem. Ber. 1978, 111, 869–878.
(3) (a) Suami, T.; Nakamura, K.; Hara, T. Chem. Lett. 1982, 1245–
1248. (b) Suami, T.; Nakamura, K.; Hara, T. Bull. Chem. Soc. Jpn. 1983,
56, 1431–1434.
(7) Achmatowicz, O.; Bukowksi, P.; Szechner, B.; Zwierzchowska,
Z.; Zamojski, A. Tetrahedron 1971, 27, 1973–1996.
(8) Sammes, P. G.; Thetford, D. J. Chem. Soc., Perkin Trans. I 1988,
111–123.
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(4) Konig, C. M.; Harms, K.; Koert, U. Org. Lett. 2007, 9, 4777–
4779.
(9) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 42, 6299–
6302.
r
10.1021/ol202315m
Published on Web 09/29/2011
2011 American Chemical Society