Stereoselective synthesis of α-Keto-deoxy-D-glycero-D- galactononulosonic acid glycosides by means of the 4,5-O-carbonate protecting group

Article abstract of DOI:10.1002/anie.200907178

(Figure Presented) Unrivaled: A 1-adamantyl thioglycoside derivative of the nonulosonic acid KDN, carrying a 4,5-O-carbonate protecting group, is a highly efficient and a-selective KDN donor when activated using N-iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH). Glycosylates conducted with this protecting group do not suffer from competing glycal formation.

Full text of DOI:10.1002/anie.200907178

Angewandte
Chemie
DOI: 10.1002/anie.200907178
Stereocontrolled Glycosylation
Stereoselective Synthesis of a-Keto-deoxy-d-glycero-d-galacto-
nonulosonic Acid Glycosides by Means of the 4,5-O-Carbonate
Protecting Group**
David Crich* and Chandrasekhar Navuluri
ˇ
Dedicated to Professor Jan Rocek
2-Keto-deoxy-d-glycero-d-galacto-nonulosonic acid (KDN)
is a member of the sialic acid family of carbohydrates that are
commonly found at the nonreducing terminus of cell surface
glycans and in the form of homopolymers.[1] KDN and its
glycosides have been long known in marine organisms and
have more recently been detected in humans, thanks to
improved analytical techniques, opening the way to potential
applications as markers of disease states.[2] The minute
quantities of these materials available by isolation, and their
microheterogeneous nature, points to a strong need for
efficient, versatile methods for the synthesis of homogeneous
substances by enzymatic[3] or, as described here, chemical
methods.
Scheme 1. Donor synthesis. Ada=1-adamantanyl, pTSA=para-tolu-
The chemical synthesis of KDN glycosides presents
problems similar to those of the neuraminic acid glycosides,
but KDN glycoside synthesis has been much less extensively
investigated.[4] With this in mind, and building upon the recent
successes of Takahashi and co-workers,[5] De Meo and co-
workers,[6] as well as those of our[7] group, using 4-O,5-N-
oxazolidinone-protected neuraminic acid donors,[8,9] we have
prepared a novel 4,5-O-carbonyl-protected KDN donor and
report herein, its application in highly efficient and selective
a glycosylations.
We began with a modification of the Zbiral synthesis of
KDN from peracetyl N-acetylneuraminic acid methyl ester,[10]
which upon nitrosylation with nitrosyl tetrafluoroborate gave
the N-nitrosyl-N-acetyl neuraminic acid derivative 1 essen-
tially quantitatively. Exposure to sodium isopropoxide and
then acetic acid with a subsequent ozonolytic[11] work-up gave
the KDN derivative 2 in 51% yield (Scheme 1). Conversion
of 2 into the adamantanyl thioglycoside, selected because of
the anticipated ease of activation at À788C,[7b,c] was achieved
under standard conditions and gave a separable mixture of
enesulfonic acid.
the two anomers 3 in excellent yield. Saponification of each
anomer gave the corresponding pentaols that were immedi-
ately protected as the 8,9-O-acetonides 4. The optimum
conditions found for the installation of the 4,5-O-carbonate
group involved reaction with 4-nitrophenyl carbonate and
Hꢀnigꢁs base to give 5 in high yield for both anomers.
Removal of the acetonide with HCl in THF and then
peracetylation gave the desired donors 6 (Scheme 1).
With two anomeric donors in hand we proceeded to
examine their coupling reactions with a variety of acceptor
alcohols, by activation using N-iodosuccinimide (NIS) and
trifluoromethanesulfonic acid (TfOH) in a mixture of aceto-
nitrile and dichloromethane at À788C (Table 1).
The results laid out in entries 1–7 of Table 1, uniformly
show high yield and excellent a selectivity for reactions
conducted with the NIS/TfOH combination in a 2:1 dichloro-
methane/acetonitrile mixture.[12] Comparison of entries 1 and
2 of Table 1 reveals that neither the efficiency nor the
anomeric selectivity is dependent upon the configuration of
the donor and consequently all subsequent work was con-
ducted with the more abundant b isomer. The result in entry 3
of Table 1 illustrates the successful application of this
chemistry to a tertiary alcohol, and the data in entries 4 and
5 demonstrate applicability to the important galactopyranose
[*] Prof. Dr. D. Crich, C. Navuluri
Department of Chemistry, Wayne State University
5101 Cass Avenue, Detroit, MI 48202 (USA)
Prof. Dr. D. Crich
Centre de Recherche de Gif
Institut de Chimie des Substances Naturelles, CNRS
Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
Fax: (+33)1-6907-7752
À
C6 OH group in the presence of two different protecting
group arrays. The substrates in entries 6 and 7 of Table 1 show
À
the glycosylation of the galactopyranose C3 OH group, in the
E-mail: dcrich@icsn.cnrs-gif.fr
À
À
presence of the C4 OH group and with the C4 OH protected
in the form of a benzyl ether. Comparison of the results in
entries 5 and 8 of Table 1 reveals that while the selectivity
[**] We thank the NIH (GM62160) for partial support of this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200907178.
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Table 1: Glycosylation with donors 6a and 6b.
Table 1 reveals the major by-prod-
uct to be the hemiacetal resulting
from hydrolysis of the donor.
To probe the influence of the
cyclic carbonate protecting group
upon the glycosylation reactions, a
smaller series of coupling reactions
was also conducted with the pera-
cetylated donors 3 as set out in
Table 2. With acceptors bearinf a
primary alcohol, these couplings
gave good albeit reduced a selec-
tivity; they however, suffered from
considerably lower yields owing to
the formation of the glycal 20 as a
significant by-product in every case.
For the acceptor bearing a secon-
dary alcohol, both the yield and
selectivity were considerably re-
duced from those observed in the
carbonate series.
Entry
1[a]
6
Acceptor
Product
Yield,
a/b ratio
86%,
a only
6a
81%,
a only
2[a]
3[a]
4[a]
6b
6b
6b
86%,
a only
84%,
a only
82%,
a only
Finally, cleavage of the carbon-
ate group along with that of the
acetate esters was achieved in
essentially quantitative yield under
standard Zemplen deacetylation
conditions (Table 3).
5[a]
6b
81%,
a only
6[a]
6b
6b
80%,
a only
Clearly, as with the oxazolidi-
none and N-acetyl oxazolidinone
groups in the neuraminic acid
series, the 4,5-O-carbonate protect-
ing group confers distinct advan-
tages upon the KDN donors 6a and
6b. These advantages include excel-
lent a selectivity and the virtual
absence of glycal formation.
Although the underlying reasons
for these improved properties are
unclear at present and are the sub-
ject of ongoing investigations, we
suggest the increased dipole
moment of the cyclic carbonate
group, with respect to two individ-
ual esters, renders it more electron
withdrawing and is more likely to
7[a]
84%
13:1
8[b]
6b
6b
6b
78%
9:1
9[c]
73%
(7:1)
10[d]
[a] Reaction conducted in a 2:1 mixture of dichloromethane and acetonitrile at À788C with activation by
NIS and TfOH. [b] Reaction conducted in dichloromethane at À788C with activation by NIS and TfOH.
[c] Reaction conducted in a 2:1 mixture of dichloromethane and acetonitrile at À788C with activation by
diphenyl sulfoxide and trifluoromethanesulfonic anhydride (Tf2O). [d] Reaction conducted in a 2:1
mixture of dichloromethane and acetonitrile at À788C with activation by 1-benzenesulfinyl piperidine
(BSP) and Tf2O.
remains high in the absence of acetonitrile, the presence of
this solvent is certainly advantageous. Finally, the results of
entries 9 and 10 of Table 1 indicate that moderate selectivity is
possible through other means of activation, notably the
combinations of diphenyl sulfoxide and BSP with Tf2O.[13]
Scheme 2. Synthesis of an authentic sample of glycal. mCPBA=meta-
Interestingly, the coupling reactions illustrated in Table 1
appeared to be devoid of the usual type of by-product in
sialidation chemistry; namely the elimination product. The
synthesis of an authentic sample of this glycal (Scheme 2, 19),
by elimination of the glycosyl sulfoxide, enabled us to confirm
this observation. Indeed, inspection of the crude reaction
mixtures of the examples from the experiments presented in
chloroperoxybenzoic acid.
stabilize any intermediate adducts in acetonitrile
(Scheme 3).[14] In this manner, the transition state for
displacement of the acetonitrile by the acceptor alcohol will
be tighter, that is to say, will have greater SN2 character.[15]
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Table 2: Glycosylation with donors 3a and 3b.
Scheme 3. Hypothetical intermediate stabilized by the presence of the
cyclic carbonate.
Experimental Section
Standard protocol for glycosylation with donor 6a or 6b: A mixture of
donor (0.1 mmol), acceptor (0.11 mmol), and powdered AW-300
molecular sieves (2 gmmolÀ1 of donor) dissolved in CH2Cl2/CH3CN
(2:1, 2 mL) was stirred for 2 h at room temperature, then cooled to
À788C, and treated with NIS (0.12 mmol) and one drop of TfOH (2–
3 mL, 0.02 mmol). The resulting mixture was stirred for 1 h, at À788C,
then quenched by addition of diisopropylethylamine (18 mL,
0.1 mmol), and warmed to room temperature. The molecular sieves
were filtered off, and the organic layer was washed with 20% aqueous
Na2S2O3, brine, dried over Na2SO4, and concentrated. The crude
mixture was purified by flash chromatography eluting with ethyl
acetate/hexanes.
Donor,
Product
Yield,
Yield of
acceptor
a/b ratio
glycal 20
60%
12:1
3a, 10
3b, 10
3b, 7
29%
28%
26%
34%
60%
12:1
62%
13:1
Received: December 19, 2009
Revised: February 10, 2010
Published online: March 23, 2010
52%
1.6:1
3b, 11
Keywords: carbonate · glycosylation · sialic acid ·
.
stereoselectivity · thioglycoside
Table 3: Deprotection of carbonate-protected saccharides.
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Communications
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3
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3052
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