Simple and rapid procedures for the synthesis of 5-acylated 4β-acylamido-and 4β-acetoxyneuraminic acid glycals

Article abstract of DOI:10.1002/ejoc.201201001

Two simple and rapid procedures affording 4β-acylamido-and 4β-acetoxyneuraminic acid glycals acylated or perfluoroacylated at the 5-amino group are reported. The first protocol avoids the formation of oxazolines to synthesize the 4β-acetamido glycals through the Ritter reaction. The second passes through the oxazoline derivative to prepare 4β-acetoxyneuraminic acid glycals. Both protocols start from peracetylated methyl neuraminate, acylated at the amino group with a normal, a glycolyl, or a perfluoroacyl group, or with the corresponding peracetylated glycal methyl esters (of the DANA or FANA series).

Full text of DOI:10.1002/ejoc.201201001

FULL PAPER
DOI: 10.1002/ejoc.201201001
Simple and Rapid Procedures for the Synthesis of 5-Acylated 4β-Acylamido-
and 4β-Acetoxyneuraminic Acid Glycals
Irene S. Agnolin,[a] Paola Rota,*[a] Pietro Allevi,[a] Antonio Gregorio,[a] and
Mario Anastasia[a]
Keywords: Medicinal chemistry / Synthetic methods / Carbohydrates / Sialic acids / Fluorine / Cell recognition
Two simple and rapid procedures affording 4β-acylamido-
and 4β-acetoxyneuraminic acid glycals acylated or per-
fluoroacylated at the 5-amino group are reported. The first
protocol avoids the formation of oxazolines to synthesize the
4β-acetamido glycals through the Ritter reaction. The second
passes through the oxazoline derivative to prepare 4β-acet-
oxyneuraminic acid glycals. Both protocols start from per-
acetylated methyl neuraminate, acylated at the amino group
with a normal, a glycolyl, or a perfluoroacyl group, or with
the corresponding peracetylated glycal methyl esters (of the
DANA or FANA series).
Introduction
Sialic acids, a family of carbohydrates including N-acet-
ylneuraminic acid (Neu5Ac; 1a), N-glycolylneuraminic acid
(Neu5Gc; 1b), and 3-deoxy-d-glycero-d-galacto-non-2-ulo-
pyranosonic acid (KDN; 1c) as the best known members
(Scheme 1), are involved in several important cellular re-
cognition processes.[1,2] In particular, Neu5Ac (1a) repre-
sents, among other items, the ligand that is recognized in
the host’s cell membrane by various pathogenic organisms
such as bacteria and influenza A and B viruses.[3] Moreover,
terminal Neu5Ac, which is linked to the influenza virus,
can be cleaved by viral sialidases (neuraminidases, NAs),
releasing the newly formed viral particles from the infected
cells, so spreading the infection.[4] Thus, many efforts have
been devoted to the design and synthesis of NA inhibitors
as antiinfluenza drugs. Actually, one of the best of them
is the clinically used Zanamivir[5–7] (4-deoxy-4-guanidino-
Neu5Ac2en; Relenza; 2a), inspired by the 2,3-unsaturated
N-acetylneuraminic acid[5,8] (Neu5Ac2en, DANA; 2b). The
success of the latter NA inhibitor also inspired the synthesis
of perfluorinated congeners as the trifluoroacetylated glycal
of neuraminic acid[9] (FANA) 2c, and the glycal 2d, a per-
fluorinated Zanamivir analogue, both of which were found
to display interesting in vitro antiviral activity against the
influenza A and B virus NAs.[10]
Scheme 1. Structures of some sialic acids and their glycals.
On the other hand, recent reports on the emergence of
drug resistance have highlighted the need for new antiinflu-
enza drugs, and have renewed interest in the chemistry of
functionalized sialic acid glycals.
In a recent paper,[11] we briefly reported a procedure,
starting from peracetylated Neu5Ac methyl ester 3a,[12] that
provides diastereoselective access to 4β-acylamidated
glycals 4a and 4b (Scheme 2, Path A).[11] We temporarily
and reversibly transformed the peracetylated methyl ester
DANA 5a into the N-perfluoroacylated congener 6a.[13–15]
This derivative is used as a sacrificial tool to introduce, in
a stereoselective way, the 4β-acetamido function present in
glycal 7a.[11] In this way, the otherwise concurrent and
dominant formation of the oxazoline 8,[16] derived from at-
tack of the 5N-acetamido group of DANA on the adjacent
allylic carbocation, is avoided and, instead, the Ritter at-
tack[17] of the nitrile solvent occurs (Scheme 2, Path B).
Herein, we detail and noticeably expand our work on the
acetamidation of DANA and FANA glycals, extending the
reaction also to other perfluorinated congeners of FANA
and directly to their parent saturated esters. Moreover, we
also applied the Ritter reaction on some acetylated esters
of Neu5Gc 1b, thus completing the picture of the behavior
of the three sialic acid prototypes 1a–c, under Ritter reac-
[a] Dipartimento di Scienze Biomediche Chirurgiche e
Odontoiatriche, University of Milan,
Via Saldini 50, Milan, Italy
Fax: +39-0250316040
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.201201001.
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Scheme 2. A route that bypasses oxazoline formation to access 4β-acetamidate DANA and FANA glycals. (Path A) N-transacylation, 4β
acetamidation of protected FANA (6a) and selective hydrolysis. (Path B) oxazoline 8 formation.[11] Reagent and conditions: (i) MeCN,
H2SO4, 80 °C, 5 min; (ii) (CF3CO)2O, MeCN, 135 °C, 15 min; (iii) MeCN, H2SO4, 50 °C, 30 min; (iv) Et3N, aq. MeOH, 23 °C, 12 h;
(v) K2CO3, aq. MeOH, 23 °C, 12 h; (vi) CH3COCl, aq. MeOH, 23 °C, 30 min.
tion conditions. Finally, we report a simple and efficient
This result is of interest because, often, the reported
access to the 4β-acetoxy isomers of DANA and FANA preparations of oxazolines, even when they occur in high
glycals (epi-DANA and epi-FANA), passing through the yields, show the presence of the parent glycals, sometimes
oxazoline derivatives formed by acid treatment of these mixed with the glycal derived from hydrolysis of the oxazol-
glycals.
ine formed during the work-up.[18–20]
Subsequently, glycal 6a was reacted with either MeCN
or EtCN, under milder conditions (50 °C for 30 min) to im-
prove the stereoselectivity of the reaction. As expected, un-
Results and Discussion
With the aim of establishing a simple protocol for the der the new temperature conditions, the appropriate 4β-acy-
synthesis of 4β-acylamido glycals 4a and 4b, starting from lamidate glycals 7a and 9 were obtained in comparably high
peracetylated ester 3a and using the Ritter reaction,[17] we yields, as single isomers, uncontaminated by the respective
decided to prepare the peracetylated DANA methyl ester 4α-epimers (Table 1, entries 3 and 4).[11] We also performed
5a and to perform its direct N-transacylation[13,14] to the the reaction on the pentafluoropropionic amide 6b and on
perfluorinated FANA analogue 6a, a glycal that was also the heptafluorobutyramide 6c,[15] both homologues of
obtained in our laboratory[14] by direct N-transacylation of FANA, obtaining, in these cases, 4β-substituted glycals 10
the parent ester 3a (Scheme 2).
and 11, in comparably high yields and with no traces of
We considered that the simple exchange of the acetamido the corresponding 4α-epimers (Table 1, entries 5 and 6). To
group with a trifluoroacetamido analogue should disfavor inspect the behavior of Neu5Gc2en derivatives, we then suc-
attack of the 5-acetamido group, affording oxazoline 8[11,16] cessfully performed the reaction with glycal 6d, prepared
and preventing attack by external nucleophiles. In fact, from the protected FANA 6a (see Exp. Section and Sup-
when glycal 6a was reacted with MeCN, in the presence of porting Information).
H2SO4 at 80 °C for 5 min (Table 1, entry 1),[11] 4β-acet-
We were confident that the mild electron-withdrawing ef-
ylamino glycal 7a was obtained in good yield, accompanied fect of its α-benzyloxyacetamido group could disadvantage
by minor amounts of its 4α-epimer 7b (9:1, β/α). In con- the formation of the oxazoline with respect to solvent nucle-
trast, subjecting DANA glycal 5a to the same reaction con- ophilic attack. In effect, the Ritter reaction was favored and
ditions generated only oxazoline 8, which was isolated in afforded the corresponding 4β-acetamido glycal 12, in good
95% yield (Table 1, entry 2)[11] after suitable work-up that yield and with complete β-diastereoselectivity (Table 1, en-
avoided its opening (see the Exp. Section).
try 7).
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Synthesis of Neuraminic Acid Glycal Derivatives
Table 1. Preparation of 4β-acylamido or oxazoline glycal deriva- derivative, as sacrificial reversible intermediate, which is
tives of sialic acids.[a]
easily available by direct N-transacylation.[13]
On the other hand, to gain indirect support for our initial
hypothesis that electronic and not steric effects are responsi-
ble for the occurrence of the Ritter reaction, we reacted
peracetylated 2,2-dimethylpropanoic amide 6e,[11] a DANA
homologue having a more hindered but nonfluorinated
amido group at C-5, under the same reaction conditions
(Table 1, entry 8).[11] Thus, we obtained, in a very short time
and in a quantitative way, oxazoline 13 without any trace
of the starting glycal (NMR spectroscopic analysis of the
final reaction mixture).[11]
We also verified that the course of the Ritter reaction
was independent of the α or β C-4 configuration of the
starting glycal. In fact, we treated various peracetylated 4β-
FANA methyl esters 6f–h (Table 1, entries 9–11)[11] and ob-
tained, in all cases, the corresponding 4β-acetamidate gly-
cals 7a, 10 and 11. The parallel reaction of peracetylated
4β-DANA methyl ester 5b afforded, in contrast, oxazoline
8 in high yield (Table 1, entry 12). At this point, considering
the tested perfluorinated glycals are generally obtained by
acidic treatment of the corresponding perfluorinated methyl
sialates,[15] we subjected methyl esters 3b–d to the Ritter re-
action conditions, confident that they could initially form
their glycals and then should afford, in one pot, the corre-
sponding Ritter 4β-acetamido glycals 7a, 10 and 11
(Table 1, entries 13–15). In fact, in all cases, we obtained
the corresponding Ritter product. Similarly, by performing
the reaction on the 2-methyl acetal of peracetylated
Neu5Gc methyl ester 3e,23 4β-acetamidate glycal 14 was ob-
tained (Table 1, entry 16). As expected, peracetylated
methyl acetal 3f of Neu5Ac methyl ester[24] or peracetylate
derivative 3a, in parallel reactions, afforded the correspond-
ing oxazoline 8 in very high yields (Table 1, entry 17 and
18).
Finally, to shed light on the reaction mechanism and on
its regio and stereochemistry, we considered whether the
Ritter[25] reaction could come about as a result of a Ferrier
attack[26,27] on the anomeric carbon, followed by rearrange-
ment to the allylic 4-position. In fact, the literature data,
which reported reactions mainly performed on neutral pyr-
anose glycals with a leaving group at the allylic site, show
that some N-nucleophiles can initially attack the cyclic an-
omeric oxocarbenium ion to afford a glycoside that, being
the kinetic product of the reaction, subsequently rearranges
to its more stable allylic regioisomer.[27] Thus, we decided
to perform experiments aimed at detecting the presence of
possible N-glycosides in the reactions of the peracetylated
FANA glycal methyl esters 6a and 6f (Table 1, entries 19
and 20), and evaluating their ability to rearrange to the 4β-
Entry Substrate Catalyst Conditions
Product Yield [%]
T [°C]
t [min]
(β/α ratio)
1[11]
2[11]
3[11]
4[11] [b]
5
6a
5a
6a
6a
6b
6c
6d
6e
6f
6g
6h
5b
3b
3c
3d
3e
3f
3a
6a
6f
6a
6f
6a
6f
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
TMSOTf
TMSOTf
BF3·Et2O
BF3·Et2O
80
80
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
23
23
50
50
50
50
5
5
30
30
30
30
30
30
30
30
30
30
30
30
30
30
60
7a + 7b 80 (9:1)
8
7a
9
95
83 (10:0)
78 (10:0)
85 (10:0)
81 (10:0)
76 (10:0)
98
78 (10:0)
80 (10:0)
82 (10:0)
93
10
11
12
13
7a
10
11
8
6
7
8[11]
9[11]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
7a
10
11
14
8
77 (10:0)
80 (10:0)
81 (10:0)
83 (10:0)
76
60
8
78
48 h
48 h
3 h
3 h
3 h
3 h
7a
7a
73 (10:0)
70 (10:0)
7a + 7b 82 (2:1)
7a + 7b 81 (2:1)
7a + 7b 84 (2:1)
7a + 7b 86 (2:1)
[a] Reaction conditions: glycal (0.2 mmol), MeCN (1.5 mL), cata-
lyst (2.0 mmol) [b] EtCN used in place of MeCN.
The above result completes the puzzle of the behavior acetamido compounds that were isolated in our reactions.
of the glycals derived from the three most representative However, attempts to monitor or isolate possible N-glycos-
members of the sialic acid family under the Ritter reaction ide intermediates by reacting glycals 6a or 6b at lower tem-
conditions. In fact, we can conclude that this reaction, perature (23 °C), were unsuccessful. In fact, under these
which is well-known and widely utilized in the case of KDN conditions, the reaction remained incomplete even after
derivatives,[21,22] is applicable, without any artifice, also to 48 h and inspection of the reaction products shows the pres-
Neu5Gc (1b) glycals. To apply it to Neu5Ac (1a) congeners, ence of only the expected 4-acetamido glycal 7a ac-
it is enough to use the appropriate perfluorinated FANA companied by some unreacted glycal 6a or 6b. This, how-
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I. S. Agnolin, P. Rota, P. Allevi, A. Gregorio, M. Anastasia
FULL PAPER
ever, does not exclude the possible formation of labile N-
In the course of the work on the 4β-acylamido FANA
glycoside intermediates. For this reason, we carried out the and DANA glycals, we needed to prepare their 4β-acetoxy
reactions of glycals 6a and 6f under more typical Ferrier epimers 5b and 6f–h, which were necessary to verify their
conditions, i.e., using a Lewis acid (BF3·Et2O, or TMSOTf) behavior under the Ritter reaction conditions. Considering
and CH3CN in a reduced molar ratio (Table 1, entries 21– that these compounds are also of wider interest because
24). However, also in these cases, the reactions afforded ex- perfluorinated glycals 6f–h are unreported and the DANA
clusively the 4-acetamido glycals, even when 7a and 7b were epimer 5b has received little attention,[16,28] we developed a
used as a mixture of 4α and 4β-stereoisomers (in a 2:1 ra- relatively simple procedure for the preparation of 4β-
tio). We therefore discontinued our study on the possible DANA and two different approaches to 4β-FANA glycals.
2Ǟ4 shift and searched for a possible rationalization for the
observed β-product stereoselectivity, considering the steric step, the relatively straightforward and rapid quantitative
effects involved in a direct attack at C-4. formation of oxazolines, observed during this work. In fact,
For the preparation of DANA glycal 5b we used, as key
Modeling studies were performed aimed at identifying we subjected DANA glycals or their parent sialic acid esters
the preferred allylic carbocation intermediate conformation to the acidic conditions of the Ritter reaction and obtained
(Figure 1). The results indicated that the 5H6 half chair con- the corresponding pure oxazoline 8, which was isolable in
former (Figure 1, A), with a pseudoaxial chain at C-6, is a simple way by addition of Et3N to neutralize the final
6
more stable than the H5 conformer (Figure 1, B), with the reaction mixture; a procedure that, in this case, was more
same chain in a pseudoequatorial orientation [ΔE = efficient than addition of inorganic bases (Na2CO3 or
12 kJmol–1, in gas phase at the B3LYP/6-31G(d) level of NaHCO3)[16,22,28,29] (Table 1, entries 2, 12, and 17). How-
calculation]. On the basis of these data, we considered it ever, to obtain the 4β-acetoxy DANA epimer 5b, the reac-
highly probable that the exclusive β-attack observed in the tion mixture containing the oxazoline 8 was treated in a
reaction could be due to steric hindrance exerted by the different way, i.e., adding Ac2O and aqueous Et3N (see Exp.
5
chain at C-6 on the α-side of the H6 half chair conformer. Section). This work-up opened the oxazoline ring, acetyl-
Moreover, we also hypothesized that an anchimeric stabili- ated the formed 4β-hydroxy glycal, and afforded the 4β-
zation of the formed iminic carbocation by the electron lone acetoxy DANA epimer 5b in one pot (Scheme 4).[30]
pair of the adjacent acetamido nitrogen, could be operative,
forming a transient five-membered adduct (Scheme 3).
Scheme 4. Synthesis of 4β-acetoxy DANA or FANA epimers. Rea-
gents and conditions: (i) MeCN, H2SO4, 80 °C, 5 min; (ii) Ac2O,
Et3N H2O, 23 °C, 10 min; (iii) (CF3CO)2O or (CF3CF2CO)2O or
(CF3CF2CF2CO)2O MeCN, 135 °C, 5 min; (iv) BF3·Et2O, CH2Cl2,
40 °C, 15 min; (v) Ac2O, Et3N, CH2Cl2 23 °C, 12 h.
With 4β-DANA ester 5b in hand, we could then obtain
5
Figure 1. Three-dimensional plots of the most-stable H6 (A) and
of the H5 (B) conformers of the allylic carbocation.
the FANA congeners 6f–h by simple N-transacylation.[13]
6
Moreover, we were able to synthesize the 4β-FANA-methyl
esters 6f, 6g and 6h by a simpler and shorter method
(Scheme 4, Path B). In fact, with this goal in mind, we
treated FANA glycal 6a with BF3·Et2O, in dichloromethane
at reflux, in the absence of any nucleophile, confident that,
under these conditions, even the relatively unreactive 5-tri-
fluoroacetyl amido group of 6a could attack the adjacent
carbon of the allylic carbonium ion to afford oxazoline 15
or 4β-hydroxy alcohol 16, derived from its rapid opening
under the acidic reaction conditions or the aqueous work-
Scheme 3. Alternative rationalization of the stereoselective nucleo-
philic 4β-attack to protected FANA.
up. Moreover, we devised a simple treatment of the final
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Synthesis of Neuraminic Acid Glycal Derivatives
reaction mixture, under acetylating conditions, to directly ence of the 4β-hydroxy compound, which was also evident
give the 4β-acetoxy epimer 6f.[16,28] In effect, the reaction from TLC analysis.
with the BF3·Et2O occurs favorably and, in agreement with
our expectations, affords either 4β-hydroxy alcohol 16 or
Conclusions
4β-acetoxy glycal 6f, depending on the final reaction mix-
ture work-up (acidic or acetylating; see the Exp. Section).
In parallel experiments, we obtained glycals 6g and 6h by
reacting FANA homologues 6b and 6c in the same manner.
Moreover, in experiments performed using BF3·Et2O or
other Lewis acid (SnCl4, or TMSOTf) we were able to iso-
late, under nonacetylating conditions, very small amounts
(5% yield) of a compound to which the structure of the
trifluoro-substituted oxazoline 15 could be attributed on
the bases of its physicochemical properties and reactivity.
We have developed simple protocols for the synthesis of
4β-acylamido and 4β-acetoxyneuraminic acid glycals in
which the formation of an oxazoline is a protagonist in all
procedures. The oxazoline 8, which is undesired and avo-
ided in the synthesis of the 4β-acetamido glycals, provides a
useful tool for the preparation of 4β-DANA and 4β-FANA
epimers. The latter glycals can also be obtained by direct
acidic epimerization of their 4α-isomers, most probably via
the intermediary formation of an elusive oxazoline, which,
although very labile in the acidic reaction medium, was iso-
lable in trace amount from the final reaction mixture (5%).
We can also conclude that the oxazolines are opened ex-
clusively to the corresponding 4β-hydroxy or 4β-acetoxy
glycals. Therefore, any trace of the 4α-epimer ultimately
present in the final reaction mixture of 4β-hydroxy or 4β-
acetoxy glycals is the result of incomplete starting material
transformation into the oxazoline intermediate.[21,22,24]
1
In particular, as direct evidence, the H NMR spectrum of
the compound showed the absence of the NH doublet reso-
nance, typical of the Neu5Ac glycals, and of the singlet for
the allylic methyl acetate.
These NMR spectra, together with mass spectral data,
provided strong evidence for the extrusion of an acetyl
group with formation of an oxazoline ring conjugated with
the 2,3 double bond. The presence of an oxazoline ring was
also strongly supported by an evident shielding of the
doublet attributed to the H-6 proton (shifted to δ =
3.62 ppm) and by the value of the coupling constant of the
H-3 and H-4 (J = 4.1 Hz) that, in respect to the FANA 4α-
epimers 6a and 6f, shows the same significant variations
Experimental Section
General Remarks: Melting points are uncorrected. NMR spectra
were recorded at 298 K operating at 500.13 MHz for 1H and
125.76 MHz for 13C. Chemical shifts are reported in parts per mil-
lion (ppm, δ units), and in CDCl3 are relative to CDCl3 signal
(fixed at δ = 7.26 ppm for 1H and at δ = 77.0 ppm for 13C spectra).
In D2O spectra, chemical shifts are relative to D2O, referenced to
1
observed in the H NMR spectrum of the oxazoline 8 and
those of the corresponding compounds 5a and 5b (see the
Exp. Section).[31] Finally, the presence of the oxazoline ring
was unambiguously established by its easy transformation
upon treatment with aqueous trifluoroacetic acid into the
corresponding 4β-hydroxy FANA glycal 16.
In agreement with these results, by treating 4β-acetoxy
glycal 6f with BF3·Et2O in dichloromethane followed by
acidic work-up, we isolated the corresponding 4β-hydroxy
derivative 16, which apparently derives from regioselective
hydrolysis of the 4-acetoxy group of the starting glycal.
However, also in this case, the result can be reasonably ra-
tionalized as a consequence of the intermediary formation
of an allylic carbocation at C-4 that forms an unstable oxaz-
oline. This, subsequently, either in the reaction mixture or
during the acidic aqueous work-up, affords the final 4β-
hydroxyderivative 16.
1
t-BuOH as internal standards (signal fixed at δ = 1.24 ppm for H
and at δ = 30.29 ppm for 13C spectra). Proton and carbon assign-
ments were established, if necessary, on the basis of 1H-1H and 1H-
13C correlation NMR experiments. 1H NMR spectroscopic data
are tabulated in the following order: multiplicity (s, singlet; d, doub-
let; t, triplet; br. s, broad singlet; m, multiplet), coupling constant(s)
in Hertz, number of protons, assignment of proton(s). Optical rota-
tions were recorded with a polarimeter equipped with a 1 dm tube.
[α]D values are given in 10–1 deg cm2 g–1 and the concentrations
are given in g/100 mL. Mass spectrometry was performed with a
quadrupole ion trap mass spectrometer equipped with an electro-
spray (ESI) ion source. The spectra were collected in continuous
flow mode by connecting the infusion pump directly to the ESI
source. Solutions of compounds were infused at a flow rate of 5 μL/
min. 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 spectra were recorded by scanning a m/z
range of 100–2000. All reactions were monitored by thin-layer
chromatography (TLC) carried out on 0.25 mm Merck silica gel
plates (60 F254) using UV light, 50% sulfuric acid or 0.2% nin-
hydrin in ethanol and heat as developing agents. Flash chromatog-
raphy was performed with normal-phase silica gel, following the
general protocol of Still.[32]
The formation of 4β-alcohol 16, even if it represents
merely the cleavage of the 4β-acetoxy group of the starting
glycal 6f, is of interest from a synthetic point of view be-
cause it allows selective hydrolysis of the 4β-acetoxy group
in the presence of three similar acetates and of an easily
hydrolyzable trifluoroacetamido group.
In spite of the isolation of oxazoline 15 from different
reactions, and its reasonable involvement in the epimeriz-
ation of the FANA glycal 6a to its epimer 6f, all attempts
to monitor the possible transitory formation of this oxazol-
ine in the reaction mixtures by 1H NMR spectroscopic
Usual work-up, unless otherwise indicated, refers to addition of
Et3N (0.1 mL) to the reaction mixtures, solvent evaporation under
a nitrogen flow and reduced pressure, dilution with EtOAc and
successive washing of the organic layers with an ice-cold aqueous
NaHCO3 saturated solution. Finally drying of the organic layer
1
analysis, were unsuccessful. No observed change in the H
NMR spectrum was diagnostic for the presence of an oxaz-
oline ring, whereas others signals clearly indicated the pres- with Na2SO4, filtration and solvent evaporation.
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General Procedure for the Ritter Reaction and for Oxazoline Forma-
cal properties were practically superimposable to those previously
tion under Protic Acid Catalysis: The reactions were performed on reported.
0.2 mmol scale of the indicated starting compound, reacted in the
Method ii: Starting from compound 6f (105 mg, 0.2 mmol) and per-
appropriate nitrile (1.5 mL) containing concd. H2SO4 (1.9 mmol)
at the indicate temperature and time. The reaction mixtures were
worked-up as indicated above under General Remarks.
forming the reaction at 50 °C for 30 min in MeCN (Table 1, en-
try 9), glycal 7a (78 mg, 78%) was obtained as only stereoisomer
and with all physico-chemical properties practically superimposable
to those previously reported.
General Procedure for the Ritter Reaction and for Oxazoline Forma-
tion under Lewis Acid Catalysis: The reactions were performed on
0.2 mmol scale of the indicated starting compound, reacted in the
appropriate nitrile (1.5 mL) containing the indicated Lewis acid
(BF3·Et2O or TMSOTf) (2.0 mmol) at 50 °C for 3 h. Then the reac-
tion mixtures were worked-up as indicated above under General
Remarks.
Method iii: Starting from the fluorinated peracetylated Neu5Ac
methyl ester 3b (117 mg, 0.2 mmol), and performing the reaction
at 50 °C for 30 min in MeCN (Table 1, entry 13), glycal 7a (81 mg,
77%) was obtained as only stereoisomer and with all physico-
chemical properties practically superimposable to those previously
reported.
Methyl 4-Acetamido-2,6-anhydro-5-(2,2,2-trifluoroacetamido)-7,8,9-
Method iv (partial reaction from the glycal 6a): Glycal 6a (105 mg,
0.2 mmol) was stirred at 23 °C for 48 h in MeCN (Table 1, en-
try 19). The resulting mixture, after rapid chromatography (EtOAc/
hexane, 80:20 v/v), afforded, in sequence, the less polar glycal 7a
(77 mg, 73%) followed by the starting compound 6a (26 mg, 25%).
tri-O-acetyl-3,4,5-trideoxy-
Methyl 4-Acetamido-2,6-anhydro-5-(2,2,2-trifluoroacetamido)-7,8,9-
tri-O-acetyl-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonate (7b):
D-glycero-D-talo-non-2-enonate (7a) and
(a) H2SO4 Catalysis
Method i: Starting from glycal 6a (105 mg, 0.2 mmol), after 5 min
heating at 80 °C in MeCN (Table 1, entry 1), a mixture of glycals
7a and 7b was obtained. Rapid chromatography (EtOAc/hexane,
80:20 v/v) afforded, in sequence, the less polar glycal 7b (8 mg, 8%)
followed by the more polar glycal 7a (72 mg, 72%), both in pure
form.
Method v (partial reaction from the glycal 6f): Glycal 6f (105 mg,
0.2 mmol), after stirring at 23 °C for 48 h in MeCN (Table 1, en-
try 20), followed by work-up and rapid chromatography (EtOAc/
hexane, 80:20 v/v), afforded the less polar glycal 7a (73 mg, 70%)
followed by the starting compound 6f (28 mg, 27%).
Glycal 7b: M.p. 133–135 °C (CH2Cl2/diisopropyl ether). [α]2D0
+41.3 (c = 1 in CHCl3). H NMR (CDCl3): δ = 8.14 (d, JNH,5
=
=
(b) Lewis Acids Catalysis
1
Method i (TMSOTf catalysis): A solution of glycal 6a (105 mg,
0.2 mmol) in MeCN (1.5 mL), containing TMSOTf (370 μL,
2.0 mmol), was heated at 50 °C for 180 min (Table 1, entry 21).
Work-up and rapid chromatography (EtOAc/hexane, 80:20 v/v), af-
forded, in sequence, the less polar glycal 7b (28 mg, 27%) followed
by the more polar glycal 7a (58 mg, 55%), with all physico-chemi-
cal properties superimposable to those previously reported. A sim-
ilar reaction (Table 1, entry 22) starting with glycal 6f (105 mg,
0.2 mmol) afforded glycals 7b (28 mg, 27%) and 7a (57 mg, 54%).
9.9 Hz,
1
H, CF3CONH), 5.93 (d, JNH,4
=
9.7 Hz,
1
H,
CH3CONH), 5.88 (d, J3,4 = 2.0 Hz, 1 H, 3-H), 5.48 (dd, J7,6 = 1.4,
J7,8 = 4.4 Hz, 1 H, 7-H), 5.31 (m, 1 H, 8-H), 5.03 (ddd, J4,3 = 2.0,
J4,5 = J4,NH = 9.7 Hz,1 H, 4-H), 4.59 (dd, J9a,8 = 2.5, J9a,9b
=
12.4 Hz, 1 H, 9a-H), 4.49 (dd, J6,7 = 1.4, J6,5 = 9.8 Hz, 1 H, 6-H),
4.24–4.15 (overlapping, 2 H, 9b-H and 5-H), 3.80 (s, 3 H, CO-
OCH3), 2.09 (s, 3 H, CH3COO), 2.07 (s, 3 H, CH3COO), 2.05 (s,
3 H, CH3COO), 1.97 (s, 3 H, CH3CONH) ppm. 13C NMR
(CDCl3): δ = 171.3 (CH3CONH), 170.5, 170.1, 169.4 (3 C,
CH3COO), 161.5 (C-1), 158.2 (q, JC–F = 38 Hz, COCF3), 144.8 (C-
2), 119.0–112.2 (1 C, CF3), 110.2 (C-3), 76.4 (C-6), 70.6 (C-8), 67.8
(C-7), 62.1 (C-9), 52.4 (COOCH3), 48.0 (C-5), 47.7 (C-4), 22.6
(CH3CONH), 20.7, 20.5, 20.3 (3 C, CH3COO) ppm. MS (ESI+):
m/z = 527.3 [M + H]+, 549.1 [M + Na]+, 1075.5 [2M + Na]+.
C20H25F3N2O11 (526.42): calcd. C 45.63, H 4.79, N 5.32; found C
45.56, H 4.67, N 5.30.
Method ii (BF3·Et2O catalysis): A solution of glycal 6a (105 mg,
0.2 mmol) in MeCN (1.5 mL), containing BF3·Et2O (246 μL,
2.0 mmol), was heated at 50 °C for 180 min (Table 1, entry 23).
Work-up and rapid chromatography (EtOAc/hexane, 80:20 v/v), af-
forded, in sequence, the less polar glycal 7b (30 mg, 28%) followed
by the more polar glycal 7a (59 mg, 56%), with all physico-chemi-
cal properties superimposable to those previously reported. A sim-
ilar reaction (Table 1, entry 24) starting with glycal 6f (105 mg,
0.2 mmol) afforded glycals 7b (30 mg, 29%) and 7a (60 mg, 57%).
Glycal 7a: M.p. 146–148 °C (CH2Cl2/diisopropyl ether). [α]2D0
=
=
–20.3 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 7.78 (d, JNH,5
9.2 Hz,
1
H, CF3CONH), 6.59 (d, JNH,4
=
8.7 Hz,
1
H,
Methyl 2,6-Anhydro-4-propoxycarbonylamido-5-(2,2,2-trifluoroacet-
CH3CONH), 5.98 (d, J3,4 = 5.1 Hz, 1 H, 3-H), 5.49 (dd, J7,6 = J7,8
= 3.3 Hz, 1 H, 7-H), 5.27 (ddd, J8,9a = J8,7 = 3.2, J8,9b = 8.2 Hz, 1
H, 8-H), 4.90 (dd, J4,5 = J4,3 = 5.1, J4,NH = 8.7 Hz, 4-H), 4.81 (dd,
J9a,8 = 3.2, J9a,9b = 12.3 Hz, 1 H, 9a-H), 4.38 (ddd, J5,4 = 5.1, J5,6
= J5,NH = 9.2 Hz, 1 H, 5-H), 4.30 (dd, J6,7 = 3.3, J6,5 = 9.2 Hz, 1
H, 6-H), 4.15 (dd, J9b,8 = 8.2, J9b,9a = 12.3 Hz, 1 H, 9b-H), 3.78 (s,
3 H, COOCH3), 2.05–2.01 (overlapping, 9 H, 3ϫ CH3COO), 1.99
(s, 3 H, CH3CONH) ppm. 13C NMR (CDCl3): δ = 170.8, 170.7 (2
C, CH3CONH and CH3COO), 169.7, 161.8 (C-1), 157.7 (q, JC–F
= 38 Hz, COCF3), 144.7 (C-2), 119.0–112.2 (1 C, CF3), 108.5 (C-
3), 73.6 (C-6), 71.4 (C-8), 68.1 (C-7), 62.0 (C-9), 52.5 (COOCH3),
46.7 (C-5), 42.4 (C-4), 22.8 (CH3CONH), 20.8, 20.7, 20.4 (3 C,
CH3COO) ppm. MS (ESI+): m/z = 527.5 [M + H]+, 549.4 [M +
Na]+, 1076.0 [2M + Na]+. C20H25F3N2O11 (526.42): calcd. C 45.63,
H 4.79, N 5.32; found C 45.54, H 4.75, N 5.16.
amido)-7,8,9-tri-O-acetyl-3,4,5-trideoxy-D-glycero-D-talo-non-2-
enonate (9): Starting from glycal 6a (105 mg, 0.2 mmol) and heating
at 50 °C for 30 min in EtCN (Table 1, entry 4), 9 was obtained,
after rapid chromatography (EtOAc/hexane, 70:30 v/v), as a white
solid (80 mg, 78%); m.p. 129–131 °C (CH2Cl2/diisopropyl ether).
[α]2D0 = –32.3 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 7.50 (d,
JNH,5 = 9.2 Hz, 1 H, CF3CONH), 6.30 (d, JNH,4 = 8.5 Hz, 1 H,
CH3CONH), 5.98 (d, J3,4 = 5.2 Hz, 1 H, 3-H), 5.48 (t, J7,6 = J7,8
= 3.4 Hz, 1 H, 7-H), 5.26 (ddd, J8,9a = J8,7 = 3.4, J8,9b = 8.1 Hz, 1
H, 8-H), 4.91 (ddd, J4,5 = J4,3 = 5.2, J4,NH = 8.6 Hz, 1 H, 4-H),
4.84 (dd, J9a,8 = 3.4, J9a,9b = 12.3 Hz, 1 H, 9a-H), 4.40 (ddd, J5,4
= 5.2, J5,6 = J5,NH = 9.2 Hz, 1 H, 5-H), 4.32 (dd, J6,7 = 3.4, J6,5
=
9.2 Hz, 1 H, 6-H), 4.13 (dd, J9b,8 = 8.1, J9b,9a = 12.3 Hz, 1 H, 9b-
H), 3.79 (s, 3 H, COOCH3), 2.26–2.10 (m, 2 H, CH3CH2CONH),
2.1 (s, 3 H, CH3COO), 2.04 (overlapping, 6 H, 2ϫ CH3COO),
1.12 (t, JCH3,CH2 = 7.6 Hz, 3 H, CH3CH2CONH) ppm. 13C NMR
(CDCl3): δ = 174. 7 (CH3CH2NHCO), 171.4, 170.8, 169.6 (3ϫ
Performing the reaction at 50 °C for 30 min (Table 1, entry 3) gave
glycal 7a (83 mg, 83%) as the only stereoisomer. All physico-chemi-
6542
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6537–6547

Synthesis of Neuraminic Acid Glycal Derivatives
CH3COO), 161.9 (C-1), 157.7 (q, JC–F = 38 Hz, COCF3), 144.6 (C- (C1), 157.9 (t, JC–F = 26 Hz, COCF2), 144.6 (C-2), 119.2–116.0 (3
2), 119.0–112.0 (1 C, CF3), 108.5 (C-3), 73.6 (C-6), 71.1 (C-8), 68.0
C, CF2CF2CF3), 108.7 (C-3), 73.5 (C-6), 71.9 (C-8), 68.1 (C-7),
(C-7), 61.8 (C-9), 52.6 (COOCH3), 46.7 (C-5), 42.3 (C-4), 29.3 62.0 (C-9), 52.5 (COOCH3), 46.9 (C-5), 42.6 (C-4), 22.7
(CH3CH2CONH), 20.7 (2 C, CH3COO), 20.4 (CH3COO), 9.6 (CH3CONH), 20.8, 20.6, 20.3 (3 C, CH3COO) ppm. MS (ESI+):
(CH3CH2CONH) ppm. MS (ESI+): m/z = 541.0 [M + H]+, 563.1 m/z = 627.5 [M + H]+, 649.6 [M + Na]+, 1275.8 [2M + Na]+. MS
[M + Na]+, 1103.6 [2M + Na]+. C21H27F3N2O11 (540.45): calcd. C (ESI–): m/z = 625.3 [M – H]–. C22H25F7N2O11 (626.43): calcd. C
46.67, H 5.04, N 5.18; found C 46.37, H 4.97, N 5.08.
42.18, H 4.02, N 4.47; found C 42.30, H 4.15, N 4.71.
Methyl 4-Acetamido-2,6-anhydro-5-(2,2,3,3,3-pentafluoropropan-
amido)-7,8,9-tri-O-acetyl-3,4,5-trideoxy-D-glycero-D-talo-non-2-
enonate (10)
Method ii: Starting from 4β-glycal 6h (125 mg, 0.2 mmol) and heat-
ing at 50 °C for 30 min in MeCN (Table 1, entry 11), after rapid
chromatography (EtOAc/hexane, 70:30 v/v), 11 was obtained as a
white solid (103 mg, 82%) with all physico-chemical properties
practically superimposable to those previously reported.
Method i: Starting from glycal 6b (115 mg, 0.2 mmol) and heating
at 50 °C for 30 min in MeCN (Table 1, entry 5), 10 was obtained,
after rapid chromatography (EtOAc/hexane, 70:30 v/v), as a white
solid (98 mg, 85%); m.p. 144–147 °C (CH2Cl2/diisopropyl ether).
[α]2D0 = –39.2 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 7.78 (d,
JNH,5 = 9.0 Hz, 1 H, NHCOCF2CF3), 6.47 (d, JNH,4 = 8.8 Hz, 1
Method iii: Starting from the fluorinated saturated ester 3d
(137 mg, 0.2 mmol) of peracetylated methyl ester of Neu5Ac and
heating at 50 °C for 30 min in MeCN (Table 1, entry 15), after ra-
pid chromatography (EtOAc/hexane, 70:30 v/v), 11 was obtained
as a white solid (101 mg, 81%) with all physico-chemical properties
practically superimposable to those previously reported.
H, NHCOCH3), 6.01 (d, J3,4 = 5.2 Hz, 1 H, 3-H), 5.43 (dd, J7,6
=
J7,8 = 3.0 Hz, 1 H, 7-H), 5.32 (ddd, J8–9a = J8,7 = 3.0, J8,9b = 8.2 Hz,
1 H, 8-H), 4.90 (dd, J4,5 = J4,3 = 5.2, J4,NH = 8.8 Hz, 1 H, 4-H),
4.80 (dd, J9a,8 = 3.0, J9a,9b = 12.4 Hz, 1 H, 9a-H), 4.34 (ddd, J5,4
Methyl 4-Acetamido-7,8,9-tri-O-acetyl-2,6-anhydro-5-(benzyloxy-
acetamido)-4,3,5-trideoxy-D-glycero-D-talo-non-2-enonate
(12):
= 5.2, J5,6 = J5,NH = 9.0 Hz, 1 H, 5-H), 4.35 (dd, J6,7 = 3.0, J6,5
=
Starting from glycal 6d (116 mg, 0.2 mmol) and heating at 50 °C
for 30 min in MeCN (Table 1, entry 7), 12 was obtained, after rapid
chromatography (EtOAc/hexane, 90:10 v/v), as a white solid
(88 mg, 76%); m.p. 131–122 °C. [α]2D0 = –33.1 (c = 1 in CHCl3). 1H
NMR (CDCl3): δ = 7.40–7.30 (5 H, overlapping, OCH2Ph), 6.66
(d, JNH,5 = 10.0 Hz, 1 H, NHCOCH2), 6.01 (d, J3,4 = 5.2 Hz, 1 H,
3-H), 5.50–5.43 (2 H, overlapping, NHCOCH3 and 7-H), 5.32–5.28
(m, 1 H, 8-H), 4.88–4.82 (m, 1 H, 4-H), 4.68 (dd, J9a,8 = 2.5, J9a,9b
= 12.3 Hz, 1 H, 9a-H), 4.59–4.52 (2 H, overlapping, OCH2Ph), 4.48
(ddd, J5,4 = 5.0, J5,6 = J5,NH = 10.0 Hz, 1 H, 5-H), 4.17 (dd, J9b,8
9.0 Hz, 1 H, 6-H), 4.17 (dd, J9b,8 = 8.2, J9b,9a = 12.4 Hz, 1 H, 9b-
H), 3.77 (s, 3 H, COOCH3), 2.08 (s, 3 H, CH3COO), 2.05 (s, 3 H,
CH3COO), 2.03 (s, 3 H, CH3COO), 1.97 (s, 3 H, CH3CONH) ppm.
13C NMR (CDCl3): δ = 171.1 (NHCOCH3), 170.8, 170.5, 169.7 (3
C, CH3COO), 161.7 (C-1), 158.0 (t, JC–F = 26 Hz, COCF2), 144.6
(C-2), 119.2–104.0 (2 C, CF2CF3), 108.5 (C-3), 73.2 (C-6), 71.9 (C-
8), 67.9 (C-7), 62.0 (C-9), 52.5 (COOCH3), 46.7 (C-5), 42.4 (C-4),
22.7 (CH3CONH), 20.8, 20.7, 20.3 (3 C, CH3COO) ppm. MS
(ESI+): m/z = 577.2 [M + H]+, 599.3 [M + Na]+, 1175.7 [2M +
Na]+; (ESI–): m/z = 575.1 [M – H]–. C21H25F5N2O11 (576.43):
calcd. C 43.76, H 4.37, N 4.86; found C 43.55, H 4.26, N 4.71.
= 7.1, J9b,9a = 12.3 Hz, 1 H, 9b-H), 4.09 (dd, J6,7 = 2.9, J6,5
=
10.0 Hz, 1 H, 6-H), 3.94 (2 H, overlapping, CH2CONH), 3.80 (s, 3
H, COOCH3), 2.11 (s, 3 H, CH3COO), 2.08 (s, 3 H, CH3COO),
2.04 (s, 3 H, CH3COO), 1.91 (s, 3 H, CH3CONH) ppm. 13C NMR
Method ii: Starting from 4β-glycal 6g (115 mg, 0.2 mmol) and heat-
ing at 50 °C for 30 min in MeCN (Table 1, entry 10), after rapid
chromatography (EtOAc/hexane, 70:30 v/v), 10 was obtained as a
white solid (92 mg, 80%) with all physico-chemical properties su-
perimposable to those previously reported.
(CDCl3):
δ = 170.6, 170.3, 170.1 (3 C, CH3COO), 170.0
(NHCOCH3), 169.9 (NHCOCH2), 161.7 (C-1), 145.1 (C-2), 137.0–
127.8 (6 C, OCH2Ph), 108.4 (C-3), 74.6 (C-6), 73.5 (OCH2Ph), 71.3
(C-8), 69.5 (NHCOCH2), 68.0 (C-7), 62.1 (C-9), 52.5 (COOCH3),
44.8 (C-5), 43.2 (C-4), 23.2 (CH3CONH), 20.9, 20.7 (3 C,
CH3COO) ppm. MS (ESI+): m/z = 579.6 [M + H]+, 601.7 [M +
Na]+. C27H34N2O12 (578.57): calcd. C 56.05, H 5.92, N 4.84; found
C 56.28, H 6.01, N 4.99.
Method iii: Starting from the fluorinated saturated ester 3c
(127 mg, 0.2 mmol) of peracetylated methyl ester of Neu5Ac and
heating at 50 °C for 30 min in MeCN (Table 1, entry 14), after ra-
pid chromatography (EtOAc/hexane, 70:30 v/v), 10 was obtained
as a white solid (92 mg, 80%) with all physico-chemical properties
nearly superimposable to those previously reported.
Methyl Oxazolo[5,4]-Fused 7,8,9-Tri-O-acetyl-2,3,4,5-tetradeoxy-
2,3-didehydro-2,3-trideoxy-4Ј,5Ј-dihydro-2Ј-methyl-
talo-non-2-enoate (8)
D-glycero-D-
Methyl 4-Acetamido-2,6-anhydro-5-(2,2,3,3,4,4,4-heptafluorobutan-
amido)-7,8,9-tri-O-acetyl-3,4,5-trideoxy-D-glycero-D-talo-non-2-
enonate (11)
Method i: Starting from compound 5a (95 mg, 0.2 mmol) and per-
Method i: Starting from glycal 6c (125 mg, 0.2 mmol) and heating forming the reaction at 80 °C for 5 min in MeCN (Table 1, entry 2),
at 50 °C for 30 min in MeCN (Table 1, entry 6), 11 was obtained,
after rapid chromatography (EtOAc/hexane, 70:30 v/v), as a white
solid (101 mg, 81%); m.p. 158–160 °C (CH2Cl2/diisopropyl ether).
[α]2D0 = –22.0 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 7.48 (d,
oxazoline 8 (78 mg, 95%) was obtained as a glass. [α]2D0 = –60.0 (c
= 1 in CHCl3). 1H NMR (CDCl3): δ = 6.38 (d, J3,4 = 4.0 Hz, 1 H,
3-H), 5.62 (dd, J7,6 = 2.6, J7,8 = 5.9 Hz, 1 H, 7-H), 5.43 (ddd,
J8–9a = 2.6, J8,7 = 5.9, J8,9b = 6.3 Hz, 1 H, 8-H), 4.81 (dd, J4,3
=
JNH,5 = 8.9 Hz, 1 H, NHCOCF2CF2CF3), 6.22 (d, JNH,4 = 8.9 Hz, 4.0, J4,5 = 8.6 Hz, 1 H, 4-H), 4.59 (dd, J9a,8 = 2.6, J9a,9b = 12.5 Hz,
1 H, NHCOCH3), 6.00 (d, J3,4 = 5.1 Hz, 1 H, 3-H), 5.43 (dd, J7,6
= J7,8 = 3.0 Hz, 1 H, 7-H), 5.25 (ddd, J8–9a = J8,7 = 3.0, J8,9b
1 H, 9a-H), 4.22 (dd, J9b,8 = 6.3, J9b,9a = 12.5 Hz, 1 H, 9b-H), 3.95
(dd, J5,4 = 8.6, J5,6 = 10.5 Hz, 1 H, 5-H), 3.80 (s, 3 H, COOCH3),
3.42 (dd, J6,7 = 2.6, J6,5 = 10.5 Hz, 1 H, 6-H), 2.14 (s, 3 H, OC-
OCH3), 2.04 (6 H, overlapping, 2ϫ OCOCH3), 2.00 (s, 3 H,
=
7.8 Hz, 1 H, 8-H), 4.89 (dd, J4,5 = J4,3 = 5.1, J4,NH = 8.9 Hz, 1 H,
4-H), 4.77 (dd, J9a,8 = 3.0, J9a,9b = 12.4 Hz, 1 H, 9a-H), 4.45 (m, 1
H, 5-H), 4.34 (1 H, J6,7 = 3.2, J6,5 = 9.2 Hz, 6-H), 4.17 (dd, J9b,8 CCH3) ppm. 13C NMR (CDCl3): δ = 170.6, 169.8, 169.6 (3 C,
= 7.8, J9b,9a = 12.4 Hz, 1 H, 9b-H), 3.77 (s, 3 H, COOCH3), 2.08
CH3COO), 167.2 (CCH3), 161.8 (C-1), 147.0 (C-2), 107.5 (C-3),
(s, 3 H, CH3COO), 2.05 (s, 3 H, CH3COO), 2.03 (s, 3 H, 76.6 (C-6), 72.2 (C-4), 70.2 (C-8), 68.7 (C-7), 61.9 (C-9), 61.8 (C-
CH3COO), 2.00 (s, 3 H, CH3CONH) ppm. 13C NMR (CDCl3): δ
= 171.1 (NHCOCH3), 170.7, 170.5, 169.7 (3 C, CH3COO), 161.7
5), 52.4 (COOCH3), 20.7, 20.6, 20.5 (3 C, CH3COO), 14.0 (1 C,
CCH3) ppm. MS (ESI+): m/z = 414.5 [M + H]+, 437.4 [M +
Eur. J. Org. Chem. 2012, 6537–6547
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6543

I. S. Agnolin, P. Rota, P. Allevi, A. Gregorio, M. Anastasia
FULL PAPER
Na]+. C18H23NO10 (413.38): calcd. C 52.30, H 5.61, N 3.39; found
C 52.24, H 5.49, N 3.33.
+ H]+, 553.4 [M + Na]+. C22H30N2O13 (530.48): calcd. C 49.81, H
5.70, N 5.28; found C 50.1, H 5.83, N 5.37.
Preparation of the 4β-Acetoxy Glycals 5b and 6f–h
Method ii: Starting from compound 5b (95 mg, 0.2 mmol) and per-
forming the reaction at 50 °C for 30 min in MeCN (Table 1, en-
try 12), oxazoline 8 (77 mg, 93%) was obtained with all physico-
chemical properties practically superimposable to those above re-
ported.
Methyl
5-Acetamido-4,7,8,9-tetra-O-acetyl-2,6-anhydro-3,5-dide-
-talo-non-2-enonate (5b): A solution of 3a (95 mg,
oxy- -glycero-
D
D
0.2 mmol) in MeCN (1.5 mL) containing H2SO4 (106 μL,
2.0 mmol) and Ac2O (471 μL, 5.0 mmol) was heated at 80 °C for
5 min. Et3N (335 μL, 2.4 mmol) and H2O (360 μL, 20.0 mmol)
were then added and the solution was stirred for 10 min at 23 °C.
Usual work-up and rapid chromatography (EtOAc) afforded glycal
Method iii: Starting from compound 3f (101 mg, 0.2 mmol) and
performing the reaction at 50 °C for 30 min in MeCN (Table 1,
entry 17), oxazoline 8 (62 mg, 76%) was obtained with all physico-
chemical properties practically superimposable to those above re-
ported.
1
5b (88 mg, 92%). H NMR (CDCl3): δ = 6.15 (d, J3,4 = 5.4 Hz, 1
H, 3-H), 5.84 (d, JNH,5 = 10.1 Hz, 1 H, N-H), 5.45 (dd, J7,6 = 2.1,
J7,8 = 3.8 Hz, 1 H, 7-H), 5.26 (ddd, J8,9a = 2.7, J8,7 = 3.8, J8–9b
=
Method iv: Starting from compound 3a (107 mg, 0.2 mmol) and
performing the reaction at 50 °C for 30 min in MeCN (Table 1,
entry 18), oxazoline 8 (64 mg, 78%) was obtained with all physico-
chemical properties practically superimposable to those above re-
ported.
7.3 Hz, 1 H, 8-H), 5.11 (dd, J4,5 = 4.6, J4,3 = 5.4 Hz, 1 H, 4-H),
4.73 (dd, J9a,8 = 2.7, J9a,9b = 12.4 Hz, 1 H, 9a-H), 4.53 (ddd, J5,4
= 4.6, J5,6 = J5,NH = 10.1 Hz, 1 H, 5-H), 4.24 (dd, J6,7 = 2.1, J6,5
= 10.1 Hz, 1 H, 6-H), 4.14 (dd, J9b,8 = 7.3, J9b,9a = 12.4 Hz, 1 H,
9b-H), 3.75 (s, 3 H, COOCH3), 2.05 (6 H, overlapping, 2ϫ
CH3COO), 2.03 (s, 3 H, COOCH3), 2.01 (s, 3 H, COOCH3), 1.88
(s, 3 H, CH3CONH) ppm. C20H27NO12 (473.43): calcd. C 50.74, H
5.75, N 2.96; found C 50.69, H 5.67, N 3.03. The physico-chemical
properties were in agreement with those reported.[26] Similar results
were also obtained starting from the glycals 5a.
Methyl Oxazolo[5,4]-Fused 7,8,9-Tri-O-acetyl-2,3,4,5-tetradeoxy-
2,3-didehydro-2,3-trideoxy-4Ј,5Ј-dihydro-2Ј-tert-butyl-
D-
glycero- -talo-non-2-enoate (13): Starting from glycal 6e (103 mg,
D
0.2 mmol) and operating at 50 °C for 30 min in MeCN (Table 1,
entry 8), the title compound 13 was obtained as a white solid
(89 mg, 98%); m.p. 110–112 °C (CH2Cl2/diisopropyl ether). [α]2D0
–11.3 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 6.36 (d, J3,4
=
=
Methyl 4,7,8,9-Tetra-O-acetyl-2,6-anhydro-3,5-dideoxy-5-(2,2,2-tri-
fluoroacetamido)-D-glycero-D-talo-non-2-enonate (6f)
4.1 Hz, 1 H, 3-H), 5.59 (dd, J7,6 = J7,8 = 4.4 Hz, 1 H, 7-H), 5.51
(ddd, J8,9a = 2.6, J8,7 = 4.4, J8,9b = 7.3 Hz, 1 H, 8-H), 4.79 (dd, J4,3
Method i (N-transacylation of 5b): The 4β-acetoxy glycal 5b
(200 mg, 0.42 mmol) was directly N-transacylated with trifluoro-
acetic anhydride according to our procedure[13] to afford the
fluorinated compound 6f as a white solid (186 mg, 84%); m.p. 141–
143 °C. [α]2D0 = –41.2 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 6.76
(d, JNH,5 = 10.1 Hz, 1 H, N-H), 6.21 (d, J3,4 = 5.5 Hz, 1 H, 3-H),
5.45 (dd, J7,6 = 2.5, J7,8 = 4.4 Hz, 1 H, 7-H), 5.30 (ddd, J8,9a = 2.9,
= 4.1, J4,5 = 8.6 Hz, 1 H, 4-H), 4.50 (dd, J9a,8 = 2.6, J9a,9b
=
12.3 Hz, 1 H, 9a-H), 4.26 (dd, J9b,8 = 7.2, J9b,9a = 12.3 Hz, 1 H,
9b-H), 4.32 (dd, J5,4 = 8.6, J5,6 = 9.4 Hz, 1 H, 5-H), 3.80 (s, 3 H,
COOCH3), 3.41 (dd, J6,7 = 4.4, J6,5 = 9.4 Hz, 1 H, 6-H), 2.13 (s, 3
H, CH3COO), 2.06 (s, 3 H, CH3COO), 2.05 (s, 3 H, CH3COO),
1.18 [overlapping, 9 H, C(CH3)3] ppm. 13C NMR (CDCl3): δ =
176.2 [(CH3)3CC], 170.6, 170.0, 169.7 (3 C, CH3COO), 162.0 (C-
1), 146.8 (C-2), 107.6 (C-3), 77.0 (C-6), 72.0 (C-8), 70.6 (C-7), 70.1
(C-4), 62.2 (C-9), 62.1 (C-5), 52.5 (COOCH3), 33.4 [C(CH3)3], 27.6
[3 C, C(CH3)3], 20.9, 20.7 (3 C, CH3COO) ppm. MS (ESI+): m/z
= 456.3 [M + H]+, 479.2 [M + Na]+. C21H29NO10 (455.46): calcd.
C 55.38, H 6.42, N 3.08; found C 55.17, H 6.62, N 3.10.
J8,7 = 4.4, J8,9b = 7.2 Hz, 1 H, 8-H), 5.26 (dd, J4,5 = 4.2, J4,3
=
5.5 Hz, 1 H, 4-H), 4.72 (dd, J9a,8 = 2.9, J9a,9b = 12.4 Hz, 1 H, 9a-
H), 4.53 (ddd, J5,4 = 4.2, J5,6 = J5,NH = 10.1 Hz, 1 H, 5-H), 4.39
(dd, J6,7 = 2.5, J6,5 = 10.1 Hz, 1 H, 6-H), 4.17 (dd, J9b,8 = 7.2,
J9b,9a = 12.4 Hz, 1 H, 9b-H), 3.80 (s, 3 H, COOCH3), 2.10 (s, 3 H,
CH3COO), 2.09 (s, 3 H, CH3COO), 2.07 (s, 3 H, CH3COO), 2.04
(s, 3 H, CH3COO) ppm. 13C NMR (CDCl3): δ = 170.6, 170.4,
169.7, 169.5 (4 C, CH3COO), 161.3 (C-1), 157.0 (q, JC–F = 38 Hz,
COCF3), 146.4 (C-2), 115.1 (q, JC–F = 287.6 Hz, COCF3), 105.5
(C-3), 73.3 (C-6), 71.3 (C-8), 67.5 (C-7), 63.9 (C-4), 61.9 (C-9), 52.6
(COOCH3), 45.3 (C-5), 20.8, 20.7, 20.6, 20.4 (4 C, CH3COO) ppm.
MS (ESI+): m/z = 528.3 [M + H]+, 550.2 [M + Na]+, 1077.5 [2M
+ Na]+. C20H24F3NO12 (527.40): calcd. C 45.55, H 4.59, N 2.66;
found C 45.75, H 4.41, N 2.55.
Methyl 4-Acetamido-5-(acetoxyacetamido)-7,8,9-tri-O-acetyl-2,6-
anhydro-4,3,5-trideoxy-D-glycero-D-talo-non-2-enonate (14): Start-
ing from the peracetylated methyl ester of Neu5Gc 3e (113 mg,
0.2 mmol) and operating at 50 °C for 30 min in MeCN (Table 1,
entry 16), 14 was obtained, after rapid chromatography (EtOAc/
CH3OH, 85:15 v/v), as a white solid (88 mg, 83%); m.p. 152–
154 °C. [α]2D0 = –17.8 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 6.48
(d, JNH,5 = 9.5 Hz, 1 H, NHCOCH2), 6.03 (d, J3,4 = 4.9 Hz, 1 H,
Method ii (direct epimerization of the FANA glycal 6a to the 4β-
hydroxy intermediate 16 and successive acylation): A solution of
glycal 6a (105 mg, 0.2 mmol) in CH2Cl2 (1.5 mL), containing
BF3·Et2O (246 μL, 2.0 mmol), was heated at 40 °C for 15 min. Us-
ual work-up and rapid chromatography (EtOAc/hexane, 60:40 v/v),
afforded first 15 then 16.
3-H), 5.86 (d, JNH,4 = 8.2 Hz, 1 H, NHCOCH3), 5.43 (dd, J7,6
J7,8 = 4.2 Hz, 1 H, 7-H), 5.27 (ddd, J8–9a = 3.1, J8,7 = 4.2, J8,9b
=
=
7.2 Hz, 1 H, 8-H), 4.77 (dd, J4,5 = J4,3 = 4.9, J4,NH = 8.2 Hz, 1 H,
4-H), 4.67 (dd, J9a,8 = 3.1, J9a,9b = 12.4 Hz, 1 H, 9a-H), 4.53 (d,
JCH2a,CH2b = 15.1 Hz, 1 H, CH2a), 4.45 (ddd, J5,4 = 4.9, J5,6 = 8.3,
J5,NH = 9.5 Hz, 1 H, 5-H), 4.42 (d, JCH2b,CH2a = 15.1 Hz, 1 H,
CH2b), 4.24 (dd, J6,7 = 4.2, J6,5 = 8.3 Hz, 1 H, 6-H), 4.19 (dd, J9b,8
= 7.2, J9b,9a = 12.4 Hz, 1 H, 9b-H), 3.80 (s, 3 H, COOCH3), 2.10
Methyl Oxazolo[5,4]-Fused 7,8,9-Tri-O-acetyl-2,3,4,5-tetradeoxy-
2,3-didehydro-2,3-trideoxy-4Ј,5Ј-dihydro-2Ј-trifluoromethyl-
-talo-non-2-enoate (15): Yield 5 mg (5%); glass solid.
[α]2D0 = –48.4 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 6.40 (d, J3,4
D-
(s, 3 H, CH3COO), 2.09 (s, 3 H, CH3COO), 2.06 (s, 3 H, glycero-
CH3COO), 2.02 (s, 3 H, CH3COO), 2.01 (s, 3 H, CH3CONH) ppm.
D
13C NMR (CDCl3): δ = 170.6, 170.5, 170.4 (4 C, CH3COO), 170.0 = 4.0 Hz, 1 H, 3-H), 5.60 (dd, J7,6 = 2.9, J7,8 = 6.1 Hz, 1 H, 7-H),
(NHCOCH3), 167.6 (NHCOCH2), 161.7 (C-1), 144.6 (C-2), 108.8 5.44 (ddd, J8–9a = 2.8, J8,7 = 6.1, J8,9b = 8.9 Hz, 1 H, 8-H), 5.18
(C-3), 75.1 (C-6), 71.3 (C-8), 68.1 (C-7), 63.3 (NHCOCH2), 61.9 (dd, J4,3 = 4.0, J4,5 = 8.7 Hz, 1 H, 4-H), 4.52 (dd, J9a,8 = 2.8, J9a,9b
(C-9), 52.5 (COOCH3), 45.7 (C-5), 43.5 (C-4), 23.2 (CH3CONH), = 12.5 Hz, 1 H, 9a-H), 4.32 (dd, J5,4 = 8.7, J5,6 = 9.8 Hz, 1 H, 5-
20.9, 20.7, 20.6 (4 C, CH3COO) ppm. MS (ESI+): m/z = 531.5 [M
H), 4.23 (dd, J9b,8 = 6.1, J9b,9a = 12.5 Hz, 1 H, 9b-H), 3.84 (s, 3 H,
6544
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6537–6547

Synthesis of Neuraminic Acid Glycal Derivatives
COOCH3), 3.62 (dd, J6,7 = 2.9, J6,5 = 9.8 Hz, 1 H, 5-H), 2.07 (6 (C-5), 20.8, 20.6, 20.5, 20.4 (4 C, CH3COO) ppm. MS (ESI+): m/z
H, overlapping, 2ϫ OCOCH3), 2.04 (s, 3 H, OCOCH3) ppm. MS
(ESI+): m/z = 568.4 [M + H]+, 590.7 [M + Na]+. C18H20F3NO10
(467.35): calcd. C 46.26, H 4.31, N 3.00; found C 46.36, H 4.37, N
2.94.
= 578.4 [M + H]+, 600.3 [M + Na]+, 1177.9 [2M + Na]+.
C21H24F5NO12 (577.41): calcd. C 43.68, H 4.19, N 2.43; found C
44.66, H 4.83, N 2.74.
Method ii: A solution of glycal 6b (125 mg, 0.2 mmol) in CH2Cl2
(1.5 mL), containing BF3·Et2O (246 μL, 2.0 mmol), was heated at
40 °C for 15 min. The reaction mixture was treated with Et3N
(835 μL, 6.0 mmol) and Ac2O (78 μL, 1.0 mmol) for 12 h at 23 °C.
Work-up was performed by water addition and mixture extraction
(CH2Cl2) to afford, after sequential washing with ice-cold aqueous
NaCl solution, drying and solvent evaporation, a crude residue.
Rapid chromatography (EtOAc/hexane, 1:1 v/v) led to the title
compound 6g (99 mg, 79%) with all physico-chemical properties
practically superimposable to those reported above.
Methyl
fluoroacetamido)-
7,8,9-Tri-O-acetyl-2,6-anhydro-3,5-dideoxy-5-(2,2,2-tri-
-glycero- -talo-non-2-enonate (16): Yield 75 mg
D
D
(78%); white solid; m.p. 121–123 °C; [α]2D0 = –49.2 (c = 1 in CHCl3).
1H NMR (CDCl3): δ = 7.02 (d, JNH,5 = 7.4 Hz, 1 H, NHCOCF3),
6.18 (d, J3,4 = 5.5 Hz, 1 H, 3-H), 5.41 (dd, J7,6 = 1.5, J7,8 = 4.6 Hz,
1 H, 7-H), 5.32 (ddd, J8–9a = 2.7, J8,7 = 4.6, J8,9b = 7.3 Hz, 1 H, 8-
H), 4.73 (dd, J9a,8 = 2.7, J9a,9b = 12.5 Hz, 1 H, 9a-H), 4.38–4.34 (2
H, overlapping, 6-H and 5-H), 4.31 (br. s, 1 H, 4-H), 4.16 (dd, J9b,8
= 7.3, J9b,9a = 12.5 Hz, 1 H, 9b-H), 3.82 (s, 3 H, COOCH3), 2.80
(br. s, 1 H, OH at C-4), 2.11 (s, 3 H, OCOCH3), 2.08 (s, 3 H,
OCOCH3), 2.06 (s, 3 H, OCOCH3) ppm. 13C NMR (CDCl3): δ =
170.7, 169.8 (3 C, CH3COO), 161.8 (C-1), 157.1 (q, JC–F = 26 Hz,
COCF2), 145.7 (C-2), 119.2–116.0 (1 C, CF3), 108.5 (C-3), 72.5 (C-
6), 71.6 (C-8), 67.6 (C-7), 62.1 (C-9), 61.2 (C-4), 52.7 (COOCH3),
47.0 (C-5), 20.9, 20.7, 20.6 (3 C, CH3COO) ppm. MS (ESI+): m/z
= 486.5 [M + H]+, 508.5 [M + Na]+, 1193.9 [2M + Na]+; MS (ESI–
): m/z = 484.2 [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.
Methyl 4,7,8,9-Tetra-O-acetyl-2,6-anhydro-3,5-dideoxy-5-(2,2,3,3,
4,4,4-heptafluorobutanamido)-D-glycero-D-talo-non-2-enonate (6h)
Method i: 4β-Acetoxy glycal 5b (200 mg, 0.42 mmol), obtained as
described above, was directly N-transacylated with heptafluoro-
butyric anhydride according to our procedure[13] to afford the
fluorinated compound 6g (216 mg, 82%) as a white solid; m.p. 133–
135 °C. [α]2D0 = –62.5 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 6.62
(br. s, 1 H, N-H), 6.22 (d, J3,4 = 5.3 Hz, 1 H, 3-H), 5.46 (dd, J7,6
= 2.6, J7,8 = 4.5 Hz, 1 H, 7-H), 5.32 (ddd, J8,9a = 2.9, J8,7 = 4.5,
J8–9b = 6.8 Hz, 1 H, 8-H), 5.28 (dd, J4,5 = 4.3, J4,3 = 5.3 Hz, 1 H,
4-H), 4.70 (dd, J9a,8 = 2.9, J9a,9b = 12.4 Hz, 1 H, 9a-H), 4.60 (ddd,
J5,4 = 4.3, J5,6 = J5,NH = 10.2 Hz, 1 H, 5-H), 4.39 (dd, J6,7 = 2.6,
J6,5 = 10.2 Hz, 1 H, 6-H), 4.18 (dd, J9b,8 = 6.8, J9b,9a = 12.4 Hz, 1
H, 9b-H), 3.81 (s, 3 H, COOCH3), 2.11–2.08 (9 H, overlapping,
3ϫ CH3COO), 2.06 (s, 3 H, CH3COO) ppm. 13C NMR (CDCl3):
δ = 170.7, 170.5, 169.7, 169.3 (4 C, CH3COO), 161.4 (C-1), 157.4
To a solution of compound 16 (75 mg, 0.15 mmol) in CH2Cl2
(1.0 mL), Et3N (104 μL, 0.75 mmol) and Ac2O (140 μL, 1.5 mmol)
were added. The resulting mixture was stirred at 23 °C for 12 h.
Water was then added and the mixture was extracted with CH2Cl2.
The organic layer was washed with ice-cold aqueous NaCl solution
and water, dried, and the solvent evaporated to give a crude residue.
Rapid chromatography (EtOAc/hexane, 1:1 v/v) gave the title com-
pound 6f (72 mg, 91%) as a white solid; m.p. 142–144 °C; [α]D
=
(t, JC–F
= 26 Hz, COCF2), 146.3 (C-2), 119.0–110.0 (3 C,
–42.3 (c = 1 in CHCl3). All other physico-chemical properties were
in agreement with those above reported.
CF2CF2CF3), 105.6 (C-3), 73.3 (C-6), 71.3 (C-8), 67.5 (C-7), 63.7
(C-4), 61.9 (C-9), 52.7 (COOCH3), 45.4 (C-5), 20.8, 20.7, 20.5, 20.4
(4 C, CH3COO) ppm. MS (ESI+): m/z = 628.3 [M + H]+, 650.5
[M + Na]+. C22H24F7NO12 (627.42): calcd. C 42.11, H 3.86, N 2.23;
found C 44.03, H 3.51, N 1.98.
Method iii (one-pot epimerization of 6a and acetylating work-up):
A solution of glycal 6a (105 mg, 0.2 mmol) in CH2Cl2 (1.5 mL),
containing BF3·Et2O (246 μL, 2.0 mmol), was heated at 40 °C for
15 min. The reaction mixture was then treated with Et3N (835 μL,
6.0 mmol) and Ac2O (78 μL,1.0 mmol) for 12 h, at 23 °C. The reac-
tion mixture was diluted with water and extracted with CH2Cl2 to
afford, after sequential washing with an ice-cold aqueous solution
of NaCl, drying of the organic layers (Na2SO4) and solvent evapo-
ration, a crude residue. Rapid chromatography (EtOAc/hexane, 1:1
v/v) afforded the title compound 6f (81 mg, 77%), the analytical
data of which was identical in all respects to that above reported.
Method ii: A solution of glycal 6c (116 mg, 0.2 mmol) in CH2Cl2
(1.5 mL), containing BF3·Et2O (246 μL, 2.0 mmol), was heated at
40 °C for 15 min. The reaction mixture was treated with Et3N
(835 μL, 6.0 mmol) and Ac2O (78 μL,1.0 mmol) for 12 h at 23 °C.
Work-up was performed by water addition and mixture extraction
(CH2Cl2) to afford, after a sequential washing with ice-cold aque-
ous NaCl solution, drying, and solvent evaporation, a crude resi-
due. Rapid chromatography (EtOAc/hexane, 1:1 v/v) led to the title
compound 6h (93 mg, 80%) with all its physico-chemical properties
practically superimposable to those previously reported.
Methyl 4,7,8,9-Tetra-O-acetyl-2,6-anhydro-5-(2,2,3,3,3-pentafluoro-
propionamido)-3,5-dideoxy-D-glycero-D-talo-non-2-enonate (6g)
Method i: 4β-Acetoxy glycal 5b (200 mg, 0.42 mmol), obtained as
reported above, was directly N-transacylated with pentafluoro-
propionic anhydride according to our procedure[15] to afford the
fluorinated compound 6g (209 mg, 86%); white solid; m.p. 149–
151 °C; [α]2D0 = –53.8 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 6.85
(d, JNH,5 = 9.7 Hz, 1 H, N-H), 6.20 (d, J3,4 = 5.4 Hz, 1 H, 3-H),
5.44 (dd, J7,6 = 2.5, J7,8 = 4.4 Hz, 1 H, 7-H), 5.32–5.27 (2 H, over-
lapping, 8-H and 4-H), 4.69 (dd, J9a,8 = 2.8, J9a,9b = 12.5 Hz, 1 H,
Preparation of Starting Compounds 3e, 6d, and 6e
Methyl 5-(Acetoxyacetamido)-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-
O-methyl-D-glycero-D-galcto-non-2-enonate (3e): Acetic anhydride
(1.0 mL) was added dropwise to a stirred solution of 2-O-methyl-
5-N-glycolyl methyl β-neuraminate[23] (375 mg, 1.06 mmol) in an-
hydrous pyridine (2.0 mL) containing 4-(dimethylamino)pyridine
(ca. 1 mg) at 23 °C. The mixture was stirred at 23 °C for 12 h, then
9a-H), 4.55 (ddd, J5,4 = 4.4, J5,NH = 9.7, J5,6 = 10.3 Hz, 1 H, 5-H), poured into an ice-cold aqueous HCl and extracted with EtOAc.
4.39 (dd, J6,7 = 2.5, J6,5 = 10.3 Hz, 1 H, 6-H), 4.16 (dd, J9b,8 = 7.0, The organic layers were washed with water, aqueous NaHCO3, and
J9b,9a = 12.5 Hz, 1 H, 9b-H), 3.80 (s, 3 H, COOCH3), 2.09 (6 H, water. Evaporation of the solvent afforded compound 3e (538 mg;
1
overlapping, 2ϫ CH3COO), 2.07 (s, 3 H, COOCH3), 2.04 (s, 3 H,
90%); m.p. 161–163 °C; [α]2D0 = +19.7 (c = 1 in CHCl3). H NMR
COOCH3) ppm. 13C NMR (CDCl3): δ = 170.6, 170.4, 169.6, 169.4
(CDCl3): δ = 5.98 (d, JNH,5 = 10.1 Hz, 1 H, NHCOCH3), 5.34 (dd,
(4 C, CH3COO), 161.4 (C-1), 157.6 (t, JC–F = 26 Hz, COCF2), J7,6 = 2.3, J7,8 = 3.9 Hz, 1 H, 7-H), 5.31 (ddd, J4,3a = 4.9, J4,3b
146.2 (C-2), 119.0–110.0 (2 C, CF2CF3), 105.6 (C-3), 73.2 (C-6), J4,5 = 11.4 Hz, 1 H, 4-H), 5.22 (ddd, J8,9a = 2.6, J8,7 = 3.9, J8,9b
=
=
71.2 (C-8), 67.4 (C-7), 63.6 (C-4), 61.9 (C-9), 52.7 (COOCH3), 45.2 6.6 Hz, 1 H, 8-H), 4.79 (dd, J9a,8 = 2.6, J9a,9b = 12.4 Hz, 1 H,
Eur. J. Org. Chem. 2012, 6537–6547
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6545

I. S. Agnolin, P. Rota, P. Allevi, A. Gregorio, M. Anastasia
FULL PAPER
9a-H), 4.58 (d, JCH2a,CH2b = 15.3 Hz, 1 H, COCH2aO), 4.29 (d,
JCH2b,CH2a = 15.3 Hz, 1 H, COCH2bO), 4.16–4.08 (2 H, overlap-
ping, 9b-H and 5-H), 4.00 (dd, J6,7 = 2.3, J6,5 = 10.5 Hz, 1 H, 6-
12 h at 23 °C. Water was added and the mixture was extracted with
CH2Cl2 and the organic layer was washed with ice-cold aqueous
NaCl solution, dried, and the solvent was evaporated to give a
crude residue. Rapid chromatography (EtOAc/hexane, 3:7 v/v) gave
H), 3.81 (s, 3 H, COOCH3), 3.27 (s, 3 H, OCH3), 2.44 (dd, J3a,4
=
4.9, J3a,3b = 12.8 Hz, 1 H, 3a-H), 2.17 (s, 3 H, CH3COO), 2.13 (s, the title compound 6e (80 mg, 78%) as a white solid; m.p. 144–
3 H, s, CH3COO), 2.06 (s, 3 H, CH3COO), 2.02 (s, 3 H, CH3COO),
1.99 (s, 3 H, CH3COO), 1.88 (dd, J3b,4 = 11.4, J3a,3b = 12.8 Hz, 1
H, 3a-H) ppm. 13C NMR (CDCl3): δ = 171.1 (NHCOCH3), 170.7,
146 °C (CH2Cl2/diisopropyl ether); [α]2D0 = +51.1 (c = 1 in CHCl3).
1H NMR (CDCl3): δ = 5.97 (d, J3,4 = 2.9 Hz, 1 H, 3-H), 5.68–5.62
(overlapping, 2 H, N-H and 4-H), 5.43 (dd, J7,6 = 3.3, J7,8 = 4.8 Hz,
170.6, 170.2, 169.6, 167.6 (5 C, CH3COO), 167.2 (C-1), 98.9 (C-2), 1 H, 7-H), 5.31 (ddd, J8,9a = 3.2, J8,7 = 4.8, J8,9b = 7.0 Hz, 1 H, 8-
72.0 (C-8), 71.6 (C-6), 68.4 (C-7), 68.0 (C-4), 62.7 (NHCOCH2), H), 4.61 (dd, J9a,8 = 3.2, J9a,9b = 12.3 Hz, 9a-H), 4.45 (dd, J6,7
=
=
62.3 (C-9), 52.7 (COOCH3), 51.4 (OCH3), 49.2 (C-5), 37.4 (C-3),
21.0, 20.8, 20.6 (5 C, CH3COO) ppm. MS (ESI+): m/z = 536.5 [M
+ H]+, 558.6 [M + Na]+, 1093.9 [2M + Na]+; MS (ESI–): m/z 534.5
[M – H]–. C22H33NO14 (535.50): calcd. C 49.34, H 6.21, N 2.62;
found C 49.51, H 6.33, N 2.78.
3.3, J6,5 = 9.3 Hz, 1 H, 6-H), 4.32 (m, 1 H, 5-H), 4.19 (dd, J9b,8
7.0, J9b,9a = 12.3 Hz, 1 H, 9b-H), 3.80 (s, 3 H, 1 H, COOCH3),
2.10 (s, 3 H, CH3COO), 2.06 (s, 3 H, CH3COO), 2.04 (overlapping,
6 H, 2ϫ CH3COO), 1.14 [overlapping, 9 H, (CH3)3CCONH] ppm.
13C NMR (CDCl3): δ = 178.4 [(CH3)3CONH], 170.7, 170.5, 170.4
(4 C, CH3COO), 161.6 (C-1), 145.2 (C-2), 108.2 (C-3), 76.6 (C-6),
70.8 (C-8), 67.8 (C-7), 67.6 (C-4), 61.9 (C-9), 52.5 (COOCH3), 47.0
(C-5), 38.8 [(CH3)3CCONH], 27.2 [3 C, NHCOC(CH3)3], 20.8, 20.7
(4 C, CH3COO) ppm. MS (ESI+): m/z = 516.3 [M + H]+, 538.5
[M + Na]+. C23H33NO12 (515.51): calcd. C 53.59, H 6.45, N 2.72;
found C 53.66, H 6.45, N 2.74.
Methyl 4,7,8,9-Tetra-O-acetyl-2,6-anhydro-5-(benzyloxyacetamido)-
3,5-dideoxy-D-glycero-D-galacto-non-2-enonate (6d): Glycal 6a
(300 mg, 0.57 mmol) was treated with a saturated moist methanolic
solution of K2CO3 (3.0 mL), at 23 °C for 24 h. BnOCH2COCl
(387 μL, 2.5 mmol) was added and the reaction mixture was stirred
at 23 °C for 3 h. The reaction mixture was acidified by addition of
aqueous HCl (0.1 m) and the solvent was removed under reduced
pressure. The residue was dissolved in methanol (5.0 mL), treated
with acidic resin (100 mg; Dowex 50WX8, H+) and stirred for 24 h
at 23 °C. The resin was filtered off, washed with methanol/water,
and the solvent was then removed under reduced pressure to afford
a residue that was dissolved in pyridine (1.5 mL) and treated with
Ac2O (540 μL, 5.7 mmol) for 12 h at 23 °C. The reaction mixture
was poured into ice-cold aqueous NaCl solution and extracted with
CH2Cl2. The organic layer was washed with water, dried, and the
solvent was evaporated to give a crude residue. Rapid chromatog-
raphy (EtOAc/hexane, 1:1 v/v) gave the title compound 6d (118 mg,
Preparation of Glycal 16 by Direct Selective Hydrolysis of Glycal
6f: A solution of glycal 6f (105 mg, 0.2 mmol) in CH2Cl2 (1.5 mL),
containing BF3·Et2O (246 μL, 2.0 mmol), was heated at 40 °C for
15 min. Work-up and rapid chromatography (EtOAc/hexane, 60:40
v/v), afforded the intermediate compound 16 (72 mg, 74%) as a
white solid with all physico-chemical properties superimposable to
those previously reported.
Theoretical Calculations: A search of the conformational space of
the intermediate allylic carbocation was performed by using the
quantum mechanical AM1 method implemented within the Hyper-
Chem. software package,[33] varying all the dihedral angles in a
Metropolis Monte–Carlo conformational search. The search was
performed with a range for acyclic or ring torsion variation of
Ϯ10–120°. The Random Walk, and Metropolis Criterion use T =
300 K, switching to 400 K. The ten lowest energy conformations
found for each 5H6 and 6H5 with 5,6-pseudodiequatorial chain con-
formers were fully reoptimized in the Gaussian 03 program pack-
age[34] by a DFT approach at the B3LYP level. The 6-31G(d) basis
set was used for all the atoms of the molecules. Vibrational fre-
quencies were computed, for all conformers, at the same level of
theory to verify that the optimized structures were minima of po-
tential energy.
55%) as a white solid; m.p. 124–126 °C (diisopropyl ether); [α]2D0
=
+25.3 (c = 1 in CHCl3). 1H NMR (CDCl3): δ = 7.40–7.30 (5 H,
overlapping, OCH2Ph), 6.66 (d, JNH,5 = 9.3 Hz, 1 H, NHCOCH2),
6.00 (d, J3,4 = 3.1 Hz, 1 H, 3-H), 5.54–5.47 (2 H, overlapping, 4-H
and 7-H), 5.37 (ddd, 1 H, J8–9a = 3.2, J8,7 = 5.3, J8,9b = 6.7 Hz, 8-
H), 4.36–4.56 (3 H, overlapping, 9a-H and OCH2Ph), 4.47–4.38 (2
H, overlapping, 5-H and 6-H), 4.18 (dd, 1 H, J9b,8 = 6.7, J9b,9a
=
12.3 Hz, 9b-H), 3.91 (2 H, overlapping, CH2CONH), 3.80 (s, 3 H,
COOCH3), 2.21 (s, 3 H, CH3COO), 2.07–2.04 (6 H, overlapping,
2ϫ CH3COO), 2.03 (s, 3 H, CH3COO) ppm. 13C NMR (CDCl3):
δ = 170.5, 170.0 (3 C, CH3COO), 169.9 (NHCOCH2), 169.7
(CH3COO), 161.5 (C-1), 145.1 (C-2), 136.7–128.0 (6 C, OCH2Ph),
107.9 (C-3), 76.4 (C-6), 73.6 (OCH2Ph), 70.3 (C-8), 69.2
(NHCOCH2), 67.9 (C-7), 67.5 (C-4), 61.9 (C-9), 52.5 (COOCH3),
46.0 (C-5), 20.8, 20.7 (4 C, CH3COO) ppm. MS (ESI+): m/z =
580.6 [M + H]+, 602.6 [M + Na]+. C27H33NO13 (579.56): calcd. C
55.96, H 5.74, N 2.42; found C 56.10, H 5.91, N 2.52.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra and a scheme for the synthesis of
starting compound 6d are reported.
Acknowledgments
Methyl 4-Acetamido-7,8,9-tri-O-acetyl-2,6-anhydro-5-(tert-butan-
amido)-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonate (6e): The
We gratefully acknowledge Ms Irene Delcarro for her skilled tech-
nical assistance. A part of this work was supported by the Fondo
Sociale Europeo (FSE) (grant “Dote ricerca”), and by the Regione
Lombardia.
title ester 6e was prepared by complete hydrolysis of glycal 5a
(300 mg, 0.57 mmol), performed by treatment with a saturated
moist methanolic solution of K2CO3 (3.0 mL), kept at 23 °C for
24 h. The free amino acid obtained was amidated in one pot by
addition of tBuCOCl (328 μL, 2.5 mmol) at 23 °C for 30 min. At
this time, the reaction mixture was acidified by addition of HCl
(0.1 m) and the solvent was removed under reduced pressure. The
residue was dissolved in methanol (5.0 mL), treated with acidic
resin (100 mg; Dowex 50WX8, H+) and stirred for 24 h at 23 °C.
The resin was filtered off, washed with water, and the solvent was
removed under reduced pressure. The residue was then dissolved in
pyridine (1.5 mL) and treated with Ac2O (540 μL, 5.7 mmol) for
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Received: July 26, 2012
Published Online: October 8, 2012
Eur. J. Org. Chem. 2012, 6537–6547
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6547