Convenient syntheses of deoxypyranose sugars from glucuronolactone

Article abstract of DOI:10.1016/j.tetlet.2007.01.127

One of the characteristic reactions of glucuronic acid derivatives is the base-catalysed elimination of a 4-(substituted) hydroxy group to generate a Δ_4,5 pyranose. Following hydrogenation, proceeding mainly from the α-face provided the anomeri

Full text of DOI:10.1016/j.tetlet.2007.01.127

Tetrahedron Letters 48 (2007) 2361–2364
Convenient syntheses of deoxypyranose sugars
from glucuronolactone
Deborah Stanford (nee Sinnott) and Andrew V. Stachulski*
The Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
Received 20 December 2006; revised 15 January 2007; accepted 24 January 2007
Available online 30 January 2007
Abstract—One of the characteristic reactions of glucuronic acid derivatives is the base-catalysed elimination of a 4-(substituted)
hydroxy group to generate a D4,5 pyranose. Following hydrogenation, proceeding mainly from the a-face provided the anomeric
configuration is b, the initial C(5)-configuration is restored. This sequence affords access to a number of 4-deoxypyranoses: thus
4-deoxyglucoses are readily available by reduction at C(6). Conversion to a glycal, then cis-dihydroxylation at C(2)/C(3) leads to
the D-lyxo configuration (found in neosidomycin). Finally a less obvious relationship to the KDO series is revealed, again by
dihydroxylation.
Ó 2007 Elsevier Ltd. All rights reserved.
Deoxypyranose sugars1 are common in Nature, espe-
cially the 6-deoxy L-series sugars fucose 1 (mammals
and higher organisms) and rhamnose 2 (plants and bac-
teria).
rides containing GlcA.4 The resulting hexenuronic acids,
viz. 4, have been rather little used synthetically, but
clearly they offer a convenient route to 4-deoxypyra-
noses provided good facial selectivity can be obtained
on reduction. We now report the successful use of this
approach for the synthesis of a number of deoxysugars.
OH
OH
OH
O
O
HO
OH
OH
The sequence to the key glycal intermediate (Scheme 1)
began with glucuronolactone 5, which was converted to
tetraisobutyrate 6 via base-catalysed methanolysis fol-
lowed by treatment with excess PriCOCl and pyridine;5
after recrystallisation, b-tetraester 6 was obtained in
excellent anomeric purity in 50–60% yield. The advanta-
ges of the isobutyrate esters are several, namely, the
crystallinity of key intermediates (v.i.), superior glycosi-
dation, especially reduced transacylation,5a and a better
yield in the later NaBH4 reduction step. Numerous
bases could effect elimination from 6; the most conve-
nient was DBU6 (1.1 equiv, THF, 0–20 °C), which gave
an excellent (96%) yield of unsaturated ester 7. It was
noteworthy that the 1a-ester corresponding to 6 did
not undergo b-elimination easily. The trisubstituted
double bond in 7 was not easily reduced by catalytic
transfer hydrogenation, but classical hydrogenation in
isopropanol led to clean reduction with 5b-ester 8 as
the major product (5b:5a = 4:1). Recrystallisation from
hexane gave pure 5b-CO2Me product 8 in 58% yield.
OH
OH
1
2
CO2H
OH
O
O
OR
HO
HO
OH
OH
HO
4
3
Access to pyranoses with ring deoxygenation, however,
usually requires synthesis, and of the other positions,
4-deoxygenation is relatively the most difficult to
achieve. Previously 4-deoxy-D-glucose 3 has been ob-
tained via radical chemistry, for example, from a 4-thio
derivative,2 or by a sequence3 from D-galactose involv-
ing selective acylation, then conversion to a 4-iodosugar
and reduction.
The relative ease of base-catalysed elimination of 4-sub-
stituents from glucuronic acid (GlcA) derivatives is well
known from early degradation studies on polysaccha-
For later adjustment of the stereochemistry at C(2) and
C(3), 8 was converted to a glycal. Glycosyl bromide 9
was readily obtained from 8 using HBrÆAcOH–CH2Cl2
*
Corresponding author. Tel.: +44 0 151 794 3542; fax: +44 0 151 794
3588; e-mail: stachuls@liv.ac.uk
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.127

2362
D. Stanford (nee Sinnott), A. V. Stachulski / Tetrahedron Letters 48 (2007) 2361–2364
O
CO Me
2
CO Me
2
HO
O
i
i)
O
ii)
OH
O
Pr CO
2
O
i
i
O CPr
i
Pr CO
2
O CPr
2
i
2
Pr CO
2
i
Pr CO
2
i
OH
Pr CO
2
5
6
7
iii)
CO Me
2
CO Me
2
CO Me
2
O
O
O
v)
iv)
i
O CPr
i
i
i
2
Pr CO
Pr CO
Pr CO
2
i
2
i
2
Pr CO
Pr CO
2
2
Br
9
8
10
Scheme 1. Syntheses of 4-deoxyglucuronate ester 8 and derived glycal 10. Reagents, yields: (i) Et3N, MeOH, then AcOH, evap., PriCOCl, pyridine,
59%; (ii) DBU, THF, 0–20 °C, 96%; (iii) H2–Pd/C, PriOH, remove 5a-isomer by crystallisation, 58%; (iv) HBrÆAcOH, CH2Cl2, 80%; (v) Zn, vitamin
B12, MeOH, 60%.
in the usual way; though 9 proved fairly unstable at
20 °C, it was readily converted to glycal 10. In our hands
the best procedure was the relatively recent7 non-aqueous
method employing Zn and catalytic vitamin B12 in
MeOH: this is a fast, reproducible reaction. With the
reactions summarised in Scheme 1, all key intermediates
were in place.
addition from the b-face, as expected for a ‘non-direct-
ing’ substituent12,13 at C(1). This represents an entry to
the D-lyxo-hexopyranose series as found in neosidomy-
cin14 and, at seven steps from 5 to 15, is shorter than
the previous route. In the previous synthesis of neosido-
mycin derivatives,14 the acetonide of compound 15 was
made and because of the close correspondence in NMR
shifts and coupling constants [the acetonide showed d
4.92 (1H, d, J = 1.3 Hz) and 15 showed d 4.91 (1H, d,
J = 2.4 Hz) for H-1 in each case] we are confident of
the assignment of 15. The acetonide J (H1–H2) value
is consistent with an eq–eq coupling: in the same com-
pound the ax–eq coupling [H-5 to H-4eq] was 5 Hz.14
Also the dihydroxylation of normal (viz. 4-oxygenated)
2,3-dideoxypyranoses of 1a-configuration is known to
give mainly mannoside products.15
For entry to the 4-deoxyglucose series, (Scheme 2), 4-
deoxyester
8 was first converted to a glycoside
[Ph(CH2)2OH, TMSOTf], affording a-product 11 to-
gether with a small amount (ca. 10%) of the ester-
exchanged product 12. The 1a-configuration did not
hinder the subsequent reduction, but this interesting re-
sult was in complete contrast to the TMSOTf-mediated
glucuronidation of alcohols using 6, where only the
kinetic b-product was seen.8 Clearly, the 4-deoxygena-
tion has a profound influence here. Selective reduction
Alternatively, conversion of 10 to a C-glycoside afforded
convenient entries to other higher monosaccharides by
dihydroxylation, with the facial preference of addition
dependent on the new substituent added. Thus (Scheme
1) the Pd-catalysed reaction of 10 with Me3SiCN16 affor-
ded very largely a-nitrile 16a (a:b = 8:1) in a very good
yield of 80%. The minor nitrile 16b could be crystallised
and a single crystal X-ray structure determination con-
firmed the stereochemistry, Figure 1.17 Upjohn dihydr-
9
of the 6-CO2Me group with NaBH4 then led to
4-deoxyglucoside 13 in good yield.
To obtain a dihydroxylation substrate, a Ferrier reac-
tion10 of 10 with methanol was performed, giving
a-glycoside 14 in good yield, Scheme 3. Under the
Upjohn conditions (catalytic OsO4 with NMO as
reoxidant),11 this substrate afforded solely diol 15 by
O
Ph
CO Me
CO Me
2
i)
O
2
O
O
O
i
i
i
O CPr
Pr CO
+
i
2
Pr CO
2
2
Pr CO
2
i
i
Pr CO
Pr CO
2
i
2
11
Pr CO
O(CH ) Ph
2
2 2
8
12 O(CH ) Ph
2 2
ii)
CH OH
2
O
i
Pr CO
2
i
Pr CO
2 13
O(CH ) Ph
2 2
Scheme 2. Conversion to a 4-deoxyglucoside. Reagents and conditions: (i) TMSOTf, Ph(CH2)2OH, CH2Cl2, 0–20 °C, 59% 11 + 10% 12; (ii) NaBH4,
53%.

D. Stanford (nee Sinnott), A. V. Stachulski / Tetrahedron Letters 48 (2007) 2361–2364
2363
CO Me
O
CO Me
O
CO Me
O
2
2
2
OH
i)
ii)
i
Pr CO
HO
2
OMe
OMe
15
10
14
iii)
CO Me
O
CO Me
O
2
2
CO Me
2
OH
O
iv)
+
HO
HO
CN
CN
HO
CN
16α
v)
17
18
CO Me
O
2
CO Me
2
OH
O
vi)
HO
CONH
2
CONH
2
20
21 anti-only
Scheme 3. Dihydroxylation studies. Reagents, yields: (i) MeOH, BF3ÆEt2O, 52%; (ii) cat. OsO4, N-methylmorpholine N-oxide, 41%; (iii) Pd(OAc)2,
Me3SiCN, 80%, a:b = 8:1; (iv) as (ii), or using quinuclidine-N-oxide (QNO) as reoxidant, 28%; (v) TiCl4, AcOH, 40%; (vi) as (iv), 23%.
Figure 1. ORTEP representation for single crystal X-ray structures of 16b and 18.17
oxylation of 16a gave a mixture of anti and syn diols 17
and 18 in a 3:2 ratio.
By rotation, diol 18 may be drawn as 18a whose alter-
native chair conformation is 18b (v.s.): it can be seen
that the absolute stereochemistry of 18b is the same
as that of 2b-deoxy KDO 19,20 with the nitrile replac-
ing the 1,2-dihydroxyethyl side chain of the latter.
Compound 19 is of considerable interest as an antibac-
terial agent since it is a potent inhibitor of CMP-KDO
synthetase,20,21 a key enzyme in Gram-negative bacte-
rial cell wall assembly. A further X-ray structure deter-
mination17 (Fig. 1) confirmed the stereochemistry of
18. Unsurprisingly, the small nitrile substituent can
adopt an axial setting, whereas the much bulkier 1,2-
dihydroxyethyl side chain in 19 is known to be
equatorial.22
In contrast to the results of Donohoe13 and others,18
where allylic hydroxy or methoxy substituents usually
direct dihydroxylation entirely to the opposite face, this
is an interesting result. Either the nitrile substituent pre-
sents a relatively small bulk, so that appreciable syn
dihydroxylation is sterically possible, or the nitrile may
be exerting some directing effect. However, we found
that both the yield and syn:anti ratio were virtually unaf-
fected on using quinuclidine-N-oxide (QNO)13,19 as
reoxidant, so that currently we cannot offer a definite
interpretation of this result.
OH
OH
CN
OH
HO
HO
CO Me
2
CN
O
O
O
O
CO Me
2
CN
HO
H
H HO
CO Me
HO
CO H
2
2
16β
18a
19 2β-Deoxy KDO
18b

2364
D. Stanford (nee Sinnott), A. V. Stachulski / Tetrahedron Letters 48 (2007) 2361–2364
Alternatively (Scheme 3), partial hydrolysis23 of nitrile
16a (TiCl3, AcOH) afforded amide 20 in an acceptable
(40%) yield. Dihydroxylation of 20 using either Upjohn
conditions or QNO afforded a single product, namely
anti diol 21. Here the H(6)-proton [the carboxamide-
bearing carbon is numbered C(6)] resonates at d 4.10
(1H, d, J = 1.6 Hz), consistent with eq–eq coupling.
This J value is strikingly similar to that in 15 and offers
convincing evidence for the stereochemistry shown,
though in this case we could not obtain a satisfactory
crystalline sample. Apparently either the greater steric
bulk of the amide over the nitrile directs the Os reagent
entirely to the opposite face, or the amide NHs are
insufficiently acidic to donate to Os, in contrast to the
examples reported by Donohoe et al.24 where a more
acidic amide or carbamate NH was present. It is also
noteworthy that examples featuring effective amide
and carbamate donors have had the NH directly linked
to the ring at the allylic position.25 The C-glycosidic
amide 20, where the NH2 unit is further away from
the alkene, may have relatively unfavourable geometry
to exert a donor effect.
5. (a) Brown, R. T.; Carter, N. E.; Mayalarp, S. P.;
Scheinmann, F. Tetrahedron 2000, 56, 7591–7594; (b)
Stachulski, A. V.; Scheinmann, F.; Ferguson, J. R.; Law,
J. L.; Lumbard, K. W.; Hopkins, P.; Patel, N.; Clarke, S.;
Gloyne, A.; Joel, S. P. Bioorg. Med. Chem. Lett. 2003, 13,
1207–1214.
6. For related DBU eliminations on glucuronic acid deriv-
atives, see: (a) Oscarson, S.; Svahnberg, P. J. Chem. Soc.,
Perkin Trans. 1 2001, 873–879; (b) Bazin, H. G.; Wolff, M.
W.; Linhardt, R. J. J. Org. Chem. 1999, 64, 144.
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8. (a) Scheinmann, F.; Lumbard, K. W.; Brown, R. T.;
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Patent, WO 93/3051, 1993; Chem. Abs. 1993, 119, 226341;
(b) Stachulski, A. V., unpublished observations.
9. Cottrell, J. A.; Harding, J. R.; King, C.; Sinnott, D.;
Stachulski, A. V. Org. Lett. 2003, 5, 4545–4548.
10. (a) Rutjes, F.; Kooistra, T. M.; Hiemstra, H.; Schoe-
maker, H. E. Synlett 1998, 192–193; (b) Ferrier, R. J.;
Prasad, N. J. Chem. Soc. C 1969, 570–574.
11. VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron
Lett. 1976, 17, 1973–1974.
12. Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett. 1983,
24, 3943–3944.
13. Donohoe, T. J.; Moore, P. R.; Waring, M. J.; Newcombe,
N. J. Tetrahedron Lett. 1997, 38, 5027–5030; The ‘directed’
dihydroxylation has been reviewed: Donohoe, T. J. Synlett
2002, 1223–1232.
14. Buchanan, J. G.; Stoddart, J.; Wightman, R. H. J. Chem.
Soc., Perkin Trans. 1 1994, 1417–1426.
In conclusion, we have demonstrated convenient routes
from glucuronolactone to a variety of deoxypyranose
sugars, including some of the potentially interesting bio-
logical activities. In addition the stereochemical prefer-
ences shown in the dihydroxylation reactions offer an
interesting contribution to this topic.
15. (a) Ferrier, R. J.; Prasad, N. J. Chem. Soc. C 1969, 575–
580; (b) Lemieux, R. U.; Kullnig, R. K.; Moir, R. Y. J.
Am. Chem. Soc. 1958, 80, 2237.
16. Hayashi, M.; Kawabata, H.; Nakayama, S. Z. Chirality
2003, 15, 10–16.
17. The crystallographic data of 16b and 18 have been
deposited with the Cambridge Crystallographic Data
Centre as Supplementary Publication Numbers CCDC
631165 and CCDC 631166, respectively. Copies of the
data can be obtained free of charge from the CCDC via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
We are grateful to the EPSRC for funding (DTA award
to D.S.), to Jamie Bickley (formerly of this Department)
for the X-ray structure determinations and to Professor
Tim Donohoe (University of Oxford) for valuable dis-
cussions on the directed dihydroxylation reaction.
18. Kennedy, A.; Nelson, A.; Perry, A. Chem. Commun. 2005,
1646–1647.
Supplementary data
19. O’Neil, I. A.; Lai, J. Y. Q.; Wynn, D. Chem. Commun.
1999, 59–60; O’Neil, I. A.; Bhamra, I.; Gibbons, P. D.
Chem. Commun. 2006, 4545–4547. QNO is conveniently
prepared by the reaction of quinuclidine with ozone:
O’Neil, I. A., personal communication.
20. (a) Goldman, R.; Kohlbrenner, W.; Lartey, P.; Pernet, A.
Nature 1987, 329, 162–164; (b) Claesson, A.; Luthman, K.;
Gustafsson, K.; Bondesson, G. Biochem. Biophys. Res.
Commun. 1987, 143, 1063–1068.
Spectroscopic and analytical data for all new com-
pounds reported, together with selected experimental
procedures, are included in a supplementary file. Supple-
mentary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2007.01.127.
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