Use of N-pivaloyl imidazole as protective reagent for sugars

Article abstract of DOI:10.1055/s-1998-2224

N-Pivaloyl imidazole was prepared and used as a selective protective reagent of different monosaccharides (D-glucose, D-mannose, D-galactose, 2- acetamido-2-deoxy-D-glucose and 2-acetamido-2-deoxy-β-D-glucopyranosyl azide) and lactose. A variety of pivalates were obtained with moderate or good regioselectivity.

Full text of DOI:10.1055/s-1998-2224

SYNTHESIS
December 1998
1787
Use of N-Pivaloyl Imidazole as Protective Reagent for Sugars
Francisco Santoyo-González,* Clara Uriel, José A. Calvo-Asín
Instituto de Biotecnología, Facultad de Ciencias, Universidad de Granada, 18071 Granada, Spain
Fax +34958243186; E-mail: fsantoyo@goliat.ugr.es
Received 19 March 1998; revised 9 May 1998
mannopyranoside,28 benzyl β-D-galactopyranoside,29
methyl 2-acetamido-2-deoxy-α- and β-D-glucopyrano-
sides,30 methyl a-D-glycoside of N-acetyl-D-muramic
acid30 and methyl β-D-xylopyranoside26), free monosac-
charides (D-glucose31,32 and 2-acetamido-2-deoxy-D-
glucose30), unprotected disaccharides (sucrose,33
trehalose34 and maltose35).
Abstract: N-Pivaloyl imidazole was prepared and used as a selec-
tive protective reagent of different monosaccharides (D-glucose,
D-mannose, D-galactose, 2-acetamido-2-deoxy-D-glucose and 2-
acetamido-2-deoxy-β-D-glucopyranosyl azide) and lactose. A
variety of pivalates were obtained with moderate or good regiose-
lectivity.
Key words: N-pivaloyl imidazole, selective acylation, monosac-
charides, pivaloylation, protective reagent
In search of new protecting reagents, we have prepared N-
pivaloyl imidazole which should increase the regioselec-
tivity in the protection of carbohydrate as it combines the
hindrance of the pivaloyl group with the advantages of the
N-acylimidazole reagents. To study its reactivity a variety
of free monosaccharides (D-glucose, D-mannose, D-ga-
lactose, 2-acetamido-2-deoxy-D-glucose), 2-acetamido-
2-deoxy-β-D-glucopyranosyl azide and lactose were cho-
sen. The reactions were performed in anhydrous DMF at
room temperature or 60°C using variable amounts of N-
pivaloyl imidazole and reaction times in order to study the
influence of the reaction conditions on the selectivity.
Esters are important protecting groups in carbohydrate
chemistry.1–6 Selective acylation in carbohydrates is pos-
sible by the combination of the different reactivity of the
hydroxy groups with the use of hindered carboxylic acid
chlorides (such as pivaloyl chloride and diphenylacetyl
chloride7) or the use of less reactive esterifying reagents
that transfer acyl groups (such as N-acyl imidazoles,3,8–12
benzoyl cyanide,13,14 3-acylthiazolidine-2-diones and 3-
acyl-5-methyl-1,3,4-thiadiazole-2(3H)-thiones15–17). Piv-
aloyl esters with their great steric hindrance can be formed
very selectively with pivaloyl chloride in pyridine at low
temperature.18 Additional advantages of this protecting
group are, first, their slow reactivity with NH3 in methanol
or guanidine, that allows the selective removal of the
widely used acetates in the presence of pivaloates,19–21
and, second, the decrease tendency to give orthoesters
during Koenigs–Knorr glycosidation.22–25 More recently
enzymic regioselective deacylations of pivaloyl monosac-
charide derivatives with esterases from mammaliam sera
have been reported.26 The ability of pivaloyl chloride to
acylate sugars selectively has been previously exploited in
the synthesis of various pivaloylated monosaccharide gly-
cosides (methyl α-D-glucopyranoside,27 methyl α-D-
Reaction of free D-glucose with 6 equivalents of N-piv-
aloyl imidazole at room temperature for 8 hours led to a
mixture of the tripivalated protected derivatives 1,3,6-tri-
O-pivaloyl-β-D-glucopyranoside (1), as the minor prod-
uct (33%), and 1,2,6-tri-O-pivaloyl-β-D-glucopyranoside
(2), as the major product (48%) (Tables 1 and 2). Howev-
er, an increase of the reaction time to 48 hours or perform-
ing the reaction at 60°C for 8 hours gave a crude product
from which only compound 1 could be isolated in 43 and
50%, respectively. In these cases, TLC (Et2O/hexane, 1:1)
of the crude product showed traces of 3 and 4 that were

SYNTHESIS
Papers
1788
not isolated. A more complex mixture of compounds was was prolonged to 48 hours. In this case, compound 10
formed when the reaction time was risen up to 48 hours (α,β mixture) was isolated as the major product (47%) to-
and the reaction was performed at 60°C. In this case, com- gether with the penta-pivalates 12 and 13 (17%) in the ra-
pounds 1 (37%) was isolated together with the 1,2,4,6-tet- tio of ~2:1.
ra-pivalate 3 (20%), 1,2,3,6-tetra-pivalate 4 (22%) and the
D-Galactose shows a different behaviour and the acylat-
penta-pivalate 5 (5%). In the light of these results and
ing reactions led to protected furanoside derivatives. The
from a survey of the literature, it can be concluded that
reaction with 5 equivalents of N-pivaloyl imidazole for 60
1,2,3,6-tetra-pivalate 4 is obtained with high selectivity
hours at room temperature gave 1,2,3,6-tetra-O-pivaloyl-
using pivaloyl chloride as reported by Becker et al.31
α-D-galactofuranoside (14), as the major product (47%),
However, the use of N-pivaloyl imidazole allows more se-
and a mixture of the α,β-anomers of 1,2,3,5,6-penta-O-
lectivity in the preparation of the 1,3,6- and 1,2,6-tri-piv-
pivaloyl-D-galactofuranoside (15), as the minor product
alates (1 and 2).
(8%). The yield of the tetra-pivalate 14 was slightly im-
When the substrate was free D-mannose and 5 equivalents proved (55%) when the reaction was performed at 60°C
of N-pivaloyl imidazole were used, a mixture of 2,6-di-O- for 24 hours, however, simultaneously compound 15 was
pivalolyl-α,β-D- (6, 6%) and 3,6-di-O-pivaloyl-α,β-D- also isolated in higher yields (19%). The furanoside na-
mannopyranoside (7, 36%) was formed after 24 hours at ture of the carbohydrate ring of compound 14 was estab-
room temperature. Quenching of the reaction after 48 lished by the analysis of its 1H and 13C NMR data as well
hours using the same conditions led to the same two com- as those obtained from its acetylated derivative 16, which
pounds 6 and 7 but with improved yields (12 and 55%, was synthesised by standard acetylation. This is supported
respectively). A complex mixture of protected com- by the low-field shift observed in the signal of the H-5
pounds was obtained when the reaction was performed at from δ = 3.90 in 14 to 5.25 in 16. The α- anomeric config-
60°C for 24 hours: 1,3,6-tri-O-pivaloyl-β-D- (8, 11%), uration of compound 14 was established from the J1,2 val-
2,3,6-tri-O-pivaloyl-α-D- (9, 18%), 1,2,3,6-tetra-O-piv- ue of 4.6 Hz that is in agreement with previously reported
aloyl-α-D- (10α, 10%), 1,2,3,6-tetraO--pivaloyl-β-D- data for D-galactofuranosides.36,37 In addition, the 13C
(10β, 14%), 1,2,4,6-tetraO- -pivaloyl-α-D- (11α, 4%), NMR spectrum of 14 showed the signal of C-1 at δ = 93.3,
1,2,4,6-tetra-O-pivaloyl-β-D-mannopyranoses (11β, 5%) characteristic of the α-anomer of galactofuranose deriva-
together with an inseparable mixture of 1,2,3,4,6-penta- tives.38 The selective access to protected galactofuranoside
O-pivaloyl-β-D-mannopyranose (12) and 1,2,3,5,6-pen- derivatives such as compound 14 in one step from the free
ta-O-pivaloyl-β-D-mannofuranose (13, 5%). However, a sugar is of interest because the glycobiology of galactofura-
better selectivity was observed when the reaction time nose is a topic of increasing attention11,36,37 (Tables 3–5).
Table 1. Regioselective Pivaloylation of Sugars
Substrate
Gluc
Piv-imidazole Temperature
Time
(h)
Solventa
Products [pattern of substitution] {Rf} (yield, %)
(Equiv)
(°C)
6
6
6
6
r.t.
r.t.
60
60
8
48
8
A
B
B
B
1 [1,3,6] {0.38} (33), 2 [1,2,6] {0.1} (48)
1 [1,3,6] {0.15} (43)
1 [1,3,6] {0.15} (50)
1 [1,3,6] {0.15} (37), 3 [1,2,4,6] {0,38} (20), 4 [1,2,3,6] {0.22} (22),
5 [1,2,3,4,6] {0.62} (5)
48
Man
5
5
5
r.t.
r.t.
60
24
48
24
C
C
D
6 [2,6] {0.25} (6), 7 [3,6] {0.37} (36)
6 [2,6] {0.25} (12), 7 [3,6] {0.37} (55)
8 [1,3,6] {0.14}c (11), 9 [2,3,6] {0.10}c (18), 10α [1,2,3,6] {0.20}c
(10), 10β [1,2,3,6] {0.34}c (19), 11α [1,2,4,6] {0.28}c (4), 11β
[1,2,4,6] {0.44}c (5), 12 [1,2,3,4,6] + 13 [1,2,3,5,6] {0.6}c (5)
10α [1,2,3,6] {0.20}c (13), 10β [1,2,3,6] {0.34}c (34), 12 [1,2,3,4,6]
+ 13 [1,2,3,5,6] {0.60}c (17)
5
60
48
D
Gal
5
5
r.t.
60
60
24
D
D
14 [1,2,3,6] {0.19} (47), 15α,β [1,2,3,5,6] {0.53} (8)
14 [1,2,3,6] {0.19} (55), 15α,β [1,2,3,5,6] {0.53} (19)
GlucNAc
4
55
r.t.
45
18
24
48
E
F
17 [1,4,6] {0.0} (28), 18 [1,3,6] {0.17} (61), 19 [1,3,4,6] {0.28} (10)
20 [4,6] {0.0} (30), 21 [3,6] {0.12} (62), 22 [3,4,6] {0.22} (1.5)
23 [1,2,3',6,6'] {0.20} (69)
N3-GlucNAcb 2.5
Lactose
9
G
a
Solvent for column chromatography: Et2O/hexane: A (7:3); B (1:1); C (9:1); D (3:7); E (4:1); F (7:1); G (3:2).
N3-GlucNAc corresponds to 2-acetamido-2-deoxy-β-D-glucopyranosyl azide44 that was obtained by Zemplen de-O-acetylation from 3,4,6-
tri-O-acetyl-2-acetamido-2-deoxy-β-D-glucopyranosyl azide.45
b
c
Rf measures were made using solvent B.

SYNTHESIS
December 1998
1789
Table 2. Physical Data of Pivalated Derivatives 1–22
2-Acetamido-2-deoxy-D-glucose (GlcNAc) was investi-
gated next. It was reacted with 4 equivalents of N-pivaloyl
imidazole for 18 hours at 55°C. Under these conditions,
2-acetamido-2-deoxy-1,4,6-tri-O-pivaloyl-β-D-glucopyr-
anose (17, 28%) and 2-acetamido-2-deoxy-1,3,6-tri-O-
pivaloyl-α,β-D-glucopyranose (18, 61%, α,β ratio ~1:10)
were formed together with the fully protected 2-acetami-
do-2-deoxy-1,3,4,6-tri-O-pivaloyl-α,β-D-gluco-
pyranoside (19) which was isolated only in 10% yield.
Similar results were obtained in the reaction with 2-acet-
amido-2-deoxy-β-D-glucopyranosyl azide that was per-
formed using 2.5 equivalents of N-pivaloyl imidazole at
room temperature for 24 hours. In this case, the 4,6-dipiv-
alate 20 and the 3,6-dipivalate 21 were obtained as the
major products in a ~ 1:2 proportion (30 and 62% yield,
respectively) together with a small amount of the tripiv-
alate 22 (1.5%). These results improve the previously re-
ported study30 in the selective protection of GlucNAc us-
ing pivaloyl chloride in which complex mixture are ob-
tained.
Product
mp (°C)
[α]D (c, CHCl3) HRMS-FAB (M++Na)
Calc.
Found
1
130–132
126–128
140–141
154
118
syrup
syrup
syrup
syrup
syrup
syrup
syrup
syrup
syrup
101–102
syrup
–10 (1)
455.2257
–
–
–
–
455.2263
–
–
–
–
2b
+19 (0.2)
+14 (0.4)
–12 (0.1)
+15 (0.3)
–17 (0.2)
+5 (0.3)
+14 (0.7)
+3 (2.3)
–28 (2.8)
+27 (2.6)
–14 (0.5)
+32 (1)
–
+13 (0.4)
–9 (2.6)
+23 (1)
+8 (1)
–13 (1)
+19 (1)
–7 (1)
3b
4b
5b
6
7
8
9
371.1681
371.1681
455.2257
455.2257
539.2832
539.2832
539.2832
539.2832
623.3407
539.2832
623.3407
581.2937
496.2552
–
371.1680
371.1692
455.2269
455.2242
539.2840
539.2836
539.2822
539.2827
623.3400
539.2851
623.3415
581.2939
496.2543
–
10α
10β
11α
11β
12+13
14
15
16
17
68–70
139–140
86–87
134–135
86–87
149
18b
19b
20b
21b
22b
A high selectivity was obtained in the protection of the
disaccharide lactose. Reaction with 9 equivalents of the
acylating reagent at 45°C for 48 hours allowed after
workup the exclusive isolation of the 1,2,3',6,6'-penta-O-
pivaloyl-β-lactose (23) in 69% yield. Elucidation of the
structure of this compound was made on the basis of its
–
–
–
–
–
–
–
–
–19 (0.2)
–42 (0.1)
81–82
a
[α]D at 25°C.
b
Satisfactory microanalyses obtained: C ± 0.40, H ± 0.20.
Table 3. Characteristic 1H NMR Data for 1–22 and 25 (CDCl3/TMS, δ)
Product H-1
H-2
H-3
H-4
H-5
H-6
H-6'
Others
1a
2
5.61d
3.60dd
4.91dd
4.99dd
4.82dd
5.17dd
5.13dd
4.06m
–
4.03dd
5.23dd
5.44dd
5.23m
5.41dd
5.12dd
5.27dd
–
5.43dd
5.39dd
5.08d
5.41dd
4.06m
–
4.28m
4.40ddd 5.23dd
4.00ddd 5.07dd
5.03t
3.49t
3.40dd 3.59ddd
4.91dd 3.76m
3.73m
4.34m
4.28dd
4.12m
4.13dd
4.06dd
4.28dd
4.42m
–
4.34dd
4.33dd
4.33dd
4.31dd
4.23dd
4.15dd
4.11dd
–
4.11dd
3.97dd
4.15dd
4.02dd
4.20m
–
4.30dd
4.11m
4.37dd
4.06dd
4.15dd
4.27dd
4.29dd
4.34m
4.49dd
4.12m
4.27dd
4.12dd
4.55dd
4.42m
–
4.42dd
4.51dd
4.51dd
4.51dd
4.29dd
4.24dd
4.17dd
–
4.18dd
4.44dd
4.40dd
4.41dd
4.20m
–
4.52dd
4.11m
4.48dd
4.13dd
4.27dd
4.36dd
4.35dd
1.18, 1.20, 1.22 (3s, t-Bu)
1.18, 1.20, 1.22 (3s, t-Bu)
–
1.35, 1.39, 1.43, 1.46 (4s, t-Bu)
1.10, 1.13, 1.16, 1.19, 1.22 (5s, t-Bu)
1.23, 1.26 (2s, t-Bu)
5.65d
5.63d
5.71d
5.66d
5.17d
5.26d
4.87d
6.07d
5.16d
5.80d
6.00d
5.79d
6.06d
6.00d
6.15d
6.35d
6.29d
6.09s
6.33d
5.70d
6.14d
5.58d
5.60d
4.56d
4.87d
4.59d
6.20d
5.58d
3.69dd
3.76m
5.12t
3a
4a,b
5
6
3.48t
5.12dd 3.82ddd
3.70t 4.01m
3.87dd 3.50ddd
3.80dd
3.88m
3.86t
3.82t
3.90m
5.18t
5.23t
5.53t
–
3.78ddd
5.33t
4.13dd
5.17dd
4.85dd
5.04dd
5.30dd
5.02dd
5.23m
3.95m
4.09m
5.33dd
–
5.61dd
5.58bt
5.15bdd 4.32t
5.60t
4.97t
–
7α
1.25, 1.27 (2s, t-Bu)
1.24, 1.26 (2s, t-Bu)
7βc
8
–
4.20m
4.08m
3.63ddd
3.90m
3.83ddd
3.99ddd
4.02ddd
5.18ddd
1.20, 1.23, 1.25 (3s, t-Bu)
1.20, 1.24, 1.25 (3s, t-Bu)
1.15, 1.17, 1.23, 1.26 (4s, t-Bu)
1.17, 1.20, 1.21, 1.23 (4s, t-Bu)
1.21, 1.24, 1.25, 1.33 (4s, t-Bu)
1.21, 1.25, 1.27, 1.29 (4s, t-Bu)
1.11, 1.16, 1.20, 1.26, 1.27 (5s, t-Bu)
1.12, 1.26, 1.17, 1.18 (4s, t-Bu)
1.16, 1.17, 1.18, 1.21 (4s, t-Bu)
1.17, 1.18, 1.19, 1.20, 1.22, 1.23, 1.24 (7s, t-Bu)
–
1.18, 1.19, 1.20, 1.26 (4s, t-Bu), 2.09 (s, Ac)
1.22, 1.23, 1.24 (3s, t-Bu), 2.01 (s, Ac)
–
6.12 (NH)
6.36 (NH)
9
10α
10β
11α
11β
12β
13c
14
4.06dd 3.91m
4.25dd 5.23ddd
15α
15β
16
5.33ddd
5.25m
3.80m
–
4.23t
3.80m
–
3.55dd 3.63ddd
5.14t 3.52ddd
3.54dd 3.64ddd
17a
18α c
18β
19
4.97dd
20a
21a
22
1.22 (s, t-Bu) 5.94 (NH)
1.14 (2s, t-Bu), 1.96 (s, Ac) 6.34 (NH)
5.48 (NH)
1.21, 1.24, 1.29 (3s, t-Bu) 1.92 (s, Ac) 5.40 (NH)
1.18, 1.19, 1.23 (3s, t-Bu) 1.87 (s, Ac) 5.48 (NH)
3.39m
4.14m
4.87ddd 5.19dd
4.61m 4.97dd
3.91p-t 4.79p-t 3.72ddd
5.19–5.22m
3.83ddd
4.08m
3.86m
25α
25β
4.08m
3.96m
a Resonances were assigned by 1H-1H COSY correlation experiments.
b Measured in DMSO-d6
c Selected signals.

SYNTHESIS
Papers
Table 4. J Values (Hz) for the 1H NMR Data of 1–22 and 25 (cf. Table 3)
1790
spectroscopic data together with those corresponding to
its acetylated derivative 24 which was obtained by stan-
dard acetylation. This simple and selective access to a par-
tially O-protected lactose derivative is a relevant result
because lactose is an important constituent of the oli-
gosaccharide moiety of various glycoconjugates, espe-
cially of glycosphingolipids.39
Product J1,2
J2,3
9.3
J3,4
9.3
8.9
–
J4,5
9.3
9.7
–
9.5
10.0
9.7
9.8
9.9
–
9.9
9.8
–
9.7
10.2
10.1
–
3.7
8.4
5.5
6.8
–
J5,6
J6,6'
J2,NH
1
2
8.2
8.3
8.4
8.3
8.3
1.4
1.2
1.7
1.9
1.5
1.1
1.5
1.2
1.8
1.9
4.3
4.6
4.7
–
–
–
12.3
–
12.0
12.4
12.3
–
9.5
9.5
9.5
9.4
3.5
3.1
3.2
3.1
3.3
3.2
–
3.4
3.5
3.2
–
7.9
7.4
1.6
7.8
–
2.5, 4.5
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
3
4
5
9.5
9.4
9.7
9.9
9.8
9.0
9.9
9.8
–
9.7
10.2
10.2
–
2.4, 5.6
2.6, 5.0
2.1, 3.4
2.6, 4.5
–
1.8, 4.8
2.3, 3.6
2.4, 4.3
1.5, 4.2
2.3, 4.2
1.8, 4.5
1.9, 4.3
–
6α
7α
7β
8
In order to show the potential of the selective access to
protected sugars by the use of N-pivaloyl imidazole, the
synthesis of N-acetylgalactosamine was performed start-
ing from compound 18. N-Acetylgalactosamine is an im-
portant 2-amino-2-deoxyglycopyranoside mainly because
of its natural occurrence in numerous oligosaccharides
widely distributed in living organisms.40,41 Triflation of
the free 4-OH group of compound 18 was followed by re-
action with sodium nitrite in DMF42,43 that allows the in-
version of the configuration at C-4 and the synthesis of
–
12.0
12.2
12.2
12.3
12.3
12.3
12.3
–
11.6
12.3
11.9
12.0
–
9
10α
10β
11α
11β
12
13
14
15α
15β
16
17
18
19
20
21
22
25α
25β
6.7
6.4
5.3
6.8
–
5.3, 5.9
3.2, 5.3
3.7, 7.3
3.8, 6.1
–
–
–
and
2-acetamido-2-deoxy-1,3,6-tri-O-pivaloyl-α,β-D-
galactopyranose (25, 70% overall yield) (Scheme).
4.6
8.7
8.8
8.9
9.2
9.2
9.3
3.6
8.8
–
–
10.9
10.2
10.4
–
–
11.3
11.2
8.8
9.5
9.2
–
–
2.9
3.1
9.8
9.5
9.7
10.0
9.9
–
2.3, 4.0
3.4, 3.4
2.4, 4.2
2.2, 5.4
2.0, 4.9
5.0, 7.0
6.3, 6.3
12.3
–
9.7
9.9
–
7.6
9.4
9.4
9.6
12.3
12.3
12.4
11.7
11.4
–
Scheme
In conclusion, the results described herein show that N-
pivaloyl imidazole is a useful and efficient reagent in the
selective protection of sugars. In addition, the preparation
of the protecting reagent is easy and inexpensive.
Table 5. Characteristic 13C NMR Data for 1–22 and 25 (CDCl3/TMS,
δ)
Product
C-1
C-2
C-3, C-4, C-5
C-6
Melting points were determinated with a Reichert hotplate micro-
scope and are uncorrected. Solutions were dried (Na2SO4) before
concentration under diminished pressure. NMR spectra were ob-
tained with a Bruker AM-300 spectrometer. Micraanalyses were
performed with a Perkin-Elmer analyzer 240C. MS data (m/z) were
obtained by the chemical ionization mode using methane as the ion-
izing gas with a Hewlett-Packard 5988A instrument and molecular
weights were obtained was a Kratos MS-80-RFA instrument. Spe-
cific optical rotations were measured with a Perkin-Elmer Polarim-
eter 141 at 25°C. TLC and column chromatography were performed
on precoated silica gel plates (Merck 60 F245) and on Kieselgel 60
(Merck 230–400 mesh), respectively, with the solvent systems indi-
cated in Table 1. All the evaporations were carried out under dimin-
ished pressure at 40°C.
1
2
3
94.0
91.9
91.7
92.0
91.9
92.6
93.9
92.9
92.5
90.9
90.8
91.1
90.6
90.8
98.6
93.3
93.5
99.1
93.2
92.3
92.7
92.8
88.7
87.7
88.9
91.3
93.2
69.4,
70.7,
71.8, 74.8, 78.1
72.4, 74.7, 75.3
70.7, 72.8, 74.3
69.7, 75.0, 75.2
70.2, 72.4, 72.9
69.7, 70.7, 72.2
69.8, 71.2, 73.8
65.2, 68.2, 73.5
70.3, 71.2, 71.6
68.3, 73.1, 75.4
65.4, 71.5, 73.4
70.3, 71.8, 72.9
69.7, 70.7, 71.0
68.3, 68.4, 71.3
69.4, 70.8, 76.0
73.4, 74.9, 81.1
73.7, 75.5, 78.7
75.6, 80.9, 82.1
72.9, 75.1, 78.5
70.8, 73.0, 73.4
69.1, 74.8, 75.0
70.3, 72.3, 73.2
68.9, 74.6, 76.4
71.0, 72.4, 74.2
67.1, 71.9, 74.5
67.4, 70.1, 70.6
66.8, 72.4, 73.4
63.0
62.7
61.8
62.6
61.5
63.2
63.3
63.0
63.1
62.8
62.9
61.9
62.0
61.8
62.2
64.5
61.7
62.5
61.7
62.0
62.8
61.5
62.8
62.1
61.6
63.3
62.0
4
5
67.8,
67.7,
66.1,
6αa
7
8
9
66.4,
65.8,
65.6,
68.7,
68.4,
64.6,
67.9,
69.1,
71.4,
69.1,
70.9,
55.9
52.7
52.9
53.5,
57.7
53.9
47.2
49.4
10α
10β
11α
11β
12
13
14
15α
15β
16
17
18
19
20
21
22
25α
25β
Pivaloyl Imidazole:
Pivaloyl chloride (10.82 mL, 88 mmol) was added dropwise to a
cooled (0°C) solution of imidazole (12 g, 176.3 mmol) in EtOH free
CHCl3 (200 mL). After stirring for 10 min at 0°C and 45 min at r.t.,
the mixture was washed with H2O (2 × 100 mL). The organic phase
was dried (MgSO4) and concentrated in vacuo. The residue was tritu-
rated with hexane and the resulting solid was filtered giving the title
compound in 85% yield.
1H NMR (CDCl3, 300 MHz): δ = 1.47 [s, 9 H, C(CH3)3], 7.05 (br s,
1 H, H-4), 7.55 (br s, 1 H, H-5), 8.29 (br s, 1 H, H-2).
13C NMR (CDCl3): δ = 27.8 [C(CH3)3], 40.9 [C(CH3)3], 117.4 (C-5),
129.7 (C-4), 137.2 (C-2), 174.9 (CO).
a Measured in DMSO-d6.
HRMS(FAB): m/z calcd for C8H12N2O 152.0949, found 152.0946.

SYNTHESIS
December 1998
1791
Acylation of Sugars with Pivaloyl Imidazole; General Procedure:
Pivaloyl imidazole was added to a stirred solution of the sugar
(2.8 mmol) in anhyd DMF (10 mL). The mixture was kept at the tem-
perature and for the period indicated in Table 1. The solution was
diluted with Et2O (75 mL) and toluene (25 mL) and then washed with
5% HCl solution (50 mL), H2O (50 mL) and aq satd NaHCO3 solution
(50 mL). The aqueous layer was extracted with Et2O (100 mL) and
the combined organic layers were dried (MgSO4) and concentrated in
vacuo. The resulting crude product was purified by column chroma-
tography using eluents as indicated in Table 1.
tography (Et2O/hexane 5:1). Compound 25β was eluted first as a sol-
id; mp 110–111ºC ; [α]D +21 (c = 1, CHCl3).
Anal Calcd for C23H39NO9: C, 58.32; H, 8.31; N, 2.96. Found: C,
58.10; H, 8.42; N, 2.92.
Compound 25α was eluted next as a solid; mp 92–93ºC ; [α]D +71 (c
= 1, CHCl3).
Anal. calcd for C23H39NO9: C, 58.32; H, 8.31; N, 2.96. Found: C,
58.40; H, 8.40; N, 3.06.
We thank Dirección General de Investigación Científica y Tecnica for
financial support (PB92-1207).
(3',6'-Di-O-pivaloyl-β-D-galactopyranosyl)-(1→4)-1,2,6-tri-O-piv-
aloyl-β-D-glucopyranose (23): [α]D +17 (c = 0.2, CHCl3); mp 108-
109°C.
(1) Kociénski, P.J. Protecting Groups; Thieme: Stuttgart,1994.
(2) Greene, T.W.; Wuts, P.G.M. Protecting Groups in Organic
Synthesis; Wiley: New York, 1991
1H NMR (CDCl3, 300 MHz): δ = 1.17, 1.18, 1.19, 1.20, 1.26 [s, 45 H,
5 × C(CH3)3], 3.43 (dd, 1 H, J = 8.5, 9.8 Hz, H-4), 3.66 (m, 1 H, H-
5'), 3.79 (dd, 1 H, J = 8.5, 9.7 Hz, H-3), 3.85 (m, 1 H, H-5), 3.92 (dd,
1 H, J = 7.7, 10.1 Hz, H-2'), 3.99 (d, 1 H, J = 3.2 Hz, H-4'), 4.19 (dd,
1 H, J = 5.4, 12.1 Hz, H-6), 4.23 (dd, 1 H, J = 7.9, 11.9 Hz, H-6), 4.37
(d, 1 H, J = 7.7 Hz, H-1'), 4.36–4.42 (m, 1 H, H-6), 4.58 (m, 1 H, H-
6), 4.83 (dd, 1 H, J = 3.2, 10.1 Hz, H-3'), 5.02 (dd, 1 H, J = 8.5, 9.7
Hz, H-2), 5.62 (d, 1 H, J = 8.5 Hz, H-1).
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13C NMR (CDCl3, 75 MHz): δ = 26.9, 27.0, 27.1 [5 × C(CH3)3], 38.7,
38.8, 38.9, 39.0, 39.1 [5 × C(CH3)3], 62.8, 63.4 (C-6, 6'), 67.3 (C-4'),
69.1, 71.2, 73.3, 73.6, 74.5 (C-2,2',3, 3',5, 5'), 82.2 (C-4), 91.7 (C-1),
104.7 (C-1'), 176.8, 178.1, 178.8 (5 × CO).
HRMS(FAB): m/z calcd for C37H62O16Na 785.3935, found 785.3935.
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(2',4'-Di-O-acetyl-3',6'-di-O-pivaloyl-â-D-galactopyranosyl)-
(1→4)-3-O-acetyl-1,2,6-tri-O-pivaloyl-â-D-glucopyranose (24):
Conventional acetylation of 23 (100 mg) with Ac2O/pyridine gave 24
(95%) as an amorphous solid after usual workup; mp 92°C; [α]D +11
(c = 1, CHCl3).
1H NMR (CDCl3, 300 MHz): δ = 1.09, 1.12, 1.15, 1.21, 1.23 [s, 45 H,
5 × C(CH3)3], 2.02 (s, 6 H, 2 × COCH3), 2.13 (s, 3 H, COCH3), 3.75–
4.18 (m, 6 H, H-4,5,6,6,5',6'), 4.46 (d, 1 H, J = 8.1 Hz, H-1'), 4.50 (m,
1 H, H-6), 4.91 (dd, 1 H, J = 3.4, 10.3 Hz, H-3'), 5.02 (dd, 1 H, J =
8.4, 9.7 Hz, H-2), 5.17 (dd, 1 H, J = 8.1, 10.1 Hz, H-2'), 5.30 (dd, 1 H,
J = 8.7, 9.8 Hz, H-3), 5.40 (br d, 1 H, J = 3.0 Hz, H-4'), 5.64 (d, 1 H,
J = 8.4 Hz, H-1).
13C NMR (CDCl3, 75 MHz): δ = 20.6, 20.7 ( 3 × CH3CO), 26.8, 26.9,
27.0, 27.1, 27.2 [5 × C(CH3)3], 38.7, 38.8, 38.9 [5 × C(CH3)3], 61.2,
66.7 (C-6, 6'), 69.2, 70.0, 71.1, 72.2, 73.7, 76.0 (C-2,2',3, 3',4,4',5, 5'),
91.7 (C-1), 101.1 (C-1'), 168.9, 169.5, 169.8, 176.4, 176.7, 177.2,
177.7 (5 × CO).
HRMS(FAB): m/z calcd for C43H68O19Na 911.4252, found 911.4252.
2-Acetamido-2-deoxy-1,3,6-tri-O-pivaloyl-α,â-D-galactopyrano-
side (25):
Triflic anhydride (0.84 mL, 5 mmol) in anhyd CH2Cl2 (5 mL) was
added to a solution of pyridine (0.83 mL, 10 mmol) in anhyd CH2Cl2,
stirred under pure N2 at –15°C. After 15 min, a solution of 18 (1.5 g,
3.2 mmol) in anhyd CH2Cl2 was added, and stirring was continued for
45 min, the temperature being allowed to rise gradually to 0°C. After
this time, TLC (Et2O/hexane, 5:1) showed complete disappearance of
the starting material. CH2Cl2 (100 mL) was added and the solution
washed successively with 5% HCl solution (100 mL), aq satd
NaHCO3 solution (100 mL) and H2O (50 mL). The organic phase was
dried (Na2SO4) and evaporated. The resulting crude product was dis-
solved in anhyd DMF (6 mL) and then NaNO2 (2 g) was added. After
18 h the reaction mixture was diluted with Et2O (100 mL) and toluene
(50 mL) and then washed with NaHCO3 saturated solution (50 mL)
and water (50 mL). The organic layer was dried (Na2SO4) and con-
centrated in vacuo. The resulting crude product was purified by col-
umn chromatography (Et2O/hexane, 5:1) to give the title compound
(1.05 g, 70%) as an α,β-mixture of anomers (ratio 1:10). A small
amount (~100 mg) of this mixture was separated by column chroma-

SYNTHESIS
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