Preparation of 1-C-glycosyl aldehydes by reductive hydrolysis

Article abstract of DOI:10.1016/j.carres.2011.04.019

Reductive hydrolysis of various protected glycosyl cyanides was carried out using DIBAL-H to form aldimine alane intermediates which were then hydrolyzed under mildly acidic condition to provide the corresponding aldehyde derivatives. While 1-C-formyl gly

Full text of DOI:10.1016/j.carres.2011.04.019

Carbohydrate Research 346 (2011) 1503–1510
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Preparation of 1-C-glycosyl aldehydes by reductive hydrolysis
⇑
Szabolcs Sipos, István Jablonkai
Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, PO Box 17, 1525 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Reductive hydrolysis of various protected glycosyl cyanides was carried out using DIBAL-H to form aldim-
ine alane intermediates which were then hydrolyzed under mildly acidic condition to provide the corre-
sponding aldehyde derivatives. While 1-C-formyl glycal and 2-deoxy glycosyl derivatives were stable
during isolation and storage 1-C-glycosyl formaldehydes in the gluco, galacto and manno series were sen-
sitive and decomposition occurred by 2-alkyloxy elimination. A one-pot method using N,N0-diphenyle-
thylenediamine to trap these aldehydes in stable form was developed. Reductive hydrolysis of glycosyl
cyanides offers valuable aldehyde building blocks in a convenient way which can be applied in the syn-
thesis of complex C-glycosides.
Received 3 February 2011
Received in revised form 7 April 2011
Accepted 12 April 2011
Available online 21 April 2011
Dedicated to Professor Dr. András Lipták on
the occasion of his 75th birthday
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Glycosyl cyanides
1-C-Glycosyl aldehydes
DIBAL-H
b-Elimination
1,3-Imidazolidine derivative
1. Introduction
followed by unmasking the aldehyde functionality is another
way to introduce formyl group at the anomeric position. However,
The design of glycomimetics offers a useful tool to modify the
structure of biologically active peptides and glycoconjugates. Intro-
duction of formyl group at the anomeric position of carbohydrates
affords valuable intermediates for synthesis of complex C-glyco-
sides. In addition to regular C-glycosides, by the use of unsaturated
analogs the conformation of glycopeptides can be further modified.
The most practical methods for the preparation of multigram
quantities of 1-formyl-C-glycosides include oxidative cleavage of
aldehyde precursor C-glycosides possessing alkenyl or nitromethyl
substituents or introduction of an aldehyde-equivalent group at
the anomeric center followed by unmasking the aldehyde function-
ality. Ozonolysis of C-glycosyl-allene,1 prop-1-ene,2 styrene,3–6 and
1-allyl-4-phenyl-1,2,4-triazolidine-3,5-dione7 derivatives provided
the respective anomer carbon-linked aldehydes. pH-controlled
ozonolysis of C-glycosylated nitromethane8 as well as
two-step oxidation of C-glycosyl-enoxysilane9 have also been
developed for the synthesis of 1-formyl-C-glycosides. Due to the
harsh oxidizing conditions by which the anomeric substituents
were converted to a formyl group the common hydroxyl protecting
group such as benzyl was readily oxidized10 and the conversion
of the desired aldehyde to an acid8 was also observed. Addition
of an aldehyde-equivalent group such as thiazole11,12 benzothia-
zole,13 dithiane5 and bis-(methylthio)methyl14 to glyconolactones
these syntheses are often strenuous and offer
a/b anomeric
mixtures.11
Glycosyl cyanides can be readily available starting materials as
aldehyde equivalents for the preparation of 1-formyl-C-glycosides
by reductive hydrolysis. Reductive hydrolysis of nitriles employing
various metal hydrides as reducing agents such as lithium trialk-
oxyaluminum hydrides, sodium dialkylaluminum hydrides, and
diisobutylaluminum hydride (DIBAL-H) have been described for
mostly aromatic nitriles.15 Nevertheless no such hydrides have
been applied for the conversion of glycosyl cyanides to the corre-
sponding aldehydes. Raney nickel and sodium hypophosphite in
aqueous pyridine-acetic acid16–18 as well as LiAlH4 in THF19 were
used exclusively in the preparation of 1-formyl-C-glycosides by
reductive hydrolysis. However, formation of unsaturated alde-
hydes by 2- and 3-acetoxy/benzoyloxy elimination was observed
with Raney Ni/NaH2PO2 that can be avoided by trapping the result-
ing saturated aldehyde with N,N0-diphenylethylenediamine
(Wanzlick’s reagent).16,17,19 Reduction of perbenzylated
a-D-gluco-
pyranosyl cyanide with LiAlH4 in THF followed by hydrolysis of the
intermediate aldimine was reported to afford the respective C-1-
formyl derivative.20 However, in the reported NMR spectrum the
chemical shift (9.20 ppm) of the CHO proton is rather consistent
with the formation of 3,4,6-tri-O-benzyl-D-glucal aldehyde since
in all 1-formyl-C-glycosyl derivatives of thegluco, galacto, and man-
no series higher chemical shifts (9.60–9.98 ppm) were reported12
for the CHO proton. In contrast, no synthetic procedure for the
⇑
Corresponding author. Tel.: +36 1 438 1100x130; fax: +36 1 4381145.
E-mail address: jabi@chemres.hu (I. Jablonkai).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.04.019

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S. Sipos, I. Jablonkai / Carbohydrate Research 346 (2011) 1503–1510
preparation of 1-formyl-2-deoxy-C-glycosyl derivatives has been
published.
galactosyl nitrile about 20% of tribenzyl galactal cyanide (3a) was
isolated. 1-Cyano-3,4,6-tri-O-benzyl- -glucal (3b) was obtained in
12% yield during the benzylation of b- -glucopyranosyl nitrile. On
the other hand, exclusively 3b formed during the perbenzylation
of -mannosyl nitrile. To our best knowledge no such benzylated
D
The objective of this study was to prepare 1-C-glycosyl, 1-C-2-
deoxy-glycosyl formaldehydes and 1-C-formyl-glycals by reduc-
tive hydrolysis of the corresponding cyanides employing complex
aluminum-hydrides such as DIBAL-H and RedAl (sodium bis(2-
methoxyethoxy)aluminum dihydride). The effect of solvent and
temperature on the product formation was also studied.
D
a-D
glycal nitriles were reported in the literature. Acetylated 1-cyano-
glycals were prepared by direct elimination of acetic acid from the
appropriate peracetylated glycosyl nitriles with 1,8-diazabicy-
clo[5.4.0]undec-7-ene in aprotic solvents.27,28 2-Deoxy-b-
D-galacto-
syl (5a-b) and glucosyl (5b-b) cyanides were prepared from the
respective glycal cyanide by hydrogenation over palladium on char-
coal at atmospheric pressure. The amount of catalyst seemed to be
important in the formation of desired product since in addition to
the saturation of the double bond the reduction of the cyano group
to an amine also took place. When 5% (w Pd/w substrate) of palla-
dium on charcoal catalyst was used at atmospheric pressure, the
reaction proceeded quickly but both functionalities were reduced.
Reducing the amount of the catalyst to 1% the reaction was sluggish
and only the double bond reduction occurred yielding the deoxy ni-
triles (5a-b and 5b-b) in moderate yields (50–60%). Surprisingly,
hydrogenation of these glycal cyanides was stereospecific and re-
sulted in almost exclusively the b-anomers indicating that the
2. Results and discussion
Protected glycosyl cyanides (Scheme 1, Table 1) were prepared
by standard literature methods. Perbenzyl
a
-galactosyl and gluco-
syl cyanides (1a-
a
and 1d-
a
) were synthesized via -trichloroace-
a
timidate derivatives.21 Perbenzyl b-galactosyl cyanide (1a-b) was
obtained from peracetyl b-galactopyranosyl cyanide22 after Zem-
plen deacetylation23 and benzylation.
Permethyl
a- and b-
D
-galactosyl cyanides (1b-
a
and 1b-b) were
/b- -galact-
synthesized from 1-O-acetyl-2,3,4,6-tetra-O-methyl-
a
D
ose24 with TMSCN in the presence of boron trifluoride etherate20
and the anomers were separated by column chromatography. Peral-
lyl b-
dure as described for 1a-b. Perbenzyl b-
was obtained from benzobromoglucose25 which was transformed
into the benzoylated b-
-glucopyranosyl cyanide26 followed by
deacetylation23 and benzylation. Permethyl
- and b- -glucosyl
and mannosyl cyanides (1e- , 1e-b, 1f- , and 1f-b) were synthesized
from 1-O-acetyl-2,3,4,6-tetra-O-methyl- /b-
-glucose/mannose24
as described earlier for 1b- and 1b-b. Benzyl-protected glycal ni-
D
-galactosyl cyanide (1c-b) was prepared by the same proce-
hydrogen addition occurs from the less hindered a-face of the sugar.
D
-glucosyl cyanide (1d-b)
Depending on the batch of the catalyst the amount of the
a-anomer
accounted for 6%.
D
The reductive hydrolysis of various glycosyl, 2-deoxy-glycosyl
and glycal cyanides was carried out with DIBAL-H and RedAl
(Scheme 1). In these experiments the workup of the resulting
aldimine alane from the reaction of the nitrile and the hydride
was crucial on the product formation. Initially when the aldimine
alane was hydrolyzed with 1 N HCl almost exclusively 1-formyl-
C-glycal formation was observed. The use of 1 N NH4Cl for the
hydrolysis of the aldimine greatly reduced the glycal aldehyde for-
mation by 2-benzyloxy elimination. In order to find the optimal
a
D
a
a
a
D
a
triles (3a and 3b) were available in our laboratory as unexpected
products during the standard benzylation (NaH, benzylbromide,
DMF) of b-
D-glucopyranosyl, b-
D
-galactopyranosyl, and
a
-D
-manno-
pyranosyl cyanides by 2-benzyloxy elimination. When b-
syl nitrile was benzylated in addition to the perbenzylated b-D-
D
-galacto-
OR
R1
R2
RO
O
CN
3
i
OR
R1
OR
R3
OR
R1
R1
R3
R2
RO
O
R2
RO
O
i
R2
RO
O
+
CHO
CN
CHO
R4
1
R4
2
4
OR
OR
OR
R1
R1
R1
ii
i
R2
RO
O
R2
RO
O
R2
RO
O
CN
CN
CHO
3
5
6
Scheme 1. Preparation of 1-C-glycosyl aldehydes by reductive hydrolysis (see Table 1 for structural details). Reagents and conditions: (i) DIBAL-H, ꢀ78 °C, 30 min then 1 M
NH4Cl; (ii) Pd/C, EtOH.

S. Sipos, I. Jablonkai / Carbohydrate Research 346 (2011) 1503–1510
1505
Table 1
Structure of glycosyl cyanides and the derived aldehydes as well as synthesis methods for the preparation of the starting cyanides
Cyanide
1a-
1a-b
Method of preparation
R1
R2
R3
R4
R
Aldehyde
2a-
2a-b
a
Ref.20
OBn
OBn
OMe
OMe
OAll
H
H
H
H
H
H
OBn
H
OBn
H
H
H
H
H
H
H
H
H
H
H
H
H
OBn
OBn
OMe
OMe
OAll
OBn
OBn
OMe
OMe
H
OBn
OBn
OMe
OMe
OAll
OBn
OBn
OMe
OMe
OMe
OMe
OBn
OBn
OBn
OBn
a
Refs.21,22
1b-a
Refs.19,23
2b-
2b-b
4ca
a
1b-b
1c-b
Refs.19,23
Refs.21,22
H
1d-a
Ref.20
OBn
OBn
OMe
OMe
OMe
OMe
H
OBn
H
OBn
2d-a
2d-b
1d-b
Refs.22,24,25
1e-
1e-b
1f-
a
Refs.19,23
2e-
2e-b
2f-
a
Refs.19,23
H
a
Refs.19,23
OMe
OMe
—
—
—
a
1f-b
3a
3b
5a-b
5b-b
Refs.19,23
H
—
—
—
2f-b
4a
4b
6a-b
6b-b
Formed during benzylation of unprotected cyanides
Hydrogenation of 3a, 3b
—
—
a
Only galactal derivative formed by b-allyloxy elimination.
reaction conditions experiments with 1a-b were carried out by
changing the temperature and amount of the respective hydride
(Table 2).
place during the chromatography 1H NMR spectrum of crude prod-
ucts was always taken immediately after the work-up. Results sug-
gested that the aldehydes were pure enough to be used in further
synthesis without purification. All glycosyl cyanides except 1c-b
were converted into the expected aldehyde derivatives. Interest-
When 2 equiv of DIBAL-H was used no expected 2a-b formed,
instead 1-C-formyl galactal derivative 4a and a significant amount
of amine byproduct were detected. Lowering the excess of DIBAL-H
up to 1.4 equiv 52% isolated yield of 2a-b was obtained and only
low amount of 2-benzyloxy-eliminated galactal aldehyde was ob-
served with no over-reduction to the amine. At 1.2 equiv of DI-
BAL-H no b-eliminated product 4a was detected in the crude
product but during the chromatography decomposition of 2a-b
led to this compound. These results suggested that purification of
the crude product should be avoided in case of 1-C-glycosyl form-
aldehydes since the acidity of silica gel appears to favor the elimi-
nation reaction. During flash chromatography decomposition and
ingly when tetraallyl b-D-galactosyl cyanide 1c-b was subjected
to reductive hydrolysis only unsaturated product (4c) formation
was noticed. Despite similar leaving group abilities of benzyloxy
and methoxy groups replacement of the benzyl protective groups
in the galactosyl derivatives with methyl groups (1b-
a and 1b-b)
increased the stability of these derivatives during purification. No
byproduct formation was found in the reaction of glycal (3a and
3b) and 2-deoxy-b-D-glycosyl (5a-b and 5b-b) cyanides and yields
for the respective aldehydes were moderate (52–63%). Such
2-deoxy-glycosyl aldehydes have not been previously reported.
b-Elimination has also been noticed in the synthesis and reaction
of such 1-C-glycosyl aldehydes.1,12,29,30 Under mild basic condi-
epimerization were also reported when 1-C-formyl-a-D-glucosyl
derivative was purified.12 Nevertheless, elevation of temperature
favored for over-reduction to the amine and only 2-benzyloxy-
eliminated product was observed.
tions epimerization of benzyl-protected
a-
D-glycopyranosyl alde-
hydes were transformed into an equilibrium
a/b ratio 1:8–20
Red-Al in toluene or THF at ꢀ78 °C was unreactive and no prod-
uct formation during 2 h was detected. However, at room temper-
ature formation of both aldehydes was observed. We could not find
conditions using RedAl which favored exclusively for the formation
of 2a-b therefore RedAl was considered unsuitable for reductive
hydrolysis of such glycosyl cyanides.
accompanied by b-elimination of the benzyloxy groups.1 In case
of mannose derivative the degree of elimination was not signifi-
cantly different from that of galactose and glucose derivatives de-
spite the favorable trans-diaxial disposition between the C-1
hydrogen and C-2 O-benzyl group. Nevertheless, in a Mannich
reaction from benzyl-protected b-D-mannosyl and b-D-arabinosyl
Further reductive hydrolysis experiments with various
D
-glyco-
aldehydes promoted by Lewis acid (InCl3) formation of glycal alde-
hydes was also observed.31 Decomposition of selected aldehydes
was studied by 1H NMR spectroscopy in CDCl3. The benzyl-pro-
tected 2a-b decomposed fairly rapidly and half of the starting alde-
syl, 2-deoxy- -glycosyl and -glycal cyanides were accomplished
D
D
with 1.4 equiv of DIBAL-H at ꢀ78 °C (Table 3). Since in the initial
experiments decomposition of 2a-b yielding glycal aldehyde took
Table 2
Reductive hydrolysis of 1a-b using DIBAL-H and RedAl and effect of reaction conditions on the product formation and the yields
Hydride
Equiv
Solvent
Temp (°C)
Time (min)
Products
Yield (%)a
2a-b
3a
b
DIBAL-H
DIBAL-H
DIBAL-H
DIBAL-H
DIBAL-H
DIBAL-H
RedAl
RedAl
RedAl
RedAl
RedAl
2.0
1.8
1.4
1.2
1.4
1.8
2.0
2.5
1.0
2.5
2.5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene or THF
THF
Toluene or THF
THF
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ40
ꢀ40
ꢀ78
20
30
30
30
30
30
30
120
120
120
120
20 + 30
4a + Gal(OBn)4CH2NH2
—
45
51
10
12
38
27
—
54
12
50
30
2a-b + 4a + Gal(OBn)4CH2NH2
2a-b + 4a
12
52
23
—
—
—
Traces
—
10
2a-b + 1a-b
4a + Gal(OBn)4CH2NH2
4a + Gal(OBn)4CH2NH2
—
2a-b + 4a
2a-b + 4a
20
20
2a-b + 4a
2a-b + 4a
Toluene
ꢀ20 then rt
36
a
Yields of the respective aldehyde after silica gel flash chromatography.
The amine byproduct was not isolated but detected in the reaction mixture by MS and TLC.
b

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S. Sipos, I. Jablonkai / Carbohydrate Research 346 (2011) 1503–1510
Table 3
Reductive hydrolysis of various glycosyl, 2-deoxy-glycosyl, and glycal cyanides. Effect of purification on decomposition of glycosyl aldehydes by 2-alkyloxy elimination.
Cyanide
Hydride
Aldehyde in crude product (%)a
1-C-Glycosyl aldehyde 1-Formyl-C-glycal
Isolated aldehyde (%)
1-C-Glycosyl aldehyde
1-Formyl-C-glycal
1a-
1a-b
1a-b
1b-
1b-b
1c-b
1c-b
1d-
1d-
a
DIBAL-H
DIBAL-H
Red-Al
DIBAL-H
DIBAL-H
DIBAL-H
Red-Al
90
91
N/A
100
100
0
0
92
N/A
98b (0c)
95
98
88
80
—
—
—
—
10
9
N/A
0
0
100
100
8
18
52
36
71
60
0
0
0
0
0
N/A
N/A
29
38
—
—
53
59
36
10
30
8
a
0
63
22
38
54
41
N/A
N/A
26
28
63
52
—
a
a
DIBAL-H
Red-Al
N/A
1d-b
1e-
1e-b
1f-
DIBAL-H
DIBAL-H
DIBAL-H
DIBAL-H
DIBAL-H
DIBAL-H
DIBAL-H
DIBAL-H
DIBAL-H
2b (100c)
a
5
2
a
12
20
—
—
—
—
1f-b
3a
3b
5a-b
5b-b
—
a
b
c
Based on the ratio of integral values for CHO protons in the 1H NMR spectrum of crude products.
Work-up of the aldimine alane was with 1 M NH4Cl.
Work-up of the aldimine alane was with 1 M HCl.
hyde converted to 4a in 180 min at 40 °C while the same degree of
decomposition for the methyl protected mannosyl aldehyde 2f-b
required 60 days at 20 °C. Storage of these aldehydes in freezer
however is strongly recommended.12 Addition of a strong base
DBU (0.2 equiv) to 2a-b increased the rate of decomposition and
as stable derivatives was developed. Reductive hydrolysis of glyco-
syl cyanides offers valuable aldehyde building blocks in a conve-
nient way which can gain application in the synthesis of complex
C-glycosyl derivatives.
the epimerized product 2a-
a is also appeared. In the presence of
4. Experimental
0.2 equiv of TFA b-benzyloxy elimination took place instantly. Nev-
ertheless, both glycal and 2-deoxy aldehydes were stable for a
longer period in refrigerator. Since 2a-f glycosyl aldehydes cannot
be prepared in high purity form and were not stable for long-term
storage the reductive hydrolysis procedure was modified to trap
the aldehyde as 1,3-diphenylimidazolidine derivative.16,17 In our
procedure 1a-b was treated with DIBAL-H (1.4 equiv) at ꢀ78 °C
for 30 min then the excess of hydride was quenched with acetic
acid followed by addition of the Wanzlick’s reagent19 (2 equiv)
(Scheme 2). The product formed overnight at room temperature
was purified without decomposition by silica gel chromatography
to provide 7a-b (57%).
4.1. General methods
All chemicals and solvents were purchased from Sigma–Aldrich
Kft. (Budapest, Hungary). TLC aluminum sheets (Silica Gel 60 F254
,
0.2 mm layer thickness) for following the proceeding of the reac-
tions and silica gel for column chromatography (Silica Gel 60,
0.040–0.063 mm) was from Merck Kft. (Budapest, Hungary). Spots
of compounds were visualized under UV light or heating the plates
after immersion in 5% (v/v) H2SO4 in EtOH or 0.4% (w/v) 2,4-dini-
trophenylhydrazine in 2 N HCl or 0.2% (w/v) ninhydrin in EtOH.
Melting points were determined by a Boetius PHMK05 melting
point apparatus (MLW, Dresden, Germany) and are uncorrected.
The NMR spectra were recorded with Varian Gemini-3000
(300 MHz for 1H and 75 MHz for 13C) spectrometer (Varian Inc.,
Palo Alto, CA, USA). Mass spectrometric measurements were run
on an Applied Biosystems 3200QTrap hybrid mass spectrometer
in electrospray ionization mode. Optical rotations were measured
using an Optical Activity AA-10R polarimeter (Optical Activity
Ltd, Ramsey, UK) at 20 °C.
3. Conclusion
In conclusion, reductive hydrolysis of various protected glycosyl
cyanides was carried out using DIBAL-H to form aldimine alane
intermediates which were then hydrolyzed under mildly acidic
condition to provide the corresponding aldehyde derivatives.
While 1-C-formyl glycal and 2-deoxy glycosyl derivatives were sta-
ble during isolation and storage 1-C-glycosyl formaldehydes in the
gluco, galacto and manno series were sensitive and decomposition
occurred by 2-alkyloxy elimination. A one-pot method using
N,N0-diphenylethylenediamine to trap these sensitive aldehydes
4.2. 2,3,4,6-Tetra-O-benzyl-a-D-galactopyranosyl cyanide (1a-a)
Preparation of 1a-
a was carried out via an a-trichloroacetimi-
date intermediate as described previously.21 Mp 45–49 °C; ½a D20
ꢁ
+3.0 (c 1.3, CHCl3); Rf 0.35 (hexanes–EtOAc, 8:2); 1H NMR (CDCl3):
d 3.50 (m, 2H, H-6a, H-6b), 3.82 (dd, 1H, J3,4 2.8 Hz, H-3), 3.99 (m,
2H, H-4, H-5), 4.11 (dd, 1H, J2,3 9.8 Hz, H-2), 4.68 (d, 1H, J1,2 6 Hz, H-
1), 4.4–4.8 (m, 8H, PhCH2), 7.20–7.40 (m, 20H, Ph); 13C NMR
(CDCl3): d 67.6 (C-1), 68.0 (C-6), 73.3, 73.4, 73.6, 75.0 (PhCH2),
73.6 (C-2), 74.0, 74.2 (C-4, C-5), 80.3 (C-3), 115.8 (CN), 127.0–
129.0 (Ph), 137.5, 137.6, 138.0, 138.1 (Cq); MS (ESI): m/z 550.7
[M+H]+.
Ph
OBn
O
OBn
BnO
i. 1.4 eq DIBAL-H
N
-78o, CH2Cl2, 30 min
1a-β
ii. 1.8 eq AcOH, -78o, 5 min
iii. 2.0 eq Wanzlick's reagent, rt, 16 h
N
BnO
Ph
57%
7a-β
Scheme 2. Preparation of 1,3-diphenylimidazolidine derivative from 1a-b.

S. Sipos, I. Jablonkai / Carbohydrate Research 346 (2011) 1503–1510
1507
4.3. 2,3,4,6-Tetra-O-benzyl-b-
D
-galactopyranosyl cyanide (1a-b)
(CN), 127.0–130.0 (Ph), 137.0, 137.4, 138.3, 138.5 (Cq); MS (ESI):
m/z 572.7 [M+Na]+.
Synthesis of 1a-b was started from acetobromogalactose from
which peracetyl b-galactopyranosyl cyanide22 was prepared fol-
lowed by Zemplen deacetylation23 and benzylation. Mp 87–
4.8. 2,3,4,6-Tetra-O-benzyl-b-
D-glucopyranosyl cyanide (1d-b)
88 °C; ½a 2D0
ꢁ
+25.1 (c 3.0, CHCl3); Rf 0.30 (hexanes–EtOAc, 8:2); 1H
Synthesis of 1d-b was started from benzobromoglucose25 which
NMR (CDCl3): d 3.4–3.6 (m, 3H, H-5, H-6a, H-6b), 3.49 (dd, 1H,
J3,4 3.0 Hz, H-3), 3.93 (d, 1H, H-4), 4.02 (d, 1H, J1,2 11.0 Hz, H-1),
4.17 (dd, 1H, J2,3 9.0 Hz, H-2), 4.30–5.0 (8H, PhCH2), 7.18–7.41
(m, 20H, Ph); 13C NMR (CDCl3): d 68.0 (C-1), 68.3 (C-6), 72.7,
73.3, 73.7, 74.8 (PhCH2), 76.0 (C-2), 76.3 (C-4), 78.2 (C-5), 83.0
(C-3), 116.8 (CN), 127.0–129.0 (Ph), 137.2, 137.5, 137.7, 138.1
(Cq); MS (ESI): m/z 550.8 [M+H]+.
was transformed into the benzoylated b-D-glucopyranosyl cya-
nide26 followed by deacetylation23 and benzylation. ½a 2D0
ꢁ
+25.0 (c
1.5, CHCl3); Rf 0.23 (hexanes–EtOAc, 8:2); 1H NMR (CDCl3): d
3.40 (ddd, 1H, J5,6a 3.8 Hz, J5,6b 2.4 Hz, H-5), 3.59 (dd, 1H, J3,4
9.2 Hz, H-3), 3.64 (dd, 1H, J4,5 9.4 Hz, H-4), 3.69 (m, 2H, H-6a, H-
6b), 3.76 (dd, 1H, J2,3 8.6 Hz, H-2), 4.05 (d, 1H, J1,2 10.0 Hz, H-1),
4.40–5.0 (m, 8H, PhCH2), 7.00–7.40 (m, 20H, Ph); 13C NMR (CDCl3):
d 67.64 (C-1), 68.29 (C-6), 73.70, 75.28, 75.84, 77.02 (C-4), 79.75
(C-2), 80.00 (C-5), 85.60 (C-3), 116.85 (CN), 127.74 ꢀ 128.59 (Ph),
136.93, 137.58, 137.77, 138.08 (Cq); MS (ESI): m/z 572.6 [M+Na]+.
4.4. 2,3,4,6-Tetra-O-methyl-a-D-galactopyranosyl cyanide (1b-a)
Permethyl -galactopyranosyl cyanide (1b-
a
-
D
a) was synthe-
sized from 1-O-acetyl-2,3,4,6-tetra-O-methyl-
a
/b-
D
-galactopyra-
4.9. 2,3,4,6-Tetra-O-methyl-a-D-glucopyranosyl cyanide (1e-a)
nose24 with TMSCN in the presence of boron trifluoride
etherate20 and the anomeric mixture was separated by column
Permethyl ) was synthesized
a
-
D
-glucopyranosyl cyanide (1e-
a
chromatography. ½a D20
ꢁ
+110.3 (c 1.1, CHCl3); Rf 0.28 (hexanes–
from 1-O-acetyl-2,3,4,6-tetra-O-methyl-a/b-D
-glucopyranose24
EtOAc, 1:1); 1H NMR (CDCl3): d 3.35–3.70 (m, 6H, H-2, H-3, H-4,
H-5, H-6a, H-6b), 3.40, 3.55, 3.56, 3.57 (s, 12H, CH3), 4.95 (d, 1H,
J1,2 5.8 Hz, H-1); 13C NMR (CDCl3): d 58.51, 59.28, 59.71, 61.59
(CH3), 66.93 (C-1), 70.39 (C-6), 74.81, 75.14, 75.33, 81.98 (CH),
115.61 (CN), MS (ESI): m/z 268.3 [M+Na]+.
with TMSCN in the presence of boron trifluoride etherate20 and
the anomers were separated by column chromatography. Mp 73–
75 °C; ½a 2D0
ꢁ
+108 (c 0.80, CHCl3); Rf 0.35 (hexanes–EtOAc, 1:1); 1H
NMR (CDCl3): d 3.21 (dd, 1H, J 9.0, 9.3 Hz, CH), 3.34 (m, 1H, CH),
3.38 (m, 1H, CH), 3.41, 3.53, 3.55, 3,66 (s, 12H, CH3), 3.62 (m, 2H,
H-6a, H-6b), 3.69 (m, 1H, CH), 4.90 (d, 1H, J1,2 5.7 Hz, H-1), 13C
NMR (CDCl3): d 59.13, 59.38, 60.59, 61.07 (CH3), 66.12 (C-1),
70.29 (C-6), 75.87 (CH), 77.94 (CH), 79.00 (CH), 84.52 (CH),
115.10 (CN); MS (ESI): m/z 246.3 [M+H]+.
4.5. 2,3,4,6-Tetra-O-methyl-b-
D
-galactopyranosyl cyanide (1b-b)
Permethyl
from
a-galactopyranosyl cyanide (1b-b) was synthesized
1-O-acetyl-2,3,4,6-tetra-O-methyl-a
/b-galactopyranose24
with TMSCN in the presence of boron trifluoride etherate20 and
the anomers were separated by column chromatography. Mp 73–
4.10. 2,3,4,6-Tetra-O-methyl-b-D-glucopyranosyl cyanide (1e-b)
75 °C; ½a 2D0
ꢁ
+36.4 (c 1.1, CHCl3); Rf 0.22 (hexanes–EtOAc, 1:1); 1H
Permethyl b-
D
-glucopyranosyl cyanide (1e-b) was synthesized
/b-
-glucopyranose24
NMR (CDCl3): d 3.11 (m, 1H, CH), 3.33–3.73 (m, 5H, CH, H-6a,
H-6b), 3.36, 3.50, 3.53, 3.64 (s, 12H, CH3), 3.88 (d, 1H, J1,2 9.8 Hz,
H-1); 13C NMR (CDCl3): d 58.34, 59.34, 61.50, 61.52 (CH3), 67.83
(C-1), 70.58 (C-6), 74.97, 75.29, 78.02, 84.96 (CH), 116.86 (CN);
MS (ESI): m/z 268.3 [M+Na]+.
from 1-O-acetyl-2,3,4,6-tetra-O-methyl-
a
D
with TMSCN in the presence of boron trifluoride etherate20 and
the anomers were separated by column chromatography. ½a D20
ꢁ
+44.0 (c 1.0, CHCl3); Rf 0.46 (hexanes–EtOAc, 1:1); 1H NMR (CDCl3):
d 3.14 (dd, 1H, J3,4 8.3, H-3), 3.17 (dd, 1H, J2,3 8.6 Hz, H-2), 3.25 (m,
1H, H-5), 3.33 (m, 1H, H-4), 3.40, 3.53, 3.65, 3,68 (s, 12H, CH3), 3.57
(m, 1H, H-6a), 3.60 (m, 1H, H-6b), 3.91 (d, 1H, J1,2 10.0 Hz, H-1); 13
C
4.6. 2,3,4,6-Tetra-O-allyl-b-D-galactopyranosyl cyanide (1c-b)
NMR (CDCl3): d 59.61, 60.91, 61.31, 61.39 (CH3), 67.59 (C-1), 70.92
(C-6), 78.67 (C-2), 79.84 (C-5), 81.83 (C-4), 87.70 (C-3), 116.88
(CN); MS (ESI): m/z 268.3 [M+Na]+.
Synthesis of 1c-b was started from acetobromogalactose from
which peracetyl b-galactopyranosyl cyanide22 was prepared fol-
lowed by Zemplen deacetylation23 and allylation using allyl bro-
4.11. 2,3,4,6-Tetra-O-methyl-a-D-mannopyranosyl cyanide (1f-a)
mide. ½a 2D0
ꢁ
ꢀ41.1 (c 1.1, CHCl3); Rf 0.35 (hexanes–EtOAc, 8:2); 1H
NMR (CDCl3): d 3.32 (m, 1H, CH), 3.53–3.83 (m, 5H, CH, H-6a, H-
6b), 3.91–4.41 (m, 8H, OCH2), 5.12–5.35 (m, 8H, CH2@CH), 5.64
(m, 1H, H-1), 5.81–6.07 (m, 4H, CH2@CH); 13C NMR (CDCl3): d
67.59 (C-6), 71.92, 72.94, 73.46, 73.95 (OCH2), 72.63, 75.23,
77.00, 77.59, 81.93 (CH), 114.62 (CN), 116.26, 116.49, 116.62,
117.00 (CH2@CH), 133.44, 133.67, 134.10, 134.44 (CH2@CH); MS
(ESI): m/z 350.2 [M+H]+.
Permethyl
a
-
D
-mannopyranosyl cyanide (1f-
a
) was synthesized
from 1-O-acetyl-2,3,4,6-tetra-O-methyl-
a/b-D
-mannopyranose24
with TMSCN in the presence of boron trifluoride etherate20 and
the anomers were separated by column chromatography. ½a D20
ꢁ
+11.9 (c 1.0, CHCl3); Rf 0.35 (hexanes–EtOAc, 1:1); 1H NMR (CDCl3):
d 3.46 (dd, 1H, J4,5 9.0 Hz, H-4), 3.53 (dd, 1H, J3,4 9.0 Hz, H-3), 3.38,
3.49, 3.51, 3.69 (s, 12H, CH3), 3.64 (m, 1H, H-5), 3.60 (m, 2H, H-6a,
H-6b), 3.74 (dd, 1H, J2,3 3.0 Hz, H-2), 4.87 (d, 1H, J1,2 2.4 Hz, H-1);
13C NMR (CDCl3): d 58.18, 58.65, 59.19, 60.73 (CH3), 64.38 (C-1),
70.85 (C-6), 75.34 (C-4), 76.59 (C-5), 77.20 (C-2), 81.32 (C-3),
115.32 (CN); MS (ESI): m/z 268.3 [M+Na]+.
4.7. 2,3,4,6-Tetra-O-benzyl-a-D-glucopyranosyl cyanide (1d-a)
Preparation of 1d-
a
was carried out via an
a
½ ꢁ
-trichloroacetimi-
date intermediate as described previously.21
a 2D0
+34.7 (c 2.2,
CHCl3); Rf 0.30 (hexanes–EtOAc, 8:2); 1H NMR (CDCl3): d 3.70
(dd, 1H, J5,6a 2.2 Hz, J6a,6b 11.0 Hz, H-6a), 3.71 (dd, 1H, J4,5 9.9 Hz,
H-4), 3.72 (dd, 1H, J2,3 9.5 Hz, H-2), 3.77 (dd, 1H, J5,6b 3.3 Hz, H-
6b), 3.88 (1H, ddd, H-5), 3.95 (1H, dd, J3,4 9.3 Hz, H-3), 4.67 (d,
1H, J1,2 6 Hz, H-1), 4.50–5.0 (m, 8H, PhCH2), 7.00–7.40 (m, 20H,
Ph); 13C NMR (CDCl3): d 67.0 (C-1), 67.9 (C-6), 73.6, 74.0, 75.2,
76.0 (PhCH2), 76.2 (C-5), 76.3, 76.4 (C-2, C-4), 83.2 (C-3), 115.5
4.12. 2,3,4,6-Tetra-O-methyl-b-
D-mannopyranosyl cyanide (1f-b)
Permethyl -mannopyranosyl cyanide (1f-b) was synthesized
a
-D
from 1-O-acetyl-2,3,4,6-tetra-O-methyl-a/b-D
-mannopyranose24
with TMSCN in the presence of boron trifluoride etherate20 and
the anomeric mixture was separated by column chromatography.
½
a 2D0
ꢁ
ꢀ9.9 (c 1.2, CHCl3), Rf 0.30 (hexanes–EtOAc, 1:1); 1H NMR

1508
S. Sipos, I. Jablonkai / Carbohydrate Research 346 (2011) 1503–1510
(CDCl3): d 3.18 (dd, 1H, J3,4 9.2 Hz, H-3), 3.25 (m, 1H, H-5), 3.40 (dd,
1H, J4,5 8.8 Hz, H-4), 3.38, 3.49, 3.51, 3.69 (s, 12H, CH3), 3.56 (dd,
1H, J5,6a 5.4 Hz, J6a,6b 11.0 Hz, H-6a), 3.61 (dd, 1H, J5,6b 2.2 Hz, H-
6b), 3.80 (dd, 1H, J2,3 3.0 Hz, H-2), 4.19 (d, 1H, J1,2 1.3 Hz, H-1);
13C NMR (CDCl3): d 58.16, 59.37, 60.90, 61.62 (CH3), 67.11 (C-1),
71.26 (C-6), 75.47 (C-4), 76.47 (C-2), 80,07 (C-5), 84.3 (C-3),
115.76 (CN); MS (ESI): m/z 268.3 [M+Na]+.
PhCH2), 7.02–7.41 (m, 20H, Ph), 9.65 (d, 1H, J 1.6 Hz, CHO); MS
(ESI): m/z 585.6 [M+Na]+.
4.13.7. (2,3,4,6-Tetra-O-methyl-a-D-glucopyranosyl)methanal
(2e-a
)
Rf 0.12 (hexanes–EtOAc, 1:1); 1H NMR (CDCl3): d 3.14–3.68 (m,
4H, CH), 3.40, 3.53, 3.55, 3.66 (s, 12H, CH3), 3.59 (m, 2H, H-6a, H-
6b), 4.47 (d, 1H, J1,2 6.3 Hz, H-1), 9.88 (s, 1H, CHO); 13C NMR
(CDCl3): d 59.44, 59.68, 60.88, 61.38 (CH3), 66.45 (CH), 71.26 (C-
6), 76.21, 78.29, 79.35, 84.86 (CH), 201.81 (CHO); MS (ESI): m/z
249.4 [M+H]+.
4.13. General procedure for the reductive hydrolysis of glycosyl
cyanides
Glycosyl cyanides (1a-f, 3a-b, 5a-b, 0.2 mmol) were dissolved in
dry CH2Cl2 (3 mL) and DIBAL-H (280
l
L of 1 M soln in CH2Cl2,
4.13.8. (2,3,4,6-Tetra-O-methyl-b-D-glucopyranosyl)methanal
0.28 mmol) was added by a syringe at ꢀ78 °C under N2 and the
reaction mixture was stirred for 30 min. The reaction mixture
was diluted with CH2Cl2 (10 mL) and 1 M NH4Cl solution (8 mL)
was added and stirred at room temperature for 10 min. The layers
were separated and the organic layer was dried over Na2SO4 and
the solvent evaporated in vacuo. The residue was purified by silica
gel column chromatography with hexanes–EtOAc eluents.
(2e-b)
Rf 0.10 (hexanes–EtOAc, 1:1); 1H NMR (CDCl3): d 3.09–3.40 (m,
4H, H-2, H-3, H-4, H-5), 3.33, 3.47, 3.60, 3.68 (s, 12H, CH3), 3.65 (m,
2H, H-6a, H-6b), 3.91 (m, 1H, H-1), 9.68 (d, 1H, J 1.5 Hz, CHO); 13
C
NMR (CDCl3): d 59.49, 60.38, 60.61, 61.35 (CH3), 68.08 (CH), 71.84
(C-6), 78.63 (CH), 79.33 (CH), 79.92 (CH), 89.07 (CH), 197.87 (CHO);
MS (ESI): m/z 271.5 [M+Na]+.
4.13.1. (2,3,4,6-Tetra-O-benzyl-
a-
D
-galactopyranosyl)methanal
4.13.9. (2,3,4,6-Tetra-O-methyl-a-D-mannopyranosyl)methanal
(2a-
a
)
(2f-
a)
Rf 0.19 (hexanes–EtOAc, 6:4); 1H NMR (CDCl3): d 3.61 (m, 1H, H-
5), 3.64 (dd, 1H, J3,4 4.4 Hz, H-3), 3.85 (dd, 1H, J2,3 10.6 Hz, H-2),
4.01 (m, 1H, H-6a), 4.12 (m, 1H, H-6b), 4.29 (d, 1H, H-4), 4.32
(m, 1H, H-1), 4.45–4.91 (m, 8H, PhCH2), 7.11–7.41 (m, 20H, Ph),
9.79 (s, 1H, CHO); MS (ESI): m/z 553.6 [M+H]+.
Rf 0.14 (hexanes–EtOAc, 1:1); 1H NMR (CDCl3): d 3.07 (dd, 1H,
J3,4 9.0 Hz, H-3), 3.39 (dd, 1H, J4,5 8.8 Hz, H-4), 3.38, 3.42, 3.44,
3.46 (s, 12H, CH3), 3.53 (m, 1H, H-5), 3.58 (dd, 1H, J5,6 5.2 Hz,
J6a,6b 9.9 Hz, H-6a), 3.63 (dd, 1H, J5,6b 1.6 Hz, H-6b), 3.98 (dd, 1H,
J2,3 3.3 Hz, H-2), 4.39 (d, 1H, J1,2 2.8 Hz, H-1), 9.87 (s, 1H, CHO);
13C NMR (CDCl3): d 57.6, 58.1, 59.2, 60.6 (CH3), 71.8 (C-6), 74.9
(C-2), 75.6 (C-4), 76.9 (C-5), 79.1 (C-1), 81.6 (C-3), 202.90 (CHO);
MS (ESI): m/z 271.4 [M+Na]+.
4.13.2. (2,3,4,6-Tetra-O-benzyl-b-
(2a-b)
D-galactopyranosyl)methanal
Rf 0.17 (hexanes–EtOAc, 6:4); 1H NMR (CDCl3): d 3.50–3.65 (m,
3H, H-5, H-6a, H-6b), 3.66 (dd, 1H, J3,4 2.7 Hz, H-3), 3.75 (dd, 1H, J1,2
9.8 Hz, H-1), 3.98 (d, 1H, H-4), 4.05 (dd, 1H, J2,3 9.4 Hz, H-2), 4.42–
4.99 (m, 8H, PhCH2), 7.03–7.41 (m, 20H, Ph), 9.64 (d, 1H, J 1.4 Hz,
CHO); MS (ESI): m/z 585.4 [M+Na]+.
4.13.10. (2,3,4,6-Tetra-O-methyl-b-
(2f-b)
D-mannopyranosyl)methanal
Rf 0.12 (hexanes–EtOAc, 1:1); 1H NMR (CDCl3): d 3.19 (m, 1H,
CH), 3.30–3.70 (m, 17H, m, CH, H-6a, H-6b, CH3), 4.01 (m, 1H,
CH), 9.67 (s, 1H, CHO); 13C NMR (CDCl3): d 57.8, 59.3, 60.9, 61.3
(CH3), 72.0 (C-6), 76.2, 76.5, 79.2, 82.1, 85.6 (CH), 201.9 (CHO);
MS (ESI): m/z 271.4 [M+Na]+.
4.13.3. (2,3,4,6-Tetra-O-methyl-
(2b-
a-D-galactopyranosyl)methanal
a
)
Rf 0.15 (hexanes–EtOAc, 1:1); 1H NMR (CDCl3): d 3.32–3.99 (dd,
5H, H-4), 3.40, 3.53, 3.56, 3.57 (s, 12H, CH3), 4.27 (m, 1H, CH), 4.42
(d, 1H, J1,2 4.0 Hz, H-1), 9.81 (s, 1H, CHO); 13C NMR (CDCl3): d 58.57,
59.20, 59.32, 59.75 (CH3), 66.99 (CH), 70.42 (C-6), 74.86, 75.20,
75.40, 82.04 (CH), 202.49 (CHO); MS (ESI): m/z 271.3 [M+Na]+.
4.14. Preparation of glycal cyanides
Unprotected b-D
-glucosyl32 or galactosyl23,32 nitrile (5 mmol)
was dissolved in DMF (60 mL) and sodium hydride (1.3 equiv per
OH group) were added portionwise in 30 min at ice-bath temper-
ature under nitrogen with vigorous stirring. Benzyl bromide
(1.5 equiv per OH group) was added dropwise to the cooled solu-
tion and the mixture was allowed to stir at 0 °C for 4 h then over-
night at room temperature. The excess sodium hydride was
quenched with methanol under cooling and the solvents were re-
moved in motor vacuum. The residue was diluted with CH2Cl2
and was washed with water. The organic layer was dried (MgSO4)
and the solvent was evaporated. The residue was chromatographed
on silica gel with hexanes–EtOAc (9:1) eluent to afford the corre-
sponding glycal nitriles.
4.13.4. (2,3,4,6-Tetra-O-methyl-b-
(2b-b)
D-galactopyranosyl)methanal
Rf 0.12 (hexanes–EtOAc, 1:1); 1H NMR (CDCl3): d 3.15 (m, 1H,
CH), 3.30–3.79 (m, 5H, CH), 3.40, 3.50, 3.55, 3.58 (s, 12H, CH3),
4.27 (m, 1H, CH), 3.93 (m, 1H, H-1), 9.69 (s, 1H, CHO); 13C NMR
(CDCl3): d 58.51, 59.28, 59.70, 61.59 (CH3), 66.94 (CH), 70.55 (C-
6), 74.80 (CH), 75.13 (CH), 75.34 (CH), 85.02 (CH), 202.46 (CHO);
MS (ESI): m/z 249.3 [M+H]+.
4.13.5. (2,3,4,6-Tetra-O-benzyl-a-D-glucopyranosyl)methanal
(2d-a)
Rf 0.18 (hexanes–EtOAc, 6:4); 1H NMR spectrum was identical
with the reported one.13 MS (ESI): m/z 553.4 [M+H]+.
4.14.1. 1-Cyano-3,4,6-tri-O-benzyl-D-galactal (3a)
½
a 2D0
ꢁ
ꢀ49.6 (c 2.06, CHCl3); Rf 0.26 (hexanes–EtOAc, 8:2); 1H
NMR (CDCl3): d 3.65 (m, 2H, H-6a, H-6b), 3.97 (dd, 1H, J4,5
,
4.13.6. (2,3,4,6-Tetra-O-benzyl-b-
(2d-b)
D
-glucopyranosyl)methanal
1.8 Hz, H-4), 4.16 (m, 1H, H-5), 4.22 (dd, 1H, J3,4 4.0 Hz, H-3),
4.20–4.90 (m, 6H, PhCH2), 5.65 (dd, 1H, J2,3 2.0 Hz, H-2), 7.20–
7.40 (m, 15H, Ph); 13C NMR (CDCl3): d 67.77 (C-6), 69.37, 71.66,
71.91 (CH), 73.65, 74.45, 77.85 (PhCH2), 114.03 (CN), 115.17 (C-
2), 127.80–128.85 (Ph), 129.68 (C-1), 137.61, 137.75, 138.15 (Cq);
MS (ESI): m/z 464.4 [M+Na]+.
Rf 0.18 (hexanes–EtOAc, 6:4); 1H NMR (CDCl3): d 3.52 (ddd, 1H,
J5,6a 4.3 Hz, J5,6b 2.0 Hz, H-5), 3.63 (dd, 1H, J4,5 9.6 Hz, H-4), 3.67 (dd,
1H, J2,3 8.7 Hz, H-2), 3.70–3.75 (m, 2H, H-6a, H-6b), 3.76 (dd, 1H,
J3,4 8.4 Hz, H-3), 3.82 (dd, 1H, J1,2 9.8 Hz, H-1), 4.52–4.90 (m, 8H,

S. Sipos, I. Jablonkai / Carbohydrate Research 346 (2011) 1503–1510
1509
4.14.2. 1-Cyano-3,4,6-tri-O-benzyl-
D
-glucal (3b)
7.17–7.35 (m, 15H, Ph); 13C NMR (CDCl3): d 30.86 (C-2), 64.40
(C-1), 69.21 (C-6), 70.71 (PhCH2), 72.22 (C-4), 73.88, 74.77 (PhCH2),
77.31, 78.85 (CH), 117.34 (CN), 127.68–128.88 (Ph), 137.97,
137.99, 138.67 (Cq); MS (ESI): m/z 444.0 [M+H]+.
½
a 2D0
ꢁ
ꢀ1.80 (c 1.08, CHCl3); Rf 0.30 (hexanes–EtOAc, 8:2); 1H
NMR (CDCl3): d 3.75 (m, 1H, H-6a), 3.79 (m, 1H, H-6b), 3.91 (dd,
1H, J4,5 8.4 Hz, H-4), 4.13 (m, 1H, H-5), 4.20 (dd, 1H, J3,4 6.0 Hz,
H-3), 4.49–4.81 (m, 6H, PhCH2), 5.68 (d, 1H, J2,3 3.0 Hz, H-2),
7.18–7.39 (m, 15H, Ph); 13C NMR (CDCl3): d 67.73 (C-6), 71.74,
73.85, 74.33 (PhCH2), 73.26, 75.18, 78.95 (CH), 113.95 (CN),
114.55 (C-2), 128.00 ꢀ 129.25 (Ph), 130.13 (C-1), 137.56, 137.86,
137.89 (Cq); MS (ESI): m/z 459.4 [M+NH4]+.
4.18.2. 2-Deoxy-3,4,6-tri-O-benzyl-b-D-glucopyranosyl cyanide
(5b-b)
½
a 2D0 +24.4 (c 0.90, CHCl3); Rf 0.34 (hexanes–EtOAc, 8:2); 1H
ꢁ
NMR (CDCl3): d 1.97 (m, 1H, H-2a), 2.40 (m, 1H, H-2b), 3.38 (m,
1H, H-4), 3.51–3.65 (m, 2H, H-3, H-5), 3.70 (m, 2H, H-6a, H-6b),
4.19 (dd, 1H, J1,2a 12.0 Hz, J1,2b 2.1 Hz, H-1), 4.47–4.90 (m, 6H,
PhCH2), 7.17–7.35 (m, 15H, Ph); 13C NMR (CDCl3): d 35.33 (C-2),
63.89 (C-1), 68.85 (C-6), 72.16 (PhCH2), 73.85 (PhCH2), 75.51
(PhCH2), 77.24 (CH), 79.42 (CH), 80.27 (C-4), 117.13 (CN),
127.95–128.78 (Ph), 138.00, 138.06, 138.19 (Cq); MS (ESI): m/z
444.3 [M+H]+.
4.15. 1-C-Formyl-3,4,6-tri-O-benzyl-D-galactal (4a)
Reductive hydrolysis of 3a was carried out according to the gen-
eral procedure described in Section 4.13. ½a D20
ꢀ84.0 (c 1.10,
ꢁ
CHCl3); Rf 0.18 (hexanes–EtOAc, 8:2); 1H NMR (CDCl3): d 3.75 (m,
2H, H-6a, H-6b), 4.10 (dd, 1H, J3,4 3.5 Hz, H-3), 4.17 (m, 1H, H-5),
4.41 (m, 1H, H-4), 4.30–5.00 (m, 6H, PhCH2), 5.81 (dd, 1H, J2,3
2.2 Hz, H-2), 7.20–7.40 (m, 15H, Ph), 9.16 (s, 1H, CHO); 13C NMR
(CDCl3): d 67.70 (C-6), 69.53 (C-4), 71.57 (PhCH2), 73.03 (C-3),
73.78, 74.62 (PhCH2), 76.75 (C-5), 119.25 (C-2), 127.78–128.82
(Ph), 137.83, 137.84, 138.38 (Cq), 151.64 (C-1), 186.28 (CHO); MS
(ESI): m/z 467.2 [M+Na]+.
4.19. (2-Deoxy-3,4,6-tri-O-benzyl-b-
anal (6a-b)
D-galactopyranosyl)meth-
Reductive hydrolysis of 5a-b was carried out according to the
general procedure described in Section 4.13. ½a D20
ꢁ
+5.50 (c 0.37,
CHCl3); Rf 0.17 (hexanes–EtOAc, 6:4); 1H NMR (CDCl3): d 1.99 (q,
1H, J 12.3 Hz, H-2a), 2.11 (m, 1H, H-2b), 3.59 (m, 2H, H-6a, H-
6b), 3.60 (dd, 1H, J5,6a 5.1 Hz, J5,6b 5.4 Hz, 1H, H-5), 3.62 (dd, J 2.1,
9.0 Hz, 1H, CH), 3.80 (dd, 1H, J 2.7, 12.0 Hz, 1H, CH), 3.86 (br, 1H,
H-4), 4.41–4.96 (m, 6H, PhCH2), 7.18–7.39 (m, 15H, Ph), 9.68 (s,
1H, CHO); 13C NMR (CDCl3): d 27.44 (CH2), 69.77 (C-6), 70.45
(PhCH2), 72.86 (C-4), 73.85 (PhCH2), 74.69 (PhCH2), 78.13 (CH),
78.20 (C-5), 80.34 (CH), 127.55–128.74 (Ph), 138.05, 138.31,
138.78 (Cq), 201.43 (CHO); MS (ESI): m/z 469.4 [M+Na]+.
4.16. 1-C-Formyl-3,4,6-tri-O-benzyl-D-glucal (4b)
Reductive hydrolysis of 3b was carried out according to the gen-
eral procedure described in Section 4.13. ½a D20
ꢀ23.90 (c 0.50,
ꢁ
CHCl3); Rf 0.20 (hexanes–EtOAc, 85:15); 1H NMR (CDCl3): d 3.85
(m, 2H, H-6a, H-6b), 3.99 (dd, 1H, J4,5 8.7 Hz, H-4), 4.16, (ddd, 1H,
J5,6a 3.4, J5,6b 3.4 Hz, H-5), 4.35 (dd, 1H, J3,4 6.4 Hz, H-3), 4.50–
4.80 (m, 6H, PhCH2), 5.82 (d, 1H, J2,3 3.0 Hz, H-2), 7.19–7.36 (m,
15H, Ph), 9.21 (s, 1H, CHO); 13C NMR (CDCl3): d 67.95 (C-6),
71.80, 73.81 (PhCH2), 73.87 (C-4), 74.30 (PhCH2), 75.93 (C-3),
77.90 (C-5), 117.26 (CN), 127.93–138.15 (Cq), 151.79 (C-1),
186.40 (CHO); MS (ESI): m/z 467.4 [M+Na]+.
4.20. (2-Deoxy-3,4,6-tri-O-benzyl-b-
(6b-b)
D-glucopyranosyl)methanal
Reductive hydrolysis of 5b-b was carried out according to the
4.17. 1-C-Formyl-3,4,6-tri-O-allyl-
D
-galactal (4c)
general procedure described in Section 4.13. ½a D20
ꢁ
+17.0 (c 0.94,
CHCl3); Rf 0.15 (hexanes–EtOAc, 6:4); 1H NMR (CDCl3): d (ppm):
1.50 (m, 1H, H-2a), 2.39 (m, 1H, H-2b), 3.41–3.82 (m, 6H, H-1, H-
3, H-4, H-5, H-6, H-60), 4.42–4.93 (m, 6H, PhCH2), 7.17–7.34 (m,
15H, Ph), 9.70 (s, 1H, CHO); 13C NMR (CDCl3): d (ppm): 31.54 (C-
2), 69.13 (C-6), 71.43, 73.57, 75.15 (PhCH2), 77.74, 79.14, 79.44,
80.27 (C-1, C-3, C-4, C-5), 127.61–128.48 (Ph), 137.94, 138.11,
138.21 (Cq), 200.76 (CHO); MS (ESI): m/z 469.4 [M+Na]+.
Reductive hydrolysis of 1c-b carried out as described in Section
4.13. resulted in only this product. ½a D20
ꢀ117 (c 0.60, CHCl3). Rf
ꢁ
0.32 (hexanes–EtOAc, 1:1); 1H NMR (CDCl3): d 3.58 (m, 1H, CH),
3.71–3.83 (m, 4H, CH), 3.96–4.40 (m, 8H, OCH2), 5.12–5.38 (m,
8H, CH2@CH), 5.78 (m, 1H, H-2), 5.75–6.03 (m, 4H, CH2@CH),
9.14 (s, 1H, CHO); 13C NMR (CDCl3): d 67.51 (C-6), 69.18 (CH),
70.45, 72.94, 73.70 (OCH2), 72.56, 72.75, 76.48 (CH), 117.41,
117.56, 117.70 (CH2@CH), 134.21, 134.33, 134.96 (CH2@CH),
151.51 (C-1), 186.09 (CHO); MS (ESI): m/z 312.1 [M+H]+.
4.21. 1,3-Diphenyl-2-(2,3,4,6-tetra-O-benzyl-b-
D-
galactopyranosyl)-imidazolidine (7a-b)
4.18. Preparation of 2-deoxy-3,4,6-tri-O-benzyl-b-
glycopyranosyl cyanides (5a-b, 5b-b)
D
-
Compound 1a-b (55 mg, 0.1 mmol) was dissolved in dry CH2Cl2
(2 mL) and DIBAL-H (140 L of 1 M soln in CH2Cl2, 0.14 mmol) was
added by a syringe at ꢀ78 °C under N2 and the reaction mixture
was stirred for 30 min. Glacial acetic acid (10 L, 0.18 mmol) was
added and the mixture was stirred for 5 min at ꢀ78 °C. Then
N,N0-diphenylethylenediamine (43 mg, 0.2 mmol) dissolved in
methanol (2 mL) was added and the stirring was continued over-
night at room temperature. The mixture was diluted with CH2Cl2
(10 mL) and washed with 1 M NH4Cl solution (8 mL). The organic
layer was dried over Na2SO4 and the solvent evaporated in vacuo.
The residue was purified by silica gel column chromatography
(hexanes–EtOAc, 9:1) to give 7a-b as a white crystalline material.
l
Protected glycal cyanides (3a, 3b) (1 mmol) were dissolved in
ethanol (60 mL) and palladium on carbon (0.8% w/w catalyst/sub-
strate, 36 mg, 10% Pd/C) was added under H2 in a round-bottomed
flask sealed with septum. The mixture was stirred for 4 days sup-
plying H2 from a balloon. The catalyst was filtered off and the fil-
trate was evaporated. The residue was chromatographed on silica
gel with hexanes–EtOAc (95:5) eluent to afford the corresponding
deoxy derivatives.
l
4.18.1. 2-Deoxy-3,4,6-tri-O-benzyl-b-
(5a-b)
D
-galactopyranosyl cyanide
Mp 38–39 °C; ½a 2D0
ꢁ
+80.0 (c 1.0, CHCl3); Rf 0.37 (hexanes–EtOAc,
8:2); 1H NMR (CDCl3): d (ppm): 3.42 (m, 2H, NCH2), 3.51 (m, 1H,
H-5), 3.52 (m, 2H, NCH2), 3.55 (m, 1H, H-4), 3.62 (d, 1H, J1,2
9.9 Hz, H-1), 3.70 (d, 2H, J 6.6 Hz, H-6a, H6b), 3.92 (m, 1H, H-2),
3.93 (br s, 1H, H-3), 4.41–5.09 (m, 8H, PhCH2), 5.50 (s, 1H, NCHN),
6.68–6.75 (m, 4H, CH), 6.85 (m, 2H, Ph), 7.13–7.35 (m, 24H, Ph);
Mp 56–58 °C; ½a 2D0
ꢁ
+4.6 (c 1.97, CHCl3); Rf 0.30 (hexanes–EtOAc,
8:2); 1H NMR (CDCl3): d 2.08 (m, 1H, H-2a), 2.44 (m, 1H, H-2b),
3.43–3.60 (m, 4H, H-3, H-5, H-6a, H-6b), 3.83 (m, 1H, H-4), 4.18
(dd, 1H, J1,2a 12.0 Hz, J1,2b 2.0 Hz, H-1), 4.38–4.94 (m, 6H, PhCH2),

1510
S. Sipos, I. Jablonkai / Carbohydrate Research 346 (2011) 1503–1510
13C NMR (CDCl3): d (ppm): 46.38, 47.15 (NCH2), 69.49 (C-6), 72.05,
73.72, 74.25, 74.37 (PhCH2), 73.74 (C-3), 75.26 (C-2), 76.76 (C-5),
76.83 (NCHN), 80.63 (C-1), 86.12 (C-4), 112.89, 114.14, 117.18,
117.69 (Ph), 126.81–129.55 (Ph), 138.16, 138.36, 139.43, 139.74,
146.31, 147.13 (Cq); MS (ESI): m/z 747.6 [M+H]+.
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Supplementary data
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