A simple synthetic access to differently 4-substituted Neu5Ac2en glycals combining elements of molecules with anti-neuraminidase activity

Article abstract of DOI:10.1002/ejoc.201300154

A protocol for direct access to C-4-functionalized Neu5Ac2en derivatives by allylic substitution of an α-acetoxy group with various nucleophiles is reported. The DANA acetamido group is exchanged for a trifluoroacetylamido group (as in FANA) to avoid the formation of a stable 4,5-oxazoline. With thiols, the reaction involves an initial attack at the anomeric carbon (Ferrier reaction) under kinetic control, followed by an equilibration of the nucleophile to the thermodynamically more stable 4-position. A general access to C-4-substituted Neu5Ac glycals combining elements of molecules showing anti-neuraminidase activity. Copyright

Full text of DOI:10.1002/ejoc.201300154

FULL PAPER
DOI: 10.1002/ejoc.201300154
A Simple Synthetic Access to Differently 4-Substituted Neu5Ac2en Glycals
Combining Elements of Molecules with Anti-Neuraminidase Activity
Pietro Allevi,[a] Paola Rota,*[a] Irene Sofia Agnolin,[a] Antonio Gregorio,[a] and
Mario Anastasia[a]
Keywords: Carbohydrates / Sialic acids / Glycals / Nucleophilic substitution / Rearrangement
A protocol for direct access to C-4-functionalized Neu5Ac2en
derivatives by allylic substitution of an α-acetoxy group with
various nucleophiles is reported. The DANA acetamido
group is exchanged for a trifluoroacetylamido group (as in
FANA) to avoid the formation of a stable 4,5-oxazoline. With
thiols, the reaction involves an initial attack at the anomeric
carbon (Ferrier reaction) under kinetic control, followed by
an equilibration of the nucleophile to the thermodynamically
more stable 4-position.
As a part of our research into C-4-substituted sialic acid
glycals combining elements of molecules with anti-NA ac-
tivity, we have recently reported[12,13] a simple synthetic
strategy for the transformation of DANA and FANA glyc-
als 3 and 4 into the 4β-acylamidated FANA and DANA
glycals, by a Ritter reaction (Scheme 1).[14] To achieve this,
we reversibly transformed peracetylated DANA ester 3[15]
into peracetylated FANA methyl ester 4[16] to avoid the in-
tramolecular β-attack of the 5-acetamido group onto the
adjacent 4-position of the DANA glycal, which would inev-
itably form stable oxazoline[17] 5 (Scheme 1). This allowed
a Ritter reaction to take place to give 4β-acetamido deriva-
tive 6b, which could be transformed into DANA analogue
glycal 7, by a simple and selective exchange of its 5β-acyl-
amido group (Scheme 1).
Introduction
Various glycals of N-acetylated neuraminic acid 1
(Neu5Ac; Figure 1), such as, for example, 5-acetamido-2,6-
anhydro-3,5-dideoxy-d-glycero-d-galacto-non-2-enoic acid
2a (Neu5Ac2en, DANA),[1–5] its 5-perfluoroacetylated ana-
logue 2b (FANA),[6] and the 4-deoxy-4-guanidino conge-
ners of DANA (i.e., Zanamivir, 2c)[1–3,7] and of FANA (i.e.,
2d),[8] are potent inhibitors of sialidases (neuraminidases,
NA). Sialidases are important surface glycoproteins of bac-
terial and viral membranes that play crucial roles in the
spreading of infection to new host cells.[3,7,8] For this
reason, much effort has been put into the preparation of
various DANA and FANA congeners substituted at C-4, as
possible NA inhibitors.[1,5,6–11]
Continuing our interest in NA inhibitors, we searched
for a possible extension of the aforementioned Ritter reac-
tion that could be used to insert many other different
groups at the 4-position of a fluorinated Neu5Ac glycal. In
this paper, we report the successful results obtained with a
variety of nucleophiles together with a possible rationaliza-
tion of the regio- and stereochemical outcomes of the reac-
tion. For thiol nucleophiles, this involved a Ferrier reac-
tion,[18] a rearrangement that has been almost completely
ignored in sialic acid glycal chemistry, apart from a study
by K. Ikeda et al. on sialic acid 4,5-oxazoline 5.[19]
Figure 1. Structures of Neu5Ac and its glycals.
Results and Discussion
[a] Dipartimento di Scienze Biomediche Chirurgiche e
Odontoiatriche, University of Milan,
Initially, we verified that our Ritter reaction could be
performed using acetonitrile as a reagent, in a different sol-
vent, and in the presence of a Lewis acid promoter. In pre-
liminary experiments, we obtained encouraging results with
BF3·Et2O and with TMSOTf (TMS = trimethylsilyl), op-
erating at 40 °C in dichloromethane or nitromethane
via Saldini 50, 20133 Milano, Italy
Fax: +39-02-50316040
E-mail: paola.rota@unimi.it
Homepage: http://www.unimi.it/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300154.
Eur. J. Org. Chem. 2013, 4065–4077
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4065

P. Allevi, P. Rota, I. S. Agnolin, A. Gregorio, M. Anastasia
FULL PAPER
Scheme 1. Avoidance of oxazoline formation, and 4β-acetamidation of Neu5Ac glycals by a Ritter reaction. Reagents and conditions:
(i) (CF3CO)2O, CH3CN, 135 °C, 15 min; (ii) CH3CN, H2SO4, 50 °C, 30 min; (iii) K2CO3, MeOH (aq.), 23 °C, 12 h, then CH3COCl,
MeOH (aq.), 23 °C, 30 min.
(Table 1). Under the best-found conditions, glycals 6a and Table 1. Ritter reaction conditions using CH3CN as a reagent.[a]
6b were formed in satisfactory yields and in very short reac-
tion times (Table 1, entries 1, 2, and 7), although a decrease
in the β-stereoselectivity was observed compared to the re-
actions where acetonitrile was used as the solvent (α/β =
2:3 rather than α/β = 0:10).[12,13] The stereoselectivity was
not improved by varying the reaction conditions (tempera-
ture, solvent, Lewis acid, amount of reagent, etc.; Table 1,
entries 3–6, 8, and 9), or even by using H2SO4, the typical
protic acid catalyst of the Ritter reaction[14] (Table 1, en-
tries 10 and 11). Since under milder conditions (lower tem-
perature and less of the Lewis acid), the reaction appeared
to take too long without any improvement of the stereose-
lectivity, we decided to perform our reaction at 40 °C, a
temperature that would give convenient reaction times,
using BF3·Et2O (10 equiv.) as promoter and dichlorometh-
ane as solvent. Under these conditions, the reaction worked
satisfactory with several nucleophiles (Table 2), including
sulfonamides (Table 2, entries 1–3), simple and less simple
primary and secondary alcohols (Table 2, entries 4–10),
substituted phenols (Table 2, entries 13–14), thiols, thio-
phenols, and amino acidic thiols (Table 2, entries 15–18),
hydrides (Table 2, entry 19), and halogen ions (Table 2, en-
Entry Lewis acid Glycal
Conditions Solvent
Glycal 6
α/β ratio; yield [%]
[mmol] T [°C] (t [h])
1
2
3
4
5
6
7
8
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
BF3·Et2O
TMSOTf
TMSOTf
TMSOTf
H2SO4
10 40 (1)
10 40 (1)
1
10
1
10
10
1
CH2Cl2
CH3NO2
CH2Cl2
CH2Cl2
CH3NO2
CH3NO2
CH2Cl2
CH3NO2
CH2Cl2
THF
2:3; 81
2:3; 81
2:3; 75
2:3; 52
2:3; 68
2:3; 70
2:3; 79
2:3; 65
2:3; 64
2:3; 27
2:3; 20
40 (48)
25 (48)
40 (48)
25 (48)
40 (1)
40 (1)
9
10
11
10
10
10
25 (48)
50 (48)
25 (48)
H2SO4
THF
[a] Experimental conditions: glycal (0.2 mmol) in solvent (1.5 mL),
CH3CN (2 mmol).
tries 20–21). The results were poor only with tertiary of a thioglycoside alone, or together with a 3-thioglycal as
alcohols and simple phenols (Table 2, entries 11–12). In all a minor regioisomer. The former is the kinetic product of
the successful cases, the formation of a 4-substituted glycal reaction, the latter the thermodynamic product. These
was observed, apart from the reactions with cysteine and authors isolated the rearranged isomer in increased
triethylsilane (TESH), where an SN2-like reaction was ob- amounts after prolonged treatment of the reaction mixture
served with a shift of the double bond to give 2-substituted with the Lewis acid, or even after chromatography of the
α glycosides 23a and 24a, respectively (Table 2, entries 18 reaction mixture on silica.[24,25]
and 19). Such a reaction, known as a Ferrier rearrange-
Thus, we considered that the different regiochemistry ob-
ment, has been widely studied in neutral carbohydrate served in the reaction with protected cysteine (Table 2, en-
chemistry,[18] where it has also been used to access thiogly- try 18) and simpler thiols (Table 2, entries 15–17) could sig-
copyranoside-containing S-linked disaccharides,[20] but only nify that, in sialic acid glycals, thiols first attack the anom-
recently has it received attention the sialic acid glycal eric carbon in a kinetically controlled reaction, and then
series.[19]
undergo equilibration to thermodynamically more stable
In their pioneering studies on the Ferrier reaction of glycals with the nucleophile bound to the carbon bearing
thiols with neutral hex-2-enopyranosides, A. Zamojski and the leaving group. This is consistent with the well-known
W. Priebe,[21] and then other authors,[20,22,23] observed that, ability of sulfides to rearrange under Lewis or Brønsted
depending on the nature of the nucleophile and the reaction acidic conditions.[20–23] The equilibration could be easier for
conditions, the rearrangement may result in the formation simple thiols and more difficult for cysteine, probably as a
4066
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4065–4077

4-Substituted Neu5Ac2en Glycals
Table 2. Intermolecular nucleophilic attack on Neu5-perfluoroacet- thioglycals obtained with simple thiols (Table 2, entries 15–
ylated glycals.[a]
17) could derive from the equilibration of first-formed 2-
substituted sialosides.
Entry Nucleophile
t [min] Products; a = α, b = β α/β ratio; yield [%]
1
2
3
4
5
6
7
8
9
10
MeSO2NH2
PhSO2NH2
pCH3PhSO2NH2 15
MeOH
EtOH
nPrOH
nBuOH
iPrOH
BnOH
15
15
8b
9b
10b
11b
12b
4β only; 87
4β only; 88
4β only; 86
4β only; 81
4β only; 79
4β only; 71
4β only; 74
1:2; 75
Scheme 2. Acidic rearrangement of cysteine Ferrier sialoside. Rea-
gents and conditions: (i) BF3·Et2O (20 equiv.), CH2Cl2, 40 °C, 2 h.
15
15
30
30
60
60
This hypothesis could also explain their α stereochemis-
try at C-4, opposite to that observed with other nucleo-
philes that could arise from direct attack at C-4 from the
most favoured β face of the molecule.[12]
13b
14b
15a + 15b
16b
4β only; 83
To ascertain this, we designed two experiments. The first
aimed to trap the possible Ferrier glycosides formed in the
reactions, the second to verify the ability of these possible
first-formed sialosides to rearrange into their 4-substituted
regioisomers. Thus, we first treated FANA glycal 4 with
MeOH, MeSO2NH2, and EtSH (O, N, and S nucleophiles)
under milder conditions (23 °C) in separate experiments,
and monitored the course of the reactions by TLC and
NMR spectroscopy. In this way, in the first two reactions,
we observed only the presence of the 4β-substituted epimers
(i.e., 11b or 8b, respectively; Scheme 3, Path A and Path B).
They formed after a few minutes and increased until the
end of the reaction, i.e., the complete consumption of stat-
ing glycal 4.[28] In contrast, in the reaction of glycal 4 with
EtSH, we initially observed the formation of the 2α and 2β
isomeric sialosides (i.e., 28a and 28b),[27] together with the
two 4α- and 4β-substituted analogues (i.e., 20a and 20b; as
120
17b
4β only; 58
11
12
13
14
15
16
17
18
tBuOH
phenol
60
120
60
60
15
–
–
18b
0
0
4-chlorophenol
4-methylphenol
EtSH
C8H17SH
PhSH
4β only; 67
4α only; 56
2:1; 85
4α only; 61
5:1; 84
19a
20a + 20b
21a
22a + 22b
30
15
60
23a
2α only; 79
1
shown by H NMR spectroscopy and TLC), all of which
19
20
21
TESH
TMSCl
TMSBr
15
15
30
24a
25a + 25b
26b
2α only; 86
1:3; 78
4β only; 73
remained present until the complete disappearance of the
starting glycal. After the reaction was complete, we isolated
epimeric thioglycosides 28a and 28b, together with re-
gioisomer 20b, as an inseparable mixture, and also glycal
20a as a pure compound. Both the pairs of diastereomers
showed the prevalence of the α over the β epimer (2:1; see
[a] Experimental conditions: glycal (0.2 mmol) in solvent (1.5 mL),
CH3CN (2 mmol).
consequence of the amino acidic functionality, which may Experimental section). Moreover, after heating the reaction
coordinate to the acetoxy leaving group, or which, in some mixture at 40 °C for an additional time (15 min), we iso-
way, may cause a major difference in energy between glycos- lated only the diastereomeric pair of thioesters 20a and 20b
ide 23a and its allylic regioisomer(s).[26]
(2:1 ratio) in 80% yield.
In order to ascertain whether cysteine sialoside 23a[27]
These results strongly suggest that the reaction of pro-
could really be equilibrated to its 4α-substituted re- tected FANA glycal 4 with thiols could follow a different
gioisomer, or to a mixture of 4α and 4β epimers, we heated course from that of oxygen or nitrogen nucleophiles, since
it in dichloromethane containing an increased amount they first give Ferrier products that are subsequently iso-
(20 equiv.) of BF3·Et2O, for 2 h. After this treatment, sialo- merized to give a pair of glycalic 4-substituted thioethers
side 23a gave 4-substituted glycals 27a and 27b (α/β ratio: 20a and 20b. Moreover, since thioethers 20a and 20b were
2:1; Scheme 2), which suggests that also the 4α-substituted isolated with the same α/β ratio as the parent sialosides (i.e.,
Eur. J. Org. Chem. 2013, 4065–4077
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4067

P. Allevi, P. Rota, I. S. Agnolin, A. Gregorio, M. Anastasia
FULL PAPER
Scheme 3. Allylic substitution and internal S-rearrangement. Reagents and conditions: (i) BF3·Et2O (1 equiv.), CH2Cl2, 25 °C;
(ii) BF3·Et2O (10 equiv.), CH2Cl2, 40 °C.
28a and 28b), it appeared to be possible that a concerted
To support or exclude this idea, we N-transacylated
mechanism of isomerization could be operating in the equil- Ferrier glycosides 29a and 29b[19] to give O-sialosides 30a
ibration of simpler thiols, probably through two parallel and 30b, and subjected these compounds to acidic treat-
SN2Ј processes (Scheme 4).
ment with BF3·Et2O (10 equiv., for 15 min) in dichloro-
methane in separate experiments (Scheme 5). In neither of
the reactions did we obtain any glycal deriving from isomer-
ization of the acetalic groups; we observed only the forma-
tion of perfluorinated oxazoline 31, which was isolated as
such or as 4β-hydroxy FANA glycal 32.[13] Clearly, the
acidic treatment causes a simple elimination of the 2-meth-
oxy groups, the rearrangement of which is probably hin-
dered by the immediate formation of oxazoline 31. This re-
sult strongly supports the possibility that, in our reaction,
alcohols directly attack C-4 of FANA glycal 4, attacking
the molecule from the less hindered β-side (Table 2).[12]
In a parallel experiment, we prepared thioglycosides 28a
and 28b,[27] in pure form, as single isomers, by an indepen-
dent route, and tested their possible rearrangement into
glycals 20a and 20b (Scheme 6). For their preparation, we
first treated oxazoline 5 with ethanethiol in the presence of Bi-
(OTf)3, and obtained unfluorinated thioglycosides 33a and
Scheme 4. Possible concerted equilibration of thiolic sialosides.
Scheme 5. Synthesis and acidic equilibration of Ferrier sialosides 30a and 30b. Reagents and conditions: (i) (CF3CO)2O, Et3N, CH3CN,
135 °C, 5 min; (ii) CH3OH (10 equiv.), BF3·Et2O (10 equiv.), CH2Cl2, 40 °C, 15 min, then Et3N (0.1 mL), CH2Cl2, H2O; (iii) CH3OH
(10 equiv.), BF3·Et2O (10 equiv.), CH2Cl2, 40 °C, 15 min, then H2O, CH2Cl2.
4068
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4065–4077

4-Substituted Neu5Ac2en Glycals
Scheme 6. Synthesis and acidic equilibration of diastereomerically pure Ferrier thiosialosides 28a and 28b. (ii) (CF3CO)2O, Et3N, CH3CN,
135 °C, 5 min; (iii) EtSH (10 equiv.), BF3·Et2O (10 equiv.), CH2Cl2, 40 °C, 15 min.
33b,[27] which could be separated by rapid chromatography of alternative pathways, which we have summarized in
and transformed, by direct N-transacylation, into the corre- Scheme 7. The possibility of an equilibration of the 4α- and
sponding perfluorinated thioglycosides (i.e., 28a and 28b; 4β-substituted epimers (i.e., 20a and 20b) was excluded by
Scheme 6). Each of them was completely characterized and an experiment involving the separate acidic treatment of
then subjected to separate treatment with EtSH and these two thioethers (BF3·Et2O for 15 min at 40 °C). In the
BF3·Et2O in dichloromethane, for 15 min at 40 °C, a pro- Scheme, we hypothesized that, under our reaction condi-
cess that transformed them into two very similar mixtures tions, different routes can contribute to the final result. We
of the 4α- and 4β-thioether derivatives (i.e., 20a and 20b), considered a concerted mechanism, and the intermediate
which were obtained in comparably high yields and with formation of a discrete carboxonium ion and/or of a pos-
very close epimeric ratios (α/β: 2.3:1.0).
sible transient perfluorinated oxazoline. However, in ab-
These results confirm that the 4-substituted glycals sence of other evidence, we cannot decide which is the
formed in the reactions with thiols, can derive from isomer- major contributing mechanism.
ization of first-formed thioglycosides.[28] Moreover, they
also show that the isomerization reactions of the simple
thiol derivatives follow a course similar to that of sialosyl
cysteine 23a. A single mechanism has not been identified
Conclusions
for this process, but it may involve, in combination, a series
In conclusion, we have developed a general protocol for
the synthesis of 4-substituted 2,3-unsaturated neuraminic
acid derivatives (FANA and DANA glycals) containing ele-
ments of molecules with anti-NA activity. The protocol in-
volves the reaction of a protected FANA glycal with various
nucleophiles in the presence of a Lewis acid. Under our
reaction conditions, direct allylic substitution at C-4 occurs
with oxygen or nitrogen nucleophiles, while with thiols, the
reaction goes through a Ferrier reaction and a subsequent
equilibration. Thus, our results expand the applicability of
Ferrier reaction to C-4-functionalized sialic acid glycals,
highlighting its synthetic utility for the preparation of these
highly sought after compounds.
Experimental Section
General Remarks: Nuclear magnetic resonance spectra were re-
1
corded at 298 K operating at 500.13 MHz for H and 125.76 MHz
for 13C. Chemical shifts are reported in parts per million (ppm, δ
units). In CDCl3, chemical shifts were calibrated to the residual
CDCl3 signal (δ = 7.26 ppm for 1H and at δ = 77.0 ppm for 13C
spectra). In D2O spectra, chemical shifts were calibrated to tBuOH
as an internal standard (δ = 1.24 ppm for 1H and at δ = 30.29 ppm
for 13C spectra). Proton and carbon assignments were established,
if necessary, using 1H–1H and 1H–13C correlated NMR experi-
1
ments. H NMR spectroscopic data are tabulated in the following
order: multiplicity (s, singlet; d, doublet; t, triplet; br. s, broad sing-
let; m, multiplet), coupling constant(s) in Hertz, number of pro-
Scheme 7. Possible contributing events resulting in the formation
of 4-substituted thioglycals 20a and 20b.
Eur. J. Org. Chem. 2013, 4065–4077
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4069

P. Allevi, P. Rota, I. S. Agnolin, A. Gregorio, M. Anastasia
FULL PAPER
tons, assignment of proton(s). Optical rotations were recorded
using a polarimeter equipped with a 1 dm cell. [α]D values are given
in 10–1 degcm2 g–1, and the concentrations are given in g100 mL–1.
Mass spectrometry was performed using a quadrupole ion trap
mass spectrometer equipped with an electrospray (ESI) ion source.
The spectra were collected in continuous flow mode by connecting
the infusion pump directly to the ESI source. Solutions of com-
pounds were infused at a flow rate of 5 μLmin–1. The spray voltage
was set at 5.0 kV in the positive and at 4.5 kV in the negative ion
mode, with a capillary temperature of 220 °C. Full-scan mass spec-
tra were recorded by scanning a m/z range of 100–2000. All reac-
tions were monitored by thin-layer chromatography (TLC) carried
out on 0.25 mm E. Merck silica gel plates (60F 254), visualized
using UV light, 50% sulfuric acid, or 0.2% ninhydrin in ethanol
and heat. Usual work-up, unless otherwise indicated, refers to the
following sequence: Et3N (0.1 mL) was added to the reaction mix-
tures, the solvents were evaporated under a nitrogen flow and re-
duced pressure, the residue was diluted with EtOAc, and the or-
ganic phase was washed with ice-cold NaHCO3 (saturated aq.).
Finally, the organic phase was dried with Na2SO4 and filtered, and
the solvents were evaporated.
J3,4 = 5.7 Hz, 1 H, 3-H), 5.58 (d, JNH,4 = 9.0 Hz, 1 H, H-NSO2),
5.48 (dd, J7,6 = 2.2, J7,8 = 4.1 Hz, 1 H, 7-H), 5.36 (ddd, J8,9a = 2.7,
J8,7 = 4.1, J8,9b = 7.9 Hz, 1 H, 8-H), 4.78 (dd, J9a,8 = 2.7, J9a,9b
=
12.4 Hz, 1 H, 9a-H), 4.40 (ddd, J5,4 = 4.7, J5,6 = J5,NH = 10.0 Hz,
1 H, 5-H), 4.28 (dd, J6,7 = 2.2, J6,5 = 10.0 Hz, 1 H, 6-H), 4.19–4.10
(overlapping, 2 H, 9b-H and 4-H), 3.81 (s, 3 H, COOCH3), 3.03 (s,
3 H, NHSO2CH3), 2.09 (s, 3 H, OCOCH3), 2.08 (s, 3 H, OCOCH3),
2.05 (s, 3 H, OCOCH3) ppm. 13C NMR (CDCl3): δ =171.0, 170.9
(2 C, OCOCH3 at C-8 and OCOCH3 at C-9), 169.8 (OCOCH3 at
C-7), 161.6 (C-1), 157.6 (q, JC,F = 38 Hz, COCF3), 145.5 (C-2),
119.0–110.0 (CF3), 106.7 (C-3), 72.9 (C-6), 71.4 (C-8), 67.9 (C-7),
62.2 (C-9), 52.8 (COOCH3), 47.1 (C-4), 46.3 (C-5), 41.2 (SO2CH3),
20.9, 20.7, 20.4 (3C, OCOCH3) ppm. MS (ESI+): m/z = 563.7 [M
+ H]+, 585.5 [M + Na]+, 1150.1 [2M + Na]+. C19H25F3N2O12S
(562.47): calcd. C 40.57, H 4.48, N 4.98; found C 40.81, H 4.57, N
5.11.
Method 2: Glycal 8b was also obtained by treating glycal 4 (105 mg,
0.2 mmol) in CH2Cl2 (1.5 mL) with MeSO2NH2 (190 mg,
2.0 mmol) and BF3·Et2O (25 μL, 0.2 mmol) at 25 °C for 48 h. Gly-
cal 8b (62 mg, 55%) was obtained as a white solid together with
starting glycal 4 (32 mg, 30%).
Ritter Reaction Using CH3CN as a Reagent, with Different Solvents
and Lewis Acids
Data for 8b: MS (ESI+): m/z = 563.5 [M + H]+, 585.2 [M + Na]+.
C19H25F3N2O12S (562.47): calcd. C 40.57, H 4.48, N 4.98; found
C 40.68, H 4.51, N 5.01. All other physico-chemical properties were
practically identical to those previously reported.
Methyl
deoxy-5-[(trifluoroacetyl)amino]-
(6a) and Methyl 7,8,9-Tri-O-acetyl-4-(acetylamino)-2,6-anhydro-
3,4,5-trideoxy-5-[(trifluoroacetyl)amino]- -glycero- -galacto-non-2-
7,8,9-Tri-O-acetyl-4-(acetylamino)-2,6-anhydro-3,4,5-tri-
D
-glycero- -talo-non-2-enonate
D
Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-3,4,5-trideoxy-4-[(phenyl-
sulfonyl)amino]-5-[(trifluoroacetyl)amino]-D-glycero-D-talo-non-2-en-
D
D
enonate (6b): Glycal 4 was dissolved in the appropriate solvent
(1.5 mL) and treated with CH3CN (2.0 mmol). The parameters that
were modified (i.e., temperature, time, and catalyst, as well as the
yields) are reported in Table 1. The reaction mixtures were worked
up as indicated in the General Remarks to give, after flash
chromatography, eluting with EtOAc/hexane (80:20 v/v), the less
polar glycal (i.e., 6b), followed by the more polar glycal (i.e., 6a),
both in pure form.
onate (9b): Glycal 9b (110 mg, 88%) was obtained as a white solid
by the reaction of glycal 4 (105 mg, 0.2 mmol) with PhSO2NH2
(314 mg), heating for 15 min at 40 °C in CH2Cl2, m.p. 127–129 °C
(CH2Cl2/diisopropyl ether). [α]2D0 = –15.7 (c = 1 in CHCl3). 1H
NMR (CDCl3): δ = 7.88–7.83 (overlapping, 2 H, SO2Ph), 7.75 (d,
JNH,5 = 9.2 Hz, 1 H, N-H), 7.64–7.57 (m, 1 H, SO2Ph), 7.55–7.45
(overlapping, 2 H, SO2Ph), 6.01 (d, JNH,4 = 8.5 Hz, 1 H, H-NSO2),
5.52 (d, J3,4 = 5.8 Hz, 1 H, 3-H), 5.49 (dd, J7,6 = 1.8, J7,8 = 5.0 Hz,
1 H, 7-H), 5.39 (ddd, J8,9a = 2.7, J8,7 = 5.0, J8,9b = 7.4 Hz, 1 H, 8-
H), 4.66 (dd, J9a,8 = 2.7, J9a,9b = 12.4 Hz, 1 H, 9a-H), 4.36–4.29
(m, 1 H, 5-H), 4.28 (dd, J6,7 = 1.8, J6,5 = 10.8 Hz, 1 H, 6-H), 4.14
(dd, J9b,8 = 7.4, J9b,9a = 12.4 Hz, 1 H, 9b-H), 3.80–3.85 (m, 1 H,
4-H), 3.71 (s, 3 H, COOCH3), 2.09 (s, 3 H, OCOCH3), 2.08 (s, 3
H, OCOCH3), 2.04 (s, 3 H, OCOCH3) ppm. 13C NMR (CDCl3): δ
= 170.9, 169.7 (3 C, OCOCH3), 161.6 (C-1), 157.6 (q, JC,F = 38 Hz,
COCF3), 145.4 (C-2), 139.5, 133.4, 129.5, 126.9 (6 C, Ph), 119.0–
110.0 (CF3), 106.1 (C-3), 72.7 (C-6), 70.8 (C-8), 67.8 (C-7), 62.3
(C-9), 52.6 (COOCH3), 46.9 (C-4), 46.2 (C-5), 20.7, 20.6, 20.4 (3
C, OCOCH3) ppm. MS (ESI+): m/z = 625.2 [M + H]+, 647.3 [M +
Na]+, 1271.4 [2M + Na]+. C24H27F3N2O12S (624.54): calcd. C
46.16, H 4.36, N 4.49; found C 45.97, H 4.21, N 4.33.
Data for Glycal 6b: M.p. 133–135 °C (CH2Cl2/diisopropyl ether).
C20H25F3N2O11 (526.41): calcd. C 45.63, H 4.79, N 5.32; found C
45.56, H 4.67, N 5.30.
Data for Glycal 6a: M.p. 146–148 °C (CH2Cl2/diisopropyl ether).
C20H25F3N2O11 (526.41): calcd. C 45.63, H 4.79, N 5.32; found C
45.56, H 4.67, N 5.30. All other physico-chemical properties were
practically identical to those previously reported.
Reaction of Perfluorinated Glycal 4 with Different Nucleophiles un-
der BF3·Et2O Catalysis: The reactions were performed on starting
glycal 4 (0.2 mmol) dissolved in CH2Cl2 (1.5 mL), using the appro-
priate nucleophile (2.0 mmol) and BF3·Et2O (246 μL, 2.0 mmol) at
40 °C for the time indicated in Table 2. Then, the reaction mixtures
were worked-up as indicated in the General Remarks to give, after
flash chromatography, the appropriate glycal.
Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-3,4,5-trideoxy-4-{[(4-meth-
ylphenyl)sulfonyl]amino}-5-[(trifluoroacetyl)amino]-D-glycero-D-
talo-non-2-enonate (10b): Glycal 10b (110 mg, 86%) was obtained
as a white solid by the reaction of glycal 4 (105 mg, 0.2 mmol)
with p-toluenesulfonamide (342 mg), heating for 15 min at 40 °C in
CH2Cl2, m.p. 133–135 °C (CH2Cl2/diisopropyl ether). [α]2D0 = –21.3
In some cases, the reactions were additionally performed on glycal
4 (0.2 mmol) dissolved in CH2Cl2 (1.5 mL), with the appropriate
nucleophile (2.0 mmol) and BF3·Et2O (25 μL, 0.2 mmol) at 25 °C.
Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-3,4,5-trideoxy-4-[(methyl-
1
(c = 1 in CHCl3). H NMR (CDCl3): δ = 7.74–7.69 (overlapping,
sulfonyl)amino]-5-[(trifluoroacetyl)amino]-D-glycero-D-talo-non-2-en-
2 H, SO2PhCH3), 7.49 (d, JNH,5 = 9.3 Hz, 1 H, N-H), 7.25–7.30
(overlapping, 2 H, SO2PhCH3), 5.61 (d, JNH,4 = 8.0 Hz, 1 H, H-
NSO2), 5.54 (d, J3,4 = 5.8 Hz, 1 H, 3-H), 5.48 (dd, J7,6 = 2.0, J7,8
= 5.1 Hz, 1 H, 7-H), 5.40 (ddd, J8,9a = 2.7, J8,7 = 5.1, J8,9b = 7.4 Hz,
onate (8b)
Method 1: Glycal 8b (98 mg, 87%) was obtained as a white solid
by the reaction of glycal 4 (105 mg, 0.2 mmol) with MeSO2NH2
(190 mg), heating for 15 min at 40 °C in CH2Cl2, m.p. 155–157 °C 1 H, 8-H), 4.65 (dd, J9a,8 = 2.7, J9a,9b = 12.4 Hz, 1 H, 9a-H), 4.36–
(CH2Cl2/diisopropyl ether). [α]2D0 = –72.8 (c = 1 in CHCl3). 1H
NMR (CDCl3): δ = 7.63 (d, JNH,5 = 10.0 Hz, 1 H, N-H), 6.09 (d,
4.30 (m, 1 H, 5-H), 4.23 (dd, J6,7 = 2.0, J6,5 = 10.9 Hz, 1 H, 6-H),
4.13 (dd, J9b,8 = 7.4, J9b,9a = 12.4 Hz, 1 H, 9b-H), 3.84 (ddd, J4,5
4070
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4065–4077

4-Substituted Neu5Ac2en Glycals
= 4.6, J4,3 = 5.8, J4,NH = 8.0 Hz, 1 H, 4-H), 3.74 (s, 3 H, COOCH3), 514.5 [M + H]+, 536.4 [M + Na]+. C20H26F3NO11 (513.42): calcd.
2.44 (s, 3 H, SO2PhCH3), 2.08 (s, 3 H, OCOCH3), 2.06 (s, 3 H,
C 46.79, H 5.10, N 2.73; found C 46.51, H 5.01, N 2.50.
OCOCH3), 2.03 (s, 3 H, OCOCH3) ppm. 13C NMR (CDCl3): δ =
Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-3,5-dideoxy-4-O-propyl-5-
[(trifluoroacetyl)amino]-D-glycero-D-talo-non-2-enonate (13b): Glyc-
170.9, 170.8, 169.7 (3 C, OCOCH3), 161.6 (C-1), 157.7 (q, JC,F
=
38 Hz, COCF3), 145.6 (C-2), 144.6, 135.2, 130.1, 127.1 (6 C, Ph),
119.0–110.0 (CF3), 106.0 (C-3), 72.8 (C-6), 70.8 (C-8), 67.7 (C-7),
62.2 (C-9), 52.6 (COOCH3), 47.0 (C-4), 46.1 (C-5), 21.6 (PhCH3),
20.8, 20.6, 20.4 (3 C, OCOCH3) ppm. MS (ESI+): m/z = 639.4 [M
+ H]+, 661.3 [M + Na]+, 1300.0 [2M + Na]+. C25H29F3N2O12S
(638.56): calcd. C 47.02, H 4.58, N 4.39; found C 47.21, H 4.57, N
4.31.
al 13b (75 mg, 71%) was obtained as a white solid by the reaction
of glycal 4 (105 mg, 0.2 mmol) with nPrOH (150 μL), heating for
30 min at 40 °C in CH2Cl2, m.p. 124–127 °C (CH2Cl2/diisopropyl
ether). [α]2D0 = –38.2 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 6.71
(d, JNH,5 = 9.5 Hz, 1 H, N-H), 6.24 (d, J3,4 = 5.3 Hz, 1 H, 3-H),
5.41 (dd, J7,6 = 2.2, J7,8 = 5.0 Hz, 1 H, 7-H), 5.35 (ddd, J8,9a = 2.8,
J8,7 = 5.0, J8,9b = 6.9 Hz, 1 H, 8-H), 4.68 (dd, J9a,8 = 2.8, J9a,9b
=
12.4 Hz, 1 H, 9a-H), 4.40–4.35 (m, 1 H, 5-H), 4.32 (dd, J6,7 = 2.2,
J6,5 = 10.6 Hz, 1 H, 6-H), 4.15 (dd, J9b,8 = 6.9, J9b,9a = 12.4 Hz, 1
H, 9b-H), 3.88 (dd, J4,5 = 4.0, J4,3 = 5.3 Hz, 1 H, 4-H), 3.81 (s, 3
H, COOCH3), 3.69–3.63 (m, 1 H, OCH2aCH2CH3), 3.41–3.34 (m,
1 H, OCH2bCH2CH3), 2.10 (s, 3 H, OCOCH3), 2.07 (s, 3 H, OC-
OCH3), 2.05 (s, 3 H, OCOCH3), 1.67–1.54 (overlapping, 2 H,
OCH2CH2CH3), 0.92 (m, 3 H, OCH2CH2CH3) ppm. 13C NMR
(CDCl3): δ = 170.6, 170.1, 169.7 (3 C, OCOCH3), 161.8 (C-1),
157.0 (q, JC,F = 38 Hz, COCF3), 145.6 (C-2), 119.0–110.0 (CF3),
106.8 (C-3), 73.1 (C-6), 71.0 (C-8), 70.9 (OCH2CH2), 67.8 (C-7),
67.6 (C-4), 62.1 (C-9), 52.6 (COOCH3), 46.3 (C-5), 22.9
(OCH2CH2CH3), 20.9, 20.7, 20.6 (3 C, OCOCH3), 10.4
(OCH2CH2CH3) ppm. MS (ESI+): m/z = 528.4 [M + H]+, 551.4
[M + Na]+. C21H28F3NO11 (527.44): calcd. C 47.82, H 5.35, N 2.66;
found C 47.69, H 5.40, N 2.62.
Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-3,5-dideoxy-4-O-methyl-5-
[(trifluoroacetyl)amino]-D-glycero-D-talo-non-2-enonate (11b)
Method 1: Glycal 11b (81 mg, 81%) was obtained as a white solid
by the reaction of glycal 4 (105 mg, 0.2 mmol) with MeOH (81 μL),
heating for 15 min at 40 °C in CH2Cl2, m.p. 122–124 °C (CH2Cl2/
diisopropyl ether). [α]2D0 = –11.3 (c = 1 in CHCl3). 1H NMR
(CDCl3): δ = 6.71 (d, JNH,5 = 9.5 Hz, 1 H, N-H), 6.26 (d, J3,4
=
5.3 Hz, 1 H, 3-H), 5.39 (dd, J7,6 = 2.1, J7,8 = 5.0 Hz, 1 H, 7-H),
5.33 (ddd, J8,9a = 2.8, J8,7 = 5.0, J8,9b = 6.9 Hz, 1 H, 8-H), 4.66
(dd, J9a,8 = 2.8, J9a,9b = 12.4 Hz, 1 H, 9a-H), 4.41–4.36 (m, 1 H,
5-H), 4.33 (dd, J6,7 = 2.1, J6,5 = 10.7 Hz, 1 H, 6-H), 4.14 (dd, J9b,8
= 6.9, J9b,9a = 12.4 Hz, 1 H, 9b-H), 3.82 (s, 3 H, COOCH3), 3.80
(dd, J4,5 = 3.9, J4,3 = 5.3 Hz, 1 H, 4-H), 3.44 (s, 3 H, OCH3), 2.10
(s, 3 H, OCOCH3), 2.07 (s, 3 H, OCOCH3), 2.05 (s, 3 H, OCOCH3)
ppm. 13C NMR (CDCl3): δ = 170.6, 170.1, 169.7 (3 C, OCOCH3),
161.7 (C-1), 157.0 (q, JC,F = 38 Hz, COCF3), 145.9 (C-2), 119.0–
110.0 (CF3), 105.9 (C-3), 73.1 (C-6), 71.0 (C-8), 69.2 (C-4), 67.6
(C-7), 62.1 (C-9), 56.6 (OCH3), 52.6 (COOCH3), 46.2 (C-5), 20.9,
20.7, 20.6 (3 C, OCOCH3) ppm. MS (ESI+): m/z = 500.6 [M +
H]+, 523.5 [M + Na]+. C19H24F3NO11 (499.39): calcd. C 45.70, H
4.84, N 2.80; found C 45.88, H 5.02, N 2.88.
Methyl
[(trifluoroacetyl)amino]-
7,8,9-Tri-O-acetyl-2,6-anhydro-4-O-butyl-3,5-dideoxy-5-
-glycero- -talo-non-2-enonate (14b): Glyc-
D
D
al 14b was obtained as a white solid (80 mg, 74%) by the reaction
of glycal 4 (105 mg, 0.2 mmol) with nBuOH (183 μL), heating for
30 min at 40 °C in CH2Cl2, m.p. 118–121 °C (CH2Cl2/diisopropyl
ether). [α]2D0 = –36.1 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 6.72
(d, JNH,5 = 9.5 Hz, 1 H, N-H), 6.24 (d, J3,4 = 5.3 Hz, 1 H, 3-H),
5.41 (dd, J7,6 = 2.2, J7,8 = 4.9 Hz, 1 H, 7-H), 5.34 (ddd, J8,9a = 2.8,
Method 2: Glycal 11b was also obtained by treating glycal 4
(105 mg, 0.2 mmol) in CH2Cl2 (1.5 mL) with MeOH (81 μL,
2.0 mmol) and BF3·Et2O (25 μL, 0.2 mmol), at 25 °C for 48 h. Gly-
cal 11b (45 mg, 45%) was obtained as a white solid together with
starting glycal 4 (37 mg, 35%).
J8,7 = 4.9, J8,9b = 7.0 Hz, 1 H, 8-H), 4.69 (dd, J9a,8 = 2.8, J9a,9b
=
12.4 Hz, 1 H, 9a-H), 4.40–4.34 (m, 5-H), 4.32 (dd, J6,7 = 2.2, J6,5
= 10.6 Hz, 1 H, 6-H), 4.16 (dd, J9b,8 = 7.0, J9b,9a = 12.4 Hz, 1 H,
9b-H), 3.87 (dd, J4,5 = 4.0, J4,3 = 5.3 Hz, 1 H, 4-H), 3.82 (s, 3 H,
COOCH3), 3.73–3.67 [m, 1 H, OCH2a(CH2)2CH3], 3.45–3.38 [m, 1
H, OCH2b(CH2)2CH3], 2.11 (s, 3 H, OCOCH3), 2.07 (s, 3 H, OC-
OCH3), 2.05 (s, 3 H, OCOCH3), 1.60–1.52 (overlapping, 2 H,
Data for 11b: MS (ESI+): m/z = 500.1 [M + H]+, 523.7 [M +
Na]+. C19H24F3NO11 (499.39): calcd. C 45.70, H 4.84, N 2.80;
found C 45.93, H 5.00, N 2.79. All other physico-chemical proper-
ties were practically identical to those previously reported.
OCH2CH2CH2CH3), 1.42–1.31 [overlapping,
2 H, O(CH2)2-
CH2CH3], 0.93 (m, 3 H, OCH2CH2CH3) ppm. 13C NMR (CDCl3):
δ = 170.6, 170.2, 169.7 (3 C, OCOCH3), 161.8 (C-1), 157.0 (q, JC,F
= 38 Hz, COCF3), 145.6 (C-2), 119.0–110.0 (CF3), 106.8 (C-3), 73.2
(C-6), 71.1 (C-8), 69.1 [OCH2(CH2)2CH3], 67.8 (C-7), 67.6 (C-4),
62.1 (C-9), 52.6 (COOCH3), 46.3 (C-5), 31.7 (OCH2CH2CH2CH3),
20.9, 20.7, 20.6 (3 C, OCOCH3), 19.2 [O(CH2)2CH2CH3], 13.7
[O(CH2)3CH3] ppm. MS (ESI+): m/z = 542.4 [M + H]+, 564.5 [M
+ Na]+. C22H30F3NO11 (541.47): calcd. C 48.80, H 5.58, N 2.59;
found C 48.98, H 5.48, N 2.43.
Methyl
[(trifluoroacetyl)amino]-
7,8,9-Tri-O-acetyl-2,6-anhydro-3,5-dideoxy-4-O-ethyl-5-
-glycero- -talo-non-2-enonate (12b): Glyc-
D
D
al 12b (81 mg, 79%) was obtained as a white solid by the reaction
of glycal 4 (105 mg, 0.2 mmol) with EtOH (117 μL), heating for
15 min at 40 °C in CH2Cl2, m.p. 135–137 °C (CH2Cl2/diisopropyl
ether). [α]2D0 = –55.3 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 6.71
(d, JNH,5 = 9.3 Hz, 1 H, N-H), 6.24 (d, J3,4 = 5.3 Hz, 1 H, 3-H),
5.41 (dd, J7,6 = 2.1, J7,8 = 4.9 Hz, 1 H, 7-H), 5.33 (ddd, J8,9a = 2.8,
Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-3,5-dideoxy-4-O-isopropyl-5-
J8,7 = 4.9, J8,9b = 7.1 Hz, 1 H, 8-H), 4.69 (dd, J9a,8 = 2.8, J9a,9b
=
[(trifluoroacetyl)amino]-
and Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-3,5-dideoxy-4-O-iso-
propyl-5-[(trifluoroacetyl)amino]- -glycero- -talo-non-2-enonate (15b):
D-glycero-D-galacto-non-2-enonate
(15a)
12.4 Hz, 1 H, 9a-H), 4.40–4.35 (m, 1 H, 5-H), 4.33 (dd, J6,7 = 2.1,
J6,5 = 10.6 Hz, 1 H, 6-H), 4.15 (dd, J9b,8 = 7.1, J9b,9a = 12.4 Hz, 1
H, 9b-H), 3.89 (dd, J4,5 = 4.0, J4,3 = 5.3 Hz, 1 H, 4-H), 3.82 (s, 3
H, COOCH3), 3.78–3.73 (m, 1 H, OCH2CH3), 3.53–3.46 (m, 1 H,
OCH2CH3), 2.11 (s, 3 H, OCOCH3), 2.07 (s, 3 H, OCOCH3), 2.05
(s, 3 H, OCOCH3), 1.24–1.20 (m, 3 H, OCH2CH3) ppm. 13C NMR
(CDCl3): δ = 170.6, 170.2, 169.7 (3 C, OCOCH3), 161.8 (C-1),
157.1 (q, JC,F = 38 Hz, COCF3), 145.6 (C-2), 119.0–110.0 (CF3),
106.8 (C-3), 73.1 (C-6), 71.1 (C-8), 67.7 (C-4), 67.6 (C-7), 64.8
(OCH2CH3), 62.1 (C-9), 52.6 (COOCH3), 46.2 (C-5), 20.9, 20.7,
D
D
Starting from glycal 4 (105 mg, 0.2 mmol) and iPrOH (153 μL),
after heating for 60 min at 40 °C in CH2Cl2, a mixture of glycals
15b and 15a was obtained. This mixture was separated by rapid
chromatography, eluting with hexane/EtOAc (80:20 v/v), to give
less polar glycal 15b (53 mg, 50%), followed by more polar glycal
15a (26 mg, 25%), both in pure form.
Data for Glycal 15a: M.p. 136–138 °C (CH2Cl2/diisopropyl ether).
20.6 (3 C, OCOCH3), 15.3 (OCH2CH3) ppm. MS (ESI+): m/z = [α]2D0 = +33.1 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 6.65 (d,
Eur. J. Org. Chem. 2013, 4065–4077
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4071

P. Allevi, P. Rota, I. S. Agnolin, A. Gregorio, M. Anastasia
FULL PAPER
JNH,5 = 8.0 Hz, 1 H, N-H), 6.10 (d, J3,4 = 3.3 Hz, 1 H, 3-H), 5.48
(dd, J7,6 = J7,8 = 4.7 Hz, 1 H, 7-H), 5.39 (ddd, J8,9a = 3.9, J8,7
=
4.7, J8,9b = 5.6 Hz, 1 H, 8-H), 4.56 (dd, J6,7 = 4.7, J6,5 = 7.7 Hz, 1
H, 6-H), 4.49 (dd, J9a,8 = 3.9, J9a,9b = 12.2 Hz, 1 H, 9a-H), 4.33
(dd, J4,3 = 3.3, J4,5 = 6.3 Hz, 1 H, 4-H), 4.20 (dd, J9b,8 = 5.6,
J9b,9a = 12.2 Hz, 1 H, 9b-H), 4.00–3.93 (m, 1 H, 5-H), 3.84–3.77
[overlapping, 4 H, COOCH3 and OCH(CH3)2], 2.12 (s, 3 H, OC-
OCH3), 2.06 (s, 3 H, OCOCH3), 2.03 (s, 3 H, OCOCH3), 1.18 [d,
JCH,(CH3)2a = 6.1 Hz, 3 H, OCH(CH3)2a], 1.15 [d, JCH,(CH3)2b
=
6.1 Hz, 3 H, OCH(CH3)2b] ppm. 13C NMR (CDCl3): δ = 170.5,
170.2, 169.7 (3 C, OCOCH3), 161.8 (C-1), 157.1 (q, JC,F = 38 Hz,
COCF3), 143.2 (C-2), 119.0–105.5 (CF3), 109.8 (C-3), 74.5 (C-6),
71.7 [OCH(CH3)2], 69.7 (C-8), 68.8 (C-4), 67.9 (C-7), 61.6 (C-9),
52.5 (COOCH3), 50.1 (C-5), 22.9 [OCH(CH3)2a], 21.7 [OCH-
(CH3)2b], 20.8, 20.7, 20.5 (3 C, OCOCH3) ppm. MS (ESI+): m/z =
528.3 [M + H]+, 551.4 [M + Na]+. C21H28F3NO11 (527.44): calcd.
C 47.82, H 5.35, N 2.66; found C 47.62, H 5.48, N 2.53.
Glycal 17b (92 mg, 58%) was obtained as a white solid by the reac-
tion of glycal 4 (105 mg, 0.2 mmol) with protected cytidine
(130 mg, 0.4 mmol), heating for 120 min at 40 °C in CH2Cl2, m.p.
129–131 °C (CH2Cl2/diisopropyl ether). [α]2D0 = –63.1 (c = 1 in
1
Data for 15b: M.p. 141–143 °C. [α]D = 24.2 (c = 1 in CHCl3). H
1
CHCl3). H NMR (CDCl3): δ = 9.67 (br. s, 1 H, NHAc), 9.29 (br.
NMR (CDCl3): δ = 6.70 (d, JNH,5 = 9.4 Hz, 1 H, N-H), 6.17 (d,
J3,4 = 5.3 Hz, 1 H, 3-H), 5.41 (dd, J7,6 = 2.2, J7,8 = 4.8 Hz, 1 H, 7-
H), 5.34 (ddd, J8,9a = 2.8, J8,7 = 4.8, J8,9b = 7.1 Hz, 1 H, 8-H), 4.70
(dd, J9a,8 = 2.8, J9a,9b = 12.4 Hz, 1 H, 9a-H), 4.37–4.31 (m, 1 H,
5-H), 4.29 (dd, J6,7 = 2.2, J6,5 = 10.6 Hz, 1 H, 6-H), 4.16 (dd, J9b,8
s, 1 H, NHCOCF3), 7.52 (d, J6,5 = 7.4 Hz, 1 H, 6-H), 7.46 (d, J5,6
= 7.4 Hz, 1 H, 5-H), 6.19 (d, J3ЈЈ,4ЈЈ = 5.3 Hz, 1 H, 3ЈЈ-H), 5.67–
5.61 (overlapping, 2 H, 7ЈЈ-H and 8ЈЈ-H), 5.54 (d, J2Ј,3Ј = 6.3 Hz, 1
H, 2Ј-H), 5.36 (s, 1 H, 1Ј-H), 5.20–5.15 (m, 1 H, 3Ј-H), 5.11 (dd,
J9aЈЈ,8ЈЈ = 1.6, J9aЈЈ,9bЈЈ = 12.1 Hz, 1 H, 9aЈЈ-H), 4.43–4.31 (overlap-
ping, 2 H, 5ЈЈ-H and 6ЈЈ-H), 4.20–4.14 (overlapping, 2 H, 4Ј-H and
9bЈЈ-H), 4.01 (dd, J5aЈ,4Ј = 1.8, J5aЈ,5bЈ = 10.3 Hz, 1 H, 5aЈ-H), 3.86
(dd, J4ЈЈ,5ЈЈ = 3.8, J4ЈЈ,3ЈЈ = 5.3 Hz, 1 H, 4ЈЈ-H), 3.79 (s, 3 H, CO-
OCH3), 3.48 (dd, J5bЈ,4Ј = 1.1, J5bЈ,5aЈ = 10.3 Hz, 1 H, 5bЈ-H), 2.22
(s, 3 H, NHCOCH3), 2.13 (s, 3 H, OCOCH3), 2.11 (s, 3 H, OC-
OCH3), 2.0 (s, 3 H, OCOCH3), 1.54 [s, 3 H, C(CH3)a], 1.34 [s, 3
H, C(CH3)b] ppm. 13C NMR (CDCl3): δ = 171.4 (NHCOCH3 at
C-4), 170.8 (CH3COO at C-9ЈЈ), 170.5 (CH3COO at C-8ЈЈ), 169.5
= 7.1, J9b,9a = 12.4 Hz, 1 H, 9b-H), 3.95 (dd, J4,5 = 4.0, J4,3
=
5.3 Hz, 1 H, 4-H), 3.84–3.75 [overlapping, 4 H, COOCH3 and
OCH(CH3)2], 2.10 (s, 3 H, OCOCH3), 2.07 (s, 3 H, OCOCH3), 2.05
(s, 3 H, OCOCH3), 1.20 [d, JCH,(CH3)2a = 6.1 Hz, 3 H, OCH-
(CH3)2a], 1.16 [d, JCH,(CH3)2b = 6.1 Hz, 3 H, OCH(CH3)2b] ppm.
13C NMR (CDCl3): δ = 170.6, 170.2, 169.7 (3 C, OCOCH3), 161.9
(C-1), 157.0 (q, JC,F = 38 Hz, COCF3), 145.3 (C-2), 119.0–105.5
(CF3), 107.8 (C-3), 73.1 (C-6), 71.4 [OCH(CH3)2], 71.2 (C-8), 67.6
(C-7), 65.8 (C-4), 62.1 (C-9), 52.6 (COOCH3), 46.3 (C-5), 23.3
[OCH(CH3)2a], 21.7 [OCH(CH3)2b], 20.9, 20.7, 20.6 (3 C, OC-
OCH3) ppm. MS (ESI+): m/z = 528.3 [M + H]+, 551.4 [M +
Na]+. C21H28F3NO11 (527.44): calcd. C 47.82, H 5.35, N 2.66;
found C 47.62, H 5.48, N 2.49.
(CH3COO at C-7ЈЈ), 163.9 (C-4), 161.9 (C-1ЈЈ), 157.3 (q, JC,F
=
38 Hz, COCF3), 154.4 (C-2), 148.8 (C-6), 145.5 (C-2ЈЈ), 119.0–
110.0 (CF3), 114.1 [C(CH3)2], 106.3 (C-3ЈЈ), 99.3 (C-5), 97.1 (C-1Ј),
88.0 (C-4Ј), 83.8 (C-2Ј), 80.0 (C-3Ј), 72.8 (C-6ЈЈ), 72.5 (C-8ЈЈ), 69.0
(C-7ЈЈ), 68.7 (C-5Ј), 67.1 (C-4ЈЈ), 62.9 (C-9Ј), 52.5 (COOCH3), 46.7
(C-5ЈЈ), 27.2 [C(CH3)2], 24.8 [C(CH3)2], 24.6 (NHCOCH3 at C-4),
21.3, 20.8, 20.6 (3 C, OCOCH3) ppm. MS (ESI+): m/z = 793.7 [M
+ H]+, 816.6 [M + Na]+. C32H39F3N4O16 (792.66): calcd. C 48.49,
H 4.96, N 7.07; found C 48.71, H 4.70, N 6.98.
Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-4-O-benzyl-3,5-dideoxy-5-
[(trifluoroacetyl)amino]-D-glycero-D-talo-non-2-enonate (16b): Glyc-
al 16b (96 mg, 83%) was obtained as a white solid by the reaction
of glycal 4 (105 mg, 0.2 mmol) with BnOH (207 μL), heating for
60 min at 40 °C in CH2Cl2, m.p. 119–121 °C (CH2Cl2/diisopropyl
ether). [α]2D0 = –31.1 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 7.43–
7.27 (overlapping, 5 H, Ph), 6.75 (d, JNH,5 = 8.0 Hz, 1 H, N-H),
6.28 (d, J3,4 = 5.3 Hz, 1 H, 3-H), 5.42 (dd, J7,6 = 1.4, J7,8 = 5.2 Hz,
1 H, 7-H), 5.37 (ddd, J8,9a = 2.8, J8,7 = 5.2, J8,9b = 6.8 Hz, 1 H, 8-
H), 4.76 (d, JCH2a,CH2b = 11.4 Hz, 1 H, OCH2aPh), 4.70 (dd, J9a,8
= 2.8, J9a,9b = 12.5 Hz, 1 H, 9a-H), 4.49 (d, JCH2b,CH2a = 11.4 Hz,
1 H, OCH2bPh), 4.42–4.38 (overlapping, 2 H, 5-H and 6-H), 4.17
(dd, J9b,8 = 6.8, J9b,9a = 12.5 Hz, 1 H, 9b-H), 4.00–3.98 (m, 1 H,
4-H), 3.85 (s, 3 H, COOCH3), 2.12 (s, 3 H, OCOCH3), 2.09 (s, 3
H, OCOCH3), 2.07 (s, 3 H, OCOCH3) ppm. 13C NMR (CDCl3): δ
= 170.6, 170.1, 169.7 (3 C, OCOCH3), 161.8 (C-1), 157.0 (q, JC,F
= 38 Hz, COCF3), 145.9 (C-2), 136.6, 128.8, 128.6, 128.2 (6 C, Ph),
119.0–110.0 (CF3), 106.2 (C-3), 73.1 (C-6), 71.1 (OCH2Ph), 70.9
(C-8), 67.5 (C-7), 66.9 (C-4), 62.1 (C-9), 52.6 (COOCH3), 46.2 (C-
5), 20.9, 20.7, 20.6 (3 C, OCOCH3) ppm. MS (ESI+): m/z = 576.4
[M + H]+, 598.5 [M + Na]+. C25H28F3NO11 (575.49): calcd. C
52.18, H 4.90, N 2.43; found C 52.07, H 5.00, N 2.32.
Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-4-O-(4-chlorophenyl)-3,5-di-
deoxy-5-[(trifluoroacetyl)amino]-D-glycero-D-talo-non-2-enonate
(18b): 18b (80 mg, 67%) was obtained as a white solid by the reac-
tion of glycal 4 (105 mg, 0.2 mmol) with 4-chlorophenol (347 μL),
heating for 60 min at 40 °C in CH2Cl2, m.p. 129–131 °C (CH2Cl2/
diisopropyl ether). [α]2D0 = –63.1 (c = 1 in CHCl3). 1H NMR
(CDCl3): δ = 7.33–7.28 (overlapping, 2 H, Ph), 6.91–6.87 (overlap-
ping, 2 H, Ph), 6.84 (d, JNH,5 = 9.0 Hz, 1 H, N-H), 6.25 (d, J3,4
=
5.3 Hz, 1 H, 3-H), 5.54 (dd, J7,6 = 2.0, J7,8 = 4.8 Hz, 1 H, 7-H),
5.40 (ddd, J8,9a = 2.8, J8,7 = 4.8, J8,9b = 6.9 Hz, 1 H, 8-H), 4.78
(dd, J4,5 = 3.7, J4,3 = 5.3 Hz, 1 H, 4-H), 4.75 (dd, J9a,8 = 2.8, J9a,9b
= 12.5 Hz, 1 H, 9a-H), 4.65–4.56 (overlapping, 2 H, 5-H and 6-H),
4.21 (dd, J9b,8 = 6.9, J9b,9a = 12.5 Hz, 1 H, 9b-H), 3.83 (s, 3 H,
COOCH3), 2.14 (s, 3 H, OCOCH3), 2.12 (s, 3 H, OCOCH3), 2.09
(s, 3 H, OCOCH3) ppm. 13C NMR (CDCl3): δ = 170.6, 170.3, 169.7
(3 C, OCOCH3), 161.4 (C-1), 157.2 (q, JC,F = 38 Hz, COCF3),
154.9 (Ph), 146.5 (C-2), 129.9, 117.5 (5 C, Ph), 119.0–105.5 (CF3),
104.9 (C-3), 73.0 (C-6), 71.2 (C-8), 67.9 (C-7), 67.5 (C-4), 62.0 (C-
9), 52.8 (COOCH3), 46.2 (C-5), 20.9, 20.7, 20.5 (3 C, CH3COO)
ppm. MS (ESI+): m/z = 596.4 [M + H]+, 618.6 [M + Na]+.
C24H25ClF3NO11 (595.90): calcd. C 48.37, H 4.23, N 2.35; found
C 48.41, H 4.20, N 2.61.
Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-3,5-dideoxy-4-O-[N-acetyl-
2Ј,3Ј-O-(1-methylethylidene)-cytidinyl]-5-[(trifluoroacetyl)amino]-D-
glycero-D-talo-non-2-enonate (17b):
4072
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4065–4077

4-Substituted Neu5Ac2en Glycals
Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-3,5-dideoxy-4-O-(4-meth-
oxyphenyl)-5-[(trifluoroacetyl)amino]-D-glycero-D-galacto-non-2-en-
COCF3), 143.0 (C-2), 119.0–110.0 (CF3), 109.6 (C-3), 73.8 (C-6),
70.8 (C-8), 67.6 (C-7), 61.9 (C-9), 52.5 (COOCH3), 45.9 (C-5), 42.2
(C-4), 28.7 (SCH2CH3), 20.9, 20.7, 20.5 (3 C, OCOCH3), 15.1
(SCH2CH3) ppm. MS (ESI+): m/z = 530.8 [M + H]+, 552.1 [M +
Na]+. C20H26F3NO10S (529.48): calcd. C 45.37, H 4.95, N 2.65;
found C 45.21, H 5.01, N 2.73.
onate (19a): Glycal 19a (66 mg, 56%) was obtained as a white solid
by the reaction of glycal 4 (105 mg, 0.2 mmol) with 4-chlorophenol
(347 μL), heating for 60 min at 40 °C in CH2Cl2, m.p. 116–118 °C.
1
[α]2D0 = +21.7 (c = 1 in CHCl3). H NMR (CDCl3): δ = 6.93–6.86
(overlapping, 4 H, Ph), 6.66 (d, JNH,5 = 7.9 Hz, 1 H, N-H), 6.10
(d, J3,4 = 2.5 Hz, 1 H, 3-H), 5.43 (dd, J7,6 = 2.1, J7,8 = 4.5 Hz, 1
H, 7-H), 5.35 (ddd, J8,9a = 2.7, J8,7 = 4.5, J8,9b = 7.2 Hz, 1 H, 8-
H), 4.77 (dd, J9a,8 = 2.7, J9a,9b = 12.4 Hz, 1 H, 9a-H), 4.58 (dd, J6,7
= 2.1, J6,5 = 9.7 Hz, 1 H, 6-H), 4.35 (dd, J4,3 = 2.5, J4,5 = 10.1 Hz,
1 H, 4-H), 4.19 (dd, J9b,8 = 7.2, J9b,9a = 12.4 Hz, 1 H, 9b-H), 4.08–
4.01 (m, 1 H, 5-H), 3.81 (s, 3 H, COOCH3), 2.23 (s, 3 H, PhCH3),
2.09 (s, 3 H, OCOCH3), 2.07 (s, 3 H, OCOCH3), 2.05 (s, 3 H,
OCOCH3) ppm. 13C NMR (CDCl3): δ = 170.8, 170.6, 170.2 (3 C,
OCOCH3), 162.2 (C-1), 157.5 (q, JC,F = 38 Hz, COCF3), 151.4
(Ph), 144.2 (C-2), 130.7, 129.5, 128.9, 124.6, 115.2 (5 C, Ph), 119.0–
105.5 (CF3), 113.4 (C-3), 76.9 (C-6), 71.5 (C-8), 68.2 (C-7), 62.3
(C-9), 52.4 (COOCH3), 51.0 (C-5), 37.2 (C-4), 20.9 (PhCH3), 20.7,
20.5 (3 C, CH3COO) ppm. MS (ESI+): m/z = 592.5 [M + H]+,
514.5 [M + Na]+. C25H28F3NO12 (575.49): calcd. C 50.18, H 4.90,
N 2.43; found C 50.11, H 4.84, N 2.39.
Method 2: Glycals 20a and 20b were also obtained by treating glyc-
al 4 (105 mg, 0.2 mmol) in CH2Cl2 (1.5 mL) with EtSH (148 μL)
and BF3·Et2O (25 μL, 0.2 mmol), at 25 °C for 48 h. After this time,
the starting glycal had completely disappeared, and after general
work-up, 1H NMR spectroscopic analysis of the crude product
showed a mixture of the major regioisomers as a pair of dia-
stereomers (i.e., 20a and 20b; α/β, 2.3:1) and of their parent sialos-
ides, the minor regioisomers, as a pair of diastereomers (i.e., 28a
and 28b; α/β, 2.3:1). The crude mixture of thioglycoside 28a, 28b,
30a, and 30b showed: MS (ESI+): m/z = 530.6 [M + H]+, 552.8 [M
+ Na]+.
i) Flash chromatography, eluting with hexane/EtOAc (80:20 v/v),
first gave less polar glycal 20b as an inseparable mixture together
with parent sialosides 28a and 28b (46 mg, 43%; based on 1H
NMR spectroscopy), then more polar glycal 20a (39 mg, 37%), in
pure form, as a white solid.
Data for Glycal 20a: MS (ESI+): m/z = 530.5 [M + H]+, 552.2 [M
+ Na]+. C20H26F3NO10S (529.48): calcd. C 45.37, H 4.95, N 2.65;
found C 45.45, H 5.01, N 2.74. All other physico-chemical proper-
ties were practically identical to those previously reported.
Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-3,5-dideoxy-4-S-ethyl-4-
thio-5-[(trifluoroacetyl)amino]-
D-glycero-D-galacto-non-2-enonate
(20a) and Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-3,5-dideoxy-4-S-
ethyl-4-thio-5-[(trifluoroacetyl)amino]-
ate (20b)
D-glycero-D-talo-non-2-enon-
ii) Alternatively, on heating the reaction mixture of thioglycosides
28a, 28b, 30a, and 30b for 15 min at 40 °C in CH2Cl2, a mixture of
glycals 20a and 20b was obtained that, after flash chromatography,
eluting with hexane/EtOAc (80:20 v/v), gave less polar glycal 20b
(27 mg, 26%), followed by more polar glycal 20a (55 mg, 54%),
both in pure form.
Method 1: Starting from glycal 4 (105 mg, 0.2 mmol) and EtSH
(148 μL), and heating for 15 min at 40 °C in CH2Cl2, a mixture of
glycals 20a and 20b was obtained. This mixture was separated by
flash chromatography, eluting with hexane/EtOAc (80:20 v/v), to
give less polar glycal 20b (30 mg, 28%), followed by more polar
glycal 20a (60 mg, 57%), both in pure form.
Data for Glycal 20a: MS (ESI+): m/z = 530.3 [M + H]+, 552.26 [M
+ Na]+. C20H26F3NO10S (529.48): calcd. C 45.37, H 4.95, N 2.65;
found C 45.40, H 4.87, N 2.60.
Data for Glycal 20a: M.p. 121–123 °C. [α]2D0 = +33.5 (c = 1 in
CHCl3). H NMR (CDCl3): δ = 6.70 (d, JNH,5 = 9.0 Hz, 1 H, N-
1
H), 6.13 (d, J3,4 = 3.0 Hz, 1 H, 3-H), 5.45 (dd, J7,6 = 2.8, J7,8
=
Data for Glycal 20b: MS (ESI+): m/z = 530.0 [M + H]+, 552.23 [M
+ Na]+. C20H26F3NO10S (529.48): calcd. C 45.37, H 4.95, N 2.65;
found C 45.45, H 4.99, N 2.62. All other physico-chemical proper-
ties were practically identical to those previously reported.
5.6 Hz, 1 H, 7-H), 5.37 (ddd, J8,9a = 2.9, J8,7 = 5.6, J8,9b = 6.3 Hz,
1 H, 8-H), 4.63 (dd, J9a,8 = 2.9, J9a,9b = 12.4 Hz, 1 H, 9a-H), 4.39
(dd, J6,7 = 2.8, J6,5 = 6.4 Hz, 1 H, 6-H), 4.19 (dd, J9b,8 = 6.3,
J9b,9a = 12.4 Hz, 1 H, 9b-H), 4.02–3.94 (m, 1 H, 5-H), 3.81 (s, 3 H,
COOCH3), 3.70 (dd, J4,3 = 3.0, J4,5 = 9.0 Hz, 1 H, 4-H), 2.64–2.55
(overlapping, 2 H, SCH2CH3), 2.14 (s, 3 H, OCOCH3), 2.07 (s, 3
H, OCOCH3), 2.05 (s, 3 H, OCOCH3), 1.25 (t, JCH3,CH2S = 7.4 Hz,
3 H, SCH2CH3) ppm. 13C NMR (CDCl3): δ = 170.6, 170.3, 170.0
(3 C, OCOCH3), 161.6 (C-1), 157.4 (q, JC,F = 38 Hz, COCF2),
144.0 (C-2), 119.0–110.0 (CF3), 112.1 (C-3), 75.7 (C-6), 70.4 (C-8),
68.0 (C-7), 61.8 (C-9), 52.5 (COOCH3), 49.0 (C-5), 42.1 (C-4), 23.9
(SCH2CH3), 20.8, 20.6 (3 C, OCOCH3), 14.5 (SCH2CH3) ppm. MS
(ESI+): m/z = 530.6 [M + H]+, 552.5 [M + Na]+. C20H26F3NO10S
(529.48): calcd. C 45.37, H 4.95, N 2.65; found C 45.51, H 5.05, N
2.77.
Methyl
7,8,9-Tri-O-acetyl-2,6-anhydro-3,5-dideoxy-4-S-octyl-4-
-glycero- -galacto-non-2-enonate
thio-5-[(trifluoroacetyl)amino]-
D
D
(21a): Glycal 21a (75 mg, 61%) was obtained as a white solid by
the reaction of glycal 4 (105 mg, 0.2 mmol) with 1-octanethiol
(347 μL), heating for 30 min at 40 °C in CH2Cl2, m.p. 109–111 °C.
[α]2D0 = +46.1 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 6.86 (d,
JNH,5 = 9.1 Hz, 1 H, N-H), 6.11 (d, J3,4 = 2.9 Hz, 1 H, 3-H), 5.45
(dd, J7,6 = 2.6, J7,8 = 5.2 Hz, 1 H, 7-H), 5.33 (ddd, J8,9a = 2.9, J8,7
= 5.2, J8,9b = 6.7 Hz, 1 H, 8-H), 4.67 (dd, J9a,8 = 2.9, J9a,9b
=
12.4 Hz, 1 H, 9a-H), 4.37 (dd, J6,7 = 2.6, J6,5 = 9.3 Hz, 1 H, 6-H),
4.17 (dd, J9b,8 = 6.7, J9b,9a = 12.4 Hz, 1 H, 9b-H), 4.00–3.95 (m, 1
H, 5-H), 3.81 (s, 3 H, COOCH3), 3.66 (dd, J4,3 = 2.9, J4,5 = 9.3 Hz,
1 H, 4-H), 2.60–2.47 [overlapping, 2 H, SCH2(CH2)6CH3], 2.13 (s,
3 H, OCOCH3), 2.06 (s, 3 H, OCOCH3), 2.04 (s, 3 H, OCOCH3),
1.58–1.50 [overlapping, 2 H, SCH2CH2(CH2)5CH3], 1.38–1.22
Data for Glycal 20b: M.p. 133–135 °C. [α]2D0 = –29.9 (c = 1 in
1
CHCl3). H NMR (CDCl3): δ = 6.85 (d, JNH,5 = 10.0 Hz, 1 H, N-
H), 6.20 (d, J3,4 = 5.4 Hz, 1 H, 3-H), 5.46 (dd, J7,6 = 2.8, J7,8
=
5.0 Hz, 1 H, 7-H), 5.32 (ddd, J8,9a = 3.0, J8,7 = 5.0, J8,9b = 6.7 Hz,
1 H, 8-H), 4.65 (dd, J9a,8 = 3.0, J9a,9b = 12.4 Hz, 1 H, 9a-H), 4.62– [overlapping, 10 H, SCH2CH2(CH2)5CH3], 0.87 [t, JCH3,CH2(CH2)6S
4.56 (m, 1 H, 5-H), 4.19–4.13 (overlapping, 2 H, 9b-H and 6-H),
3.80 (s, 3 H, COOCH3), 3.54 (dd, J4,3 = J4,5 = 5.4 Hz, 1 H, 4-H),
2.67–2.54 (overlapping, 2 H, SCH2CH3), 2.10 (s, 3 H, OCOCH3),
= 7.4 Hz, 3 H, S(CH2)7CH3] ppm. 13C NMR (CDCl3): δ = 170.8,
170.3, 170.2 (3 C, OCOCH3), 161.6 (C-1), 157.4 (q, JC,F = 38 Hz,
COCF3), 144.0 (C-2), 119.0–110.0 (CF3), 112.4 (C-3), 75.9 (C-6),
2.08 (s, 3 H, OCOCH3), 2.06 (s, 3 H, OCOCH3) 1.29 (t, JCH3,CH2S 70.7 (C-8), 68.0 (C-7), 61.9 (C-9), 52.5 (COOCH3), 48.7 (C-5), 42.4
= 7.4 Hz, 3 H, SCH2CH3) ppm. 13C NMR (CDCl3): δ = 170.6, (C-4), 31.8 [SCH2(CH2)6CH3], 29.6, 29.4, 29.1, 28.8, 22.6 [6 C,
170.1, 169.7 (3 C, OCOCH3), 161.6 (C-1), 156.8 (q, JC,F = 38 Hz,
SCH2(CH2)6CH3], 20.8, 20.6, (3 C, OCOCH3), 14.0 [S(CH2)7CH3]
4073
Eur. J. Org. Chem. 2013, 4065–4077
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

P. Allevi, P. Rota, I. S. Agnolin, A. Gregorio, M. Anastasia
FULL PAPER
ppm. MS (ESI+): m/z = 614.5 [M + H]+, 636.6 [M + Na]+.
C26H38F3NO10S (613.64): calcd. C 50.89, H 6.24, N 2.28; found C
50.01, H 6.13, N 2.17.
JCHb,CHa = 14.4 Hz, 1 H, SCH2bCH), 2.14 (s, 3 H, OCOCH3), 2.10
(overlapping, 6 H, 2 OCOCH3), 2.05 (s, 3 H, OCOCH3) ppm. 13C
NMR (CDCl3): δ = 170.8 (NHCOCH3), 170.7 (COOMe), 170.7,
170.3, 169.8 (3 C, OCOCH3), 167.7 (C-1), 157.4 (q, JC,F = 38 Hz,
COCF3), 130.1 (C-4), 126.4 (C-3), 119.0–110.0 (CF3), 84.2 (C-2),
70.6 (C-6), 70.2 (C-8), 68.4 (C-7), 62.4 (C-9), 53.3 (CHCOOCH3),
52.8 (COOCH3), 51.2 (CHCOOCH3), 43.3 (C-5), 33.6 (SCH2CH),
23.0 (CH3CONH), 21.0, 20.7, 20.5 (3 C, OCOCH3) ppm. MS
(ESI+): m/z = 645.5 [M + H]+, 667.5 [M + Na]+. C24H31F3N2O13S
(644.57): calcd. C 44.72, H 4.85, N 4.35; found C 44.15, H 4.32, N
4.09.
Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-3,5-dideoxy-4-S-phenyl-4-
thio-5-[(trifluoroacetyl)amino]-
(22a) and Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-3,5-dideoxy-4-S-
phenyl-4-thio-5-[(trifluoroacetyl)amino]- -glycero- -talo-non-2-en-
D-glycero-D-galacto-non-2-enonate
D
D
onate (22b): Starting from glycal 4 (105 mg, 0.2 mmol) and PhSH
(205 μL), after heating for 15 min at 40 °C in CH2Cl2, a mixture
of glycals 22a and 22b was obtained. This was separated by flash
chromatography, eluting with hexane/EtOAc (80:20 v/v), to give
less polar glycal 22b (16 mg, 14%), followed by more polar glycal
22a (81 mg, 70%), both in pure form.
Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-3,4,5-trideoxy-5-[(tri-
fluoroacetyl)amino]-D-glycero-D-galacto-non-3-enonate (24a): Cyclic
ether 24a (81 mg, 86%) was obtained as a white solid by the reac-
tion of glycal 4 (105 mg, 0.2 mmol) with triethylsilane (319 μL),
heating for 15 min at 40 °C in CH2Cl2, m.p. 108–110 °C (CH2Cl2/
diisopropyl ether). [α]2D0 = +34.2 (c = 1 in CHCl3). 1H NMR
Data for Glycal 22a: M.p. 111–112 °C. [α]2D0 = +44.1 (c = 1 in
CHCl3). 1H NMR (CDCl3): δ = 7.51–7.46 (overlapping, 2 H, SPh),
7.35–7.29 (overlapping, 3 H, SPh), 7.12 (d, JNH,5 = 9.1 Hz, 1 H,
N-H), 6.15 (d, J3,4 = 2.7 Hz, 1 H, 3-H), 5.36 (dd, J7,6 = 1.8, J7,8
=
(CDCl3): δ = 6.89 (d, JNH,5 = 8.6 Hz, 1 H, N-H), 6.04 (ddd, J3,5
J3,2 = 2.2, J3,4 = 10.3 Hz, 1 H, 3-H), 5.82 (ddd, J4,5 = J4,2 = 2.5,
J4,3 = 10.3 Hz, 1 H, 4-H), 5.41 (ddd, J8,9a = 2.3, J8,7 = J8,9b
=
5.1 Hz, 1 H, 7-H), 5.24 (ddd, J8,9a = 2.6, J8,7 = 5.1, J8,9b = 7.0 Hz,
1 H, 8-H), 4.68 (dd, J9a,8 = 2.6, J9a,9b = 12.4 Hz, 1 H, 9a-H), 4.32
(dd, J6,7 = 1.8, J6,5 = 10.0 Hz, 1 H, 6-H), 4.12 (dd, J9b,8 = 7.0, J9b,9a
= 12.4 Hz, 1 H, 9b-H), 4.02 (dd, J4,3 = 2.7, J4,5 = 9.6 Hz, 1 H, 4-
H), 3.94–3.87 (m, 1 H, 5-H), 3.76 (s, 3 H, COOCH3), 2.07 (s, 3 H,
OCOCH3), 2.02 (overlapping, 6 H, 2 OCOCH3) ppm. 13C NMR
(CDCl3): δ = 170.9, 170.4 (3 C, OCOCH3), 161.6 (C-1), 157.4 (q,
JC,F = 38 Hz, COCF3), 144.1 (C-2), 134.7, 129.2, 129.0 (6 C, SPh),
119.0–110.0 (CF3), 111.8 (C-3), 75.6 (C-6), 70.9 (C-8), 67.8 (C-7),
61.9 (C-9), 52.5 (COOCH3), 48.9 (C-4), 46.0 (C-5), 20.8, 20.6 (3 C,
OCOCH3) ppm. MS (ESI+): m/z = 578.3 [M + H]+, 600.5 [M +
Na]+. C24H26F3NO10S (577.52): calcd. C 49.91, H 4.54, N 2.43;
found C 50.07, H 4.63, N 2.53.
=
6.2 Hz, 1 H, 8-H), 5.25 (dd, J7,6 = 2.0, J7,8 = 6.2 Hz, 1 H, 7-H),
4.82–4.78 (m, 1 H, 2-H), 4.50 (dd, J9a,8 = 2.3, J9a,9b = 12.5 Hz, 1
H, 9a-H), 4.45–4.39 (m, 1 H, 5-H), 4.21 (dd, J9b,8 = 6.2, J9b,9a
=
12.5 Hz, 1 H, 9b-H), 3.92 (dd, J6,7 = 2.0, J6,5 = 9.3 Hz, 1 H, 6-H),
3.77 (s, 3 H, COOCH3), 2.13 (s, 3 H, OCOCH3), 2.07 (s, 3 H,
OCOCH3), 2.02 (s, 3 H, OCOCH3) ppm. 13C NMR (CDCl3): δ =
170.6, 170.1 (3 C, OCOCH3), 168.4 (C-1), 157.1 (q, JC,F = 38 Hz,
COCF3), 127.6 (C-4), 126.3 (C-3), 119.0–110.0 (CF3), 74.8 (C-2),
73.8 (C-6), 70.1 (C-8), 68.4 (C-7), 62.3 (C-9), 52.6 (COOCH3), 44.6
(C-5), 20.8, 20.6 (3 C, OCOCH3) ppm. MS (ESI+): m/z = 470.4 [M
+ H]+, 492.3 [M + Na]+. C18H22F3NO10 (469.36): calcd. C 46.06,
H 4.72, N 2.98; found C 46.18, H 4.22, N 3.00.
Data for Glycal 22b: M.p. 144–146 °C. [α]2D0 = –35.3 (c = 1 in
CHCl3). 1H NMR (CDCl3): δ = 7.41–7.28 (5 H, overlapping, SPh),
6.71 (d, JNH,5 = 10.1 Hz, 1 H, N-H), 6.30 (d, J3,4 = 5.6 Hz, 1 H,
3-H), 5.47 (dd, J7,6 = 2.6, J7,8 = 5.1 Hz, 1 H, 7-H), 5.33 (ddd, J8,9a
= 3.0, J8,7 = 5.1, J8,9b = 6.7 Hz, 1 H, 8-H), 4.68–4.62 (overlapping,
2 H, 9a-H and 5-H), 4.31 (dd, J6,7 = 2.6, J6,5 = 9.8 Hz, 1 H, 6-H),
4.19–4.12 (overlapping, 2 H, 9b-H and 4-H), 3.81 (s, 3 H, CO-
OCH3), 2.08 (s, 3 H, OCOCH3), 2.06 (s, 3 H, OCOCH3), 2.05 (s,
3 H, OCOCH3) ppm. 13C NMR (CDCl3): δ = 170.6, 170.1, 169.7
(3 C, OCOCH3), 161.5 (C-1), 157.0 (q, JC,F = 38 Hz, COCF3),
144.0 (C-2), 130.9, 129.8, 128.3 (6 C, SPh), 119.0–105.0 (CF3),
108.3 (C-3), 73.6 (C-6), 70.8 (C-8), 67.5 (C-7), 61.9 (C-9), 52.6 (CO-
OCH3), 46.7 (C-5), 45.8 (C-4), 20.9, 20.7, 20.5 (3 C, OCOCH3)
ppm. MS (ESI+): m/z = 578.2 [M + H]+, 600.5 [M + Na]+.
C24H26F3NO10S (577.52): calcd. C 49.91, H 4.54, N 2.43; found C
49.52, H 4.41, N 2.33.
Methyl
[(trifluoroacetyl)amino]-
and Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-4-chloro-3,4,5-trideoxy-
5-[(trifluoroacetyl)amino]- -glycero- -talo-non-2-enonate (25b):
7,8,9-Tri-O-acetyl-2,6-anhydro-4-chloro-3,4,5-trideoxy-5-
D
-glycero- -galacto-non-2-enonate (25a)
D
D
D
Starting from glycal 4 (105 mg, 0.2 mmol) and TMSCl (254 μL,
2.0 mmol), heating for 15 min at 40 °C in CH2Cl2, a mixture of
glycals 25b and 25a was obtained. This was separated by rapid
chromatography, eluting with hexane/EtOAc (80:20 v/v), to give
less polar glycal 25b (55 mg, 19.5%), followed by more polar glycal
25a (18 mg, 58.5%), both in pure form.
Data for Glycal 25a: M.p. 115–117 °C (CH2Cl2/diisopropyl ether).
[α]2D0 = +51.2 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 7.18 (d,
JNH,5 = 8.6 Hz, 1 H, N-H), 6.07 (d, J3,4 = 2.5 Hz, 1 H, 3-H), 5.39
(dd, J7,6 = 1.6, J7,8 = 5.6 Hz, 1 H, 7-H), 5.31 (ddd, J8,9a = 2.6, J8,7
= J8,9b = 6.0 Hz, 1 H, 8-H), 4.99 (dd, J4,3 = 2.5, J4,5 = 8.9 Hz, 1
H, 4-H), 4.65 (dd, J9a,8 = 2.6, J9a,9b = 12.5 Hz, 1 H, 9a-H), 4.53
(dd, J6,7 = 1.6, J6,5 = 10.4 Hz, 1 H, 6-H), 4.18 (dd, J9b,8 = 6.0,
J9b,9a = 12.5 Hz, 1 H, 9b-H), 4.07–4.00 (m, 1 H, 5-H), 3.82 (s, 3 H,
COOCH3), 2.15 (s, 3 H, OCOCH3), 2.06 (s, 3 H, OCOCH3), 2.04
(s, 3 H, OCO CH3), ppm. 13C NMR (CDCl3): δ = 170.8, 170.5,
170.2 (3 C, OCOCH3), 161.2 (C-1), 157.5 (q, JC,F = 38 Hz,
COCF3), 144.3 (C-2), 119.0–110.0 (CF3), 110.1 (C-3), 75.3 (C-6),
70.4 (C-8), 67.6 (C-7), 61.7 (C-9), 52.9 (C-4), 52.7 (COOCH3), 52.5
(C-5), 20.8, 20.6 (3 C, OCOCH3) ppm. MS (ESI+): m/z = 504.7 [M
+ H]+, 526.7 [M + Na]+. C18H21ClF3NO10 (503.81): calcd. C 42.91,
H 4.20, N 2.78; found C 42.11, H 4.01, N 2.47.
Methyl 2-(S-2-Acetylamino-2-methoxycarbonylethyl)-7,8,9-tri-O-
acetyl-3,4,5-trideoxy-5-[(trifluoroacetyl)amino]-2-thio-α-D-manno-
non-3-en-2-ulopyranosidonate (23a): Thioglycoside 23a (102 mg,
79%) was obtained as a white solid by the reaction of glycal 4
(105 mg, 0.2 mmol) with N-acetyl-l-cysteine methyl ester (71 mg,
0.4 mmol), heating for 60 min at 40 °C in CH2Cl2, m.p. 141–143 °C
(CH2Cl2/diisopropyl ether). [α]2D0 = +19.4 (c = 1 in CHCl3). 1H
NMR (CDCl3): δ = 7.81 (d, JNH,5 = 9.1 Hz, 1 H, 1 H, N-H), 6.37–
6.29 (overlapping, 2 H, 3-H and CHNHAc), 5.91 (dd, J4,5 = 2.0,
J4,3 = 10.2 Hz, 1 H, 4-H), 5.33–5.28 (overlapping, 2 H, 7-H and 8-
H), 4.94 (ddd, JCH,CH2a = 3.7, JCH,CH2b = JCH,NH = 9.6 Hz, 1 H,
CH2CHNHAc), 4.75–4.69 (m, 1 H, 5-H), 4.55 (dd, J9a,8 = 2.3,
J9a,9b = 12.5 Hz, 1 H, 9a-H), 4.48 (dd, J6,7 = 1.8, J6,5 = 10.0 Hz, 1
H, 6-H), 4.19 (dd, J9b,8 = 6.2, J9b,9a = 12.5 Hz, 1 H, 9b-H), 3.84 (s,
Data for Glycal 25b: M.p. 109–111 °C (CH2Cl2/diisopropyl ether).
[α]2D0 = –19.3 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 6.71 (d,
3 H, COOCH3), 3.78 (s, 3 H, COOCH3), 3.28 (dd, JCHa,CH = 3.7, JNH,5 = 9.6 Hz, 1 H, N-H), 6.23 (d, J3,4 = 5.6 Hz, 1 H, 3-H), 5.47
JCHa,CHb = 14.4 Hz, 1 H, SCH2aCH), 2.84 (dd, JCHb,CH = 9.6, (dd, J7,6 = 2.1, J7,8 = 5.4 Hz, 1 H, 7-H), 5.36 (ddd, J8,9a = 2.8, J8,7
4074
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4065–4077

4-Substituted Neu5Ac2en Glycals
= 5.4, J8,9b = 6.4 Hz, 1 H, 8-H), 4.74 (dd, J4,5 = 4.0, J4,3 = 5.6 Hz,
ppm. MS (ESI+): m/z = 645.6 [M + H]+, 668.5 [M + Na]+.
1 H, 4-H), 4.73–4.67 (m, 1 H, 5-H), 4.66 (dd, J9a,8 = 2.8, J9a,9b
=
C24H31F3N2O13S (644.57): calcd. C 44.72, H 4.85, N 4.35; found
12.5 Hz, 1 H, 9a-H), 4.52 (dd, J6,7 = 2.1, J6,5 = 10.0 Hz, 1 H, 6- C 45.31, H 4.78, N 4.37.
H), 4.15 (dd, J9b,8 = 6.4, J9b,9a = 12.5 Hz, 1 H, 9b-H), 3.83 (s, 3 H,
Data for Glycal 27b: M.p. 156–158 °C (CH2Cl2/diisopropyl ether).
COOCH3), 2.10 (s, 3 H, OCOCH3), 2.09 (s, 3 H, OCOCH3), 2.06
(s, 3 H, OCOCH3) ppm. 13C NMR (CDCl3): δ = 170.6, 170.1, 169.6
(3 C, OCOCH3), 161.2 (C-1), 157.0 (q, JC,F = 38 Hz, COCF3),
145.3 (C-2), 119.0–110.0 (CF3), 107.8 (C-3), 72.6 (C-6), 70.7 (C-8),
67.2 (C-7), 61.8 (C-9), 53.8 (C-4), 52.8 (COOCH3), 46.4 (C-5), 20.8,
20.7, 20.5 (3 C, OCOCH3) ppm. MS (ESI+): m/z = 504.8 [M +
H]+, 526.7 [M + Na]+. C18H21ClF3NO10 (503.81): calcd. C 42.91,
H 4.20, N 2.78; found C 42.01, H 3.98, N 2.42.
[α]2D0 = –38.1 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 7.75 (d,
JNH,5 = 9.6 Hz, 1 H, N-H), 6.33 (d, JNH,CH = 7.6 Hz, 1 H,
CHNHAc), 6.10 (d, J3,4 = 5.3 Hz, 1 H, 3-H), 5.48 (dd, J7,6 = 2.8,
J7,8 = 4.8 Hz, 1 H, 7-H), 5.35 (ddd, J8,9a = 3.1, J8,7 = 4.8, J8,9b
=
6.9 Hz, 1 H, 8-H), 4.84 (ddd, JCH,CH2a = 4.9, JCH,CH2b = 6.3,
JCH,NH = 7.6 Hz, 1 H, CH2CHNHAc), 4.66–4.58 (overlapping, 2
H, 9a-H and 5-H), 4.26 (dd, J6,7 = 2.8, J6,5 = 9.7 Hz, 1 H, 6-H),
4.17 (dd, J9b,8 = 6.9, J9b,9a = 12.4 Hz, 1 H, 9b-H), 3.80 (overlap-
ping, 6 H, 2 COOCH3), 3.66 (dd, J4,3 = J4,5 = 5.3 Hz, 1 H, 4-H),
3.14 (dd, JCH2a,CH = 4.8, JCH2a,CH2b = 14.1 Hz, 1 H, SCH2aCH),
2.97 (dd, JCHb,CH = 6.3, JCHb,CHa = 14.1 Hz, 1 H, SCH2bCH), 2.09
(s, 3 H, OCOCH3), 2.08 (s, 3 H, OCOCH3), 2.07 (s, 3 H, OC-
OCH3), 2.06 (s, 3 H, NHCOCH3) ppm. 13C NMR (CDCl3): δ =
170.6 (2 C, NHCOCH3 and COOMe), 170.4, 170.1, 169.7 (3 C,
OCOCH3), 161.5 (C-1), 157.4 (q, JC,F = 38 Hz, COCF3), 143.4 (C-
2), 119.0–110.0 (CF3), 108.4 (C-3), 73.5 (C-6), 70.7 (C-8), 67.8 (C-
7), 61.9 (C-9), 53.0 (CHCOOCH3), 52.6 (COOCH3), 52.4
(CHCOOCH3), 46.4 (C-5), 44.0 (C-4), 36.9 (SCH2CH), 23.0
(NHCOCH3), 20.9, 20.7, 20.5 (3 C, OCOCH3) ppm. MS (ESI+):
m/z = 645.6 [M + H]+, 668.5 [M + Na]+. C24H31F3N2O13S (644.57):
calcd. C 44.72, H 4.85, N 4.35; found C 45.05, H 4.44, N 4.02.
Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-4-bromo-3,4,5-trideoxy-5-
[(trifluoroacetyl)amino]-D-glycero-D-talo-non-2-enonate (26b): Glyc-
al 26b (80 mg, 73%) was obtained as a white solid by the reaction
of glycal 4 (105 mg, 0.2 mmol) with bromotrimethylsilane (319 μL),
heating for 30 min at 40 °C in CH2Cl2, m.p. 103–105 °C (CH2Cl2/
diisopropyl ether). [α]2D0 = –23.4 (c = 1 in CHCl3). 1H NMR
(CDCl3): δ = 6.75 (d, JNH,5 = 9.6 Hz, 1 H, N-H), 6.31 (d, J3,4
=
5.9 Hz, 1 H, 3-H), 5.47 (dd, J7,6 = 2.0, J7,8 = 6.0 Hz, 1 H, 7-H),
5.37 (ddd, J8,9a = 2.6, J8,7 = J8,9b = 6.0 Hz, 1 H, 8-H), 4.91 (dd,
J4,5 = 4.0, J4,3 = 5.9 Hz, 1 H, 4-H), 4.69–4.61 (overlapping, 2 H,
9a-H and 6-H), 4.55–4.49 (m, 1 H, 5-H), 4.15 (dd, J9b,8 = 6.0,
J9b,9a = 12.5 Hz, 1 H, 9b-H), 3.82 (s, 3 H, COOCH3), 2.10 (s, 3 H,
OCOCH3), 2.09 (s, 3 H, OCOCH3), 2.06 (s, 3 H, OCOCH3) ppm.
13C NMR (CDCl3): δ = 170.7, 170.1, 169.6 (3 C, OCOCH3), 161.1
(C-1), 157.0 (q, JC,F = 38 Hz, COCF3), 144.7 (C-2), 119.0–110.0
(CF3), 109.1 (C-3), 73.4 (C-6), 70.7 (C-8), 67.3 (C-7), 61.9 (C-9),
52.8 (COOCH3), 47.2 (C-4), 45.8 (C-5), 20.8, 20.7, 20.5 (3 C, O
COCH3) ppm. MS (ESI+): m/z = 549.3 [M + H]+, 571.2 [M +
Na]+. C18H21BrF3NO10 (548.26): calcd. C 39.43, H 3.86, N 2.55;
found C 38.88, H 3.56, N 2.31.
Dimethyl
amino]-α-
7,8,9-tri-O-acetyl-3,4,5-trideoxy-5-[(trifluoroacetyl)-
D-manno-non-3-en-2-ulopyranosidonate (30a) and Di-
methyl 7,8,9-tri-O-acetyl-3,4,5-trideoxy-5-[(trifluoroacetyl)amino]-
α- -manno-non-3-en-2-ulopyranosidonate (30b)
D
Method 1: Methyl ketoside 29b (90 mg, 0.2 mmol), obtained ac-
cording to the procedure of Ikeda et al.,[19] was N-transacylated in
CH3CN (0.6 mL) with TFAA (142 μL, 1.0 mmol) containing Et3N
(306 μL, 2.2 mmol)[16] to give sialoside 30b (75 mg, 61%) in pure
form as a white solid, m.p. 111–112 °C (CH2Cl2/diisopropyl ether).
[α]2D0 = –36.1 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 5.95 (d,
JNH,5 = 9.0 Hz, 1 H, N-H), 5.93 (dd, J4,5 = 2.5, J4,3 = 10.1 Hz, 1
H, 3-H), 5.91 (dd, J4,5 = 1.7, J4,3 = 10.1 Hz, 1 H, 4-H), 5.35–5.30
(overlapping, 2 H, 7-H and 8-H), 4.58–4.52 (overlapping, 2 H, 9a-
H and 5-H), 4.24 (dd, J9b,8 = 5.3, J9b,9a = 12.5 Hz, 1 H, 9b-H),
4.19 (dd, J6,7 = 2.0, J6,5 = 10.3 Hz, 1 H, 6-H), 3.81 (s, 3 H, CO-
OCH3), 3.29 (s, 3 H, OCH3), 2.15 (s, 3 H, OCOCH3), 2.09 (s, 3 H,
OCOCH3), 2.04 (s, 3 H, OCOCH3) ppm. 13C NMR (CDCl3): δ =
Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-3,5-dideoxy-4-S-(S-2-acet-
ylamino-2-methoxycarbonylethyl)-4-thio-5-[(trifluoroacetyl)amino]-
D
-glycero-
acetyl-2,6-anhydro-3,5-dideoxy-4-S-(S-2-acetylamino-2-methoxy-
carbonylethyl)-4-thio-5-[(trifluoroacetyl)amino]- -glycero- -talo-
D-galacto-non-2-enonate (27a) and Methyl 7,8,9-Tri-O-
D
D
non-2-enonate (27b): Starting from glycal 23a (50 mg, 0.08 mmol)
in CH2Cl2, and treating with BF3·Et2O (492 μL, 4.0 mmol) for 2 h
at 40 °C, a mixture of glycals 27b and 27a was obtained. It was
separated by flash chromatography, eluting with hexane/EtOAc
(50:50 v/v), to give less polar glycal 27b (27 mg, 53%), followed by
more polar glycal 27a (14 mg, 27%), both in pure form.
170.6, 170.3, 170.1 (3 C, OCOCH3), 167.2 (C-1), 157.2 (q, JC,F
=
38 Hz, COCF3), 131.3 (C-4), 126.9 (C-3), 119.0–110.0 (CF3), 96.5
(C-2), 70.3 (C-6), 69.3 (C-8), 68.1 (C-7), 62.0 (C-9), 52.9 (CO-
OCH3), 51.1 (OCH3), 44.2 (C-5), 20.8, 20.6, 20.5 (3 C, OCOCH3)
ppm. MS (ESI+): m/z = 500.4 [M + H]+, 522.4 [M + Na]+.
C19H24F3NO11 (499.39): calcd. C 45.70, H 4.84, N 2.80; found C
45.76, H 4.92, N 2.93.
Data for Glycal 27a: M.p. 160–162 °C (CH2Cl2/diisopropyl ether).
1
[α]2D0 = +42.7 (c = 1 in CHCl3). H NMR (CDCl3): δ = 7.68 (br. s,
1 H, N-H), 6.33 (d, JNH,CH = 9.0 Hz, 1 H, CHNHAc), 6.04 (d, J3,4
= 1.8 Hz, 1 H, 3-H), 5.45 (dd, J7,6 = 2.3, J7,8 = 5.9 Hz, 1 H, 7-H),
5.37 (ddd, J8,9a = 2.7, J8,7 = J8,9b = 5.9 Hz, 1 H, 8-H), 4.76 (ddd,
JCH,CHa
= 4.8, JCH,CHb = 7.6 JCH,NH = 9.0 Hz, 1 H,
Method 2: A mixture of methyl ketosides 29a and 29b (1:1.3 ratio;
90 mg, 0.2 mmol), obtained according to the procedure of Ikeda et
al.,[19] was N-transacylated in CH3CN (0.6 mL) with TFAA
(142 μL, 1.0 mmol) containing Et3N (306 μL, 2.2 mmol)[16] to give
an inseparable mixture of glycosides 30a and 30b (1:1.3 ratio;
75 mg, 75%) in pure form as a white solid.
CH2CHNHAc), 4.60–4.53 (overlapping, 2 H, 9a-H and 6-H), 4.18
(dd, J9b,8 = 5.9, J9b,9a = 12.4 Hz, 1 H, 9b-H), 3.89–3.83 (overlap-
ping, 2 H, 5-H and 4-H), 3.82 (s, 3 H, COOCH3), 3.77 (s, 3 H,
COOCH3), 3.03 (dd, JCH2a,CH = 4.8, JCH2a,CH2b = 14.2 Hz, 1 H,
SCH2aCH), 2.84 (dd, JCH2b,CH = 7.6, JCH2b,CH2a = 14.2 Hz, 1 H,
SCH2bCH), 2.13 (s, 3 H, OCOCH3), 2.07 (s, 3 H, OCO CH3), 2.06
1
(s, 3 H, OCOCH3), 2.05 (s, 3 H, NHCOCH3) ppm. 13C NMR Data for Glycoside 30a, Minor Compound: H NMR (CDCl3): δ =
(CDCl3): δ = 170.9 (NHCOCH3), 170.8 (COOMe), 170.7, 170.1, 6.65 (d, JNH,5 = 8.0 Hz, 1 H, N-H), 6.10 (dd, J = 2.0, J = 10.1 Hz,
170.0 (3 C, OCOCH3), 161.6 (C-1), 157.9 (q, JC,F = 38 Hz, 1 H, 3-H or 4-H), 5.91 (dd, J = 2.5, J = 10.1 Hz, 1 H, 3-H or 4-
COCF3), 145.5 (C-2), 119.0–110.0 (CF3), 111.2 (C-3), 75.9 (C-6),
70.2 (C-8), 67.7 (C-7), 61.9 (C-9), 53.0 (CHCOOCH3), 52.6 (CO-
OCH3), 51.9 (CHCOOCH3), 49.9 (C-5), 42.6 (C-4), 31.8
H), 5.44 (ddd, J8,9a = 2.3, J8,9b = 4.9, J8,7 = 7.5 Hz, 1 H, 1 H, 8-
H), 5.27 (dd, J7,6 = 2.0, J7,8 = 7.5 Hz, 1 H, 7-H), 4.45–4.40 (overlap-
ping, 2 H, 9a-H and 6-H), 4.38–4.27 (m, 1 H, 5-H), 4.24 (dd, J9b,8
(SCH2CH), 23.1 (CH3CONH), 20.9, 20.7, 20.6 (3 C, CH3COO) = 4.9, J9b,9a = 12.5 Hz, 1 H, 9b-H), 3.79 (s, 3 H, COOCH3), 3.35
Eur. J. Org. Chem. 2013, 4065–4077
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4075

P. Allevi, P. Rota, I. S. Agnolin, A. Gregorio, M. Anastasia
(s, 3 H, OCH3), 2.14 (s, 3 H, OCOCH3), 2.08 (s, 3 H, OCOCH3), 3), 126.4 (C-4 or C-3), 85.7 (C-2), 71.4 (C-8), 70.7 (C-6), 68.5 (C-
FULL PAPER
2.04 (s, 3 H, OCOCH3) ppm. The NMR signals of compound 30b
were practically identical to those above previously reported. Data
for the mixture of glycosides 30a and 30b: MS (ESI+): m/z = 522.4
[M + Na]+, 1020.5 [M + Na]+. C19H24F3NO11 (499.39): calcd. C
45.70, H 4.84, N 2.80; found C 45.70, H 4.95, N 2.90.
7), 62.5 (C-9), 52.8 (COOCH3), 43.1 (C-5), 24.4 (SCH2CH3), 23.3
(NHCOCH3), 21.0, 20.7 (3 C, OCOCH3), 14.1 (SCH2CH3) ppm.
MS (ESI+): m/z = 476.1 [M + H]+, 498.5 [M + Na]+. C20H29NO10S
(475.51): calcd. C 50.52, H 6.15, N 2.95; found C 50.41, H 6.03, N
2.70.
Data for Thioglycoside 33b: M.p. 120–124 °C. [α]2D0 = –14.1 (c = 1
in CHCl3). H NMR (CDCl3): δ = 5.93 (dd, J = 2.5, J = 10.1 Hz,
Methyl Oxazolo[5,4]-Fused 7,8,9-Tri-O-acetyl-2,3,4,5-tetradeoxy-
1
2,3-didehydro-2,3-trideoxy-4,5-dihydro-2-trifluoromethyl-
D-glycero-
1 H, 3-H or 4-H), 5.86 (dd, J = 1.6, J = 10.1 Hz, 1 H, 3-H or 4-
H), 5.47–5.41 (overlapping, N-H and 8-H), 5.40 (dd, J7,6 = 2.0, J7,8
= 6.3 Hz, 1 H, 7-H), 4.54 (dd, J9a,8 = 2.4, J9a,9b = 12.4 Hz, 1 H,
D
-talo-non-2-enoate (31) and Methyl 7,8,9-Tri-O-acetyl-2,6-anhy-
dro-3,5-diideoxy-5-[(trifluoroacetyl)amino]-
onate (32)
D-glycero-D-talo-non-2-en-
9a-H), 4.48–4.42 (m, 1 H, 5-H), 4.28 (dd, J9b,8 = 5.9, J9b,9a
=
BF3·Et2O Treatment of the Pure Glycoside 29b and of 29a and 29b
Mixture: The reactions were performed separately on sialoside 29b
or on an inseparable mixture of glycosides 29a and 29b (100 mg,
0.2 mmol), dissolved in CH2Cl2 (1.5 mL), using MeOH (81 μL,
2.0 mmol) and BF3·Et2O (246 μL, 2.0 mmol) at 40 °C for 15 min.
Then, the reaction mixtures were worked up:
12.4 Hz, 1 H, 9b-H), 3.94 (dd, J6,7 = 1.9, J6,5 = 9.8 Hz, 1 H, 6-H),
3.76 (s, 3 H, COOCH3), 2.75–2.58 (overlapping, 2 H, SCH2CH3),
2.13 (s, 3 H, OCOCH3), 2.11 (s, 3 H, OCOCH3), 2.05 (s, 3 H,
OCOCH3), 1.97 (s, 3 H, CH3CONH), 1.25 (t, 3 H, SCH2CH3)
ppm. 13C NMR (CDCl3): δ = 170.7 (CH3CONH), 170.5, 170.2,
169.8 (3 C, OCOCH3), 168.8 (C-1), 131.4 (C-4 or C-3), 126.5 (C-4
or C-3), 84.6 (C-2), 74.2 (C-8), 70.4 (C-6), 68.0 (C-7), 62.2 (C-9),
52.9 (COOCH3), 43.2 (C-5), 23.4 (2 C, NHCOCH3 and SCH2CH3),
21.2, 20.8, 20.7 (3 C, OCOCH3), 14.5 (SCH2CH3) ppm. MS (ESI+):
m/z = 476.4 [M + H]+, 498.7 [M + Na]+. C20H29NO10S (475.51):
calcd. C 50.52, H 6.15, N 2.95; found C 50.410, H 6.00, N 2.85.
i) as indicated in the General Remarks to give, after flash
chromatography (EtOAc/hexane, 1:1 v/v), methyl oxazolo[5,4]-
fused 31 (17 mg, 18%) together with compound 32 (31 mg, 58%).
Data for 31: MS (ESI+): m/z = 568.7 [M + H]+, 590.2 [M + Na]+.
C18H20F3NO10 (467.35): calcd. C 46.26, H 4.31, N 3.00; found C
46.32, H 4.40, N 2.92. All other physico-chemical properties were
practically identical to those previously reported.
Next, in separate experiments, methyl ketosides 33a and 33b
(95 mg, 0.2 mmol) were N-transacylated in CH3CN (0.6 mL) with
TFAA (142 μL, 1.0 mmol) containing Et3N (306 μL, 2.2 mmol),[16]
to give thioglycosides 28a (83 mg, 78%) and 28b (85 mg, 81%),
respectively, both in pure form as white solids.
Data for 32: MS (ESI+): m/z = 486.0 [M + H]+, 508.4 [M + Na]+.
C18H22F3NO11 (485.37): calcd. C 44.54, H 4.57, N 2.89; found C
44.08, H 4.20, N 2.70. All other physico-chemical properties were
practically identical to those previously reported.
Data for Thioglycoside 28a: M.p. 119–122 °C. [α]2D0 = –18.1 (c = 1
in CHCl3). 1H NMR (CDCl3): δ = 6.54 (br. s, 1 H, N-H), 6.21 (dd,
ii) by the addition of water and extraction of the mixture with
CH2Cl2 to give, after subsequent washing with ice-cold NaCl (aq.),
drying, and solvent evaporation, a crude residue. Rapid chromatog-
raphy (EtOAc/hexane, 1:1 v/v) gave compound 32 (76 mg, 78%).
MS (ESI+): m/z = 486.4 [M + H]+, 508.7 [M + Na]+, 1194.1 [2M
+ Na]+. MS [ESI]: m/z = 484.1 [M – H]. C18H22F3NO11 (485.37):
calcd. C 44.54, H 4.57, N 2.89; found C 44.11, H 4.23, N 2.76. All
other physico-chemical properties were practically identical to
those previously reported.
J3,5 = 1.5, J3,4 = 10.1 Hz, 1 H, 3-H), 5.78 (dd, J4,5 = 1.1, J4,3
=
10.1 Hz, 1 H, 4-H), 5.31 (dd, J7,6 = 1.3, J7,8 = 6.1 Hz, 1 H, 7-H),
5.30–5.27 (m, 1 H, 8-H), 4.55 (dd, J9a,8 = 2.4, J9a,9b = 12.6 Hz, 1
H, 9a-H), 4.50–4.47 (overlapping, 2 H, 5-H and 6-H), 4.28 (dd,
J9b,8 = 5.5, J9b,9a = 12.6 Hz, 1 H, 9b-H), 3.83 (s, 3 H, COOCH3),
2.68–2.54 (overlapping, 2 H, SCH2CH3), 2.14 (s, 3 H, OCOCH3),
2.11 (s, 3 H, OCOCH3), 2.04 (s, 3 H, OCOCH3), 1.18 (t, JCH3,CH2S
= 7.4 Hz, 3 H, SCH2CH3) ppm. 13C NMR (CDCl3): δ = 170.5,
170.4, 170.2 (3 C, OCOCH3), 167.1 (C-1), 157.1 (q, JC,F = 38 Hz,
COCF3), 128.2 (C-4), 127.7 (C-3), 119.0–110.0 (CF3), 85.9 (C-2),
70.4, (C-6), 69.3 (C-8), 68.3 (C-7), 62.1 (C-9), 53.0 (COOCH3), 44.5
(C-5), 24.6 (SCH2CH3), 21.0, 20.7 (3 C, OCOCH3), 14.0
(SCH2CH3) ppm. MS (ESI+): m/z = 530.4 [M + H]+, 552.5 [M +
Na]+. C20H26F3NO10S (529.48): calcd. C 45.37, H 4.95, N 2.65;
found C 45.31, H 4.90, N 2.60.
Ethyl Methyl 7,8,9-Tri-O-acetyl-3,4,5-trideoxy-2-thio-5-[(trifluoro-
acetyl)amino]-α-
Ethyl Methyl 7,8,9-Tri-O-acetyl-3,4,5-trideoxy-2-thio-5-[(trifluoro-
acetyl)amino]-β- -manno-non-3-en-2-ulopyranosidonate (28b):
D-manno-non-3-en-2-ulopyranosidonate (28a) and
D
A
solution of oxazoline 5 (100 mg, 0.24 mmol) in CH3CN (0.2 mL)
was treated with EtSH (100 μL, 1.4 mmol) and Bi(OTf)3 (5 mg,
0.07 mmol), following the procedure of Ikeda et al.,[19] to give a
mixture of thioglycosides 33a and 33b. This was separated by rapid
chromatography, eluting with hexane/EtOAc (80:20 v/v), to give
less polar thioglycoside 33a (38 mg, 33%), then more polar thio-
glycoside 33b (59 mg, 52%).
1
Data for Thioglycoside 28b: H NMR (CDCl3): δ = 6.56 (d, JNH,5
= 8.5 Hz, 1 H, N-H), 6.07 (dd, J = 2.6, J = 10.1 Hz, 1 H, 3-H or
4-H), 5.93 (dd, J = 1.7, J = 10.1 Hz, 1 H, 3-H or 4-H), 5.47 (ddd,
J8,9a = 2.4, J8,9b = 4.8, J8,7 = 7.3 Hz, 1 H, 8-H), 5.30 (dd, J7,6
1.8, J7,8 = 7.3 Hz, 1 H, 7-H), 4.55 (dd, J9a,8 = 2.4, J9a,9b = 12.6 Hz,
1 H, 9a-H), 4.35–4.29 (overlapping, 2 H, 9b-H and 5-H), 4.11 (dd,
=
Data for Thioglycosides 33a: M.p. 123–124 °C. [α]2D0 = –30.1 (c = 1
1
in CHCl3). H NMR (CDCl3): δ = 6.15 (dd, J = 2.4, J = 10.1 Hz, J6,7 = 1.8, J6,5 = 9.8 Hz, 1 H, 6-H), 3.81 (s, 3 H, COOCH3), 2.79–
1 H, 3-H or 4-H), 5.78 (dd, J = 1.8, J = 10.1 Hz, 1 H, 3-H or 4-
H), 5.44 (d, JNH,5 = 9.6 Hz, 1 H, N-H), 5.40 (dd, J7,6 = 2.4, J7,8
4.9 Hz, 1 H, 7-H), 5.25 (ddd, J8,9a = 2.4, J8,7 = 4.9, J8,9b = 6.8 Hz,
1 H, 8-H), 4.68–4.58 (overlapping, 2 H, 9a-H and 5-H), 4.37 (dd, (3 C, OCOCH3), 168.3 (C-1), 157.1 (q, JC,F = 38 Hz, COCF3),
2.58 (overlapping, 2 H, SCH2CH3), 2.18 (s, 3 H, OCOCH3), 2.16
(s, 3 H, OCOCH3), 2.07 (s, 3 H, OCOCH3), 1.28 (t, JCH3,CH2S
7.4 Hz, 3 H, SCH2CH3) ppm. 13C NMR (CDCl3): δ = 170.7, 170.4
=
=
J6,7 = 2.4, J6,5 = 10.0 Hz, 1 H, 6-H), 4.28 (dd, J9b,8 = 6.8, J9b,9a
12.4 Hz, 1 H, 9b-H), 3.83 (s, 3 H, COOCH3), 2.70–2.55 (overlap-
=
128.8 (C-3 or C-4), 127.7 (C-3 or C-4), 119.0–110.0 (CF3), 84.9 (C-
2), 72.7 (C-6), 69.4 (C-8), 67.9 (C-7), 61.9 (C-9), 53.1 (COOCH3),
44.4 (C-5), 23.5 (SCH2CH3), 21.2, 20.7 (3 C, OCOCH3), 14.5
ping, 2 H, SCH2CH3), 2.13 (s, 3 H, OCOCH3), 2.08 (s, 3 H, OC-
OCH3), 2.03 (s, 3 H, OCOCH3), 1.96 (s, 3 H, CH3CONH), 1.16 (t, (SCH2CH3) ppm. MS (ESI+): m/z = 530.1 [M + H]+, 552.0 [M +
3 H, SCH2CH3) ppm. 13C NMR (CDCl3): δ = 170.5 (CH3CONH),
170.4, 170.2, 169.8 (3 C, OCOCH3), 167.3 (C-1), 130.7 (C-4 or C-
Na]+. C20H26F3NO10S (529.48): calcd. C 45.37, H 4.95, N 2.65;
found C 45.31, H 4.90, N 2.60.
4076
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4065–4077

4-Substituted Neu5Ac2en Glycals
[9] J. C. Wilson, R. J. Thomson, J. C. Dyason, P. Florio, K. J.
Quelch, S. Abo, M. von Itzstein, Tetrahedron: Asymmetry 2000,
11, 53–73.
[10] A. J. Humphrey, C. Fremann, P. Critchley, Y. Malykh, R.
Schauer, T. D. H. Bugg, Bioorg. Med. Chem. 2002, 10, 3175–
3185.
[11] M. von Itzstein, J. C. Dyason, S. W. Oliver, H. F. White, W. Y.
Wu, G. B. Kok, M. S. Pegg, J. Med. Chem. 1996, 39, 388–391.
[12] For a discussion of the less hindered side of the sialoglycals,
see: P. Rota, I. S. Agnolin, P. Allevi, M. Anastasia, Eur. J. Org.
Chem. 2012, 2508–2510.
[13] I. S. Agnolin, P. Rota, P. Allevi, A. Gregorio, M. Anastasia,
Eur. J. Org. Chem. 2012, 6537–6547.
BF3·Et2O Equilibration of Pure Sialosides 28b and of 28a: The reac-
tions were performed separately on starting sialosides 28a and 28b
(105 mg, 0.2 mmol), dissolved in CH2Cl2 (1.5 mL), using EtSH
(148 μL, 2.0 mmol) and BF3·Et2O (246 μL, 2.0 mmol) at 40 °C for
15 min. Then, the reaction mixtures were worked up as indicated
in the General Remarks to give, after flash chromatography eluting
with hexane/EtOAc (80:20 v/v), less polar glycal 20b (28–34 mg,
26–30%), followed by more polar glycal 20a (58–64 mg, 55–60%).
both in pure form.
Data for Glycal 20a: MS (ESI+): m/z = 530.2 [M + H]+, 552.3 [M
+ Na]+. C20H26F3NO10S (529.48): calcd. C 45.37, H 4.95, N 2.65;
found C 45.52, H 5.00, N 2.73. All other physico-chemical proper-
ties were practically identical to those previously reported.
[14] L. I. Krimen, D. J. Cota, J. Donald, The Ritter Reaction, in:
Organic Reactions, John Wiley & Sons, 2011.
[15] A. Marra, P. Sinay, Carbohydr. Res. 1989, 190, 317–322.
[16] P. Rota, P. Allevi, R. Colombo, M. L. Costa, M. Anastasia,
Angew. Chem. 2010, 122, 1894–1897; Angew. Chem. Int. Ed.
2010, 49, 1850–1853.
[17] G. B. Kok, D. R. Groves, M. von Itzstein, Chem. Commun.
1996, 2017–2018.
[18] R. J. Ferrier, O. A. Zubkov, Transformation of Glycals into 2,3-
Unsaturated Glycosyl Derivatives, in: Organic Reactions, John
Wiley & Sons, 2004, pp. 569–736.
Data for Glycal 20b: MS (ESI+): m/z = 530.7 [M + H]+, 552.9 [M
+ Na]+. C20H26F3NO10S (529.48): calcd. C 45.37, H 4.95, N 2.65;
found C 45.30, H 4.83, N 2.60. All other physico-chemical proper-
ties were practically identical to those previously reported.
BF3·Et2O Equilibration of Pure Glycals 20b and 20a: The reactions
were performed separately on the starting sialosides 20a and 20b
(105 mg, 0.2 mmol), dissolved in CH2Cl2 (1.5 mL), using EtSH
(148 μL, 2.0 mmol) and BF3·Et2O (246 μL, 2.0 mmol) at 40 °C for
15 min. Then, the reaction mixtures were worked up as indicated
in the General Remarks to give, after flash chromatography eluting
with hexane/EtOAc (80:20 v/v), only the starting material, un-
changed and in pure form, with all the physico-chemical properties
practically identical to those previously reported.
[19] K. Ikeda, Y. Ueno, S. Kitani, R. Nishino, M. Sato, Synlett
2008, 1027–1030.
[20] D. Ellis, S. E. Norman, H. M. I. Osborn, Tetrahedron 2008, 64,
2832–2854.
[21] W. Priebe, A. Zamojski, Tetrahedron 1980, 36, 289–297.
[22] L. V. Dunkerton, N. K. Adair, J. M. Euske, K. T. Brady, P. D.
Robinson, J. Org. Chem. 1988, 53, 845–850.
Supporting Information (see footnote on the first page of this arti-
[23] P. Nagaraj, N. G. Ramesh, Tetrahedron 2011, 67, 9322–9328.
[24] Zamojski and Priebe[21] suggest a rationalization of their re-
sults on the basis of Pearson’s hard and soft acids and bases
(HSBA) principle. However, a recent review by H. M. Mayer
et al.[25] demonstrates that the HSBA principle is contradicted
by several experiment findings, and appears to be misleading
rather than a useful guide. We avoided any speculation using
the HSBA principle.
[25] H. Mayr, M. Breugst, A. R. Ofial, Angew. Chem. 2011, 123,
6598–6634; Angew. Chem. Int. Ed. 2011, 50, 6470–6505.
[26] The hydride ion (a soft nucleophile; Table 2, entry 19), on the
basis of the HSBA hypothesis, should attack C-4 of the sialic
acid glycal or equilibrate to this, but it appeared to be difficult
for cyclic allyl ether 24a to undergo a rearrangement under our
relatively weakly acidic reaction conditions.
[27] The 2α or 2β stereochemistry of the Ferrier products was as-
signed taking into account the correct assignment of 2α and
2β methyl ketosides 29a and 29b in: J. Maudrin, B. Barrere, B.
Chantegrel, C. Deshayes, G. Quash, A. Doutheau, Bull. Soc.
Chim. Fr. 1994, 131, 400–406, confirmed by K. Ikeda et al.[19]
The assignment of the anomeric configuration was also sup-
ported by the values of the chemical shift difference between
the two protons at C-3 and at C-4 Δδ {3-H–4-H}, which were
around 0.3 ppm for α-glycosides, larger than suggested for β-
glycosides. The assignment was also supported by a compari-
son of the chemical shift values of the proton at C-6, which
was around 4.4 ppm for α-glycosides and around 4.0 ppm for
β-glycosides.
1
cle): H and 13C NMR spectra.
Acknowledgments
The authors gratefully acknowledge Miss Irene Delcarro for her
skilled technical assistance. A part of this work was supported by
the Grant “Dote ricerca” from the Fondo Sociale Europeo (FSE),
Regione Lombardia.
[1] a) J. Magano, Chem. Rev. 2009, 109, 4398–4438; b) H. P. Hsieh,
J. T. A. Hsu, Curr. Pharm. Des. 2007, 13, 3531–3542.
[2] M. C. Mann, T. Islam, J. C. Dyason, P. Florio, C. J. Trower,
R. J. Thomson, M. von Itzstein, Glycoconjugate J. 2006, 23,
127–133.
[3] P. Meindl, H. Tuppy, Hoppe-Seyler’s Z. Physiol. Chem. 1969,
350, 1088–1092.
[4] H. P. Hsieh, J. T. Hsu, Curr. Pharm. Des. 2007, 13, 3531–3542.
[5] S. Kawamura, I. Sato, T. Wada, K. Yamaguchi, Y. Li, D. Li,
X. Zhao, S. Ueno, H. Aoki, T. Tochigi, M. Kuwahara, T. Kita-
mura, K. Takahashi, S. Moriya, T. Miyagi, Cell Death Differ.
2012, 19, 170–179.
[6] L. M. von Itzstein, W. Y. Wu, B. Jin, WO 95/20583, 1995.
[7] M. von Itzstein, W. Y. Wu, G. B. Kok, M. S. Pegg, J. C. Dya-
son, B. Jin, T. Van Phan, M. L. Smythe, H. F. White, S. W. Oli-
ver, P. M. Colman, J. N. Varghese, D. M. Ryan, J. M. Woods,
R. C. Bethell, V. J. Hotham, J. M. Cameron, C. R. Penn, Na-
ture 1993, 363, 418–423.
[28] However, attempts to monitor or isolate possible N-glycoside
intermediates by conducting the reaction of glycals 6a or 6b at
lower temperature (23 °C) were unsuccessful.
[8] P. W. Smith, I. D. Starkey, P. D. Howes, S. L. Sollis, S. P. Keel-
ing, P. C. Cherry, M. von Itzstein, W. Y. Wu, B. Jin, Eur. J.
Med. Chem. 1996, 31, 143–150.
Received: January 29, 2013
Published Online: May 7, 2013
Eur. J. Org. Chem. 2013, 4065–4077
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4077