Stereoselective synthesis of oligo-α(2,8)-3-deoxy-D-manno-2- octulosonic acid derivatives

Article abstract of DOI:10.1002/anie.200503299

(Chemical Equation Presented) Iodoalkoxylation (see scheme) of a glycal with an acyclic saccharide precursor leads to an efficient stereoselective synthesis of di- and tri-α(2,8)-3-deoxy-D-manno-2-octulosonic acid (KDO; see picture). The glycal forms α-li

Full text of DOI:10.1002/anie.200503299

Communications
Synthetic Methods
tion of KDO.[3] Furthermore, in 1989, Achiwa and co-workers
reported that the glycal ester underwent glycosyloxyselena-
tion to provide a-linked 3-phenylselenyl-KDO derivatives.[4]
The feasibility of these methods was mainly demonstrated by
the synthesis of mono-KDO-containing oligosaccharides.
However, the coupling of two and three KDO units often
resulted in reduced product yields and some loss of selectivity.
Notably, the low-nucleophilicity hydroxy groups on KDO
units promote significant 2,3-elimination of the donor instead
of the coupling reaction. Therefore, an efficient method for
the stereoselective synthesis of a-linked KDO dimers and
trimers is still needed.
Previously, we investigated the synthesis of oligosacchar-
ides with acyclic glycosyl donors,[5] and reported on the
synthesis of 2,3,6-deoxyglycosides by the one-pot cyclization
and glycosidation of acyclic glycosyl donors possessing
sulfoxide and alkylsulfanyl groups at the pseudo-anomeric
position.[6] The acyclic donors were stable to various glyco-
sidation reagents such as Lewis acids and to oxidative
reagents. We envisaged that the acyclic saccharide precursors
4 could be used as glycosyl acceptors for iodoalkoxylation of
the glycal ester 3, and could be converted to a-KDO
glycosylated products 7 through diaxial opening[4,7] of the
iodonium ion 6 without decomposition of the sulfur-based
leaving groups (Scheme 1). The hydroxy groups on the acyclic
DOI: 10.1002/anie.200503299
Stereoselective Synthesis of Oligo-a(2,8)-3-deoxy-
d-manno-2-octulosonic Acid Derivatives
Hiroshi Tanaka, Daisuke Takahashi, and
Takashi Takahashi*
3-Deoxy-d-manno-2-octulosonic acid (KDO), a unique sugar
component of lipopolysaccharides (LPSs), is an important
constituent of the outer membrane of Gram-negative bac-
teria.[1] KDO is frequently present in the form of a(2,4)- and
a(2,8)-linked homooligomers 1 and 2 connected to lipid A in
LPSs. These unique di- and oligo-KDO fragments are found
only in bacterial cell walls and do not exhibit significant
biological activity. Therefore, they could serve as potential
antigens in the development of antibacterial vaccines. How-
ever, the possibility that such isolated oligosaccharides could
be heterogeneous and/or contaminated with antigenic com-
pounds cannot be excluded. Therefore, the chemical synthesis
of these ulosonic acid-containing oligosaccharides would
circumvent these issues as they relate to vaccine develop-
ment.
Recent progress in oligosaccharide synthesis has resulted
in a number of efficient glycosidation methodologies. How-
ever, the glycosidation of ulosonic acids often involves the
generation of undesirable b stereoisomers and/or the 2,3-
elimination of the donors as a result of the presence of a C1
carboxyl group and the lack of a C3 substituent.[2] In addition,
the hydroxy groups, both in the pyran ring and on the
endocyclic side chain, are less reactive toward glycosylation.
In 1987, Shiba and co-workers reported that a-ketopyranosyl
fluoride was an effective donor for the a-selective glycosida-
Scheme 1. Strategy for the synthesis of a-linked oligo-KDO by iodo-
alkoxylation.
saccharide precursors would be expected to exhibit an
enhanced reactivity toward glycosylation in comparison
with the corresponding cyclic acceptors 5, because the
opening of the pyran and furan rings of the saccharide units
is known to be an effective strategy for improving the
reactivity of hydroxy groups toward glycosylation.[8] The
coupling products 7 can be converted to the glycal ester 8 for
glycosidation. Herein, we describe the synthesis of oligosac-
charides containing tri- and di-a(2,8)-KDO units by iodoalk-
oxylation with an acyclic saccharide precursor.
[*] Dr. H. Tanaka, D. Takahashi, Prof. Dr. T. Takahashi
Department of Applied Chemistry
Graduate School of Science and Engineering
Tokyo Institute of Technology
2-12-1 Ookayama, Meguro, Tokyo 152-8552 (Japan)
Fax: ( +81)3-5734-2884
E-mail: ttak@apc.titech.ac.jp
The strategy developed for the synthesis of a(2,8)-KDO
derivatives 9 and 10 is shown in Scheme 2. These compounds
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
770
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Scheme 2. Strategy for the synthesis of tri- and di-a(2,8)-KDO derivatives 9 and 10. Bn=benzyl.
Table 1: Iodoalkoxylation of 14 with various acceptors 13 (Scheme 3).
could be prepared by the glycosylation of acceptor 13a with
the corresponding glycal esters 11 and 12 attached to a(2,8)-
KDO units. The synthesis of the glycal ester 12 could be
achieved by the regio- and stereoselective iodoalkoxylation of
the glycal ester 14 with diol 15, which contains alkylsulfanyl
and sulfoxide groups at the C2 position, followed by
subsequent cyclization and b elimination. Trisaccharide 11
was prepared from 12 by the iodoalkoxylation and b elimi-
nation protocol. Benzyl ethers were selected as O-protecting
groups to improve the reactivity of the glycal esters 11, 12, and
14 toward iodoalkoxylation. The resulting iodide and benzyl
ethers can be readily removed by hydrogenolysis. Diol 15 can
be prepared by alkylation of dithiane 17[9] with the corre-
sponding alkyl halide 16.[5,6,10]
Entry
Acceptor
Product
T [8C]
Yield [%]
a/b[a]
1
2
3
4
13a
13b
13c
13d
18a
18b
18c
18d
À50
93
77
73
–
>95:5
>95:5
92:8
–
À50 to À40
À50 to À20
–
[a] The a/b ratio was estimated by HPLC analysis with refractive index
detection.
although iodoalkoxylation of glycals in the synthesis of a-
linked 2-deoxyglycosides is known to proceed under mildly
oxidative conditions,[12] the use of a stoichiometric amount of
TfOH was critical for the iodoalkoxylation of glycal ester 14
to proceed. Glycosylation at the C3 secondary alcohol moiety
of galactoside 13b proceeded smoothly to provide disaccha-
ride a-18b in excellent yield and selectivity.[13]
Next, the glycosylation of KDO derivatives 13c–e at the
C8 position was examined. The methyl glycoside 13c was
converted to the corresponding a-glycoside a-18c in 73%
yield with a/b = 92:8.[11] On the other hand, glycosyl sulfoxide
13e was difficult to prepare because of its instability. The
glycosyl fluoride 13d decomposed under these reaction
conditions. These results suggest that, although the iodoalk-
oxylation of glycal esters would be effective for the synthesis
of a-linked KDO derivatives, it would be difficult to design
cyclic glycal precursors that are amenable to iodoalkoxyla-
tion.
We first investigated the iodoalkoxylation of the glycal
ester 15 with alcohols 13 (Scheme 3 and Table 1). Treatment
of the benzyl-protected glycal ester 14 and primary alcohols
13a with NISand TfOH provided the 3-iodo- a-glycoside a-
18a in 93% yield with excellent selectivity.[11] Notably,
We then examined the synthesis of the a(2,8)-KDO
derivatives 9 and 10. The preparation of the acyclic building
blocks 15 is shown in Scheme 4. Treatment of iodide 16[14] with
dithiane 17 in the presence of NaH in DMF provided the
alkylated product 19, which was followed by removal of the
acetal of 19 under acidic conditions to afford diol 20 in 71%
overall yield. Oxidation of thioether 20 provided sulfoxide 15
in good yield.
Iodoalkoxylation and glycal formation is shown in
Scheme 5. Treatment of the glycal ester 14 and 1.5 equivalents
of diol 15 in the presence of NIS/TfOH at À50 to À208C
Scheme 3. Iodoalkoxylation of 14 with various acceptors 13 (see also
Table 1) NIS=N-iodosuccinimide; TfOH=trifluoromethanesulfonic
acid; M.S.=molecular sieves.
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Scheme 4. Reagents and conditions: a) 17, NaH, tBuOH (cat.), DMF;
b) CSA, MeOH, THF, 71% (based on 16); c) m-CPBA, CH2Cl2, 95%.
DMF=N,N-dimethylformamide; CSA=10-camphorsulfonic acid;
CPBA=chloroperbenzoic acid.
provided a-glycoside 21 in 89% yield. These results
indicate that the opening of the pyran ring of the KDO
derivative effectively improved the coupling yield of the
C8 hydroxy group, and that sulfoxide and alkylsulfanyl
groups represent suitable protecting groups for the linear
building blocks at the pseudo-anomeric position for the
iodoalkoxylation. The sequential activation of the two
leaving groups with (COCl)2 and AgOTf in CH2Cl2
afforded the glycal ester 12 bearing an a-linked KDO
unit as a single diastereomer. AgOTf played a crucial role
in increasing the yield of the glycal ester 12. Iodoalkox-
ylation of 12 with 1.5 equivalents of 15 followed by glycal
formation provided the tri-KDO derivative 11 in good
total yield with excellent selectivity. Glycosylation of the
primary alcohol 13a with glycal esters 11 and 12 pro-
ceeded stereoselectively to provide a-glycosides 22 and 23
in good yields with excellent selectivity. Removal of the
iodide and cleavage of all the benzyl ether protecting
groups, followed by acetylation, provided the peracetyl-
protected tri- and tetrasaccharides 24 and 25 in 53 and
71% yield, respectively. Hydrolysis of the ester groups in
Scheme 5. Reagents and conditions: a) 15 (1.5 equiv), NIS, TfOH, M.S. 4 Š,
CH2Cl2, À50 to À208C, 89%; b) (COCl)2, AgOTf, M.S. 4 Š, CH2Cl2, À30 to
08C, 77%, a/b=>95:5; c) 15 (1.5 equiv), NIS, TfOH, M.S. 4 Š, CH2Cl2,
À50 to À208C, 68%; d) (COCl)2, AgOTf, M.S. 4 Š, CH2Cl2, À30 to 08C,
85%, a/b=>95:5; e) 13a (1.5 equiv), NIS, TfOH, M.S. 4 Š, CH2Cl2,
À508C to room temperature, 80%, a/b=>95:5 for 23, 55%, a/b=86:14
24 and 25 provided tri- and di-a(2,8)-KDO-containing for 22; f) 1. Pd(OH)2, n-BuOH, MeOH, ethyl acetate; 2. Ac2O, Py, CH2Cl2,
DMAP, 71% for 25, 53% for 24; g) LiOH, MeOH/H2O, 508C, quantitative
oligosaccharides 9 and 10 in good yields. The a linkages of
for 10, 89% for 9. Py=pyridine; DMAP=4-dimethylaminopyridine.
the KDO units of 24 and 25 were confirmed by analysis of
1
their H NMR spectra on the basis of reported empirical
rules.[11]
Keywords: carbohydrates · glycosides · glycosylation ·
.
In conclusion, an efficient synthesis of tri-a(2,8)-KDO
derivatives based on an iterative glycosidation strategy has
been developed. Iodoalkoxylation of the glycal esters 11, 12,
and 14 proceeded in a stereoselective manner to provide a-
linked KDO derivatives in good yields. The acyclic building
block 15 was found to be an effective glycosyl acceptor and
was converted to the glycal ester for glycosidation. The
opening of the pyran ring effectively improved the reactivity
of the C8 hydroxy group. The glycal esters 11 and 12 bearing
KDO units constitute potentially useful building blocks for
the synthesis of a-KDO-conjugated oligosaccharides.
oligosaccharides · synthetic methods
[1] F. M. Unger, Adv. Carbohydr. Chem. Biochem. 1981, 38, 324 –
387.
[2] For reviews on the synthesis of KDO glycosides, see: a) J.
Hansson, S. Oscarson, Curr. Org. Chem. 2000, 4, 535 – 564;
b) L. S. Li, Y. L. Wu, Curr. Org. Chem. 2003, 7, 447 – 475.
[3] M. Imoto, S. Kusumoto, T. Shiba, Tetrahedron Lett. 1987, 28,
6277 – 6280.
[4] K. Ikeda, S. Akamatsu, K. Achiwa, Carbohydr. Res. 1989, 189,
C1 – C4.
Received: September 16, 2005
Published online: December 22, 2005
[5] T. Takahashi, H. Tsukamoto, H. Yamada, Org. Lett. 1999, 1,
1885 – 1887.
772
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[6] T. Amaya, D. Takahashi, H. Tanaka, T. Takahashi, Angew.
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[7] P. Kosma, H. Sekljic, G. Balimt, J. Carbohydr. Chem. 1996, 15,
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[8] a) K. Heins, K. Propp, R. Harrison, H. Paulsen, Chem. Ber. 1967,
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Inage, Bull. Chem. Soc. Jpn. 1986, 59, 1411 – 1417.
[9] This compound is commercially available.
[10] a) M. Imoto, S. Kusumoto, T. Shiba, Tetrahedron Lett. 1987, 28,
6235 – 6238; b) P. A. M. van der Klein, G. J. P. H. Boons, G. H.
Veenman, G. A. van der Marel, J. H. Van Boom, Tetrahedron
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Tsukamoto, M. Kurosaki, H. Yamada, Synlett 1997, 9, 1065 –
1066.
[11] Structure determination of the a-linked 3-iodo-KDO units was
achieved by removal of the iodides and benzyl ether protecting
groups followed by acetylation, and subsequent 1H NMR
spectroscopic analysis of the acetylated products on the basis
of reported empirical rules; P. Kosma, M. Strobl, G. Allmaier, E.
Schmid, H. Brade, Carbohydr. Res. 1994, 254, 105 – 132.
[12] R. W. Frisen, S. J. Danishefsky, J. Am. Chem. Soc. 1989, 111,
6656 – 6660.
[13] The a linkage of the KDO unit of a-18b was confirmed by
3
analysis of the coupling constant JC1-H3ax (< 1 Hz) of the
corresponding deprotected product; F. M. Unger, D. Stix, G.
Schulz, Carbohydr. Res. 1980, 80, 191 – 195.
[14] Alkyl iodide 16 was prepared by standard methods. All new
compounds exhibited satisfactory spectroscopic and analytical
data (see Supporting Information).
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