Practical and scalable synthesis of α-(1→4)-linked polysaccharides composed of 6-O-methyl-D-glucose

Article abstract of DOI:10.1021/ol071334x

A second-generation synthesis of synthetic 6-O-methyl-D-glucose-containing polysaccharides (sMGPs) is reported. Glycosidation acceptor A and donor B are prepared from α-, β-, and γ-cyclodextrins in high yields. The glycosidation of A and B, followed by de

Full text of DOI:10.1021/ol071334x

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3327-3329
Practical and Scalable Synthesis of
-(1 4)-Linked Polysaccharides
Composed of 6-O-Methyl- -glucose
r
f
D
Hwan-Sung Cheon, Yiqian Lian, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
kishi@chemistry.harVard.edu
Received June 5, 2007
ABSTRACT
A second-generation synthesis of synthetic 6-O-methyl-
and donor B are prepared from -, -, and -cyclodextrins in high yields. The glycosidation of A and B, followed by deprotection, furnishes
sMGP 12-, 14-, and 16-mers. This synthesis has appealing features such as scalability, operational simplicity, and high overall yield.
D-glucose-containing polysaccharides (sMGPs) is reported. Glycosidation acceptor A
r
â
γ
In conjunction with our continuing efforts to study the
product-regulation mechanism for the fatty acid biosynthesis
in Mycobacterium smegmatis, we recently reported a syn-
thesis of synthetic 6-O-methyl-D-glucose-containing polysac-
charides (sMGPs, 7 in Scheme 1), which were designed
based on the structure of 6-O-methyl-D-glucose-containing
polysaccharides (MGPs), the saponification product of
natural 6-O-methyl-D-glucose-containing lipopolysaccharides
(MGLPs) (Figure 1).1,2
In the first-generation synthesis, we developed an efficient
method for transforming cyclodextrin (CD) derivatives into
linear oligosaccharides, which were used as building blocks
for sMGPs (Scheme 1).2 With the use of these sMGPs and
synthetic 3-O-methyl-D-mannose-containing polysaccharides
(sMMPs), we were able to demonstrate that synthetic
polysaccharides mimic the chemical and biological roles of
natural polysaccharides.3 With this exciting result in hand,
we realized that it had become critically important to secure
the supply of a relatively large quantity of sMGPs for further
studies. The first-generation synthesis is highly convergent
and has served well for us to secure a series of sMGPs.
However, we noticed that the key glycosidation in this
synthesis was not ideal for a large-scale synthesis. Namely,
this glycosidation was performed in the presence of the
Mukaiyama acid (SnCl3ClO4, prepared in situ from AgClO4
and SnCl4).4 Unlike in the sMMP series, the amount of the
Mukaiyama acid required in the sMGP series increased with
an increase in the substrate size. For large oligomers, more
(1) For isolation and characterization of MGLPs, see (a) Lee, Y. C.;
Ballou, C. E. J. Biol. Chem. 1964, 239, PC3602. (b) Forsberg, L. S.; Dell,
A.; Walton, D. J.; Ballou, C. E. J. Biol. Chem. 1982, 257, 3555. For the
revised structure of MG(L)P, see (c) Tuffal, G.; Albigot, R.; Rivie`re, M.;
Puzo, G. Glycobiology 1998, 8, 675.
(2) Meppen, M.; Wang, Y.; Cheon, H.-S.; Kishi, Y. J. Org. Chem. 2007,
72, 1941.
(3) (a) Cheon, H.-S.; Wang, Y.; Ma, J.; Kishi, Y. ChemBioChem 2007,
8, 353. (b) Papaioannou, N.; Cheon, H.-S.; Lian, Y.; Kishi, Y. ChemBio-
Chem, in press.
10.1021/ol071334x CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/21/2007

Table 1. Effects of the Solvent and Activator
Figure 1. Structures of natural MGLPs and MGPs.
entry
activator
solvent
CH2Cl2
THF
CH3CN
yielda selectivity (R:â)
than 1 equiv of the acid was required; for an example, 3
equiv of the acid were used to effectively achieve the
coupling of 14-mer 5 (n ) 14) with 6-mer 4 (n ) 6) to form
20-mer 6. The handling of a large amount of the Mukaiyama
acid presented a technical challenge, thereby urging us to
revisit the glycosidation. In this letter, we wish to report a
scalable, operationally simple, and high-yielding synthesis
of sMGPs.
1
2
3
4
5
6
7
TMSOTf
TMSOTf
TMSOTf
BF3‚Et2O CH2Cl2
HBF4
90%
10%
80%
24%
50%
88%
91%
5:1
10:1
1.4:1
3.3:1
2.5:1
20:1
20:1
CH2Cl2
Et2O
CH2Cl2-Et2Ob
TMSOTf
TMSOTf
a Combined yield of R- and â-linked isomers. b A 1:1 mixture of
CH2Cl2-Et2O.
Scheme 1. First-Generation Synthesis of sMGPs
operational simplicity. Unlike in the sMMP series,8 we could
not take advantage of the C2 acyl group for controlling the
stereochemical course of glycosidation. However, choosing
either diethyl ether or a 1:1 mixture of diethyl ether and
methylene chloride as a solvent, we can achieve a high
stereoselectivity.9 Overall, the phosphate-based glycosidation
shows several appealing features, including operational
simplicity, high stereoselectivity, and high yield.
These appealing features encouraged us to extend the
phosphate-based glycosidation to the synthesis of sMGPs.
Our first task was the preparation of oligosaccharide ano-
meric phosphates. Among several methods known for the
preparation of anomeric phosphates, we adopted the protocol
reported by Wong,10 with two modifications: (1) NaHCO3
was added to accelerate the phosphitylation with a lower
loading of Et2NP(OBn)2 and (2) 1-H 1,2,4-triazole was used
(6) Hashimoto, S.; Honda, T.; Ikegami, S. J. Chem. Soc., Chem. Commun.
1989, 685.
(7) Seeberger has extensively used anomeric phosphates for both solution-
and solid-phase syntheses. For examples of solution-phase synthesis, see
(a) Plante, O. J.; Andrade, R. B.; Seeberger, P. H. Org. Lett. 1999, 1, 211.
(b) Plante, O. J.; Palmacci, E. R.; Andrade, R. B.; Seeberger, P. H. J. Am.
Chem. Soc. 2001, 123, 9545. (c) Codee, J. D. C.; Seeberger, P. H. ACS
Symp. Ser. 2007, 960, 150-164 and references cited therein. For recent
examples of solid-phase synthesis, see (d) Plante, O. J.; Palmacci, E. R.;
Seeberger, P. H. Science 2001, 291, 1523. (e) Werz, D. B.; Castagner, B.;
Seeberger, P. H. J. Am. Chem. Soc. 2007, 129, 2770 and references cited
therein.
Using the monomeric substrates (Table 1), we screened a
variety of the glycosidation methods reported in the litera-
ture.5 Through this screening, the glycosidation via an
anomeric phosphate, originally reported by Hashimoto,
Honda, and Ikegami, emerged as the most promising
candidate;6,7 in particular, we were encouraged by the
(8) Cheon, H.-S.; Lian, Y.; Kishi, Y. Org. Lett. 2007, 9, 3323.
(9) The stereoselectivity of the coupled product was determined from
1
the H NMR spectrum of the crude product, and the stereochemistry was
(4) (a) Mukaiyama, T.; Takashima, T.; Katsurada, M.; Aizawa, H. Chem.
Lett. 1991, 533. (b) Mukaiyama, T.; Katsurada, M.; Takashima, T. Chem.
Lett. 1991, 985. (c) Mukaiyama, T.; Matsubara, K.; Sasaki, T.; Mukaiyama,
T. Chem. Lett. 1993, 1373.
(5) For comprehensive monographs, general reviews, and examples
relevant to this work, see references 9, 10, and 11 cited in Hsu, M. C.; Lee,
J.; Kishi, Y. J. Org. Chem. 2007, 72, 1931.
assigned by nuclear Overhauser effect studies. It was further confirmed
after deprotection to sMGPs; the glycosidic protons of â-linked anomers
are known to give resonances shifted to upfields compared to those of the
corresponding R-linked anomers.
(10) (a) Pederson, R. L.; Esker, J.; Wong, C.-H. Tetrahedron 1991, 47,
2643. (b) Sim, M. M.; Kondo, H.; Wong, C.-H. J. Am. Chem. Soc. 1993,
115, 2260.
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Org. Lett., Vol. 9, No. 17, 2007

to substitute potentially explosive 1-H tetrazole. In this
manner, the anomeric phosphates (ca. 2:1 anomeric mixtures)
were readily obtained from the corresponding hexoses in a
two-step, one-pot sequence, that is, the formation of phos-
phites, followed by H2O2 oxidation. The anomeric phosphates
thus prepared were stable for at least several weeks in a
refrigerator (4 °C).
R-anomers were found to be much less polar than the
â-anomers, flash column chromatography (silica gel) was
sufficient to isolate the pure desired products. By this manner,
the pure R-anomer was isolated in approximately 60% yields
for all the cases.
In conclusion, we have developed a second-generation
synthesis of sMGPs (Scheme 2). The key step in this
Unfortunately, because of the poor solubility of substrates
in the oligosaccharide series (entry 1, Table 2), we could
Scheme 2. Synthesis of sMGPs from CDsa
Table 2. Glycosidation in the Oligomer Series
a
Reagents and conditions: (a) See reference 2. (b) (1) (i)
NaOMe, CH2Cl2-MeOH; (ii) BnBr, NaH, DMF, 73%; (2)
(Ph3P)3RhCl, EtOH-toluene, reflux, followed by H3O+ workup,
76%; (3) Et2NP(OBn)2, 1H-1,2,4-triazole, NaHCO3, CH2Cl2, fol-
lowed by H2O2 workup, 85%; (c) TMSOTf, CH2Cl2, -40 f -25
°C, 60% (R-anomer). (d) (i) H2, Pd(OH)2 on C, CH2Cl2-MeOH;
(ii) NaOMe, CH2Cl2-MeOH, 73%. Note: Indicated yields are for
the â-CD series, and comparable yields were observed for both
the R- and γ-CD series.
entry
n
scale (donor)
solvent
yielda selectivity (R:â)
1
2
3
4
5
6
7
6
7
7
8
8
10 mg
29 mg
90 mg
1.17 g
110 mg
1.32 g
CH2Cl2-Et2Ob <20%
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
70%
72%
71%
71%
70%
5:1
5:1
5:1
5:1
5:1
a Combined yield of R- and â-linked isomers. b A 1:1 mixture of
CH2Cl2-Et2O.
synthesis is the phosphate-based glycosidation, 11 + 12 f
6. This glycosidation is operationally simple and suited for
gram-scale synthesis; indeed, we were able to carry out a
synthesis, starting with 6.8 g of â-CD and obtaining more
than 400 mg of sMGP 14-mer.
not employ the conditions optimized for the synthesis of
disaccharide (entries 6 and 7, Table 1). This technical
difficulty was overcome by using methylene chloride as the
solvent, and then the scalability and reliability were dem-
onstrated (Table 2). However, the use of methylene chloride
as the solvent caused the stereoselectivity of glycosidation
to decline from >20:1 to 5:1. Fortunately, the reduction in
stereoselectivity did not present a technical problem for the
isolation of the desired R-anomer in a pure form; as the
Acknowledgment. Financial support from Eisai Research
Institute, Amgen, and Eli Lilly is gratefully acknowledged.
Supporting Information Available: Experimental details
1
and H NMR spectra (12 pages). This material is available
free of charge via the Internet at http://pubs.acs.org
OL071334X
Org. Lett., Vol. 9, No. 17, 2007
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