Selective Synthesis of Partially Protected d -Talopyranosides and d -Gulopyranosides via Catalytic Asymmetric Dihydroxylation: Multiplier Effects of Substrate Control and Catalyst Control

Article abstract of DOI:10.1021/acs.orglett.6b03000

Highly selective syntheses of d-talopyranosides and d-gulopyranosides have been achieved by utilizing the multiplier effects of substrate control and catalyst control. Through the combination of an O-benzoyl-protected substrate and the AD-mix-β system, the d-talopyranoside was obtained in a ratio of 96:4. In contrast, the d-gulopyranoside was obtained in a ratio of 3:97 through the use of an O-tert-butyldimethylsilyl-protected substrate and AD-mix-α.

Full text of DOI:10.1021/acs.orglett.6b03000

Letter
pubs.acs.org/OrgLett
Selective Synthesis of Partially Protected D‑Talopyranosides and
D‑Gulopyranosides via Catalytic Asymmetric Dihydroxylation:
Multiplier Effects of Substrate Control and Catalyst Control
Yoichi Namito, Kyosuke Michigami, Takaaki Nagahashi, Ryosuke Matsubara, and Masahiko Hayashi*
Department of Chemistry, Graduate School of Science, Kobe University, Kobe 657-8501, Japan
S
* Supporting Information
ABSTRACT: Highly selective syntheses of D-talopyranosides
and D-gulopyranosides have been achieved by utilizing the
multiplier effects of substrate control and catalyst control.
Through the combination of an O-benzoyl-protected substrate
and the AD-mix-β system, the D-talopyranoside was obtained in
a ratio of 96:4. In contrast, the D-gulopyranoside was obtained in
a ratio of 3:97 through the use of an O-tert-butyldimethylsilyl-
protected substrate and AD-mix-α.
ecently, rare sugars have attracted much attention in terms
the reaction of L-2,3-unsaturated carbohydrate with Oxone to
Rof their bioactivity, such as their ability to act as inhibitors of give the epoxide, followed by hydrolysis with HClO .8 Bystom
̈
4
reported the synthesis of a β-D-mannoside and β-D-talosides
using a double-parallel inversion method and a double serial
inversion method from partially protected methyl β-D-glucoside
and methyl β-D-galactoside, respectively.9 For the synthesis of
rare aldohexoses from ketohexoses, the use of 2-aminopyridine
has also been reported.10 We also reported the synthesis of D-
allose using stereoselective reduction of bulky silyl-protected 1,5-
anhydrohex-1-en-3-uloses using the NaBH4−CeCl3·7H2O sys-
tem.11
various glycosidases. For example, Izumori and co-workers
reported that D-psicose (D-allose) inhibits intestinal α-
glucosidase and suppresses the glycemic response after ingestion
of carbohydrates and also inhibits motility, growth, and
reproductive maturity of the L1 larvae of Caenorhabditis elegans.1
In contrast, D-allose acts as a triggering molecule for rice defense
via ROS generation and also suppresses gibberellin signaling
through a hexokinase-dependent pathway in Oryza sativa L.2
However, despite their importance in medicine and pharmacy,
the bioactivity of other rare sugars has not been examined due to
the difficulty in obtaining a sufficient amount for bioassays.
Izumori proposed the “Izumoring” strategy for the bio-
production of all hexoses including the 16 aldohexoses, 8
ketohexoses, and 10 hexitols using enzymatic and micro-
biological reactions.3 By this method, some rare sugars, such as
D-psicose and D-allose, have been produced on a large enough
scale for bioassays. However, bioproduction of other rare sugars
is not always easy. Synthesizing D-talose and D-gulose by this
strategy is very difficult because these rare sugars are far from D-
glucose in the “Izumoring” map, meaning multiple enzymes are
required.
Several chemical syntheses have been reported; Mukaiyama
and Kobayashi reported the synthesis of 6-deoxy-L-talose4 and 6-
deoxy-L-allose5 using an asymmetric aldol reaction. Macmillan
also reported the synthesis of L- and D-allose based on an L- (or
D)-proline-catalyzed asymmetric aldol reaction followed by a
Mukaiyama aldol addition.6 O’Doherty and co-workers reported
the synthesis of D- and L-mannose, gulose, and talose by
dihydroxylation of unsaturated sugar derived from furfural.7
Guaragna and co-workers reported the synthesis of L-altrose by
To our knowledge, there have been no reports on how to
prepare D-gulopyranosides effectively nor any reports via the
asymmetric dihydroxylation of unsaturated sugars derived from
common pyranosides derived from D-glucose12 and D-galactose
using chiral catalysts. Here, we report novel and efficient
methods for the selective syntheses of D-talopyranosides and D-
gulopyranosides via catalytic asymmetric dihydroxylation13 of
protected unsaturated D-galactopyranoside derivatives. Among
the ald-type hexoses, D-allose, D-talose, D-gulose, D-idose, and D-
altrose are called rare sugars. Our strategy is shown in Scheme 1.
If 1,2-unsaturated D-glucopyranoside were used as a substrate,
dihydroxylative attack from the top would give D-mannopyrano-
side and attack from the bottom yields D-glucose (eq 1).
Similarly, 2,3-unsaturated D-glucopyranoside would give D-
mannopyranoside and D-allopyranoside, and 1,2-unsaturated D-
galactopyranoside would yield D-talopyranoside and D-galacto-
pyranoside (eq 2 and eq 3). We focused on using a 2,3-
unsaturated D-galactopyranoside as the substrate because it yields
Received: October 5, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03000
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Organic Letters
Letter
(entry 3). Addition of methanesulfonamide (1 equiv), K2OsO4·
2H2O (10 mol %), and (DHQD)2PHAL (10 mol %) to the AD-
mix-β reversed the selectivity (D-talopyranoside/D-gulopyrano-
side = 63:37) and gave both compounds in a combined 58% yield
(entry 4). As the choice of chiral ligand ((DHQ)2PHAL or
(DHQD)2PHAL) determined which face of the double bond in
1 was attacked, this showed that the stereoselectivity was catalyst-
controlled. The reaction of 1 with K2OsO4·2H2O (11 mol %)
and NMO (N-methylmorpholine N-oxide (1 equiv), entry 5)
gave the D-talopyranoside and D-gulopyranoside in a ratio of
38:62 and only 20% yield (1 was recovered in 73% yield). This
indicated ligand acceleration in entries 3 and 4 and that attack
from the bottom was preferred for the double bond in substrate
1, leading to the formation of the D-gulopyranosides. Thus, the
diastereoselectivity results from substrate control.
Scheme 1. Stereoselective Dihydroxylation of Unsaturated D-
Gulcose and D-Galactose Derivative
The structures of 2 and 3 were determined by NOE analysis
(Scheme 2). We then examined the effect of the protecting group
on stereoselectivity.
both D-talopyranoside and D-gulopyranoside (eq 4). Our focus
was on substrate control versus chiral catalyst control in the
diastereoselective dihydroxylation of 2,3-unsaturated D-galactal.
We first examined the reaction of methyl 4,6-di-O-benzyl-2,3-
dideoxy-α-D-threo-hex-2-enopyranoside (1) with AD-mix-α and
AD-mix-β (1.4 g/substrate mmol) at room temperature (30 °C)
for 24 h in t-BuOH/H2O (1/1). Commercially available AD-mix-
α (Aldrich) is composed of K2OsO4·2H2O, (DHQ)2PHAL,
K2CO3, and K3Fe(CN)6, and AD-mix-β (Aldrich) is composed
of K2OsO4·2H2O, (DHQD)2PHAL, K2CO3, and K3Fe(CN)6,
respectively. Reaction of 1 with AD-mix-α (Table 1, entries 1 and
Scheme 2. NOE Analysis of 2 and 3
Tables 2 and 3 show the results of the reaction of benzoyl-
protected (4) and tert-butyldimethylsilyl-protected 2,3-unsatu-
rated D-galactopyranoside (7) with K2OsO4·2H2O and NMO.
When 4 and 7 were used as substrates, the yields were moderate,
even after the addition of a stoichiometric amount of K2OsO4·
2H2O and an excess of NMO (55% and 35%, respectively, entry
2 in Table 2 and entry 2 in Table 3). However, the D-
talopyranoside/D-gulopyranoside selectivity was up to 92:8 in
the case of the benzoyl-protected D-galactopyranoside and up to
15:85 in the case of tert-butyldimethylsilyl-protected 2,3-
unsaturated D-galactopyranoside. In order to improve the
selectivity of this method, we examined the effect of the chiral
ligand, the solvent, and other additives. The results are
summarized in Tables 2 and 3. The highest D-talopyranoside
selectivity (96:4) was obtained in 74% yield (entry 5 in Table 2)
by the reaction of 4 with AD-mix-β (1.4 g/substrate mmol),
K2OsO4·2H2O (10 mol %), and (DHQD)2PHAL (10 mol %) in
t-BuOH/H2O (1/1). The highest D-gulopyranoside selectivity
was obtained (3:97) in 68% yield (entry 7 in Table 3) by the
reaction of 7 with AD-mix-α (1.4 g/substrate mmol), K2OsO4·
2H2O (50 mol %), (DHQ)2PHAL (50 mol %), and K3Fe(CN)6
in THF/H2O (1/1).
The rate enhancement is explained as a “ligand acceleration
effect”,15 and an increase of selectivity can be interpreted to
match the pair of substrate control and catalyst control. The
origin of stereoreversal by the choice of protecting group is
explained in Scheme 3. In the case of O-benzoyl-protected
substrate 4, the benzoyl group oxygen coordinates with Os, and
dihydroxylation occurs from the top side predominantly,
affording the D-talopyranoside (substrate control). The addition
of (DHQD)2PHAL (via AD-mix-β) increased the proportion of
top side attack (catalyst control) as shown in Table 3.
Conversely, in the case of tert-butyldimethylsilyl-protected
substrate 5, the bulky silyl moiety prevented top side attack,
and the resulting product was the D-gulopyranoside, formed by
Table 1. Dihydroxylation of Methyl 4,6-Di-O-benzyl-2,3-
a
dideoxy-α-D-threo-hex-2-enopyranoside (1)
additive (mol %)
b,
c
d
entry
reagent
K2OsO4·2H2O
ligand
yield (%)
2:3
1
2
3
4
AD-mix-α
AD-mix-β
AD-mix-α
AD-mix-β
none
0
0
0
0
3 (94)
0 (100)
71
nd
nd
e
10
10
11
10
38:62
63:37
38:62
f
10
58
g
5
0
20 (73)
a
All reactions were carried out using 2,3-unsaturated D-galactopyrano-
side (1), reagent (1.4 g per substrate mmol), MeSO2NH2 (1 equiv),
and additives as described in the table except for entry 5 in t-BuOH/
b
H2O (1/1) at rt, 24 h. Combined yield of 2 and 3 after silica gel
c
column chromatography. The value in the parentheses indicates the
d
recovery of 1. The ratio of D-tallopyranoside and D-gulopyranoside
was determined by both isolated yield and 1H NMR analysis. The ratio
1
after isolation agreed completely with the one by H NMR analysis.
e
f
g
(DHQ)2PHAL. (DHQD)2PHAL. K2OsO4·2H2O (0.11 equiv) and
N-methylmorpholine N-oxide (1 equiv) were used.
2) gave a dihydroxylated product in only 3% yield (1 was
recovered in 94% yield), and reaction of 1 with AD-mix-β was not
observed. Addition of methanesulfonamide (1 equiv), K2OsO4·
2H2O (10 mol %), and (DHQ)2PHAL (10 mol %) to the AD-
mix-α media, however, afforded dihydroxylated products methyl
4,6-di-O-benzyl-α-D-talopyranoside (2) and methyl 4,6-di-O-
benzyl-α-D-gulopyranoside (3) in a 38:62 ratio in 71% yield
B
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Organic Letters
Letter
a
Table 2. Catalytic Asymmetric Dihydroxylation of Methyl O-Benzoyl-2,3-unsaturated α-D-Galactopyranoside (4)
additive (mol %)
K2OsO4·2H2O
product
b
c
d
entry
reagent
ligand
solvent
yield (%)
D-talopyranoside/D-gulopyranoside
e
1
2
3
4
5
6
none
10
100
10
none
none
A
A
B
A
B
A
40
55
60
75
74
81
5 + 5′ + 5″:6 = 80:20
5 + 5′ + 5″:6 = 92:8
5 + 5′ + 5″:6 = 88:12
5 + 5′ + 5″:6 = 82:18
5 + 5′ + 5″:6 = 96:4
f
none
g
AD-mix-α
AD-mix-α
AD-mix-β
AD-mix-β
10
g
10
10
h
10
10
h
10
10
5 + 5′ + 5″:6 = 91:9
a
b
All AD-mix reactions were carried out using reagent (1.4 g per substrate mmol), MeSO2NH2 (1 equiv), and additives at rt for 24 h. A = THF/H2O
c
(1/1). B = t-BuOH/H2O (1/1). In the case of D-talopyranoside 5, the benzoyl group transfer from the 4-position to the 3- (compound 5′) and 2-
position (compound 5″) was observed, which was confirmed after benzoylation of other hydroxyl group that led the same compound. The yields
indicate the combined yield of 5, 5′, 5″, and 6 after silica gel column chromatography. The details are described in ref 14 and the Supporting
d
Information. The ratio of D-talopyranoside and D-gulopyranoside was determined by both the isolated yield and 1H NMR analysis. The ratio after
e
1
isolation agreed completely with the one obtained by H NMR analysis. N-Methylmorpholine N-oxide (1 equiv) was used in the absence of
MeSO2NH2. N-Methylmorpholine N-oxide (3 equiv) was used in the absence of MeSO2NH2. (DHQ)2PHAL. (DHQD)2PHAL.
f
g
h
a
Table 3. Catalytic Asymmetric Dihydroxylation of Methyl O-(tert-Butyldimethylsilyl)-2,3-unsaturated α-D-Galactopyranoside (7)
additive (mol %)
K2OsO4·2H2O
product
b
c
d
entry
reagent
ligand
K3Fe(CN)6
solvent
yield (%)
D-talopyranosie:D-gulopyranoside
e
1
2
3
4
5
6
7
8
none
10
100
10
none
none
0
0
A
A
B
A
B
A
B
A
9
35
30
47
62
67
68
58
8 + 8′ + 8″:9 = 22:78
8 + 8′ + 8″:9 = 15:85
8 + 8′ + 8″:9 = 3:97
8 + 8′ + 8″:9 = 11:89
8 + 8′ + 8″:9 = 9:91
8 + 8′ + 8″:9 = 6:94
8 + 8′ + 8″:9 = 3:97
f
none
g
AD-mix-α
AD-mix-α
AD-mix-α
AD-mix-α
AD-mix-α
AD-mix-β
10
0
g
10
10
0
g
10
10
300
300
0
g
10
10
g
50
50
h
10
10
300
8 + 8′ + 8″:9 = 58:42
a
b
All AD-mix reactions were carried out using reagent (1.4 g per substrate mmol), MeSO2NH2 (1 equiv), and additives at rt for 24 h. A = THF/H2O
(1/1). B = t-BuOH/H2O (1/1). In the case of D-talopyranoside 8, the silyl group transfer from the 4-position to the 3- and 2-positions was
c
observed, which was confirmed after silylation of other hydroxyl group that led the same compound. The yields indicate the combined yield of 8 and
d
its silyl migrated compounds (8′ + 8″) and 9. Details are described in ref 14 and the Supporting Information. The ratio of D-talopyranoside and D-
gulopyranoside was determined by both the isolated yield and 1H NMR analysis. The ratio after isolation agreed completely with the one determined
e
f
by 1H NMR analysis. N-Methylmorpholine N-oxide (1 equiv) was used in the absence of MeSO2NH2. N-Methylmorpholine N-oxide (3 equiv) was
g
h
used in the absence of MeSO2NH2. (DHQ)2PHAL. (DHQD)2PHAL.
attack from the bottom side (substrate control). In this case,
addition of (DHQ)2PHAL (via AD-mix-α) increased the
proportion of bottom side attacks (catalyst control) as shown
in Scheme 3.
As for benzoyl group and silyl group migration, we observed
the formation of migration products during the reaction.
In conclusion, highly selective synthesis of methyl D-
talopyranoside and methyl D-gulopyranoside dervatives has
been achieved through catalytic asymmetric dihydroxylation.
Complete reversal of diastereoselectivity of the double bond in
protected 2,3-unsaturated D-galactopyranoside was accom-
plished by the choice of protecting group, which led to the
selective formation of D-talopyranoside and D-gulopyranoside.
When benzoyl-protected 2,3-unsaturated D- galactopyranoside
was used as a substrate, D-talopyranoside was obtained
predominantly. In contrast, the reaction of tert-butyldimethylsil-
yl-protected 2,3-unsaturated D-galactopyranoside under the
same conditions afforded D-gulopyranoside in a selective
manner. The multiplier effects of substrate control and catalyst
control through the combination of an O-benzoyl-protected
substrate and AD-mix-β systems produced D-talopyranoside in a
ratio of 96:4. In contrast, D-gulopyranoside was obtained in a
C
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1379−1391. (e) Itoh, K.; Mizuno, S.; Hama, S.; Oshima, W.; Kawamata,
M.; Hossain, A.; Ishihara, Y.; Tokuda, M. J. Food Sci. 2015, 80, H1619−
H1626.
Scheme 3. Origin of Stereoreversal: Protecting Group
Dependency
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ratio of 3:97 through the combination of an O-tert-
butyldimethylsilyl-protected substrate and AD-mix-α. It should
be mentioned that this is the first example for the synthesis of two rare
sugars of D-talopyranoside and D-gulopyranoside using the matching
pair of multiplier effects of substrate control and catalyst control.
Further studies of the diastereoselectivity mechanism and
syntheses of other rare sugars based on this strategy are ongoing
in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
(12) For D-gulose, see: Liu, Z.; Yoshihara, A.; Jenkinson, S. F.;
S
́
Wormald, M. R.; Estevez, M. R.; Fleet, G. W. J.; Izumori, K. Org. Lett.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03000.
2016, 18, 4112−4115. See also: Whistler, R. L. In Methods in
Carbohydrate Chemistry; Wiley-Interscience, 1962; Vol.1, pp 135−137
(13) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J. K.; Jeong, S.; Kwong, H. L.; Morikawa, K. Z.; Wang, M. J.
Org. Chem. 1992, 57, 2768−2771.
General experimental procedures, characterization details,
and 1H and 13C NMR spectra of products (PDF)
(14) In the formation of methyl 4,6-di-O-benzoyl-α-D-talopyranoside
(5), the 4-positional benzoyl group was transferred to the 3- and 2-
position leading to formation of methyl 3,6-di-O-benzoyl-α-D-
talopyranoside (5′) and methyl 2,6-di-O-benzoyl-α-D-talopyranoside
(5″) as shown below. This was confirmed by full benzoylation after all
deprotection and benzoylation; therefore, the yield was determined as a
mixture of 5, 5′, and 5′′. A similar observation occurred in silyl-
protected product 8.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mhayashi@kobe-u.ac.jp.
ORCID
Masahiko Hayashi: 0000-0002-1716-6686
Notes
The authors declare no competing financial interest.
Part of this thesis was presented at the 96th annual spring
conference of the Chemical Society of Japan (Kyoto, March 25,
2016).
ACKNOWLEDGMENTS
■
This work was supported by the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan, and by Special
Coordination Funds for Promoting Science and Technology,
Creation of Innovation Centers for Advanced Interdisciplinary
Research Areas (Innovative Bioproduction Kobe), MEXT,
Japan.
(15) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1059−1070.
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