Stereoselective glycosylation using oxathiane glycosyl donors

Article abstract of DOI:10.1039/b913308a

A bicyclic glycosyl donor is activated as an arylsulfonium ion and used to synthesise α-glycosides with high stereoselectivity.

Full text of DOI:10.1039/b913308a

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Stereoselective glycosylation using oxathiane glycosyl donorsw
Martin A. Fascione,a Sophie J. Adshead,a Susanne A. Stalford,a Colin A. Kilner,a
Andrew G. Leachb and W. Bruce Turnbull*a
Received (in Cambridge, UK) 6th July 2009, Accepted 25th August 2009
First published as an Advance Article on the web 7th September 2009
DOI: 10.1039/b913308a
A bicyclic glycosyl donor is activated as an arylsulfonium ion
linkages remains a significant challenge.7 Although the anomeric
and used to synthesise a-glycosides with high stereoselectivity.
effect favours the formation of a-glycosides, in reality, mixtures
of a- and b-glycosides are often obtained when using glycosyl
donors bearing non-participating ether protecting groups
(Scheme 1b). Therefore, the precise control of anomeric
stereochemistry remains a major challenge to be overcome.8
Recently Boons et al. described a participating group that
could give 1,2-cis-a-glycosides (scheme 1c).9 In this method, a
chiral auxiliary adjacent to the anomeric carbon intercepts the
oxacarbenium ion intermediate to form a sulfonium ion on the
b-face of the sugar. The incoming nucleophile is thus directed
to react on the lower face to give an a-glycoside.10,11 Although
this elegant strategy gives excellent stereoselectivity, its
implementation demands a significant amount of additional
synthetic effort. The chiral auxiliary must first be synthesised
with the correct stereochemistry to match the D- or
L-configuration of the glycosyl donor. It must then be attached
regioselectively to O-2 before finally introducing the anomeric
leaving group. Incorporation of the participating group
increases the number of protecting group manipulations and
thus the length of the synthesis.
Carbohydrates form the most abundant class of biological
molecules on Earth.1 They play essential roles in energy
storage, as structural materials and for molecular recognition
to control processes as diverse as protein folding, fertilisation,
inflammation and cancer metastasis.2 Often synthetic chemistry
provides the only source of pure oligosaccharides for biological
studies. Both solid phase synthesis3 and multi-component
one-pot solution synthesis4 can provide rapid access to
complex oligosaccharides. However, if several glycosylation
reactions are to be performed in sequence without separating
the intermediate products, it is essential that each glycosylation
reaction is highly stereoselective,5 or complex mixtures of
oligosaccharides will result. While 1,2-trans-glycosides can be
formed easily through neighbouring group participation by an
ester protecting group adjacent to the anomeric centre
(Scheme 1a),6 stereoselective synthesis of cis-1,2-glycosidic
In this communication we present
a novel class of
thioglycoside donors that have an integral a-directing group
(Scheme 2). The oxathiane glycosyl donors are prepared by a
concise route involving cyclisation of simple thioglycosides.12
The stereochemistry of the participating group is thus
determined by the absolute configuration of the parent
thioglycoside. Activation of the glycosyl donor gives a bicyclic
sulfonium ion intermediate which acts as a glycosylating agent
with very high stereoselectivity.
A series of oxathiane glycosyl donors was prepared from
glucose pentaacetate 1 (Scheme 3). Lewis acid activation of the
anomeric acetate in the presence of thiourea provided a
b-isothiouronium salt which was treated with Et3N and
bromide 2 in situ.13 The resulting thioglycoside 3 was
de-esterified under Zemplen conditions to give tetraol 4. Upon
´
exposure to acidic MeOH, the ketone cyclised regio- and
Scheme
1
Strategies for controlling anomeric stereochemistry:
(a) ester participating group leads to 1,2-trans-glycosides, while
(b) non-participating benzyl ether often gives mixtures of a- and
b-glycosides; (c) Boons’ 1,2-cis-a-directing group forms a bicyclic
sulfonium intermediate.
a School of Chemistry, University of Leeds, Leeds, UK LS2 9JT.
E-mail: w.b.turnbull@leeds.ac.uk; Fax: +44 (0)1133436565;
Tel: +44 (0)1133437438
b AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK
w Electronic supplementary information (ESI) available: Crystal
structure of compound 8, and synthetic procedures. CCDC 733122.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/b913308a
Scheme 2 Oxathiane glycosyl donors.
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Scheme
3
Reagents: (a) (i) SQC(NH2)2–BF3ÁOEt2–MeCN, (ii)
2–Et3N (64%); (b) NaOMe–MeOH (99%); (c) TsOH–MeOH
(61%); (d) Ac2O–C5H5N (76%); (e) BnBr–NaH–DMF (87%);
(f) mCPBA–CH2Cl2 (8 95%, dr 91 : 9; 9 87% dr 96 : 4).
stereoselectively to give methyl ketal 5, in which the less bulky
methoxy group adopts an axial position where it can also
benefit from anomeric stabilisation. The remaining hydroxyl
groups were then protected with acetate groups or benzyl
ethers to provide compounds 6 and 7, respectively. Oxidation
of these sulfides with mCPBA gave the corresponding
sulfoxides 8 and 9, predominantly as the equatorial isomers.
It was possible to prove the structure of sulfoxide 8 by X-ray
crystallography (ESIw, Fig. S1).
Many methods have been developed for activating
thioglycoside and sulfoxide donors.14 However, as the leaving
group would remain attached to the oligosaccharide following
glycosylation, we decided to focus first on methods that
would introduce an alkyl or aryl sulfide leaving group.
Although alkylation can be used to activate strained bicyclic
thioglycosides,15 we found that methylation of donor 7 led to a
surprisingly unreactive sulfonium ion.16 The arylation of
sulfides can be achieved with hypervalent iodonium reagents
at high temperature,17 but we anticipated that milder
conditions might prove more suitable for a stereoselective
glycosylation reaction. Therefore, we have adopted a novel
strategy to activate the glycosyl donors based on electrophilic
aromatic substitution,18 which exploits the fact that triflyloxy-
sulfonium salt 10 (Fig. 1) is more electrophilic at sulfur than at
the anomeric carbon.
Fig. 1 1H NMR spectra (500 MHz, CDCl3) of (a) a mixture of
sulfoxide 8 and 1,3,5-trimethoxybenzene. Addition of triflic anhydride
at 243 K gave (b) sulfonium ion 11 which was gradually warmed
(c)–(d) to 278 K.
13 kcal molÀ1 for aryl group rotation (see ESIw). Therefore,
the arylsulfonium ion is the dominant species present in the
reaction mixture at these temperatures.
Sulfoxide donors I (Table 1) were activated with triflic
anhydride as before, and allowed to react with trimethoxy-
benzene to give sulfonium ions II.19 A range of alcohols were
glycosylated in good to excellent yields, and with essentially
complete a-stereoselectivity (Table 1).
It proved convenient to isolate the disaccharides as the
2-hydroxy derivatives III (Table 1), because the acyclic methyl
ketal O-2-protecting group was occasionally lost on work-up.
Therefore, the crude product mixture was treated with
BF3ÁOEt2 and MeOH in CH2Cl2 prior to isolation of the
product by column chromatography. While the benzyl-
protected glycosyl donors worked well with all acceptors
tested, the less reactive acetyl-protected donors occasionally
gave a poorer yield of the target glycoside (e.g., entry 3). In
this case, MeOH was released from the acyclic protecting
group during the glycosylation reaction, thus providing a
competing nucleophile for a-glycosylation. As no methyl
glycoside formed prior to addition of the acceptor alcohol,
we can rule out the possibility of intramolecular glycosylation,
or cleavage of the methyl ketal from the oxathiane-sulfonium
ion. Galactosyl oxathiane donors 12 and 13 also proved to be
effective glycosylating agents (entries 7–8). C-Glycosylation
of trimethoxybenzene predominated when 2-O-benzyl
glycosyl sulfoxide donors were subjected to the same reaction
Oxathiane-S-oxide 8 (Fig. 1) was activated with triflic
anhydride at 243 K in the presence of trimethoxybenzene.
1
The H NMR spectrum displayed the typical down-field shift
of H-1 that is associated with the formation of cyclic glycosyl
sulfonium ions.9,11 Furthermore, H-1 maintained an 8 Hz
coupling constant that was consistent with b-configured ion
11. Concomitantly, the aromatic proton signal split in two and
the aryl-methoxy group signal split in three. As the sample
was warmed up to 278 K, both the aromatic signals and two
of the methoxy signals coalesced and sharpened indicating
the aryl group was starting to rotate more rapidly. Analysis
of the NMR line-shapes above and below the coalescence
temperature provided a value for the barrier to rotation
of ca. 13 kcal molÀ1. Density functional theory calculations
(B3LYP/6-31+G*) also gave an activation energy of
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Table 1 Glycosylation reactions with oxathiane sulfoxide donors
methoxy group on the oxathiane ring facilitates both synthesis
and removal of the auxiliary group. This novel class of
glycosyl donors present a significant advance in the use of
a-directing participating groups and could provide a general
strategy for the stereoselective synthesis of oligosaccharides.
We thank the Royal Society and AstraZeneca for financial
support. WBT is a Royal Society University Research Fellow.
Yield
(%)d
Entry
1f
Donor
ROH
a/be
Notes and references
85
498 : 2
1 D. Peters, Biotechnol. J., 2006, 1, 806.
2 Essentials of Glycobiology, Cold Spring Harbor Laboratory Press,
Cold spring Harbor, NY, 2009.
3 P. H. Seeberger, Chem. Soc. Rev., 2008, 37, 19; R. R. Schmidt,
S. Jonke and K.-G. Liu, ACS Symp. Ser., 2007, 960, 209.
4 Y. Wang, X.-S. Ye and L.-H. Zhang, Org. Biomol. Chem., 2007, 5,
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2
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5 D. B. Werz, B. Castagner and P. H. Seeberger, J. Am. Chem. Soc.,
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6 R. U. Lemieux, Advances in Carbohydrate Chemistry, 1954, 9, 1.
7 A. V. Demchenko, Synlett, 2003, 1225; A. V. Demchenko, Curr.
Org. Chem., 2003, 7, 35; A. T. Carmona, A. J. Moreno-Vargas and
I. Robina, Curr. Org. Synth., 2008, 5, 81.
8 Strategies for achieving stereoselective 1,2-cis glycosylation include:
displacement of b-leaving groups; R. U. Lemieux, K. B. Hendriks,
R. V. Stick and K. James, J. Am. Chem. Soc., 1975, 97, 4056; D. Crich
and W. L. Cai, J. Org. Chem., 1999, 64, 4926; solvent optimisation;
A. Ishiwata, Y. Munemura and Y. Ito, Tetrahedron, 2008, 64, 92;
conformational constraints; R. E. J. N. Litjens, L. J. Van den Bos, J.
3
4
5
6
44
72
77
66
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498 : 2
498 : 2
498 : 2
D. C. Codee, H. S. Overkleeft and G. A. Van der Marel, Carbohydr.
´
Res., 2007, 342, 419; S. Manabe, K. Ishii and Y. Ito, Trends Glycosci.
Glycotechnol., 2008, 20, 187; J. D. M. Olsson, L. Eriksson,
M. Lahmann and S. Oscarson, J. Org. Chem., 2008, 73, 7181;
Y. Geng, L.-H. Zhang and X.-S. Ye, Chem. Commun., 2008, 597;
remote group effects; A. Imamura, H. Ando, H. Ishida and M. Kiso,
Heterocycles, 2008, 76, 883; D. Crich, T. S. Hu and F. Cai, J. Org.
Chem., 2008, 73, 8942; O. J. Plante, E. R. Palmacci, R. B. Andrade
and P. H. Seeberger, J. Am. Chem. Soc., 2001, 123, 9545; intra-
molecular aglycone delivery; A. J. Fairbanks, Synlett, 2003, 1945;
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iPrOHg
9 J. H. Kim, H. Yang, J. Park and G. J. Boons, J. Am. Chem. Soc.,
2005, 127, 12090.
7
79
78
498 : 2
498 : 2
10 It is generally assumed that the sulfonium ion undergoes an SN2-
like reaction with the acceptor alcohol; however, it has been noted
(see ref. 11) that the presence of a sulfonium ion intermediate in the
reaction mixture does not exclude the possibility of an SN1-type
mechanism leading to the products.
11 M. G. Beaver, S. B. Billings and K. A. Woerpel, J. Am. Chem. Soc.,
2008, 130, 2082; S. A. Stalford, C. A. Kilner, A. G. Leach and
W. B. Turnbull, Org. Biomol. Chem., 2009, DOI: 10.1039/b914417j.
12 Report of a natural gluco-oxathiane; B.-M. Feng, L.-X. Duan,
L. Tang, Y.-H. Pei and Y.-Q. Wang, Heterocycles, 2008, 75, 173.
13 P. Tiwari, G. Agnihotri and A. K. Misra, J. Carbohydr. Chem.,
2005, 24, 723.
14 K. P. R. Kartha and R. A. Field, Carbohydrates, 2003, 121;
D. Crich and L. B. L. Lim, Org. React. (N. Y.), 2004, 64, 115.
15 I. Lundt and B. Skelbaek-Pedersen, Acta Chem. Scand., Ser. B,
1981, 35b, 637.
16 A thiazepane glycosyl donor has been reported to be unreactive to
NIS–AgOTf and DMTST, and to give no isolable products on
activation with methyl triflate; R. Slaettegard, D. W. Gammon and
S. Oscarson, Carbohydr. Res., 2007, 342, 1943.
8
a
Unless stated otherwise, the sulfoxide was treated with 1.1 equiv.
Tf2O, 2.2 equiv. 1,3,5-trimethoxybenzene, and 1.2 equiv. DIPEA at
b
À30 1C. The temp was raised to À10 1C, and a further 6 equiv.
DIPEA and 2.5 equiv. ROH were added, before stirring at 50 1C for 18 h.
The crude reaction mixture was treated with a catalytic amount of
c
d
e
BF3ÁOEt2 to cleave the O-2 protecting group. Isolated yields. No
b-isomers were detected by NMR spectroscopy of the crude reaction
mixture prior to protecting group cleavage. 7.2 equiv. DTBMP was
f
g
used in place of DIPEA. 5 equiv.
17 A. Krief, W. Dumont and M. Robert, Synlett, 2006, 484.
18 Previous synthesis of sulfonium ions by electrophilic aromatic
substitution: E. Schaumann and S. Scheiblich, Tetrahedron Lett.,
1985, 26, 5269.
19 If the alcohol was added before the arylsulfonium salt had formed,
only reduction to the parent oxathiane resulted. Therefore the reac-
tion does not proceed via the Kahne glycosyl sulfoxide method;
D. Kahne, S. Walker, Y. Cheng and D. Vanengen, J. Am. Chem.
Soc., 1989, 111, 6881; B. W. Skelton, R. V. Stick, D. M. G. Tilbrook,
A. H. White and S. J. Williams, Aust. J. Chem., 2000, 53, 389.
conditions. Therefore, it was not possible to conduct a directly
comparable control experiment to test the importance of the
oxathiane auxiliary group. Nevertheless, our results show
substantial improvements in stereoselectivity when compared
to literature examples with perbenzylated donors (see ESIw).
In conclusion, oxathiane glycosyl donors provide practical
and highly stereoselective access to 1,2-cis-a-glycosides. A
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 5841–5843 | 5843