J. Am. Chem. Soc. 2001, 123, 3153-3154
3153
1,6-Anhydro-â-L-hexopyranoses as Potent Synthons
in the Synthesis of the Disaccharide Units of
Bleomycin A2 and Heparin
Shang-Cheng Hung,*,† Shankar R. Thopate,† Fa-Chen Chi,‡
Shu-Wen Chang,† Jinq-Chyi Lee,‡ Cheng-Chung Wang,† and
Yuh-Sheng Wen†
Figure 1. (A) The carbohydrate moiety of bleomycin A2. (B) The
disaccharide repeating unit of heparin.
Institute of Chemistry, Academia Sinica
Taipei 115, Taiwan
Department of Chemistry, National Tsing Hua UniVersity
Scheme 1
Hsinchu 300, Taiwan
ReceiVed September 27, 2000
L-Hexoses are key components of numerous biologically potent
oligosaccharides and glycopeptides. For example, bleomycin A2,1
a glycopeptide antibiotic with significant antitumor activity,
contains a carbohydrate moiety consisting of a R1 f 2 linked
3-O-carbamoyl-D-mannopyranose with L-gulopyranose (Figure 1).
Glycosaminoglycans, for example, heparin, heparan sulfate, and
dermatan sulfate, play important roles in a diverse set of biological
processes2 and have L-idopyranosiduronic acids as typical con-
stituents. Finally, L-altrose is a key structural element of the
extracellular polysaccharides from ButyriVibrio fibrisolVens strain
CF3.3 Given the importance of L-hexoses4 in the field of
glycobiology, and that these rare sugars are not readily accessible
from natural sources, we have explored herein a novel and
efficient route toward the synthesis of 1,6-anhydro-â-L-gulo, -ido
and -altropyranosyl sugars. Finally, we show how these valuable
building blocks can be used to prepare the disaccharide units of
bleomycin A2 as well as heparin.
Synthesis of the desired 1,6-anhydro-â-L-hexopyranoses was
carried out employing regioselective benzylation, benzoylation,
triflation, and nucleophilic substitution of 1,6-anhydro-â-L-
idopyranose 2 as key steps (Scheme 1). First, 1,2:3,5-di-O-
isopropylidene-â-L-idofuranose 1 was prepared in three steps from
diacetone R-D-glucose.5 Hydrolysis in acidic media at refluxing
temperature provided 2 (88%), which was selectively benzylated6
to give the 3-OBn 3 (72%) due to the steric hindrance of C2-
and C4-trimethylsilyloxy groups adjacent to the bridge-head
atoms. Owing to the inductive effect of the two oxygen atoms at
C1, the C2-oxide formed in basic solution reacts predominantly
with various electrophiles. Selective benzoylation of 3 at 0 °C
led to the 2-OBz 4 as a single isomer (85%). This result allowed
the one-pot synthesis of 5 (88%), which was subjected to SN2
substitutions with sodium nitrite and sodium azide to afford the
L-altro sugar 6 (84%) and its 4-azido derivative 7 (87%),
respectively. A similar strategy was applied to synthesize 1,6-
anhydro-â-L-gulopyranosyl sugars and the adducts 8, 9, and 10
were respectively isolated in excellent yields. The absolute
configurations of 3 (L-ido), 7 (L-altro), and 10 (L-gulo) were
determined through their single-crystal X-ray analyses, respec-
tively (see Supporting Information).
With the key synthon 9 in hand, the synthesis of the disac-
charide moiety of bleomycin A2 was carried out (Scheme 2).
Carbonylation of 117 furnished the carbonate 12 (68%) which,
upon acetolysis8 with Ac2O and TFA, provided the diacetate 13
(88%). Treatment with 30% HBr in acetic acid produced the
corresponding glycosyl bromide 14 in 94% yield. Silver triflate-
activated coupling with the glycosyl acceptor 9 yielded the
* To whom correspondence should be addressed. Phone: 886-2-2789-8646.
Fax: 886-2-2783-1237. E-mail: schung@chem.sinica.edu.tw.
† Institute of Chemistry.
‡ Department of Chemistry.
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10.1021/ja003508a CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/13/2001