High yielding N-transacylation of secondary amides in acids labile molecules by the action of perfluorinated anhydrides in the presence of a mild base

Article abstract of DOI:10.1016/j.tetasy.2010.10.019

The simple addition of mild bases (Et₃N or DIPEA) allows a high yielding N-transacylation of secondary amides, performed by perfluorinated anhydrides, in molecules that are very sensitive to acids.

Full text of DOI:10.1016/j.tetasy.2010.10.019

Tetrahedron: Asymmetry 21 (2010) 2681–2686
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
High yielding N-transacylation of secondary amides in acids labile molecules
by the action of perfluorinated anhydrides in the presence of a mild base
⇑
Paola Rota , Pietro Allevi, Maria L. Costa, Mario Anastasia
Department of Chemistry, Biochemistry and Biotechnology for the Medicine, University of Milan, via Saldini 50, Milan, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The simple addition of mild bases (Et3N or DIPEA) allows a high yielding N-transacylation of secondary
amides, performed by perfluorinated anhydrides, in molecules that are very sensitive to acids.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 21 September 2010
Accepted 21 October 2010
Available online 20 November 2010
1. Introduction
in the reaction medium.1 Thus, we continued to study this reaction
with the aim of extending its scope, and avoiding the observed
In a recent report1 we described the N-transacylation of second-
ary acylamides to perfluorinated analogues with the possibility to
revert the formed perfluorinated amide to the starting amide or to
a different amide (Scheme 1).
downsides. In fact, we considered that a successful result in this
direction could also permit the use of the perfluoroacylation reac-
tion in analytical protocols with the possibility of considering the
occurrence of the N-transacylation and reasonably excluding the
formation of artefactual compounds. Herein we report experi-
ments showing that the simple addition of a mild organic base to
the reaction mixture avoids any concurrent reaction, without
interference during the course of the N-transacylation reaction.
R
NH
R
NH
R
NH
R1COCl, Et3N
(CF3CO)2O MeCN
O
O
O
135 °C
CH3
R1
CF3
R1 = CH3 and others
Scheme 1. N-Transacylation reaction.
2. Results and discussion
Initially, we chose the peracetylated methyl ester 1a of acetyl-
neuraminic acid (Table 1), as a model compound, to study in depth
the N-transacylation with carbohydrates with a protected anomer-
ic hydroxyl that is very labile to acids. In our work,1,4 we had expe-
rienced that this choice could permit an accurate and simple
monitoring of the reaction course (by TLC and GLC–MS). In fact,
we observed that the N-transacylation reaction of the ester 1a af-
fords the 2,3-glycal 2, in 73% yields, after a 15 min reaction. Most
probably, the glycal 2 forms5 from the saturated ester 3a, since,
after a 5 min reaction, a 1:1 mixture of the glycal 2 and of the sat-
urated ester 3a is present in the reaction mixture. In successive
experiments, considering that the undesired evolution of the reac-
tion could be ascribed to the acid that forms in the N-transacyla-
tion,1 we added a different organic base to the reaction mixture
and searched for the best reaction conditions (stoichiometric ratio,
time and temperature) affording the compounds expected on the
basis of the starting amide (Table 1).
The acyl group exchange affording the perfluorinated amide oc-
curs under the same conditions reported in analytical protocols
used to volatilize polar compounds (such as amido carbohydrates
and functionalized amino acids) before GLC–MS analyses.2 In fact,
in all cases, we reacted the polar molecules with a perfluorinated
anhydride, such as trifluoroacetic anhydride (TFAA) or heptafluo-
robutyric anhydride (HFBAA), in CH3CN, at 135 °C, for a short time
(5–15 min).1,2 The reaction occurs in high yields (78–92%) and tol-
erates the presence, in the secondary amide, of stereogenic centres,
of various functional or protective groups, even those unstable to
mild acids or to the strongly basic conditions used in the two step
N-transacylation reaction.3 However, in the case of some carbohy-
drate molecules, containing an hydroxy group protected as a 2-
methoxyethoxymethylether (MEM ether), or an anomeric hydroxyl
protected as an acetoxy or a methoxy group, the reaction does not
occur (MEM ether)1 or occurs in modest yields (43–55%).1,4 Finally,
less than satisfactory results are obtained in the presence of ben-
zyloxy or benzylidene derivatives, since they are in part cleaved
As reported in the table (Table 1), satisfactory results were ob-
tained only when the reaction was performed in the presence of a
mild organic base (Et3N, DIPEA). Very similar results were obtained
in the presence of DMAP, while no useful result was obtained in
the presence of stronger bases (DBU, DBN). These bases give unsat-
isfactory results even at lower temperature and after a shorter
⇑
Corresponding author. Tel.: +39 025 031 6047; fax: +39 025 031 6040.
E-mail address: paola.rota@unimi.it (P. Rota).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.10.019

2682
P. Rota et al. / Tetrahedron: Asymmetry 21 (2010) 2681–2686
Table 1
N-Transacylation reactions in the presence of organic bases
AcO
AcO
AcO
OAc
OAc
AcO
OAc
OAc
OAc
AcO
O
AcO
CF3CONH
AcO
CF3CONH
CO2Me
O
O
CO2Me
CO2Me
AcNH
AcO
AcO
1a
3a
2
Entry
Basea
Time (min)
T (°C)
Product 2 yieldb (%)
Product 3a yieldb (%)
c
1
2
3
4
5
6
7
None
None
DBU
DBN
Et3N
15
5
5–15
5–15
5
135
135
100–135
100–135
135
73
49
—
—
—
—
48
—
—
85
73
80
DMAP
DIPEA
15
15
135
135
—
—
a
b
c
The best molar equivalent ratio of base-anhydride was 2:1.
All yields refer to pure isolated compounds.
No defined compound was isolable.
reaction time, most probably because they cause the occurrence of
other side-reactions in the molecule.
under acidic conditions (entries 1–4), but also to molecules con-
taining protective groups that are very labile to acids, such as the
1,7-lactones of sialic acid containing a MEM or trimethylsilyl group
(entries 5–6) and benzyloxy compounds (entries 7–9) which are
commonly cleaved by acyl anhydrides in the presence of Lewis
acids.6 In all cases we obtained very high yields and the expected
N-transacylated amides with the same stereochemistry as the
starting compounds. The reaction works well also with all the pre-
viously reported amides,1 even if in this case no improvement is
observed with respect to the reaction performed in the absence
of base. This is in agreement with the fact that the triethylamine
At this point, we performed the reaction on all acyl amides
which, in the absence of base, gave unsatisfactory results.1 More-
over, we also reacted some amides, selected for the presence of
protecting groups, commonly used in synthesis but, in some cases,
very labile to acids (Table 2).6 As documented by the results ob-
tained (Table 2), the simple addition of triethylamine promoted a
successful N-transacylation of all compounds tested.
Of particular interest is the possibility to apply the reaction not
only to molecules containing substituents that suffer elimination
Table 2
Selective N-transacylation of secondary amides in the presence of groups very labile to acids
Entry
Substrate
Product
Time (min)
Yield (%)a
1
2
3
4
1a: R1 = OAc
1a: R1 = OAc
3a: R1 = OAc; n = 0
3b: R1 = OAc; n = 1
5
5
5
5
85
86
89
88
AcO
AcO
OAc
OAc
AcO
R1
R1
1a: R1 = OAc
1b: R1 = OMe
3c: R1 = OAc; n = 2
3d: R1 = OMe; n = 2
AcO
AcNH
AcO
CF3(CF2)nCONH
CO2Me
CO2Me
O
O
AcO
3
1
5
6
4a: R1 = Ac;R2 = MEM
4b: R1 = R2 = TMS
5a: R1 = Ac;R2 = MEM
5b: R1 = R2 = TMS
5
5
79
74
NHAc
NHCO(CF2)2CF3
O
O
OCbz
O
O
OCbz
O
R1O
R2O
R1O
R2O
R1O
R1O
R1O
O
OR1
OR1
4
5
O
6a: R1 = Bn
7a: R1 = Bn
5
5
79
82
R1O
7
8
O
6b: R1 = PMB
7b: R1 = PMB
R1O
R1O
OCH3
OCH3
NHAc
NHCO(CF2)2CF3
6
7
O
O
O
O
Ph
Ph
O
O
AcO
AcO
OCH3
NHAc
OCH3
9
8
9
5
78
NHCO(CF2)2CF3
8
9
NHAc
NHCO(CF2)2CF3
BnO
Ph
BnO
Ph
10
11
10
12
11
13
15
15
75
88
10
11
NHAc
NHCO(CF2)2CF3
OTHP
OTHP
12
13
a
Yields refer to pure products isolated by column chromatography.

P. Rota et al. / Tetrahedron: Asymmetry 21 (2010) 2681–2686
2683
has the simple function to scavenge the acid formed during the
course of the reaction and does not effect the mechanism of the
reaction, as in the presence of strong bases.7
7:3:0.1, v/v/v), to afford the protected lactone 4b (200 mg; 86%
Y), as a white oil, showing: ½a D20
ꢁ
¼ þ10:1 (c 1, CHCl3); 1H NMR
(CD2Cl2) d 7.44–7.38 (m, 5H, Ph), 6.10 (d, JNH,5 = 7.9 Hz, 1H, N–H),
5.21 (d, JCH2a,CH2b = 12.0 Hz, 1H, CH2a), 5.11 (d, JCH2b,CH2a = 12.0 Hz,
1H, CH2b), 4.47 (br s, 1H, H-6), 4.41 (d, J8,7 = 8.5 Hz, 1H, H-7),
4.15 (br s, 1H, H-4), 4.06 (m, 1H, H-8), 3.91 (d, J5,NH = 7.9 Hz, 1H,
H-5), 3.80–3.74 (overlapping, 2H, H-9a and H-9b), 2.12–2.04 (over-
lapping, 2H, H-3a and H-3b), 1.96 (s, 3H, NHCOCH3), 0.15 (br s, 9H,
Si(CH3)3), 0.13 (br s, 18H, 2 ꢂ Si(CH3)3); 13C NMR (CD2Cl2) d 169.6
(CH3CONH), 153.4 (C-1), 152.2 (PhCH2OCO), 135.3, 129.3, 129.2,
129.0 (Ph), 94.2 (C-2), 78.1 (C-7), 72.8 (C-8), 71.9 (C-6), 70.9
(PhCH2OCO), 67.2 (C-4), 63.9 (C-9), 51.9 (C-5), 37.0 (C-3), 23.4
(CH3CONH), 0.5 (Si(CH3)3), ꢀ0.2 (Si(CH3)3), ꢀ0.3 (Si(CH3)3); MS
(ESI positive) m/z 665.1 [MꢀNa]+. Anal. Calcd for C28H47NO10Si3:
C, 52.39; H, 7.38; N, 2.18. Found: C, 52.47; H, 7.43; N, 2.16.
3. Conclusion
In conclusion, the results herein reported extend the scope of
our N-transacylation reaction1 allowing its successful synthetic
application to amides containing groups that can suffer elimination
in the presence of acids. Moreover, our results are useful in GLC–
MS analyses where they assure the possibility of detecting some
saturated and unsaturated congeners, and we can be confident that
the unsaturated compounds are really present and do not form
during the derivatization of analytes.2
4. Experimental
4.1. General
4.3. Methyl 3,4,6-O-tri-parametoxybenzyl-2-deoxy-2-N-acetyl-
a-D-glucopyranose 6b
Methyl-2-deoxy-2-N-acetyl-
a-D
-glucopyranose11
(50 mg,
Melting points were uncorrected. The progress of all reactions
was monitored by thin-layer chromatography (TLC) or by GLC–
MS using a HP-5 column (30 m, 0.32 mm, 0.25 lm film-thickness
0.21 mmol) was dissolved in anhydrous DMF (700
lL), cooled to
0 °C and treated with NaH (30 mg, 0.77 mmol). After 10 min
4-methoxybenzyl chloride (PMBCl) (104 L, 0.77 mmol) and tetra-
l
column), operating at 200 °C. Under these conditions, the previ-
ously reported4 compounds 3a showed a higher relative retention
time in respect to the glycal 2 (r.r.t. 1.11). All flash chromatogra-
phies were performed following the general protocol of Still.8
NMR spectra were recorded at 25 °C on a AM-500 spectrometer
operating at 500.13 MHz for 1H and 125.76 MHz for 13C. The chem-
ical shifts are reported in ppm and coupling constants are given in
hertz, relative to CD3OD signal fixed at 3.31 ppm for 1H spectra and
to CD3OD signal fixed at 49.05 ppm for 13C spectra, relative to
CDCl3 signal fixed at 7.26 ppm for 1H spectra and to CDCl3 signal
fixed at 77.00 ppm for 13C spectra. Proton and carbon assignments
were established, if necessary, with 1H–1H and 1H–13C correlated
NMR experiments. Data for 1H NMR are recovered as follows:
chemical shift (ppm), multiplicity (s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; br, broad), coupling constant(s) in hertz,
number of protons, assignment of proton(s). The anomeric config-
uration of Sias was established on the basis of the heteronuclear
vicinal coupling constants values obtained by 2D Selective Hetero-
nuclear J-resolved experiment with the spin-flip method.9 The data
were collected with the pulse sequences and phase-cycling rou-
tines provided in the Bruker libraries of pulse programs. Optical
butylammonium iodide (7 mg, 0.21 mmol) were added and the
solution was stirred at room temperature for 5 h. Then, the reac-
tion mixture was worked-up to afford a crude compound which
was purified by flash chromatography (eluting with hexane/AcOEt;
8:2, v/v) to give the protected compound 6b (109 mg, 86% yield) as
a glass showing: ½a D20
ꢁ
¼ þ69:3 (c 1, CHCl3); 1H NMR (CDCl3) d 7.29–
6.79 (overlapping, 12H, Ph), 5.32 (d, JNH,2 = 9.1 Hz, 1H, N–H), 4.77
(d, JCH2–CH2 = 11.4 Hz, 1H, CH2PhOMe), 4.71 (d, JCH2–CH2 = 10.4 Hz,
1H, CH2PhOMe), 4.66 (d, J1,2 = 3.3 Hz, 1H, H-1), 4.57 (overlapping,
2H, CH2PhOMe), 4.45 (d, JCH2–CH2 = 11.4 Hz, 1H, CH2PhOMe), 4.41
(d, JCH2–CH2 = 10.4 Hz, 1H, CH2PhOMe), 4.20 (m, 1H, H-2), 3.81–
3.74 (overlapping, 9H, 3 ꢂ PhOCH3), 3.72–3.59 (overlapping, 5H,
H-3, H-4, H-5, H-6a and H-6b), 3.31 (s, 3H, OCH3 at C-1), 1.85
(s, 3H, NHCOCH3 at C-2); 13C NMR (CDCl3) d 169.7 (COCH3),
159.2, 129.6, 129.5, 114.0, 113.8 (18C, Ph), 98.5 (C-1), 79.6 (C-4),
78.1 (C-3), 74.5 (CH2PhOCH3), 74.1 (CH2PhOCH3), 73.0
(CH2PhOCH3), 70.7 (C-5), 68.0 (C-6), 55.2–54.8 (4C, 3 ꢂ PhOCH3
and CH3O at C-1), 52.5 (C-2), 23.5 (COCH3); MS (ESI positive) m/z
618.9 [MꢀNa]+. Anal. Calcd for C33H41NO9: C, 66.54; H, 6.94; N,
2.35. Found: C, 66.47; H, 6.83; N, 2.36.
rotations ([a
]D) are given in 10ꢀ1 deg cm2 gꢀ1 and the concentra-
4.4. (S)-N-(1-Phenyl-3-(tetrahydro-2H-pyran-2-yloxy)propan-2-
tion are given in g/100 mL. Infrared (IR) spectra were recorded in
Nujol. Mass spectrometry was performed using a quadrupole
ion-trap mass spectrometer equipped with an ESI ion source. The
spectra were collected in continuous flow mode by connecting
the infusion pump directly to the ESI source. Solutions of com-
yl)acetamide 12
(S)-2-N-Acetylamido-3-phenyl-1-propanol12 (300 mg, 1.5 mmol),
dissolved in CH2Cl2 (10 mL) containing PPTS (5 mg), was treated
with 3,4-dihydro-2H-pyran (567 lL, 6.2 mmol) at 23 °C, for 10 h.
pounds were infused at a flow rate of 5 lL/min. The spray voltage
After evaporation of the solvent and usual work-up, the crude
product obtained was purified by flash chromatography (eluting
with hexane/AcOEt; 1:9, v/v) to afford the pyranylether 12 as a
glass mixture of diastereomers (358 mg, 86% Y) showing: 1H
NMR (CDCl3) d 7.35–7.20 (m, 10H, Ph), 6.18 (br d, JNH,2 = 7.8 Hz,
1H, N–H), 5.76 (br d, JNH,2 = 7.9 Hz, 1H, N–H), 4.59 (m, 1H,
OCH2CH), 4.47 (m, 1H, OCH2CH), 4.37 (m, 1H, H-2), 4.26 (m, 1H,
H-2), 3.92 (m, 1H, OCH2CH2), 3.85 (m, 1H, OCH2CH2), 3.72–3.64
(overlapping, 2H, H-3), 3.56–3.49 (overlapping, 2H, OCH2CH2),
3.46 (m, 1H, H-3), 3.40 (m, 1H, H-3), 2.99–2.85 (overlapping, 4H,
H-1), 1.99 (br s, 6H, NHCOCH3), 1.92–1.54 (overlapping, 12H,
CH2CH2CH2CH); 13C NMR (CDCl3) d 169.5 (NHCOCH3), 169.4 (NHC-
OCH3), 138.1, 138.2, 129.3, 128.3, 126.4, 126.3 (Ph), 100.5
(OCH2CH), 99.1 (OCH2CH), 68.4 (C-3), 67.7 (C-3), 63.6 (OCH2CH2),
62.5 (OCH2CH2), 50.4 (C-2), 50.1 (C-2), 37.6 (C-1), 37.3 (C-1),
30.9, 30.5, 25.3, 25.2 (CH2CH2CH2), 23.4 (COCH3), 20.3, 19.5
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.
Work-up refers to washing the organic layer with saturated
NH4Cl solution then with water, drying over Na2SO4 and evaporat-
ing the solvent under reduced pressure.
4.2. Benzyloxycarbonyl-4,8,9-tri-trimethylsilyl-N-acetyl-b-
neuraminic acid 1,7-lactone 4b
2-Benzyloxycarbonyl-N-acetyl-b-neuraminic acid 1,7-lactone10
(150 mg, 0.36 mmol), dissolved in THF (9.0 mL) was treated with
TMSI (780 lL) at 23 °C, for 2 h. At this time, the solvent was re-
moved under reduced pressure and the crude compound was puri-
fied by flash chromatography (eluting with hexane/AcOEt/Et3N;

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P. Rota et al. / Tetrahedron: Asymmetry 21 (2010) 2681–2686
(CH2CH2CH2); ESI-MS (positive) m/z 300.3 [M+Na]+. Anal. Calcd for
16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.39; H, 8.42; N,
5.09.
raphy, (eluting with hexane/AcOEt; 6:4, v/v) compound 3c was ob-
C
tained (122 mg, 89% Y) as a glass: ½a D20
ꢁ
¼ ꢀ22:5 (c 1, CHCl3); 1H
NMR (CDCl3) d 6.83 (d, JNH,2 = 9.1 Hz, 1H, N–H), 5.48 (ddd,
J4,3b = J4,5 = 11.0, J4,3a = 5.0 Hz, 1H, H-4), 5.28 (dd, J7,8 = 5.7,
J7,6 = 1.7 Hz, 1H, H-7), 5.09 (ddd, J8,9b = J8,7 = 5.7, J8,9a = 2.4 Hz, 1H,
H-8), 4.47 (dd, J9a,9b = 12.5, J9b,8 = 5.7 Hz, 1H, H-9a), 4.36 (dd,
J6,5 = 10.5, J6,7 = 1.7 Hz, 1H, H-6), 4.14 (dd, J9b,9a = 12.5,
J9b,8 = 5.7 Hz, 1H, H-9b), 3.99 (m, 1H, H-5), 3.80 (s, 3H, COOCH3),
2.62 (dd, J3a,3b = 13.5, J3a,4 = 5.0 Hz, 1H, H-3a) 2.16 (overlapping,
6H, 2 ꢂ CH3COO), 2.06 (s, 3H, CH3COO), 2.05–2.00 (overlapping,
7H; 2 ꢂ CH3COO and H-3b); 13C NMR (CDCl3) d 170.5, 170.4,
170.3, 170.12, 168.2, 166.1, 157.9 (1C, COCF2CF2CF3), 120.0–108.0
(3C, COCF2CF2CF3), 97.1, 71.3, 70.9, 67.6, 67.1, 61.8, 53.3, 50.6,
35.9, 20.7, 20.6 (3C) 20.5; IR 1752, 1715, 1669 cmꢀ1; MS (ESI posi-
tive) m/z 710.6 [M+Na]+. Anal. Calcd for C24H28F7NO14: C, 41.93; H,
4.11; N, 2.04. Found: C, 41.89; H, 4.08; N, 2.07.
4.5. General procedure for N-Perfluorotransacylation
The acylamide (0.2 mmol) dissolved in CH3CN (0.60 mL), con-
taining triethylamine (0.166 mL, 1.2 mmol), was reacted with the
appropriate perfluorinated anhydride (0.6 mmol) at 135 °C for
the time indicated in Table 2 (5–15 min) in a sealed tube. Then,
methanol (0.20 mL) was added and the reaction mixture was
cooled at 0 °C under stirring that was continued for 5 min. At this
time the solvent was evaporated under reduced pressure to afford
a crude residue which, after the usual work-up, and rapid chroma-
tography, eluting with the designed solvent system, afforded the
appropriate N-transacylated derivative. No methanol was added
to the reaction mixture, affording the compound 5b which was iso-
lated by rapid chromatography of the crude reaction residue, after
evaporation of the solvents.
4.9. Methyl-4,7,8,9-tetra-O-acetyl-N-(2,2,3,3,4,4,
4heptafluorobutanoyl)-b-neuraminic acid methyl ester 3d
4.6. 2,4,7,8,9-Penta-O-acetyl-5-N-(2,2,2-trifluoroacetyl)-b-neur-
aminic acid methyl ester 3a
Starting with methyl 4,7,8,9-tetra-O-acetyl-N-acetyl-b-neuram-
inic acid methyl ester 1b13 (90 mg, 0.2 mmol), after flash chroma-
tography, eluting with hexane/AcOEt (6:4; v/v), compound 3d was
Starting with 4,7,8,9-tetra-O-acetyl-5-N-acetyl-b-neuraminic
acid methyl ester 1a13 (107 mg, 0.2 mmol), after flash chromatogra-
phy, (eluting with hexane/AcOEt; 6:4, v/v), compound 3a was ob-
obtained (116 mg, 88% Y) as a glass: ½a D20
¼ þ2:0 (c 1, CHCl3); MS
ꢁ
(ESI negative) m/z 657.7 [MꢀH]ꢀ. Anal. Calcd for C23H28F7NO13
:
C, 41.89; H, 4.28; N, 2.12. Found: C, 42.45; H, 4.30; N, 2.09. Other
spectroscopic properties (1H and 13C NMR) were identical to those
previously reported.6
tained (100 mg, 85% Y) as a glass: ½a D20
ꢁ
¼ ꢀ22:3 (c 1, CHCl3); 1H
NMR (CDCl3) d 6.60 (d, JNH,2 = 9.2 Hz, 1H, N–H), 5.43 (m, 1H, H-4),
5.37 (m, 1H, H-7), 5.12 (m, 1H, H-8), 4.51 (d, J9a,9b = 12.5, 1H, H-
9a), 4.31 (br d, J6,5 = 10.5, 1H, H-6), 4.17 (dd, J9b,9a = 12.5,
J9b,8 = 5.8 Hz, 1H, H-9b), 4.08 (m, 1H, H-5), 3.83 (s, 3H, COOCH3),
2.62 (br d, J3a,3b = 13.4 Hz, 1H, H-3a), 2.18 (overlapping, 6H,
2 ꢂ CH3COO), 2.16–2.02 (overlapping, 4H, CH3COO and H-3b), 2.06
(overlapping, 6H, 2 ꢂ CH3COO); 13C NMR (CDCl3) d 171.1, 170.8,
170.6, 170.1, 168.2, 166.1, 157.4 (q, JC–F = 38 Hz, COCF3), 116.6 (1C,
JC–F = 287 Hz, CF3), 97.3, 71.8, 71.7, 67.7, 67.5, 62.0, 53.3, 49.9, 35.8,
20.9, 20.7, 20.6, 20.5; IR 1752, 1725, 1671 cmꢀ1; MS (ESI positive)
4.10. 4,8-Diacetyl-2-benzyloxycarbonyl-9-(2-methoxyethoxy)
methyl-N-(2,2,3,3,4,4,4-heptafluorobutanoyl)-b-neuraminic
acid 1,7-lactone 5a
Starting with 4,8-diacetyl-2-benzyloxycarbonyl-9-(2-methoxy-
ethoxy)methyl-N-acetyl-b-neuraminic acid 1,7-lactone1 (120 mg,
0.2 mmol), after a flash chromatography, eluting with hexane/
AcOEt; 6:4, v/v) the lactone 5a (119 mg, 79% Y) was obtained as
m/z 610.0 [M+Na]+, 1197.1 [2M+Na]+. Anal. Calcd for C22H28F3NO14
:
a glass (79% Y): ½a D20
ꢁ
¼ þ18:1 (c 1, CHCl3); 1H NMR (CDCl3) d
C, 45.98; H, 4.80; N, 2.38. Found: C, 45.94; H, 4.78; N, 2.35.
7.39–7.32 (5H, m, Ph), 7.08 (d, JNH,5 = 8.0 Hz, 1H, N–H), 5.46 (m,
1H, H-8), 5.18 (AB system, 2H, CH2Ph), 5.14 (br m, 1H, H-4), 4.79
(d, J8,7 = 7.8 Hz, 1H, H-7), 4.74 (m, 2H, OCH2O), 4.38 (br s, 1H, H-
6), 4.25 (br d, JNH,5 = 8.0 Hz, 1H, H-5), 3.99 (A part of ABX system,
J9a,9b = 11.6 Hz, J9a,8 = 3.3 Hz, 1H, H-9a), 3.88 (B part of ABX system,
J9a,9b = 11.6 Hz, J9b,8 = 2.7 Hz, 1H, H-9b), 3.70 (m, 2H, OCH2CH2O),
3.56 (m, 2H, OCH2CH2O), 3.38 (s, 3H, CH3O), 2.43 (br d,
J3a,3b = 15.0 Hz, 1H, H-3a), 2.16 (dd, J3b,3a = 15.0, J3b,4 = 3.9 Hz, 1H,
H-3b), 2.10 (s, 3H, CH3CO), 2.06 (s, 3H, CH3CO); 13C NMR (CDCl3)
d 169.8 (CH3COO at C-8), 168.7 (CH3COO at C-4), 163.9 (C-1),
157.3 (COCF2CF2CF3), 151.5 (PhCH2OCO), 133.9, 128.9, 128.7,
128.5 (Ph), 120.0–107.0 (CF2CF2CF3), 95.5 (OCH2O), 92.7 (C-2),
76.0 (C-7), 71.6 (C-6), 71.3 (OCH2CH2O), 71.2 (C-8), 70.9 (PhCH2O-
CO), 66.9 (C-4), 66.8 (OCH2CH2O), 64.9 (C-9), 59.0 (CH3O), 49.1 (C-
5), 33.0 (C-3), 20.9 (CH3COO at C-8), 20.6 (CH3COO at C-4); MS (ESI
positive) m/z 774.6 [M+Na]+. Anal. Calcd for C29H32F7NO14: C,
46.35; H, 4.29; N, 1.86. Found: C, 46.20; H, 4.31; N, 1.78.
4.7. 2,4,7,8,9-Penta-O-acetyl-5-N-(2,2,3,3,3-pentafluoroprop-
yonil)-b-neuraminic acid methyl ester 3b
Starting with 4,7,8,9-tetra-O-acetyl-5-N-acetyl-b-neuraminic
acid methyl ester 1a13 (107 mg, 0.2 mmol), after flash chromatog-
raphy, (eluting with hexane/AcOEt; 6:4, v/v) compound 3b was ob-
tained (110 mg, 86% Y) as a glass: ½a D20
ꢁ
¼ ꢀ18:5 (c 1, CHCl3); 1H
NMR (CDCl3)
d 7.00 (d, JNH,2 = 9.2 Hz, 1H, N–H), 5.42 (ddd,
J4,3b = J4,5 = 10.8, J4,3a = 4.8 Hz, 1H, H-4), 5.32 (m, 1H, H-7), 5.04
(br s, 1H, H-8), 4.51 (d, J9a,9b = 12.5, 1H, H-9a), 4.30 (br d,
J6,5 = 10.6, 1H, H-6), 4.16 (dd, J9b,9a = 12.5, J9b,8 = 6.5 Hz, 1H, H-9b),
4.08 (m, 1H, H-5), 3.85 (s, 3H, COOCH3), 2.58 (dd, J3a,3b = 13.4,
J3a,4 = 4.8 Hz, 1H, H-3a) 2.15 (overlapping, 6H, 2 ꢂ CH3COO),
2.09–2.05 (overlapping, 4H, CH3COO and H-3b), 2.03 (s, 3H,
CH3COO), 2.02 (s, 3H, CH3COO); 13C NMR (CDCl3) d 170.8, 170.6,
170.5, 170.1, 168.2, 166.1, 158.2 (COCF2CF3), 120.0–112.0 (2C,
CF2CF3), 97.1, 71.6, 71.4, 67.6, 67.3, 61.9, 53.3, 50.1, 35.9, 20.9,
20.7, 20.6, 20.5; IR 1747, 1718, 1669 cmꢀ1; MS (ESI positive) m/z
4.11. 2-Benzyloxycarbonyl-4,8,9-tri-trimethylsilyl-N-
(2,2,3,3,4,4,4-heptafluorobutanoyl)-b-neuraminic acid 1,7-
lactone 5b
660.0 [M+Na]+, 1298.3 [2M+Na]+. Anal. Calcd for C23H28F5NO14
C, 43.34; H, 4.43; N, 2.20. Found: C, 43.28; H, 4.47; N, 2.23.
:
Starting with 2-benzyloxycarbonyl-4,8,9-tri-trimethylsilyl-N-
acetyl-b-neuraminic acid 1,7-lactone 4b (130 mg, 0.2 mmol), after
rapid flash chromatography (eluting with hexane/AcOEt/Et3N;
9:1:0.1, v/v/v), compound 5b was obtained (118 mg, 74% Y) as a
4.8. 2,4,7,8,9-Penta-O-acetyl-N-(2,2,3,3,4,4,4-
heptafluorobutanoyl)-b-neuraminic acid methyl ester 3c
Starting with 4,7,8,9-tetra-O-acetyl-5-N-acetyl-b-neuraminic
acid methyl ester 1a13 (107 mg, 0.2 mmol), after flash chromatog-
glass: ½a 2D0
ꢁ
¼ þ69:1 (c 1, CHCl3); 1H NMR (CD2Cl2) d 7.41–7.33
(m, 5H, Ph), 6.87 (d, JNH,5 = 7.6 Hz, 1H, N–H), 5.22 (d,

P. Rota et al. / Tetrahedron: Asymmetry 21 (2010) 2681–2686
2685
JCH2a,CH2b = 12.0 Hz, 1H, CH2a), 5.12 (d, JCH2b,CH2a = 12.0 Hz, 1H,
CH2b), 4.54 (br s, 1H, H-6), 4.48 (d, J8,7 = 8.6 Hz, 1H, H-7), 4.17 (br
m, 1H, H-4), 4.08 (m, 1H, H-8), 4.02 (d, J5,NH = 7.6 Hz, 1H, H-5),
3.80 (dd, J9a,9b = 11.0, J9a,8 = 3.6 Hz, 1H, H-9a), 3.76 (dd,
J9b,9a = 11.0, J9b,8 = 2.4 Hz, 1H, H-9b), 2.18 (dd, J3a,3b = 14.0, J3a,4
<1.0 Hz, 1H, H-3a), 2.05 (dd, J3b,3a = 14.0, J3b,4 = 3.2 Hz, 1H, H-3b),
0.16 (s, 9H, Si(CH3)3), 0.15 (s, 9H, Si(CH3)3), 0.13 (s, 9H, Si(CH3)3);
13C NMR (CD2Cl2) d 164.9 (C-1), 157.6 (COCF2CF2CF3), 152.1
(PhCH2OCO), 135.2, 129.4, 129.2, 129.1 (Ph), 120.0–107.0
(CF2CF2CF3), 93.8 (C-2), 77.6 (C-7), 72.6 (C-8), 71.2 (C-6), 71.1
(PhCH2OCO), 66.6 (C-4), 63.7 (C-9), 52.7 (C-5), 37.0 (C-3), 0.4
(Si(CH3)3), ꢀ0.3 (Si(CH3)3), ꢀ0.4 (Si(CH3)3); MS (ESI positive) m/z
819.2 [MꢀNa]+. Anal. Calcd for C30H44NO10Si3: C, 45.27; H, 5.57;
N, 1.76. Found: C, 45.47; H, 5.49; N, 1.76.
C20H20F7NO7: C, 46.25; H, 3.88; N, 2.70. Found: C, 46.35; H, 3.87;
N, 2.65. Other spectroscopic properties (1H and 13C NMR) were
identical to those previously reported.1
4.15. trans-2-(2,2,3,3,4,4,4-Heptafluorobutanamido)cyclohexyl
benzylate 11
Starting with an enantiomeric mixture of trans-2-acet-
amidocyclohexyl benzylate15 (10, 50 mg, 0.2 mmol), after flash
chromatography (eluting with hexane/AcOEt; 6:4, v/v) the amide
11 was obtained (60 mg, 75% Y) as a white glass: 1H NMR (CDCl3)
d 7.43–7.39, m, 5H Ph), 6.23 (br s, 1H, N–H), 4.65 (d, JCH2 = 12.3 Hz,
1H, CH2Ph), 4.41 (d, JCH2 = 12.3 Hz, 1H, CH2Ph), 3.74 (m, 1H, H-2),
3.23 (ddd, J1,6b = 14.0, J1,2 = 10.1, J1,6a = 4.1 Hz, 1H, H-1), 2.27–2.16
(m, 2H, H-3a and H-6a) 1.81 (m, 1H, H-5a), 1.66 (m, 1H, H-4a),
1.43–1.26 (m, 2H, H-6b and H-4b), 1.29–1.14 (overlapping, 2H,
H-3b, and H-5b); ESI-MS (negative) m/z 352.2 [MꢀH]ꢀ. Anal. Calcd
for C17H18F7NO2: C, 50.88; H, 4.52; N, 3.49. Found: C, 50.71; H,
4.52; N, 3.40. Other spectroscopic properties (1H and 13C NMR)
were identical to those previously reported.1
4.12. Methyl 3,4,6-O-tri-benzyl-2-deoxy-2-N-(2,2,3,3,4,4,4-hep-
tafluorobutanoyl)-a-D-glucopyranose 7a
Starting with methyl 3,4,6-O-tri-benzyl-2-deoxy-2-N-acetyl-
a-
D
-glucopyranose 6a14 (100 mg, 0.2 mmol), after flash chromatogra-
phy, (eluting with hexane/AcOEt; 6:4, v/v) compound 7a was ob-
tained (104 mg, 79% Y) as a glass: ½a D20
ꢁ
¼ þ58:8 (c 1, CHCl3); 1H
4.16. 2,2,3,3,4,4,4-Heptafluoro-N-((S)-1-phenyl-3-(tetrahydro-
2H-pyran-2-yloxy)propan-2-yl)butanamide 13
NMR (CDCl3)
d 7.40–7.15 (overlapping, 15H, Ph), 6.33 (d,
JNH,2 = 9.1 Hz, 1H, N–H), 4.82 (d, JCH2–CH2 = 11.3 Hz, 1H, CH2Ph),
4.78 (d, JCH2–CH2 = 10.8 Hz, 1H, CH2Ph), 4.74 (d, J1,2 = 3.7 Hz, 1H,
H-1), 4.66–4.63 (overlapping, 2H, CH2Ph), 4.56–4.52 (overlapping,
2H, CH2Ph) 4.28 (m, 1H, H-2), 3.80–3.69 (overlapping, 5H, H-3,
H-4, H-5, H-6a and H-6b), 3.37 (s, 3H, OCH3 at C-1); 13C NMR
(CDCl3) d 157.8 (COCF2CF2CF3), 137.8, 137.7, 128.6, 128.5, 128.4,
127.9, 127.8 (18 C, Ph), 120.0–110.0 (3C, CF2CF2CF3), 97.8 (C-1),
79.3 (C-4), 78.4 (C-3), 75.0 (CH2Ph), 73.6 (2C, CH2Ph), 70.9 (C-5),
68.3 (C-6), 55.3 (CH3O at C-1), 53.5 (C-2); ESI-MS (positive) m/z
682.2 [M+Na]+. Anal. Calcd for C32H32F7NO6: C, 58.27; H, 4.89; N,
2.12. Found: C, 58.12; H, 4.83; N, 2.08.
Starting with (S)-N-1phenyl-3-(tetrahydro-2H-pyran-2-yloxy)
propan-2-yl)acetamide 12 (55 mg, 0.2 mmol), after flash chroma-
tography (eluting with hexane/AcOEt; 9:1, v/v) compound 13
was obtained (76 mg, 88% Y) as a white glass: 1H NMR (CDCl3) d
8.28 (br d, JNH,2 = 7.5 Hz, 1H, N–H), 7.38–7.22 (m, 10H, Ph), 7.06
(br d, JNH,2 = 6.0 Hz, 1H, N–H), 4.57 (m, 1H, OCH2CH), 4.43 (m,
1H, OCH2CH), 4.34 (m, 1H, H-2), 4.14 (m, 1H, H-2), 3.97 (m, 1H,
OCH2CH2), 3.88 (m, 1H, OCH2CH2), 3.79–3.73 (overlapping, 2H,
H-3), 3.60–3.52 (overlapping, 4H, OCH2CH2 and H-3), 3.09–2.87
(overlapping, 4H, H-1), 1.94–1.54 (overlapping, 12H, CH2CH2
CH2CH); 13C NMR (CDCl3) d 158.9 (1C, COCF2CF2CF3), 157.9 (1C,
COCF2CF2CF3), 137.2, 136.7, 129.5, 129.3, 128.6, 128.5, 126.9,
126.7 (Ph), 122.0–108.0 (3C, COCF2CF2CF3), 102.0 (OCH2CH), 99.7
(OCH2CH), 69.1 (C-3), 67.0 (C-3), 64.7 (OCH2CH2), 63.2 (OCH2CH2),
52.1 (C-2), 51.6 (C-2), 37.0 (C-1), 36.8 (C-1), 31.1, 30.4, 25.2,
25.0,21.0, 19.9 (CH2CH2CH2); ESI-MS (positive) m/z 454.3
[M+Na]+. Anal. Calcd for C18H20F7NO3: C, 50.12; H, 4.67; N, 3.25.
Found: C, 50.39; H, 4.52; N, 3.29.
4.13. Methyl 3,4,6-O-tri-parametoxybenzyl-2-deoxy-2-N-
(2,2,3,3,4,4,4-heptafluorobutanoyl)-a-D-glucopyranose 7b
Starting with methyl 3,4,6-O-tri-paramethoxybenzyl-2-deoxy-
2-N-acetyl- -glucopyranose 6b (100 mg, 0.2 mmol), after flash
a
-D
chromatography (eluting with hexane/AcOEt; 6:4, v/v) the trans-
acylated glucosamino derivative 7b (123 mg, 82% Y) was obtained
as a glass: ½a 2D0
ꢁ
¼ þ2:6 (c 1, CHCl3); 1H NMR (CDCl3) d 7.30–6.79
(overlapping, 12H, Ph), 6.22 (d, JNH,2 = 8.5 Hz, 1H, N–H), 4.76–
4.71 (overlapping, 2H, H-1 and CH2PhOMe), 4.69 (d, JCH2–
CH2 = 10.1 Hz, 1H, CH2PhOMe), 4.58 (br t, JCH2–CH2 = 11.4 Hz, 2H,
CH2PhOMe), 4.46 (d, JCH2–CH2 = 11.4 Hz, 1H, CH2PhOMe), 4.42 (d,
JCH2–CH2 = 10.1 Hz, 1H, CH2PhOMe), 4.20 (m, 1H, H-2), 3.82–3.76
(overlapping, 9H, 3 ꢂ PhOCH3), 3.74–3.60 (overlapping, 5H, H-3,
H-4, H-5, H-6a and H-6b), 3.34 (s, 3H, OCH3 at C-1); 13C NMR
(CDCl3) d 159.3 (3C, Ph), 157.6 (COCF2CF2CF3), 129.6, 129.5,
114.0, 113.8 (15C, Ph), 120.0–110.0 (3C, CF2CF2CF3), 97.7 (C-1),
78.7(C-4), 78.1 (C-3), 74.7 (CH2PhOCH3), 74.5 (CH2PhOCH3), 73.2
(CH2PhOCH3), 70.9 (C-5), 67.8 (C-6), 55.3–55.1 (4C, 3 ꢂ PhOCH3
and CH3O at C-1), 53.6 (C-2); ESI-MS (positive) m/z 772.8
[M+Na]+. Anal. Calcd for C35H38F7NO9: C, 56.07; H, 5.11; N, 1.87.
Found: C, 56.00; H, 5.03; N, 1.80.
Acknowledgement
Financial support from MiUR, Italian Ministry of University and
Research, is acknowledged.
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N-acetyl-
-glucopyranose 71 (75 mg, 0.2 mmol), after flash chro-
a-D
matography (eluting with hexane/AcOEt; 85:15, v/v) compound 9
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ꢁ
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