Glycosidation reactions of silyl ethers with conformationally inverted donors derived from glucuronic acid: stereoselective synthesis of glycosides and 2-deoxyglycosides.

Full text of DOI:10.1002/anie.200353196

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Stereoselective Glycoside Synthesis
Glycosidation Reactions of Silyl Ethers with
Conformationally Inverted Donors Derived from
Glucuronic Acid: Stereoselective Synthesis of
Glycosides and 2-Deoxyglycosides**
Monika Polµkovµ, Nigel Pitt, Manuela Tosin, and
Paul V. Murphy*
Stereoselective glycoside synthesis is of interest because of
the biological and medical relevance of oligosaccharides,
glycoproteins, glycolipids,[1] and other carbohydrate deriva-
tives,[2] and a range of strategies have been developed to
produce these compounds.[3] The 1,6-lactone derivative 2 (see
Scheme 1) has potential for use in the synthesis of 1,2-cis-
glycosides[4] but its application has been limited because of
the low yields obtained from its reaction with alcohols.[5] We
now report that the SnCl4-catalyzed coupling of silyl ethers[6]
with 2 provides a-O-glucuronides in significantly improved
yields without loss of stereoselectivity. The methodology has
been extended to the related 2-deoxylactones, which give a-
or b-glycosides depending on the structure of the donor.
The preparation of 2 was carried out via the mixed
anhydride 1 (Scheme 1) by an improved and shorter proce-
dure than that previously described.[5] The donors 6 and 7
were also prepared, via glycal 4, because of their potential for
the synthesis of 2-deoxyglycosides, which are of biological
interest.[7] Thus, the reaction of the allyl ester 3 with hydrogen
bromide in acetic acid gave a glycosyl bromide intermediate
[*] Dr. M. Polµkovµ, Dr. N. Pitt, M. Tosin, Dr. P. V. Murphy
Centre for Synthesis and Chemical Biology
Department of Chemistry
Conway Institute of Biomolecular and Biomedical Research
University College Dublin, Dublin 4 (Ireland)
Fax: (+353)1-716-2127
E-mail: paul.v.murphy@ucd.ie
[**] This work was supported by Enterprise Ireland (Grants SC2000/182
and SC2002/225) and IRCSET (PhD Scholarship to M.T.).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
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Scheme 1. Synthesis of glycosyl donors. Reagents and conditions:
a) Ac2O, I2; b) SnCl4, CH2Cl2; 65% over two steps; c) H2O; d) (COCl)2,
DMF; e) allyl alcohol, C5H5N; 55% over three steps; f) HBr, AcOH;
g) Zn dust, CuSO4, AcONa, 50% aq AcOH; 50% over two steps;
h) [Pd(PPh3)4], pyrrolidine, MeCN, 08C, 80%; i) NIS, MeCN, 50%;
j) Bu3SnH, AIBN, toluene, 1108C, 15 min, 90%. DMF=N,N-dimethyl-
formamide, NIS=N-iodosuccinimide, AIBN=azobisisobutyronitrile.
Scheme 3. Glycosidation products fromthe SnCl 4-mediated reactions.
The reactants and yields are listed in Table 1.
the TES acceptor 19 than with TMS acceptor 18. The TES
derivative 20 gave 26 as a result of acetate migration,
presumably mediated by the catalyst, and subsequent glyco-
sidation at the O6 position. The stereoselectivity observed for
both 2 and 8 contrasted with that of the methyl ester 9, which
provided b-glucuronides in higher yields than were obtained
with phenol or the alcohols. The 2-deoxyglycosyl donor 7
displayed the same behavior as 2 during the glycosidation,
giving a anomers with high stereoselectivity, which is con-
trasts the situation with 2-deoxy-2-iodo derivative 6, which
gave b-glycosides.
and this was subsequently converted into 4 by treatment with
zinc dust, copper(ii) sulfate, and sodium acetate in aqueous
acetic acid as described previously for the corresponding
methyl ester.[8] The allyl protecting group could be removed
from 4, to leave the glycal intact, by using [Pd(PPh3)4] and
pyrrolidine in acetonitrile to give 5.[9] The reaction of 5 with
NIS gave the lactone 6, which was subsequently reduced to
give 7 by using Bu3SnH/AIBN.
The results of the glycosidation of these donors using a
tin(iv) chloride catalyst[10] with the acceptors and products
shown in Schemes 2 and 3, respectively, are listed in Table 1.
Donor 2 gave a-glycosides in a highly stereoselective manner,
despite the presence of the 2-O-acetyl group, in higher yields
and conversions than the carboxylic acid 8. This methodology
was applied to the synthesis of glycosides derived from serine
and threonine, with these amino acids being coupled as the
azido derivatives (azido acids). An interesting observation
was that the disaccharide 26 was obtained in higher yield with
Possible mechanistic pathways for the glycosidation
reactions of the lactones are shown in Scheme 4. Donors 2
and 7 undergo reaction so that inversion of configuration at
the C1 position by an SN2 process occurs via an intermediate
of type 37. A pathway involving 38 would be expected to
provide the b-glycoside for iodide 6, a fact indicating that the
iodine residue is a better participator than the 2-O-acetyl
group. The lactone 2 is generated in situ from carboxylic acid
8 in a step that accounts for the stereoselectivity observed
with 8; the lower yields obtained result from its lower
reactivity because all of its substituents are oriented equato-
rially and destabilize positive-charge formation during acti-
vation of the 1-OAc group.[11] The greater reactivity of the
donor in the 1C4 conformation is not unexpected and may be
significant given the previously noted low reactivity of
glucuronides.[12] Another conceivable pathway involves 2 or
7 first giving a b-glycoside that rapidly isomerizes to the
a anomer. However, although anomerization of b-glucuronic
acid derivatives is observed in the presence of SnCl4, the rates
appear too slow to account for this being the only pathway
operating. The concept of using 1,6-anhydro-b-d-glucopyra-
nosides and related compounds has been investigated pre-
viously for the synthesis of O-glycosides (MeOH as
acceptor),[13] thioglycosides,[14] and C-glycosides;[15] these
reactions gave mixtures or in some cases the pure a- or b-
glycoside, for example, a b-glycoside was obtained from a 2-
Scheme 2. Acceptors used in the glycosidation reactions.
TMS=trimethylsilyl, TES=triethylsilyl, Cy=cyclohexyl.
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Table 1: SnCl4-mediated glycosidation reactions.[a]
the acid can be extracted into
aqueous sodium hydrogen carbon-
ate or can be separated from other
by-products by solid-phase extrac-
tion. In addition, 2-deoxypyranur-
onic acids synthesized by this route
should be more stable to acid than
the corresponding 2-deoxypyrano-
sides. There may be potential appli-
cations for the glycosyl azido acids
as intermediates in glycoconjugate
synthesis[17] and in Staudinger reac-
tions.[18] It is now required that b-O-
Donor
Acceptor
Donor:acceptor:SnCl4
Product[b]
(yield [%])
11
13
1:2.5:0.5
1:2.5:0.5
21a (35)
23a (32)
10
1:2.5:0.5
21a (64)
21a (88)
22a (62)
23a (11)
23a (78)
24a (51)
25a (71)
26a (<10)
26a (44)
26a (58)
26a (56)
11
1:2.5:0.5
TMSOMe
1:0.66:0.33 (10 h)
1:2.5:0.5
1:2.5:0.5
1:1.2:0.5
1:4:1 (18 h)
1:4:1 (6 h at RT, 12 h at 408C)
1:4:1 (6 h at RT, 12 h at 408C)
1:4:1 (6 h at RT, 12 h at 408C)
1:4:1 (6 h at RT, 12 h at 408C)
12
13
14
16
17
18
19
20
glucuronide
drug
conjugates,
formed in animals and humans as
part of detoxification, are tested
before the parent drug can be
approved and their synthesis is
often not trivial;[19] investigation of
coupling reactions of the appropri-
ate silyl ethers with donor 9, similar
to the two cases shown herein, may
also be worthwhile. These possibil-
ities as well as the potential of these
compounds as building blocks for
the synthesis of glycosaminoglycan
disaccharides[20] are currently being
investigated.
11
1:2.5:0.5
1:2.5:0.5
1:2.5:0.5 (5 h)
1:4:1
29b (60)
30a (29); 30b (47)
31b (39)
TMSN3
TMSOMe
16
32b (51)
TMSN3
TMSOMe
13
1:2.5:0.5
1:0.66:0.33 (8 h)
1:2.5:0.5
33a (66)
34a (59)
35a (57)
36a (41)
16
1:4:1 (12 h)
10
11
15
16
1:2.5:0.5
1:2.5:0.5
1:4:1
27b (66)
27b (92)
28b (<5)
28b (75)
1:4:1
Experimental Section
[a] All reactions were carried out in CH2Cl2 at RT for 15 h unless otherwise stated. [b] 1H NMR
spectroscopy analysis of the crude product was used to determine the ratio of a and b anomers; this
was not subsequently altered by purification. When the second anomer is not reported it could not be
detected.
Glycosidation procedure: The glycosyl
donor (0.4 mmol) was dissolved in dry
CH2Cl2 (5 mL) in an N2 atmosphere.
SnCl4 (Aldrich) and acceptor were then
added, and the reaction mixture was left
to stir (see Table 1 for reaction times).
The mixture was then diluted with dichloromethane (10 mL), then
saturated aqueous NaHCO3 solution (15 mL) was added and the
resulting mixture was stirred for 30 min. The mixture was filtered
through celite, the layers were then separated, and the aqueous layer
was acidified with acetic acid. The product was extracted with EtOAc
(up to 10 ” 10 mL), dried (Na2SO4), and filtered. The solvent was then
removed to give the glycosidic product. If the glycosidic product was
still detected in the aqueous layer then the water was removed by
freeze drying and the residue was purified by column chromatography
(EtOAc/MeOH gradient elution).
Further experimental details can be found in the Supporting
Information.
Scheme 4. Possible mechanistic pathways to the a- and b-glycosida-
tion products. L=ligand, Nu=nucleophile.
Received: October 30, 2003
Revised: February 9, 2004 [Z53196]
O-acetyl-1,6-anhydromaltose donor.[16] However, the partic-
ipation of 2-O-acetyl groups, which normally dominates
glycoside synthesis, is not important for 2 in its reaction
with a wide range of acceptors. This contrasts with the general
behavior of glucuronic acid donors, which have C1 ground-
state conformations.
Keywords: carbohydrates · glucuronic acid · glycosides ·
.
glycosylation · stereoselective synthesis
4
There are practical and strategic advantages to using such
lactones as described herein. The carboxylic acid is formally
protected in the donor and acts as the leaving group in the
glycosidation reaction; its release simplifies purification as
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