Rapid access to rare natural pyranosides using 1,2-diacetal protected intermediates

Article abstract of DOI:10.1039/a705360f

The synthesis of six rare methylpyranosides from common manno- and galacto-pyranoside starting materials has been achieved by the expedient use of 1,2-diacetal protecting group methodology highlighting its compatibility with a number of other common synthetic procedures.

Full text of DOI:10.1039/a705360f

View Article Online / Journal Homepage / Table of Contents for this issue
Rapid access to rare natural pyranosides using 1,2-diacetal protected
intermediates
Steven V. Ley,* Dafydd R. Owen and Kieron E. Wesson
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge,
UK CB2 1EW
The synthesis of six rare methylpyranosides from common
manno- and galacto-pyranoside starting materials has been
achieved by the expedient use of 1,2-diacetal protecting
group methodology highlighting its compatibility with a
number of other common synthetic procedures.
responding butane-2,3-diacetal (BDA) intermediates which
may be further manipulated in the expedient synthesis of some
rare monosaccharides using a range of standard synthetic pro-
cedures. These reactions take place with no degradation or loss
of the 1,2-diacetal protecting group.
Typically the BDA intermediates such as 3 and 5 may be
prepared by the direct reaction of butane-2,3-dione 1, which is
both cheap and commercially available, with the parent mono-
saccharide in the presence of catalytic camphorsulfonic acid
(CSA) and trimethyl orthoformate in boiling methanol
(Scheme 1).2 The protection reaction may also be carried out at
room temperature in high yield using boron trifluoride–diethyl
ether as a Lewis acid (Scheme 1). The highly crystalline BDA
products need little further purification. The protection of the
trans-1,2-diol in monosaccharide 2 in the presence of a cis-1,2-
diol pair and 1,3-related pair makes this high yielding, selective
process highly attractive. The single step BDA procedure also
eliminates several steps from conventional approaches to this
level of protecting group selectivity.4
These BDA protected intermediates were subjected to several
standard synthetic manipulations in the synthesis of some
monosaccharide targets. The protected monosaccharide 3 was
readily permethylated using sodium hydride and methyl iodide
(Scheme 2). Deprotection of the diacetal 6 in quantitative yield,
using trifluroacetic acid and water (9:1) at room temperature
yielded methyl curamicoside 7, a component of everinomycin C
8 (Fig. 1) which is a member of the orthosomycin family of
antibiotics.5 These antibiotics feature several unusual mono-
saccharide components (Fig. 1) which were readily synthesised
using this diacetal methodology. An added attractive aspect to
the deprotection process was the volatility of the reaction by-
products, leaving evaporation as the only purification process
necessary.
The use of 1,2-diacetals as protecting groups for trans-1,2-diols
has been shown to be a particularly useful method for the effi-
cient construction of complex, biologically significant oligo-
saccharides.1 Recently, several parameters for the design and
exploitation of these 1,2-dione reagents for the direct protection
of trans-1,2-diols have been established.2 Although relatively
few 1,2-diones are effective in these reactions, they have proved
to bea versatileand powerfulnewprotectinggroup protocol. The
high selectivity for trans-1,2-diols, in the presence of other
polyols, rapidly leads to protected monosaccharides amenable
for further synthetic manipulation. The additional tuning effect
on the latent glycosidation reactivity of these 1,2-diacetal pro-
tected building blocks in oligosaccharide assembly further
enhances their synthetic utility.3
In this work we describe the high yielding, selective protec-
tion reaction of methyl-α--mannopyranoside and methyl-α-
-galactopyranoside with butane-2,3-dione, affording the cor-
OH
OH
OH
OMe
O
OH
O
i. or ii.
O
O
HO
HO
+
O
O
OMe
OMe
OMe
i. 95%
ii. 99%
3
1
2
OH
OMe
OH
HO
O
HO
HO
O
O
Returning to the synthetic manipulations, selective iodin-
ation of the 6-hydroxy of 3 was possible by the procedure of
Garegg and Samuelsson 6
O
i.
+
O
HO
OMe
allowing catalytic hydrogenation to
O
OMe
OMe
convert the manno-configuration of 9 to a BDA protected
rhamnopyranoside intermediate 10 (Scheme 2). Deprotection
yielded methyl-α--rhamnopyranoside 11, the unnatural
rhamnose configuration, which is the main constituent of the
80%
1
4
5
Scheme 1 i, cat. CSA, CH(OME)3, MeOH, heat; ii, cat. BF3ؒOEt2,
CH(OMe)3, MeOH, room temp.
OH
OH
OMe
OMe
OMe
OMe
OMe
OH
O
OMe
O
O
O
HO
HO
i. NaH, ii. MeI
TFA:H2O (9:1)
94%
HO
HO
O
O
O
O
DMF
86%
OMe
3
6
7
11
OMe
OMe
OMe
OMe
OMe
OMe
OH
TFA:H2O (9:1)
I
OMe
99%
OH
O
I2, PPh3, Imidazole
O
H2, Pd/C
O
O
O
O
Et2NH, MeOH
86%
Toluene, heat
85%
OMe
OMe
OMe
OMe
9
10
i. BuLi, ii. CS2
iii. MeI, THF
S
OMe
75%
OMe
O
SMe
TFA:H2O (9:1)
85%
Bu3SnH, AIBN
O
O
O
HO
HO
O
O
O
O
Toluene, heat
73%
OMe
OMe
OMe
OMe
OMe
14
13
12
Scheme 2
J. Chem. Soc., Perkin Trans. 1, 1997
2805

View Article Online
I
OH
HO
O
OMe
HO
O
HO
O
OMe
HO
HO
OMe
O
I2, PPh3, Imidazole
Toluene, heat
H2, Pd/C
O
O
TFA:H2O (9:1)
OMe
99%
O
O
Et2NH, MeOH
90%
O
O
HO
OMe
S
OMe
OMe
55%
MeO
5
15
16
MeO
MeO
MeO
O
OMe
OMe
i. BuLi, ii. CS2
iii. MeI, THF
i. NaH, ii. MeI
MeS
O
O
O
Bu3SnH, AIBN
OMe
O
DMF
O
O
Toluene, heat
71%
90%
69%
O
O
OMe
OMe
O
OMe
MeO
96%
MeO
18
MeO
TFA:H2O (9:1)
HO
TFA:H2O (9:1)
97%
MeO
HO
O
O
HO
OMe
HO
OMe
19
17
Scheme 3
D-Galactose
D-Mannose
alkoxide with carbon disulfide followed by methyl iodide
allowed the Barton–McCombie deoxygenation of the second-
ary position to take place. Direct access to this doubly
deoxygenated pyranoside 18 via this method failed due to the
difficulties in the breakdown of primary xanthates. The sequen-
tial deoxygenation strategy was therefore adopted. Deprotec-
tion of the diacetal unit under the standard conditions led to
diol 19 which is an intermediate in Mitsunobu’s Grahamimycin
A synthesis.9
In conclusion, the protection pattern achieved rapidly by the
use of 1,2-diacetal methodology allows facile interconversion
of cheap monosaccharides to rarer, expensive or commercially
unavailable targets. The application of the method in the total
synthesis of more structurally complex natural products is cur-
rently under investigation and will be reported in due course.
The high yields obtained in the protection and deprotection of
the BDA unit suggest that this may prove to be a versatile and
strategic protecting group for use in synthesis.
OMe
O
O
O
MeO
O
O
O
O
O
O
OH HO
OMe OMe
OH
O
O
O
O
O
OH
OMe
O
O
O
O
NO2
O
O
O
D-Mannose
Acknowledgements
OMe
Cl
We gratefully acknowledge financial support from the LINK
Asymmetric Synthesis Programme (Studentship to D. R. O.),
the Zeneca Strategic Research Fund and the Novartis Research
Fellowship (to S. V. L.).
Cl
OH
8
Everninomycin C
Fig. 1
References
A-band lipopolysaccharide from the mutant Pseudomonas
aeruginosa.7 The intermediate 10 was also converted to the
xanthate ester 12 which on treatment with the conditions of
Barton and McCombie yielded the 2-deoxygenated material
13.8 Hydrolysis of the diacetal yielded the 2-deoxyrhamnose
structure 14 (Scheme 2) which is also a monosaccharide subunit
found in certain orthosomycin antibiotics.5
The BDA protected galactose intermediate 5 proved equally
as versatile in the synthesis of three further monosaccharides
(Scheme 3). Once again it was available by the straightforward,
single step BDA protection of the parent monosaccharide 4
using the conditions illustrated (Scheme 1).2 Deoxygenation of
the 6-position via iodination and hydrogenation led to the
fuco-configured intermediate 15. Deprotection yielded the rarer
-configured methylfucopyranoside 16 in quantitative yield,
giving a monosaccharide 350 times as expensive as the starting
-galactopyranoside 4 in four steps. Returning to intermediate
15, methylation of the 4-hydroxy followed by deprotection
yielded the 4-O-methylfucopyranoside 17 which is also found in
everninomycin C (Fig. 1).
1 P. Grice, S. V. Ley, J. Pietruszka and H. W. M. Priepke, Angew.
Chem., Int. Ed. Engl., 1996, 35, 197.
2 (a) N. L. Douglas, S. V. Ley, H. M. I. Osborne, D. R. Owen,
H. W. M. Priepke and S. L. Warriner, Synlett, 1996, 793;
(b) A. Hense, S. V. Ley, H. M. I. Osborn, D. R. Owen, J.-F. Poisson,
S. L. Warriner and K. E. Wesson, J. Chem. Soc., Perkin Trans. 1,
1997, 2023.
3 S. V. Ley and H. W. M. Priepke, Angew. Chem., Int. Ed. Engl., 1994,
33, 2293.
4 V. Pozgay, J.-R. Brisson and H. J. Jennings, Can. J. Chem., 1987, 65,
2764.
5 D. E. Wright, Tetrahedron, 1979, 35, 1207.
6 P. J. Garegg and B. Samuelsson, J. Chem. Soc., Perkin Trans. 1, 1980,
2866.
7 T. L. Arsenault, D. B. MacLean, W. Zou and W. A. Szarek, Can. J.
Chem., 1994, 72, 1376.
8 D. H. R. Barton and S. W. McCombie, J. Chem. Soc., Perkin Trans. 1,
1975, 1574.
9 K. Ohta, O. Miyagawa, H. Tsutsui and O. Mitsunobu, Bull. Chem.
Soc. Jpn., 1993, 66, 523.
Paper 7/05360F
Received 24th July 1997
Accepted 8th August 1997
As a final synthetic example of the BDA method, formation
of the xanthate ester at the 4-position of 15 by reaction of the
2806
J. Chem. Soc., Perkin Trans. 1, 1997