Deoxygenative olefination reaction as the key step in the syntheses of deoxy and iminosugars

Article abstract of DOI:10.1002/chem.201201060

Just a spoonful of sugar! A new synthetic strategy involving the use of a deoxygenative olefination reaction as the key step was developed for the preparation of deoxy and iminosugars in their optically active form (see scheme). This strategy has been proven successful by the use of a pentose, hexose, heptose, and disaccharide as the starting materials. Furthermore, it was applied in a formal total synthesis of iminosugar (-)-1-deoxy-l- fuconojirimycin, which can inhibit a-l-fucosidase.

Full text of DOI:10.1002/chem.201201060

DOI: 10.1002/chem.201201060
Deoxygenative Olefination Reaction as the Key Step in the Syntheses of
Deoxy and Iminosugars
[
a]
[a, b, c]
Yung Chang Hsu and Jih Ru Hwu*
Carbohydrates with significant biological activities are dis-
covered in profusion; some of which possess special struc-
tures, including deoxy sugars, iminosugars, and higher-
[1]
carbon sugars. In deoxy sugars, one or more carbon atoms
[1]
have been reduced, thus losing their hydroxyl groups. Imi-
nosugars are analogues of sugars having a nitrogen atom at
[2]
the position of the endocyclic oxygen atom. Some of these
sugars possess immense therapeutic potential in various dis-
[
3,4]
eases, such as cancer, diabetes, and viral infection.
Promi-
y
nent examples related to deoxy sugars include Lewis sphin-
goglycolipid (1), amphotericin B, and everninomicin
3,384-1; examples related to iminosugars include GDP-
iminocyclitol (2), MDL 2563, and castanospermine.
[5]
[6]
[7]
1
[8]
[9]
[10]
These sugars (e.g., compounds 1 and 2 shown in Scheme 1)
often exist as a minor component in natural resources or are
produced by artificial methods, in which naturally abundant
carbohydrates are considered as the ideal starting materials.
Deoxy sugars can be obtained mainly by three methods:
Scheme 1. Examples of biologically active carbohydrates containing
a deoxy sugar or an iminosugar unit.
1
) removal of the oxygen atom in a hydroxyl group by a sub-
[11]
stitution of the corresponding sulfonates; 2) incorporation
of a methyl group as the deoxygen unit by methyllithium ad-
dition to a carbonyl group; and 3) biosynthetic transfor-
To fulfill the need for new synthetic strategies, we have
[12]
[15]
designed a method for the synthesis of deoxy and imino-
[13]
mation with the aid of enzymes.
sugars. As shown in Scheme 2, the method involves deoxy-
On the other hand, many methods have been developed
for the syntheses of various iminosugars since the first imi-
genation, olefination, and cleavage of an endocyclic OꢀC
single bond at the glycosidic carbon center. Readily avail-
able pentoses, hexoses, and heptoses can be adopted as the
starting materials for the syntheses of the desired targets.
Herein, we report our results on approval of the feasibility
and generality associated with the new deoxygenative olefi-
nation method in sugar syntheses.
[14]
nosugar-based drug (i.e., Glyset)
961. The key steps include nucleophilic addition to cyclic
was commercialized in
1
imines and nitrones, tandem addition to aldononitriles-inter-
nal S 2 reaction, intramolecular S 2 reaction, electrophilic-
N
N
induced cyclization, ring-closing metathesis, reductive ami-
[3]
nation, aza-silyl-Prins reaction, and so forth.
We first demonstrated the feasibility of the deoxygenative
olefination method by converting (+)-d-galactose (3) to the
deoxy sugar (ꢀ)-1-deoxy-d-tagatose (8, Scheme 3). Thus, the
hexose 3 was treated with n-butylamine and carbon disulfide
in a mixture of methanol and ethanol (1:2) to produce 1,3-
[
a] Dr. Y. Chang Hsu, Prof. J. R. Hwu
Department of Chemistry, National Tsing Hua University
Hsinchu, Taiwan 30013 (R. O. C.)
Fax : +886-35-721594
[16]
thiazolidine-2-thiones 4 in 61% yield. After all of the hy-
droxyl groups therein were protected with acetic anhydride,
the resultant polyacetate 5 was mixed with 2-silylphenyl tri-
flate 6 and CsF in acetonitrile at room temperature for
1.5 h. Acyclic enol acetate 7 was isolated in 63% yield
E-mail: jrhwu@mx.nthu.edu.tw
[
b] Prof. J. R. Hwu
Frontier Research Center on Fundamental and
Applied Sciences of Matters
National Tsing Hua University
Hsinchu, Taiwan 30013 (R. O. C.)
(
based on 27% of recovered 5), which was then treated with
NaOMe in MeOH. Accordingly, the desired (ꢀ)-1-deoxy-d-
[
c] Prof. J. R. Hwu
Department of Chemistry, National Central University
Jhongli, Taiwan 32001 (R. O. C.)
[17]
tagatose (8) was generated in almost quantitative yield. In
the entire transformation of 3!8, the hydroxyl oxygen
atom on the C1 carbon of 3 was expelled. As the result,
a methyl group was generated in the pyranose 8 with a sin-
Supporting information for this article is available on the WWW
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Chem. Eur. J. 2012, 18, 7686 – 7690

COMMUNICATION
istics of the ketoses 15 and 16
are identical to those repor-
[12b,20]
ted.
Therefore, we assured
ourselves that the stereogenic
centers at C3 and C4 remain
intact under the conditions as-
sociated with the new synthetic
strategy.
At the second stage, we dem-
onstrated the efficiency and ap-
plicability of the new deoxyge-
native olefination strategy by
applying it as the key step in
the synthesis of an optically
active iminosugar (ꢀ)-1-deoxy-
Scheme 2. A new deoxygenative olefination strategy for the syntheses of deoxy sugars, acyclic polyhydroxyl
ketones, and iminosugars from naturally occurring carbohydrates.
[21]
l-fuconojirimycin (22).
compound inhibits a-l-fucosidase with an IC50 of 25 nm.
This
We started our total synthesis of fuconojirimycin 22 with
the cost-effective (+)-d-galactose (3), which can be convert-
ed to 6-azido-6-deoxy-d-galactose (17) in four steps by fol-
[
22]
lowing the procedure of Thorson and co-workers. Treat-
ment of 17 with n-butylamine and carbon disulfide followed
by acetylation with acetic anhydride afforded 1,3-thiazoli-
dine-2-thiones 18 (Scheme 4). The conditions involving the
use of 2-silylphenyl triflate 6 and CsF were then applied to
1
8 to give the enol acetate 19 in 50% yield. In the presence
of potassium carbonate in methanol, cyclization of 19 took
place to produce an epimeric mixture of 20.
Scheme 3. Syntheses of deoxy sugars and 1-deoxy ketoses. [a]=Based on
recovered starting material.
1
Scheme 4. Deoxygenative olefination as the key step in a formal total
synthesis of iminosugar (ꢀ)-1-deoxy-l-fuconojirimycin (22).
glet at d=1.43 ppm in its H NMR spectrum and a peak at
13
d=24.72 ppm in its C NMR spectrum.
After proving the feasibility on the 1-deoxy hexose
system, we extended its applicability to 1-deoxy pentoses.
Through the same procedures, (ꢀ)-d-lyxose (9) was convert-
We planned to form the piperidine ring in iminosugar 22
through an intramolecular condensation between a primary
amine and a ketonic carbonyl group followed by hydrogena-
tion of the resultant Schiff base. A potential problem might
exist, which comes from the formation of an epimeric mix-
ture at the C2 carbon of the target 22. To prevent a reducing
agent coming from both the re and si faces of the -C=N-
functionality in the Schiff base, we decided to incorporate
a bulky moiety at the adjacent C3 and C4 carbons of the in-
[18]
ed successfully to methyl ketose 15. Being acyclic as its
major form, this compound is recognized as an important in-
termediate in several biochemical pathways. Bacteria (e.g.,
E. coli) can incorporate 15 into a thiazole (vitamin B ) and
1
[19]
a pyridoxine (vitamin B ). Furthermore, the pentose 10 (a
6
diastereomer of 9) was led to the corresponding acyclic
ketose 16 by the same strategy. The spectroscopic character-
Chem. Eur. J. 2012, 18, 7686 – 7690
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7687

Y. Chang Hsu and J. R. Hwu
termediate 20 to direct the orientation of hydrogenation. Table 1. Conversion of various aldoses to 1,3-thiazolidine-2-thiones and enol
[
23]
polyacetate sugars under the conditions shown in Scheme 3.
Walsh and co-workers reported a route by using a dioxo-
lane moiety that was fused at the C3 and C4 positions (cf.,
the acetal 21). Consequently, we converted 20 to the corre-
sponding acetal 21 with acetone in the presence of sulfuric
Aldose
1,3-Thiazolidine-
-thione [%]
Enol acetate Relationship
[
a]
2
[%]
1
acid and copper(II) sulfate. The H NMR spectrum of
acetal 21 showed two singlets at d=1.30 and 1.45 ppm for
the germinal dimethyl group in 1,3-dioxolane, which are
[24]
identical to the data reported in the literature.
Finally,
the palladium-catalyzed hydrogenation of acetal 21 fol-
lowed by deprotection of all the hydroxyl groups therein
[24]
produces the target iminosugar 22.
At the third stage, our errand was to explore the scope of
the deoxygenative olefination strategy. Given our results
from a series of experiments as summarized in Table 1, we
realize that this strategy was applicable to pentoses (i.e.,
(
(
ꢀ)-d-lyxose (9), (ꢀ)-d-arabinose (24), and (+)-l-arabinose
10)), hexoses (i.e., (+)-d-galactose (3), 6-azido-6-deoxy-d-
galactose (17), and (+)-l-rhamnose (30)), and heptose (i.e.,
a-d-mannoheptose (34)). These commercially available
sugars were converted successfully to the expected 1,3-thia-
zolidine-2-thione intermediates (23, 25, 28, 4, 29, 31, and
3
1
5) and then the corresponding polyacetates 11, 26, 12, 5,
8, 32, and 36 in good yields.
During the conversions of aldoses to polyacetyl enolates,
all of the stereogenic centers remained intact except that
3
2
the sp carbons at the C2 position were converted to sp
carbons. Examples with appealing comparison include the
conversion of 9!13 versus the conversion of 24!27, of
which a pair of epimers were produced; and the conversion
of 10!14 versus the conversion of 24!27, of which a pair
of enantiomers were produced. Compound 14 possessed
the identical spectroscopic characteristics as those of 27
2
4
except that their opposite optical rotations: [a] were mea-
D
sured as ꢀ7.25 and +7.75, respectively. These results clearly
demonstrate that the conditions we applied were mild
enough to prevent undesired isomerization from occurring
at carbon centers of sugars. On the other hand, the azido
[25]
group often reacts with benzyne to give benzotriazole.
Nevertheless, we found that the activity was higher for the
,3-thiazolidine-2-thione moiety than the azido moiety
1
toward benzyne. Thus, we were able to isolate w-azido enol
acetate 19 in the reaction of w-azido 1,3-thiazolidine-2-
thione 18 with benzyne although the yield was slightly
lower.
In addition to the monosaccharides presented in Table 1,
we verified the applicability of this new strategy to disac-
charides. As shown in Scheme 5, (+)-d-maltose (38) was
transformed into the corresponding thiazolidine-2-thione 39
on the basis of the conditions described before. After acety-
lation, the resultant polyacetate 40 was treated with 2-silyl-
phenyl triflate 6 and CsF in acetonitrile at room tempera-
ture to give a deoxygenative olefin. Its spectral characteris-
tics included a glycosidic carbon with d=108.85 ppm in the
[
a] Based on recovered starting material.
13
C NMR spectrum and two terminal vinylic protons with
2
1
J =2.0 Hz at d=5.17 and 5.25 ppm in the H NMR spec-
consistent with the theoretical value 662.2058 of the com-
trum. The exact mass was measured as 662.2049, which is
pound 41. Therefore, we conclude that the presence of
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Chem. Eur. J. 2012, 18, 7686 – 7690

Synthesis of Deoxy and Iminosugars
COMMUNICATION
[26]
pathways: 1) The Amadori rearrangment takes place on
b-hydroxy imine 42 to give the corresponding 1-amino-2-
keto sugar, which subsequently adds to carbon disulfide
through the “pathway a.” Then, an intramolecular cycload-
dition occurs on the resultant dithiocarbamate 43 to produce
1
,3-thiazolidine-2-thione 23. Finally, its acetylated species 11
reacts with benzyne, generated from 2-silylphenyl triflate 6
and CsF, to afford the enol polyacetate 13 and the by-prod-
uct N-butyl-2-imino-l,3-benzodithiole (44). 2) An intramo-
lecular cycloaddition takes place between the w-hydroxyl
group and the imine moiety in 42 through the “pathway b.”
The resultant amine reacts with carbon disulfide to produce
1
,3-thiazolidine-2-thione 46 via the intermediate 45. In the
Scheme 5. Application of the deoxygenative olefination strategy to a dis-
accharide. [a]=Based on recovered starting material.
last step, the acetylated species 47 reacts with benzyne to
generate a glycal 48 and the by-product 44.
All of the examples listed in Table 1 led to the formation
of polyacetate olefins with a terminal C=C double bond.
Neither the 1,3-thiazolidine-2-thione 46 nor the glycal 48 by-
product was isolated. As a consequence, we believe that the
new method for the synthesis of deoxy sugars proceeds
through “pathway a.”
In conclusion, the benzyne-induced olefination was devel-
oped successfully as the key step in the newly developed
strategy for the synthesis of deoxy and iminosugars in an op-
tically active form. We found that the conditions associated
with this step were compatible with an acetate functionality
a second pyranose moiety in the substrate did not interfere
with the transformation.
We illustrate our design and a plausible mechanism of the
newly developed strategy by using the conversion of 9!
13+44 as an example (see Scheme 6). First, the condensa-
tion of (ꢀ)-d-lyxose (9) with n-butylamine gives the Schiff
[16]
base 42. Before reacting with carbon disulfide, this base
may turn to its corresponding amines through two possible
(
e.g., 5), an azido group (e.g., 18), and a second sugar
moiety (e.g., 40). With the exception of the C2 carbon
center, all of the remaining stereogenic centers in the carbo-
hydrate starting materials retained their original configura-
tion under the applied reaction conditions. Therefore, this
new olefination method provides a new avenue to optically
active deoxy and iminosugars.
Acknowledgements
We are grateful to the National Science Council (Grant No.: 99-2113-
M007-008-MY3) and Ministry of Education (Grant No.: 100N2017E1),
Republic of China for support of this research.
Keywords: benzyne
·
carbohydrates
·
iminosugars
·
olefination · total synthesis
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Chem. Eur. J. 2012, 18, 7686 – 7690
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7689

Y. Chang Hsu and J. R. Hwu
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Received: March 29, 2012
Published online: May 21, 2012
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Chem. Eur. J. 2012, 18, 7686 – 7690