.
Angewandte
Communications
addition of either acetic acid, thioacetic acid, or the hydrogen
fluoride/pyridine complex, resulting in the formation of the 5-
desacetamido acetoxy, acetylthio, and fluoro NeuAc deriva-
tives 8, 9, and 10, respectively, in good yield. Fluoride 10 was
however accompanied by 11% of the isopropoxy analogue 11
(Scheme 2).[8] The survival of the thioglycoside moiety is
a result of the use of pyridine, which captures the nitrosonium
ion as the N-nitrosopyridinium complex[9] 12 (Scheme 2) and
moderates its reactivity. While the formation of the 2-keto-3-
deoxy-d-glycero-d-galactononulosonic acid (KDN) deriva-
tive 8 recalls earlier studies[6] with acetic acid as nucleophile,
the formation of the acetylthio and fluoro derivatives
demonstrates the ability of the method to incorporate
a wider range of nucleophiles. The formation of the isopropyl
ether 11 as by-product alongside fluoride 10 could be avoided
by using preformed sodium trifluoroethoxide as base in
conjunction with 18-crown-6 ([18]C-6) and excluding isopro-
panol from the reaction mixture, giving fluoride 10 in 63%
yield. The formation of 11 as by-product also suggested that
conditions could be found for the use of simple alcohols as
nucleophiles in the oxidative deamination protocol. Thus,
after some experimentation we found that deacetylation with
sodium trifluoroethoxide, followed by the addition of prop-
argyl alcohol and tetrafluoroboric acid to protonate the
intermediate diazo compound, gave the propargyl ether 13 in
66% yield (Scheme 2). Next, a series of a-sialosides was
prepared from the donor 1 on activation with N-iodosucci-
nimide (NIS) and trifluoromethanesulfonic acid (TfOH) in
a mixture of dichloromethane and acetonitrile at ꢀ788C[5c]
(Table 1, entries 1–5). Alternatively, for more complex
acceptors based on the thioglycoside motif, the Wong sialyl
phosphate type donor[5e] 14 was employed with activation by
trimethylsilyl trifluoromethanesulfonate at ꢀ788C in
dichloromethane and acetonitrile (Table 1, entries 6 and 7).
In each case, the oxazolidinone then was removed under
Zemplen conditions and any acetate esters reinstalled with
acetic anhydride and pyridine (Scheme 1 and Table 1). Nitro-
sylation was achieved with NOBF4 in the presence of pyridine
and the intermediate N-nitrosoamides were substituted under
the conditions reported in Table 1.
We applied the protocol to the synthesis of KDN glyco-
sides incorporating a(1!6)-galactopyranoside, a(1!6)-glu-
copyranoside, and a(1!3)-galactopyranoside linkages, and
demonstrated the compatibility of the protocol with glyco-
sidic bonds and benzyl ethers (Table 1, entries 1–3). The
employment of thioacetic acid as nucleophile provided the
novel disaccharide 28 (Table 1, entry 4), which may be viewed
either as a 5-acetylthio-5-desacetamido derivative of a NeuAc
glycoside or as a 5-acetylthio-5-deoxy analogue of a KDN
glycoside. As selective deacetylation of thioacetates in the
presence of acetates is facile, thioacetate derivatives such as
28 enable further regioselective diversification at the 5-
position by alkylation of thiols and formation of disulfides, or
by the thiol-ene and yne click[10] and other processes.[11] As 5-
mercapto analogues of NeuAc and/or KDN have not
previously been accessible through the use of sialyl trans-
ferases,[4b,c] this example extends the range of accessible a-
sialoside derivatives modified at the 5-position and demon-
strates the versatility of the chemical approach. The forma-
tion of a 5-fluoro derivative of NeuAc and/or KDN is
illustrated in entry 5 (Table 1). The applicability of the
method to thioglycoside-containing substrates, whether of
the arylthio or alkylthio classes, is reiterated in entries 6 and 7
(Table 1). The possibility of diversification at the 5-position of
the sTn antigen (Table 1, entry 6) is especially noteworthy as
it has been previously demonstrated that modification of this
antigen at the amide can lead to analogues that display
improved antigenicity.[12] The oxidative deamination may be
applied concomitantly to two sialic acid residues in an a(2!
9)-linked disaccharide (Table 1, entry 7), representing the
first chemical synthesis of a KDN disaccharide of this class.
Such modifications of polysialic acids are of interest in view of
recent approaches to a(2!9)-linked polysialic acids because
of their potential as antibacterial agents and synthetic
vaccines.[13]
Scheme 2. Compatibility with a thioglycoside and introduction of acetoxy, acetylthio, and fluoride groups.
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!