Preparation of 2-amino-2-C-glycosyl-acetonitriles from C-glycosyl aldehydes by Strecker reaction

Article abstract of DOI:10.1016/j.carres.2011.10.023

Synthesis of new 2-amino-2-C-d-glycosyl-acetonitriles in a Strecker reaction from various C-glycosyl aldehydes, chiral amines, and HCN was carried out. While aminonitriles from glycal and 2-deoxy-β-d-glycosyl aldehydes were prepared in satisfactory yields

Full text of DOI:10.1016/j.carres.2011.10.023

Carbohydrate Research 346 (2011) 2862–2871
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Preparation of 2-amino-2-C-glycosyl-acetonitriles from C-glycosyl aldehydes
by Strecker reaction
⇑
Szabolcs Sipos, István Jablonkai , Orsolya Egyed, Mátyás Czugler
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:
Received 23 May 2011
Received in revised form 13 October 2011
Accepted 14 October 2011
Available online 20 October 2011
Synthesis of new 2-amino-2-C-
hydes, chiral amines, and HCN was carried out. While aminonitriles from glycal and 2-deoxy-b-
D
-glycosyl-acetonitriles in a Strecker reaction from various C-glycosyl alde-
-glycosyl
aldehydes were prepared in satisfactory yields, lower yields were obtained with C-glycosyl aldehydes.
Strecker reaction with the benzyl-protected 1-C-formyl- -galactal and S- or R-1-phenylethylamine
D
D
(S-PEA or R-PEA) yielded predominantly the R-configured C-glycosyl aminoacetonitrile. The direction of
the nucleophilic addition appears to be governed by the configuration of the anomeric carbon with
b-linked sugars. Since the stereochemistry of the transition state is unknown according to the configura-
tion of the major product a Felkin–Ahn selectivity can be mainly presumed.
Keywords:
1-C-Glycosyl aldehyde
Strecker reaction
Ó 2011 Elsevier Ltd. All rights reserved.
2-Amino-2-C-D-glycosyl-acetonitrile
Double asymmetric induction
1. Introduction
with TMSCN using boron trifluoride.9 In situ H2O2 oxidation of
the cyanohydrin formed from benzyl-protected formyl C-ribofur-
2-Amino-2-C-
nitriles) carrying an
D
-glycosyl-acetonitriles (C-glycosyl aminoaceto-
-aminonitrile moiety directly linked to the
anoside by treatment with aqueous NaCN and K2CO3 provided
the corresponding -hydroxy amide as appropriate intermediate
for the synthesis of b-
-ribofuranosyl glycine.10 In another exam-
ple, dehydration of a b- -ribofuranose-linked Cbz-protected gly-
cine amide carried out with trifluoroacetic anhydride and
pyridine provided the -aminonitrile connected to the anomeric
carbon.11,12 C-Glycosyl-
-alanine precursor 2-amino-2-( -glyco-
pyranosyl)propanenitrile derivatives were synthesized by asym-
metric Strecker synthesis from perbenzylated 2-C-(
a
a
anomeric carbon of carbohydrates are challenging bifunctional
intermediates which can be applied in various organic transforma-
tions. By hydrolysis these compounds can be converted into C-gly-
cosyl glycine building blocks applicable in the synthesis of
biologically important glyco-peptidomimetics. Reduction of the ni-
trile functionality may result in 1,2-diamino derivatives as starting
materials for the preparation of carbohydrate linked nitrogen het-
D
D
a
L
a-D
a-D-
erocycles. Also, deprotonated
valuable and readily accessible synthetic equivalents of acyl anions
and -aminonitriles are prepared
-aminocarbanions.1 Typically,
a
-aminonitriles have been applied as
glycopyranosyl)acetaldehydes employing S-1-phenylethylamine
as chiral inducer.13
a
a
Nevertheless, no information on the preparation of
a-amino-
by Strecker synthesis involving the reaction of aldehydes with
amines and cyanides such as HCN, KCN, TMSCN, (EtO)2P(O)CN,
Et2AlCN, Bu3SnCN, acetone cyanohydrin, or acyl cyanides.2,3 Pre-
acetonitriles directly linked to the anomeric center of -glycopyra-
D
nose derivatives as C-glycosyl glycine precursors has been available.
Our objective was to prepare various glycopyranose-linked amino-
acetonitriles from 1-C-formyl-glycosyl derivatives such as
formed imines which are intermediates of
a-aminonitrile forma-
tion during the Strecker synthesis are widely used starting
materials in catalytic asymmetric Strecker syntheses.4 Despite
their importance only few synthetic methods have been described
for C-glycosyl aminoacetonitriles. Strecker-type transformations of
sugar derived aldehydes in ‘anomeric like’ positions to C-glycosyl
aminoacetonitriles have been described.5–8 A ribofuranose-linked
D-glycal-, 2-deoxy-b-D-glycosyl-, and a- and b-D-glycosyl aldehydes
by asymmetric Strecker reaction using S- and R-1-phenylethylam-
ines. Since 1-C-formyl-glycosides have been reported as unstable
derivatives due to their decomposition by 2-benzyloxy elimina-
tion14 it was not trivial that these compounds can tolerate the con-
ditions employed in the Strecker reaction of 2-C-(a-D-
a
-aminonitrile (2-amino-2-ribofuranosyl acetonitrile) was pre-
glycopyranosyl)acetaldehydes.13 In the stereoselective formation
of C-glycosyl aminonitriles in addition to chiral amine the sugar
aldehyde reactant can also influence the stereochemical outcome
of the reaction and therefore the double asymmetric induction by
these chiral auxiliaries can also be studied. The effect of reaction
conditions such as solvents, cyanide source, and amines on yields
and diastereomeric ratios (dr) will be also discussed.
pared from chiral sulfinimine derived from 20,30-O-protected
50-formyluridine and R- or S-tert-butyl sulfinamide in a reaction
⇑
Corresponding author.
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.2011.10.023

S. Sipos et al. / Carbohydrate Research 346 (2011) 2862–2871
2863
tone derivatives by an established literature method21 introducing
aldehyde equivalent thiazole functionality at the anomeric posi-
tion followed by unmasking the formyl group in several steps.
In our hands 1-C-formyl-glycal formation by 2-benzyloxy elim-
ination always occurred during the regeneration of aldehyde func-
2. Results and discussion
2.1. Preparation of 1-C-formyl glycosyl derivatives
Our synthetic approach for the preparation of C-glycosyl
aminoacetonitriles (5a–b, 6a–b) by Strecker synthesis via 1-C-for-
tionality therefore the yields for 1-C-formyl derivatives (a-7a 31%
and glucal aldehyde 35%; b-7b 35% and galactal aldehyde 26%)
were always less than the literature21 values. When the benzyl
protecting groups were replaced with methyl groups somewhat
myl-
D
-glycal (2a–b) and 2-deoxy-b-
D
-glycosyl aldehyde (4a–b)
intermediates is outlined in Scheme 1. 1-Cyano-
D-glycals (1a–b)
were considered as common starting materials for these sugar
aldehydes. Benzyl-protected glycal nitriles (1a–b) were available
in our laboratory from previous work as unexpected by-products
during the standard benzylation (NaH, benzylbromide, DMF) of b-
improved yield (a-7a, 46%) with concomitant glycal aldehyde for-
mation was obtained. Reductive hydrolysis of perbenzylated
a-
glucopyranosyl cyanide with LiAlH4 in THF followed by hydrolysis
of the intermediate aldimine was reported to afford the respective
1-C-formyl derivative with good yields (75%).22 However, in the re-
ported 1H NMR spectrum of the product the chemical shift
(9.20 ppm) of the CHO proton is rather consistent with the forma-
D
-glucopyranosyl, b-
D
-galactopyranosyl, and
a
-D
-mannopyranosyl
-glucopyran-
cyanides by 2-benzyloxy elimination.15 2-Deoxy-b-
D
osyl (3a) and galactopyranosyl (3b) cyanides were prepared from
the respective glycal cyanide by hydrogenation over palladium on
charcoal at atmospheric pressure in moderate yields (50–60%).15
An attempt to use a diimide reduction failed since no reaction
took place with o-nitrobenzenesulfonyl-hydrazide (NBSH)16 as
diimide precursor. Nevertheless, NBSH was reported as a useful
diimide source in the preparation of 2,3-dideoxyhexoses from
derivatives having non-polarized double bond.17
tion of 1-C-formyl-3,4,6-tri-O-benzyl-D-glucal since in all 1-for-
myl-C-glycosyl derivatives of the gluco, galacto, and manno series
higher chemical shifts (9.60–9.98 ppm) were reported.15,21 Due to
this contradiction and the ability of LiAlH4 to reduce nitriles to pri-
mary amines we did not attempt to prepare the aldehydes by this
way.
Benzylated 1-C-formyl-glycals (2a–b) and 2-deoxy-glycosyl
formaldehydes (4a–b) were prepared from the corresponding ni-
triles (1a–b, 3a–b) by reductive hydrolysis carried out with Raney
nickel and NaH2PO2 in acetic acid/pyridine/water at room temper-
ature. Yields (55–72%) obtained were similar to those reported for
the same transformation of peracetylated sugar nitriles.18,19 The
reported direct lithiation of 2-phenylsulfinyl- and 2-phenylsulfo-
nyl-3,4,6-tri-O-benzyl-galactals followed by a reaction with DMF
as electrophile affording 1-C-formyl-glycals20 seemed to be less
convenient procedure than the reductive hydrolysis. C-Glycosyl
formaldehydes (7a–c, Scheme 1) were prepared from glyconolac-
2.2. Strecker synthesis of various C-glycosyl aminoacetonitriles
Strecker-reaction for the preparation of C-glycosyl aminoaceto-
nitriles (5a–b, 6a–b, and 8a–c, Scheme 1) was carried out with 1-C-
formyl-glycals (2a–b), as well as 2-deoxy-glycosyl- (4a–b) and gly-
cosyl-formaldehydes (7a–c) using chiral amines such as S- or R-
PEA or achiral (benzylamine (BA), benzhydrylamine (BHA)) amines
and various cyanide donors. Acetone cyanohydrine (ACH) was used
initially as a cyanide source but due to by-product formation it was
replaced later with NaCN/NH4Br or TMSCN in methanol. The
OBn
OBn
R1
R1
H2, Pd/C
R2
O
R2
BnO
O
CN
CN
BnO
1a - b
3a - b
Raney-Ni, NaH2PO2
Raney-Ni, NaH2PO2
HOAc, Pyr, H2O
R5
R1
HOAc, Pyr, H2O
R4
R3
O
R5
OBn
OBn
CHO
R1
R1
R2
R2
BnO
O
R2
BnO
O
7a
α− : R1= R4= H, R2=R3= R5= OBn
CHO
CHO
7b
β− : R1= R3= H, R2=R4= R5= OBn
7c
α− : R2= R4= H, R1=R3= R5= OMe
2a - b
4a - b
R
CH3
NH2
R
HCN
HCN
HCN
NH2
NH2
R5
R1
OBn
OBn
R1
R4
R1
4
6
H
N
CN
R2
O
R3
O
R2
BnO
O
CN
8
5
BnO
R5
7
N
H
2
CH3
9
N
H
3
1
R
CN
R
R2
6a - b
5a: R = CH3 (S)
5b-1: R = CH3 (S)
5b-2: R = CH3 (R)
5b-3: R = H
α−8a: R1= R4= H, R2=R3= R5= OBn R= CH3 (S)
β−8b-1: R1= R3= H, R2=R4= R5= OBn R= CH3 (S)
β−8b-2: R1= R3= H, R2=R4= R5= OBn R= Ph
a: R1 = H, R2 = OBn
b: R1 = OBn, R2 = H
R2= R4= H, R1=R3= R5= OMe R= CH3 (S)
α−8c:
Scheme 1. Preparation of glycal-(5a–b), 2-deoxy-glycosyl-(6a–b) and a- and b-glycosyl-linked (8a–c) aminoacetonitriles.

2864
S. Sipos et al. / Carbohydrate Research 346 (2011) 2862–2871
by-product,
2-methyl-2-(1-phenylethylamino)propene-nitrile,
aldehydes (4a–b) and S-PEA employing TMSCN in CH2Cl2 (entry
6) or ACH in THF (entry 7) exhibited higher dr values (8.25 and
5.17, respectively). However, low yields and diastereoselectivities
formed in the reaction of acetone cyanohydrin and S-PEA,23 con-
taminated the C-glycosyl aminoacetonitrile products due to its
similar elution pattern which made the determination of the dr
were obtained when the reaction was carried out with
a- and b-
values complicated. By the use of ACH
a
catalytic amount
linked aldehydes (7a–c) derived from glucose, galactose, and man-
nose (entries 8–11). The low yields can be attributed to the decom-
position of these unstable aldehydes by 2-alkyloxy elimination.
Higher dr values were obtained with b-linked aldehydes as com-
(0.1 equiv) of triethylamine was always added in order to increase
the dissociation of ACH into acetone and HCN.24 Diastereomeric
mixtures of aminonitriles 5a–b and 6a–b formed in the Strecker
reactions were inseparable by chromatography and therefore dr
values were calculated from the 1H NMR integral values of the
CH protons at the new stereogenic center (C-7 as indicated on
the numbered structure of 6a–b on Scheme 1) as well as those of
the CH3 protons (C-9) due to the chiral amine. On the other hand,
8a–c diastereomeric aminonitriles could be separated by column
chromatography. Yields and dr values of the Strecker reaction with
pared to those from the a-linked derivatives.
2.3. Configuration of the new stereocenter
The assignment of the configuration at the newly formed stereo-
center was a crucial problem in our work. While diastereomers of
benzyl-protected glycal- and 2-deoxy-glycosyl-linked aminonitriles
(5 and 6) were inseparable, isolated diastereomers of benzyl-pro-
protected 1-C-formyl-D-galactal 2b were superior to those with 1-
C-formyl- -glucal 2a (Table 1, entries 1–5). The reaction exhibited
D
tected C-glycosyl-acetonitriles (a-8a and b-8b) were oily materials
higher stereoselectivity when S-PEA was used as compared to R-
PEA (Table 1, entries 3 and 4) indicating that in the imine interme-
diate formed with the S-configured amine one of the diastereotopic
faces at the prochiral CH@N group was preferred. While no stereo-
unsuitable for an X-ray crystallographic structure determination.
However, the absolute configuration of the new stereocenter in
the crystalline major product of
a-8c derived from permethyl a-
mannopyranosyl aldehyde -7c (Table 2, entry 11) was established
a
differentiations were reported13 in the Strecker reaction of 2-C-
a-
R by X-ray crystallography. In this diastereomer the methine proton
(H-7) is located above the benzene ring (Fig. 1). For all other com-
pounds, the configurations of the major and minor diastereomeric
products were determined by comparing the 1H NMR chemical
shifts of methine protons (H-7) at the new stereocenter as described
in the literature.13,28–30 In the aminonitriles formed from achiral
aldehydes, the signals due to the methine protons of the new stereo-
center in the major isomers always appeared at a higher field than
those in the minor isomers. The observed upfield methine shift is
due to the magnetic shielding effect by the phenyl group from the
D-glycosyl acetaldehydes with BA and ACH, the reaction performed
with 2b and BA yielded 5b-3 with dr 2.78 (entry 5). Similarly, in
the reaction of b-7b with achiral BHA similar dr value was found
indicating the stereodifferentiating effect of these sugar aldehydes.
As stereodiscriminating auxiliaries carbohydrates offer a variety of
possibilities for spatial differentiation at various stereoselective
syntheses.25,26 The O-pivaloylated-b-
D-galactosylamine proved to
be an effective chiral auxilary in Strecker synthesis of aminonitr-
iles.27 Strecker reactions carried out with 2-deoxy-b-
D-glycosyl
Table 1
Preparation of C-glycosyl aminoacetonitriles from glycal-, 2-deoxy-glycosyl-, and glycosyl aldehydes and effects of the reaction conditions on yields and diastereomeric ratios
Entry
Aldehyde
Amine (equiv)
HCN source (equiv)
Aminonitriles
Solvent
Yield (%)
dr
1
2
3
4
5
6
7
8
9
2a
2a
2b
2b
2b
4a
4b
S-PEA (1.1)
S-PEA (1.5)
S-PEA (2.0)
R-PEA (2.0)
BA (2.0)
S-PEA (2.0)
S-PEA (2.0)
S-PEA (1.5)
S-PEA (2.0)
BHA (3.0)
ACH (1.3)
ACH (2.5)
ACH (5.0)
ACH (5.0)
ACH (5.0)
TMSCN (2.0)
ACH (5.0)
ACH (2.5)
TMSCN (2.0)
NaCN (3.0)
ACH (5.0)
5a
5a
5b-1
5b-2
5b-3
6a
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
38
48
78
72
74
70
67
47
34
43
30
1.44
1.24
3.00
2.06
2.78
8.25
5.17
1.35
3.30
2.79
2.00
6b
a-7a
a-8a
b-7b
b-7b
b-8b-1
b-8b-2
a-8c
10
11
a-7c
S-PEA (2.0)
Table 2
1H NMR shifts of anisochronous protons and the suggested configuration of the new stereocenter in the major diastereomers of various aminonitriles
Entry
Aminonitrile
Amine
1H NMR chemical shifts (ppm)
Configuration of N–CH–CN in major product
N–CH–CH3 (H-9)
N–CH–CH3 (H-8)
N–CH–CN (H-7)
Major
Minor
Major
Minor
Major
Minor
1
2
3
4
5
6
7
8
9
10
5a
5b-1
5b-2
5b-3
6a
S-PEA
S-PEA
S-PEA
R-PEA
BA
S-PEA
S-PEA
S-PEA
S-PEA
BHA
1.47
1.36
1.36
1.19
1.42
1.31
1.31
1.38
—
1.34
1.33
1.32
1.25
—
4.17
4.10
4.05
3.89
—
4.05
4.04
4.02
4.04
—
4.13
3.97
3.97
4.07
—
4.06
4.06
4.06
3.99
—
3.56
3.81
3.76
3.86
3.87
3.29
3.26
4.03
3.64
3.79
3.59
4.04
4.04
4.01
3.75
3.91
3.69
3.63
3.58
4.02
3.86
4.04
R
R
R
R
—
Ra
R
1.38
1.38
1.30
1.39
—
1.35
6b
R
S
a
-8a
b-8b-1
b-8b-2
R
10
11
Ra
Rb
a
-8c
S-PEA
1.33
4.06
4.04
Suggested configuration based on preferred re-face attack by ꢀCN in case galactal and b-
D-galactosyl derivatives.
Configuration confirmed by X-ray crystallography.
a
b

S. Sipos et al. / Carbohydrate Research 346 (2011) 2862–2871
2865
Figure 1. An ORTEP view of the R-diastereomer of aminoacetonitrile a-8c.
chiral amine in the major diastereomers.28–30 In case of aminonitr-
iles prepared from C-glycosyl aldehydes similar pattern was estab-
ever re-face control by the sugar strongly suggests the formation of
R-diastereomers. The major products formed from b-deoxy- -gly-
D
lished using S-PEA chiral auxiliary except for
a
-8a (Table 2).
cosyl aldehydes in highly diastereoselective CN addition possess
Consistent differences in the range of 0.2–0.4 ppm were noticed. In
asymmetric Strecker reaction with S-PEA and achiral aliphatic or
substituted benzaldehydes re-face selectivity was observed.28,31
Re-face addition of the cyano group to the prochiral center yields
R-configured major product since the Cahn-Ingold-Prelog priority
of C-1 (anomeric carbon) is higher than that of CN. NMR data suggest
preferred R-configured new stereocenters in the major diastereo-
R-configured new stereocenter (Table 2, entries 6 and 7). In the
Strecker reaction with glucopyranosyl aldehyde
a-7a CH proton
of the new stereocenter in the major isomer appeared at a lower
field than that in the minor isomer indicating si-face selectivity
by the formation of S-configured major product (entry 8). With
b-D-galactopyranosyl aldehyde b-7b and S-PEA the reaction pro-
vided predominantly R-configured product. Re-face selectivity
mers of all C-glycosyl aminoacetonitriles except 8a-
a
indicating a
was also observed in the reaction of dry HCN and imines prepared
predominant re-face attack by the nucleophile (Scheme 2, Table 2).
Employing R-PEA in the Strecker reaction with achiral aldehydes si
selectivity was reported.28 However, in case of 5b-2 using R-PEA
the chemical shifts of the methine protons in the major and minor
isomers appeared in a reversed order suggesting R-configured C-7
formed by re-face attack.
Lower dr values obtained with R-PEA as compared to S-PEA un-
der the same conditions suggest that 2b and S-PEA react in a
matched pair reaction (Tables 1 and 3). This indicates that the
asymmetric induction by the reacting sugar is dominant over the
1,3-asymmetric induction by the R-PEA. By the use of achiral
amines (BA, BHA) the C-7 configuration was not predictable, how-
from pivaloyl-b-D-galactosylamine as chiral template and various
achiral aldehydes in CHCl3.31 Re-face selectivities in Mannich-
and Reformatsky-type reactions were also reported with b-linked
sugar aldehydes and were explained by the polar Felkin–Ahn and
Cram-chelate models.32 The direction of the nucleophilic addition
appears to be governed by the configuration of the anomeric car-
bon in case of b-linked sugars. Since the stereochemistry of the
transition state is unknown according to the configuration of the
major product a Felkin–Ahn selectivity can be presumed in most
cases.
H
CN
NR'
NR'
O
O
O
O
H2NR'
-H2O
NR'
HCN
CHO
S
R
H
CN
H
OPg
OPg
OPg
Si-face
Re-face
OPg
Si-face
Re-face
Scheme 2. Stereochemistry of the nucleophilic cyanide addition to the intermediate glycosyl imines.

2866
S. Sipos et al. / Carbohydrate Research 346 (2011) 2862–2871
Table 3
Diastereoselectivity of Strecker reaction depending on the chirality of the amine and the effect of thiourea bifunctional organocatalysts in the hydrocyanation of preformed imines
Entry
Substrate
Amine (1 equiv)
HCN donor (1.25 equiv)
Catalyst (0.02 equiv)
Solvent
Product (C-7 config.)
Yield (%)
dr
1
2
3
4
5
6
2b
9b-1
2b
9b-2
2b
9b-3
S-PEA
—
R-PEA
—
BA
—
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
—
10
—
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5b-1 (R)
5b-1 (R)
5b-2 (R)
5b-2 (R)
5b-3 (R)b
5b-3 (R)b
65
78
61
77
72
77
5.82
4.80
2.44
2.11
3.36
2.85
10
—
11a
a
0.10 equiv of catalyst was used.
Suggested configuration based on preferred re-face attack by ꢀCN.
b
H
2.4. Studies on double asymmetric induction and the use of
organocatalysts to improve diastereoselectivities
O
CH3
N
But
S
N
In order to gain stereocontrol of the asymmetric Strecker reac-
tion resulting C-glycosyl aminoacetonitriles we conducted experi-
ments with chiral aldehyde 2b and S- as well as R-PEA to reveal
which is the matched and the mismatched pair in this asymmetric
Strecker reaction (Scheme 1). Moreover, in order to improve dia-
stereoselectivities, the hydrocyanation of previously unreported
preformed glycosyl-imines (9b-1, 9b-2, 9b-3) was studied in the
presence of thiourea organocatalysts (10–11, Schemes 3 and 4).
The ability of thioureas to activate electrophiles such as imines
bearing a wide variety of protecting groups has been demonstrated
in several enantioselective C–C bond-forming reactions.33
In the reaction of 2b with chiral amines and TMSCN predomi-
nantly R-configured products were obtained in both cases. Higher
dr value was achieved with S-PEA (dr 5.82, Table 3, entry 1) than
with R-PEA (dr 2.44, Table 3, entry 3) indicating that in the Strecker
reaction 2b and S-PEA react as a matched pair. It is noteworthy that
employing TMSCN as cyanide donor resulted in higher diastereose-
lectivities as compared to reactions carried out with ACH (Table
1).The origin of the double asymmetric induction is presently un-
known. With achiral benzylamine dr 3.66 was observed (Table 3,
entry 5).
H3C
NH
NH
N
H
O
NH
N
HO
S
NH
O
But
O
But
F3C
CF3
10
11
Scheme 4. Structure of thiourea organocatalysts.
The R/S dr value with the S-configured imine was 14.4 while with
the R-imine was 1.38 indicating that the pre-transition state
assembly of the catalyst and the S-imine favors for re-face attack
by the cyanide leading to predominant R-enantiomer. The ineffec-
tiveness of thiourea 10 in our case may be explained by the lack of
interaction between the sugar imine and the catalyst. The cin-
chona-based thiourea catalyst 11 (Scheme 4) successfully applied
in a Michael addition reaction36 was also ineffective in the hydro-
cyanation of the imine prepared from the galactal aldehyde 2b and
benzylamine. Nevertheless 11 contains no amide moiety which in
addition to the thiourea moiety of 11 actively participates in the
stabilization of the iminium ion by hydrogen bonding.34
For studying thiourea organocatalysts preformed imines (9b-1,
9b-2, 9b-3) were prepared from 1-C-formyl-tri-O-benzyl-D-galac-
tal 2b employing stoichiometric amounts of S- or R-PEA as well
as benzylamine in the presence of molecular sieves (Scheme 3).
These glycal imines were unstable during column chromatography
therefore used without purification in the aminonitrile formation.
Nucleophilic HCN addition to these imines employing thiourea cat-
alysts was performed in CH2Cl2 using a slight excess of TMSCN (Ta-
ble 3, entries 2, 4 and 6). Thiourea 10 (Scheme 4) has been shown
to promote proton transfer from HCN to imine to generate diaste-
reomeric iminium/cyanide ion pair that are bound to the catalyst
via multiple noncovalent interactions followed by a collapse of
3. Conclusions
In summary, synthesis and structure elucidation of new 2-ami-
no-2-C-D-glycosyl-acetonitriles in a Strecker reaction from various
C-glycosyl aldehydes, chiral amines, and HCN were carried out.
While aminonitriles from glycal and 2-deoxy-b-glycosyl aldehydes
were prepared in satisfactory yields, lower yields were obtained
with C-glycosyl aldehydes due to the decomposition of these alde-
hydes by b-elimination. In the reactions from 1-C-formyl-galactal
improved stereoselectivities were noticed when ACH was replaced
with TMSCN. The configurations of the major and minor diastereo-
meric products were assigned based on the 1H NMR chemical shifts
of methine protons (H-7) at the new stereocenter. Strecker reaction
ion pairs resulting in (R)-a
-aminonitrile products.34 However, in
our conditions this highly enantioselective catalyst showed no
activity with either of S- or R-configured galactal imines and even
lower dr values were found by the addition of the catalyst. In a lit-
erature example, by the use of chiral bicyclic guanidine catalyst in
the hydrocyanation of imines from benzaldehyde and S-PEA and R-
PEA greatly different R/S diastereoselectivities were obtained.35
with the benzyl-protected 1-C-formyl-
D
-galactal and S-PEA or R-PEA
OBn
OBn
OBn
OBn
OBn
R
OBn
R
H
N
O
NH2
HCN
O
O
N
BnO
CHO
BnO
BnO
MS, CH2Cl2
thiourea catalysts
R
CN
9b-1 R= CH3(S)
9b-2 R= CH3(R)
9b-3 R= H
2b
5b-1
5b-2
5b-3
Scheme 3. Preparation of D-galactal-linked a-aminonitriles via preformed galactal imines.

S. Sipos et al. / Carbohydrate Research 346 (2011) 2862–2871
2867
yielded predominantly the R-configured C-glycosyl aminoacetonit-
rile via re-face nucleophilic addition of HCN in both cases. Since
higher dr values were obtained with S-PEA as compared to R-PEA,
we can conclude that the aminonitrile formation from the 1-C-for-
2.7 Hz, 1H, H-3), 4.50–4.80 (m, 6H, PhCH2), 5.82 (d, J = 2.7 Hz, 1H,
H-2), 7.19–7.36 (m, 15H, Ph), 9.21 (s, 1H, CHO); 13C NMR
(75 MHz, CDCl3), d (ppm): 68.0 (C-6), 71.8 (PhCH2), 73.8 (PhCH2),
73.9 (C-4), 74.3 (PhCH2), 75.9 (C-3), 77.90 (C-5), 117.3 (C-2),
127.9, 128.0, 128.1, 128.2, 128.3, 128.6, 128.7, 128.8 (Ph-CH),
137.9, 138.1, 138.2 (Ph-Cq), 151.8 (C-1), 186.4 (CHO); MS (ESI):
m/z = 467.4 [M+Na]+. Anal. Calcd for C28H28O5: C, 75.65; H, 6.35.
Found: C, 75.74; H, 6.29.
myl-D-galactal derivative, S-PEA and TMSCN takes place in a
matched pair reaction. Diastereoselectivity of the reaction from pre-
formed imines prepared from galactal aldehyde was not influenced
by the use of thiourea organocatalysts. The direction of the nucleo-
philic addition appears to be governed by the configuration of the
anomeric carbon with b-linked sugars. Since the stereochemistry
of the transition state is unknown according to the configuration
of the major product a Felkin–Ahn selectivity can be presumed in
most cases.
In order to improve stereoselectivity of the Strecker reaction the
complex-forming ability of carbohydrates can be exploited. Coordi-
nation of Lewis acids to glycosyl imines formed from glycosyl
amines has been found to have strong influence on the stereodif-
ferentiation in the nucleophilic cyanide addition.37 Further studies
on applying Lewis acid catalysts in asymmetric Strecker reaction
will be performed.
4.2.2. 1-Formyl-3,4,6-tri-O-benzyl-D-galactal (2b)
Compound 2b was obtained from 1b15 as colorless syrup; yield
63%. ½a 2D0
ꢁ
ꢀ84.0 (c 1.10, CHCl3); Rf = 0.15 (hexanes–EtOAc, 8:2); 1H
NMR (400 MHz, CDCl3), d (ppm): 3.75 (m, 2H, H-60, H-600), 4.10 (dd,
J = 3.5, 2.2 Hz, 1H, H-3), 4.17 (ddd, J = 7.6, 6.0, 1.0 Hz, 1H, H-5),
4.41 (m, 1H, H-4), 4.30–5.00 (m, 6H, PhCH2), 5.81 (dd, J = 2.2,
2.0 Hz, 1H, H-2), 7.20–7.40 (m, 15H, Ph), 9.16 (s, 1H, CHO); 13C
NMR (100 MHz, CDCl3), d (ppm): 67.7 (C-6), 69.5 (C-4), 71.6 (PhCH2),
73.0 (C-3), 73.8 (PhCH2), 74.6 (PhCH2), 76.8 (C-5), 119.3 (C-2), 127.8,
128.0, 128.1, 128.2, 128.3, 128.6, 128.7, 128.8 (Ph-CH), 137.8, 137.9,
138.4 (Ph-Cq), 151.6 (C-1), 186.3 (CHO); MS (ESI): m/z = 467.4
[M+Na]+. Anal. Calcd for C28H28O5: C, 75.65; H, 6.35. Found: C,
75.81; H, 6.21.
4. Experimental
4.2.3. 3,4,6-Tri-O-benzyl-2-deoxy-b-D-glucopyranosyl
4.1. General methods
formaldehyde (4a)
Compound 4a was obtained from 3a15 as colorless syrup; yield
59%. ½a 2D0
ꢁ
+17.0 (c 0.94, CHCl3); Rf = 0.15 (hexanes–EtOAc, 6:4); 1H
All chemicals and solvents were purchased from Sigma–Aldrich
Kft. (Budapest, Hungary). TLC aluminum sheets (Silica Gel 60 F254
,
NMR (300 MHz, CDCl3), d (ppm): 1.50 (ddd, J = 13.0, 11.7, 11.0 Hz,
1H, H-2ax), 2.39 (ddd, J = 13.0, 4.7, 2.2 Hz, 1H, H-2eq), 3.41–3.82
(m, 6H, H-1, H-3, H-4, H-5, H-60, H-600), 4.42–4.93 (m, 6H, PhCH2),
7.17–7.34 (m, 15H, Ph), 9.70 (s, 1H, CHO); 13C NMR (75 MHz,
CDCl3), d (ppm): 29.7 (C-2), 69.1 (C-6), 71.4 (PhCH2), 73.6 (PhCH2),
75.2 (PhCH2), 77.7 (C–H), 79.1 (C-H), 79.4 (C–H), 80.3 (C–H), 127.6,
127.7, 127.8, 127.9, 128.0, 128.4, 138.4, 128.4, 128.5 (Ph-CH),
137.9, 138.1, 138.2 (Ph-Cq), 200.8 (CHO); MS (ESI): m/z = 469.4
[M+Na]+. Anal. Calcd for C28H30O5: C, 75.31; H, 6.77. Found: C,
75.54; H, 6.59.
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.
4.2.4. 3,4,6-Tri-O-benzyl-2-deoxy-b-D-galactopyranosyl
formaldehyde (4b)
Compound 4b was obtained from 3b15 as colorless syrup; yield
53%. ½a 2D0
ꢁ
+5.50 (c 0.37, CHCl3); Rf = 0.27 (hexanes–EtOAc, 6:4); 1H
NMR (300 MHz, CDCl3), d (ppm) 1.99 (m, 1H, H-20), 2.11 (m, 1H, 1H,
H-200), 3.59 (m, 2H, H-60, H-600), 3.60 (m, 1H, CH), 3.62 (m, 1H, CH),
3.80 (m, 1H, 1H, CH), 3.86 (m, 1H, CH), 4.41–4.96 (m, 6H, PhCH2),
7.18–7.39 (m, 15H, Ph), 9.68 (s, 1H, CHO); 13C NMR (75 MHz,
CDCl3), d (ppm) 27.4 (C-2), 69.8 (C-6), 70.5 (PhCH2), 72.9 (C-4),
73.9 (PhCH2), 74.7 (PhCH2), 78.1 (CH), 78.2 (C-5), 80.3 (CH),
127.5, 127.6, 127.9, 128.0, 128.1, 128.2, 128.4, 128.5, 128.6,
128.7, (Ph-CH), 138.1, 138.3, 138.8 (Ph-Cq), 201.4 (CHO); MS
(ESI): m/z = 469.4 [M+Na]+. Anal. Calcd for C28H30O5: C, 75.31; H,
6.77. Found: C, 75.57; H, 6.56.
4.2. General procedure for the preparation of 1-formyl-3,4,6-tri-
O-benzyl-
copyranosyl formaldehydes (4a–b) and 2,3,4,6-tetra-O-benzyl/
methyl- /b- -glycopyranosyl formaldehydes ( -7a, b-7b, -7c)
D-glycals (2a–b) and 3,4,6-tri-O-benzyl-2-deoxy-b-D-gly
a
D
a
a
A mixture of pyridine (4 ml), acetic acid (4 ml) and water (4 ml)
was added to the respective nitrile 1a–b, 3a–b (1 mmol) in a pres-
sure bottle and placed in an ice-bath. Sodium hypophosphite
(10 mmol) then Raney-nickel (6 ml, 10% w/v in water) was added
and the mixture was shaken for 3 h at room temperature. The reac-
tion mixture was filtered and the filtrate was diluted with dichlo-
romethane and washed successively with saturated sodium
hydrocarbonate solution, 1 N HCl and again using saturated so-
dium hydrocarbonate solution. The organic layer was dried
(MgSO4) and the solvent was evaporated. The residue was chro-
matographed on silica gel with hexanes–EtOAc (8:2 for 2a–b and
6:4 for 4a–b) eluent to afford the corresponding aldehyde.
4.2.5. 2,3,4,6-Tetra-O-benzyl-
a
-D
-glucopyranosyl formaldehyde
(a-7a)
Compound
a
-7a was prepared from perbenzylated -glucono-
D
lactone according to an established literature method.21 Rf = 0.18
(hexanes–EtOAc, 6:4); 1H NMR spectrum was identical with the re-
ported one. MS (ESI): m/z 553.4 [M+H]+. Anal. Calcd for C35H36O6:
C, 76.06; H, 6.57. Found: C, 76.27; H, 6.51.
4.2.6. 2,3,4,6-Tetra-O-benzyl-b-D-galactopyranosyl
4.2.1. 1-Formyl-3,4,6-tri-O-benzyl-D-glucal (2a)
formaldehyde (b-7b)
Compound 2a was obtained from 1a15 as colorless syrup; yield
Compound b-7b was prepared from perbenzylated
lactone according to an established literature method.21 Rf = 0.17
(hexanes–EtOAc, 6:4); 1H NMR (300 MHz, CDCl3),
(ppm)
3.50–3.65 (m, 3H, H-5, H-60, H-600), 3.66 (dd, 1H, J3,4 = 2.7 Hz, H-3),
D-galactono-
52%. ½a 2D0
ꢀ23.90 (c 0.50, CHCl3); Rf = 0.20 (hexanes–EtOAc, 85:15);
ꢁ
1H NMR (400 MHz, CDCl3), d ppm: 3.85 (m, 2H, H-60, H-600), 3.99
(dd, J = 8.7, 6.4 Hz, 1H, H-4), 4.16 (m, 1H, H-5), 4.27 (dd, J = 6.4,
d

2868
S. Sipos et al. / Carbohydrate Research 346 (2011) 2862–2871
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]+. Anal.
Calcd for C35H36O6: C, 76.06; H, 6.57. Found: C, 76.19; H, 6.53.
stereomer (R at C-7): 1H NMR (400 MHz, CDCl3), d (ppm): 1.36
(d, J = 6.3 Hz, 3H, H-9), 3.78 (m, 1H, H60), 3.81 (s, 1H, H-7), 3.84
(m, 1H, H-600), 3.89 (m, 1H, H-5), 4.10 (q, J = 6.3 Hz, 1H, H-8), 4.16
(m, 1H, H-4), 4.19 (m, 1H, H-3), 4.50–4.90 (m, 6H, PhCH2), 5.12
(d, J = 3.0 Hz, 1H, H-2), 7.18–7.42 (m, 20H, Ph); 13C NMR
(100 MHz, CDCl3), d (ppm): 24.7 (C-9), 50.8 (C-7), 56.3 (C-8), 68.1
(C-6), 71.0 (PhCH2), 73.5 (PhCH2), 73.8 (PhCH2), 74.4 (C-5), 75.9
(C-3), 78.2 (C-4), 99.3 (C-2), 117.6 (CN), 127.2, 127.4, 127.8,
127.9, 128.0, 128.07, 128.2, 128.5, 128.6, 128.7, 128.9, 129.0 (Ph-
CH), 138.2, 138.4, 138.5, 143.1 (Ph-Cq), 148.0 (C-1). Minor diaster-
omer (S at C-7): 1H NMR (400 MHz, CDCl3) d (ppm): 1.31 (d,
J = 6.3 Hz, 3H, H-9), 3.75 (m, 2H, H-60, H-600), 3.97 (q, J = 6.3 Hz,
1H, H-8), 4.04 (s, 1H, H-7), 4.12 (m, 1H, CH), 4.18 (m, 1H, CH),
4.24 (m, 1H, CH), 4.50–4.90 (m, 6H, PhCH2), 5.02 (d, J = 3.0 Hz,
1H, H-2), 7.18–7.42 (m, 20H, Ph); 13C NMR (100 MHz, CDCl3), d
(ppm): 23.4 (C-9), 50.3 (C-7), 55.6 (C-8), 68.0 (C-6), 71.2, 71.3,
71.6, 73.5, 73.8, 76.8, 99.7 (C-2), 117.7 (CN), 127.2, 127.4, 127.8,
127.9, 128.0, 128.1, 128.2, 128.6, 128.7, 128.9, 129.0 (Ph-CH),
138.4, 138.5, 143.9 (Ph-Cq), 148.2 (C-1); MS (ESI): m/z = 575.1
[M+H]+. Anal. Calcd for C37H38N2O4: C, 77.33; H, 6.66; N, 4.87.
Found: C, 77.51; H, 6.50; N, 4.94.
4.2.7. 2,3,4,6-Tetra-O-methyl-
formaldehyde ( -7c)
Compound -7c was prepared from permethyl D-mannonolac-
a-D-mannopyranosyl
a
a
tone according to an established literature method.21 Rf 0.14 (hex-
anes–EtOAc, 1:1); 1H NMR (CDCl3), d ppm 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,
0
00
CH3), 3.53 (m, 1H, H-5), 3.58 (dd, 1H, J5,6 = 5.2 Hz, J6 ,6 9.9 Hz, H-
60), 3.63 (dd, 1H, J5,6 1.6 Hz, H-600), 3.98 (dd, 1H, J2,3 = 3.3 Hz, H-
00
2), 4.39 (d, 1H, J1,2 = 2.8 Hz, H-1), 9.87 (s, 1H, CHO); 13C NMR
(CDCl3), d (ppm) 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]+. Anal. Calcd for C11H20O6: C, 53.21; H,
8.12. Found: C, 53.37; H, 8.04.
4.3. General procedure for the preparation of C-glycosyl
aminoacetonitriles 5a–b, 6a–b and 8a–c
Method A: To a solution of the aldehydes (2a–b, 4b,
a-7a and
a
-
4.3.3. (S/R)-2-((S)-Phenylethylamino)-2-C-(3,4,6-tri-O-benzyl-2-
7c) (0.5 mmol in 6 ml of solvent as specified in Table 1) was added
molecular sieves (100 mg) and the respective amine at ice-bath
temperature under nitrogen and the mixture was stirred for 1 h.
To this solution was added acetone cyanohydrin then Et3N
(0.1 M equiv of the cyanohydrin) and the solution was stirred at
0 °C for 1 h followed by stirring at room temperature overnight.
The reaction was filtered through Celite and the solvents were re-
moved in vacuum. The resulting residue was purified by silica gel
column chromatography using hexanes–EtOAc eluents.
Method B: To a solution of the aldehydes (2b, 4a and b-7b)
(0.5 mmol in 6 ml of CH2Cl2) was added molecular sieves
(100 mg) and the respective amine at ice-bath temperature under
nitrogen and the mixture was stirred for 1 h. In a teflon-capped
reaction vial equipped with stir bar methanol (same molar equiv-
alent as TMSCN) was added to a solution of TMSCN in dry CH2Cl2
(1 ml). The solution was allowed to stir for 1 h at ice-bath temper-
ature and then added to the reaction flask by slow syringe addition.
After 1 h at 0 °C the reaction was allowed to warm to room temper-
ature and was stirred overnight. The work-up and isolation of the
product were the same as described in Method A.
deoxy-D-lyxo-hex-1-enopyranosyl) acetonitrile (5b-1)
Compound 5b-1 was obtained from 2b as colorless syrup by
Method A (in CH2Cl2, 73%, dr = 3.0) or B (65%, dr = 5.82). Rf = 0.22
(hexanes–EtOAc, 8:2) for both diastereomers. Major diastereomer
(R at C-7): 1H NMR (400 MHz, CDCl3),
d (ppm): 1.36 (d,
J = 6.3 Hz, 1H, H-9), 3.76 (m, 3H, H-60, H-600, H-7), 3.97 (m, 1H, H-
4), 4.05 (q, J = 6.3 Hz, 1H, H-8), 4.16 (t, J = 2.7 Hz, 1H, H-3), 4.28
(ddd, J = 6.7, 6,6, 1,0 Hz, 1H, H5), 4.42–4.89 (m, 6H, PhCH2), 5.08
(d, J = 2.7 Hz, 1H, H-2), 7.18–7.42 (m, 20H, Ph). 13C NMR
(100 MHz, CDCl3) d (ppm): 24.7 (C-9), 50.8 (C-7), 56.3 (C-8), 68.0
(C-6), 71.2 (C-3), 71.3 (C-4), 71.6 (PhCH2), 73.5 (PhCH2), 73.7
(PhCH2), 76.9 (C-5), 99.3 (C-2), 117.6 (CN), 127.2, 127.4, 127.8,
127.9, 128.0, 128.1, 128.2, 128.6, 128.7, 128.9, 129.0 (Ph-CH),
138.2, 138.4, 138.5, 143.1 (Ph-Cq), 148.0 (C-1). Minor diasteromer
(S at C-7): 1H NMR (400 MHz, CDCl3), d (ppm): 1.31 (d, J = 6.3 Hz,
3H, H-9), 3.75 (m, 2H, H-60, H-600), 3.97 (q, J = 6.3 Hz, 1H, H-8),
3.99 (m, 1H, H-4), 4.01 (s, 1H, H-7), 4.18 (t, J = 3.0 Hz, 1H, H-3),
4.28 (m, 1H, H-5), 4.40–4.90 (m, 6H, PhCH2), 5.07 (d, J = 3.0 Hz,
1H, H-2), 7.18–7.42 (m, 20H, Ph); 13C NMR (100 MHz, CDCl3), d
(ppm): 23.3 (C-9), 50.4 (C-7), 56.0 (C-8), 68.1 (C-6), 71.2 (C-3),
71.3 (C-4), 71.6 (PhCH2), 73.5 (PhCH2), 73.8 (PhCH2), 76.8 (C-5),
99.7 (C-2), 117.7 (CN), 127.2, 127.4, 127.8, 127.9, 128.0, 128.2,
128.6, 128.7, 128.9, 129.0 (Ph-CH), 138.4, 138.5, 138.6, 144.0
(Ph-Cq), 148.12 (C-1); MS (ESI): m/z = 575.4 [M+H]+. Anal. Calcd
for C37H38N2O4: C, 77.33; H, 6.66; N, 4.87. Found: C, 77.53; H,
6.56; N, 4.75.
Method C: To a solution of b-7b (0.5 mmol in 4 ml of CH2Cl2)
was added molecular sieves (100 mg) and the respective amine
at ice-bath temperature under nitrogen and the mixture was stir-
red for 1 h. To this solution was added dropwise the methanol
(3 ml) solution of NaCN (1.5 mmol) and NH4Br (1.5 mmol). After
the addition the mixture was stirred at 0 °C for 1 h followed by stir-
ring at room temperature overnight. The work-up and isolation of
the product were the same as described in Method A.
4.3.4. (S/R)-2-((R)-Phenylethylamino)-2-C-(3,4,6-tri-O-benzyl-2-
deoxy-
Compound 5b-2 was obtained from 2b as colorless syrup by
Method (in CH2Cl2 67%, dr = 2.06) or (61%, dr = 2.44).
D-lyxo-hex-1-enopyranosyl) acetonitrile (5b-2)
4.3.1. Determination of diastereomeric ratios from NMR spectra
The assignment of the diastereomers was performed by 1H–13
C
A
B
heterocorrelation (HSQC, HMBC) measurements. In contrast to the
H-7 proton shifts, the C-7 carbon shifts were not remarkably influ-
enced by the stereochemistry (R or S configuration) in the two dia-
stereomers. The two H-7,C-7 cross-peaks at ꢂ50 ppm carbon shift
in the HSQC spectrum of the diastereomeric mixtures provided the
basis for the differentiation of the two stereoisomers.
Rf = 0.22 (hexanes–EtOAc, 8:2) for both diastereomers. Major dia-
stereomer (R at C-7): 1H NMR (300 MHz, CDCl3), d ppm: 1.19 (d,
J = 6.6 Hz, 3H, H-9), 3.78 (m, 2H, H-60, H-600), 3.86 (s, 1H, H-7),
3.89 (q, J = 6.6 Hz, 1H, H-8), 3.97 (m, 1H, CH), 4.12 (t, J = 3.0 Hz,
1H, CH), 4.18 (m, 1H, CH), 4.41–4.94 (m, 6H, PhCH2), 4.81 (m, 1H,
H-2), 7.18–7.42 (m, 20H, Ph); 13C NMR (75 MHz, CDCl3), d ppm:
24.2 (C-9), 50.4 (C-7), 55.1 (C-8), 67.9 (C-6), 71.0 (CH), 71.3
(PhCH2), 71.8 (CH), 73.7 (PhCH2), 73.9 (PhCH2), 76.5 (CH), 101.1
(C-2), 117.9 (CN), 127.4, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2,
128.3, 128.5, 128.6, 128.7, (Ph-CH), 138.1, 138.4, 138.7, 143.8
(Ph-Cq), 146.6 (C-1). Minor diasteromer (S at C-7): 1H NMR
(300 MHz, CDCl3), d (ppm) 1.38 (d, J = 6.6 Hz, 3H, H-9), 3.75 (s,
4.3.2. (S/R)-2-((S)-Phenylethylamino)-2-C-(3,4,6-tri-O-benzyl-2-
deoxy-D-arabino-hex-1-enopyranosyl)acetonitrile (5a)
Compound 5a was obtained as from 2a colorless syrup by Meth-
od A; yield 33%, dr = 1.44 in CH3CN and 43%, dr = 1.24 in CH2Cl2.
Rf = 0.21 (hexanes–EtOAc, 8:2) for both diastereomers. Major dia-

S. Sipos et al. / Carbohydrate Research 346 (2011) 2862–2871
2869
1H, H-7), 3.76 (m, 2H, H-60, H-600), 3.97 (m, 1H, CH), 4.07 (q,
J = 6.6 Hz, 1H, H-8), 4.13 (m, 1H, CH), 4.31 (m, 1H, CH), 4.41–4.94
(m, 6H, PhCH2), 5.05 (d, J = 3.3 Hz, 1H, H-2), 7.18–7.42 (m, 20H,
Ph); 13C NMR (75 MHz, CDCl3), d (ppm) 24.9 (C-9), 51.0 (C-7),
56.4 (C-8), 68.0 (C-6), 70.6 (CH), 71.4 (PhCH2), 71.6 (CH), 73.8
(PhCH2), 73.82 (PhCH2), 76.8 (CH), 99.3 (C-2), 117.4 (CN), 127.7,
127.74, 127.9, 127.97, 128.0, 128.1, 128.2, 128.4, 128.6, 128.64,
128.7, 128.74 (Ph-CH), 138.2, 138.4, 138.6, 142.9 (Ph-Cq), 148.0
(C-1); MS (ESI): m/z = 575.4 [M+H]+. Anal. Calcd for C37H38N2O4:
C, 77.33; H, 6.66; N, 4.87. Found: C, 77.44; H, 6.58; N, 4.91.
4.3.7. (S/R)-2-[(S)-Phenylethylamino]-2-C-(3,4,6-tri-O-benzyl-2-
deoxy-b- -galactopyranosyl) acetonitrile (6b)
D
Compound 6b was obtained from 4b as colorless syrup by
Method A; in THF yield 62%; dr = 5.17. Rf = 0.41 (hexanes–EtOAc,
7:3) for both diastereomers. Major diastereomer (R at C-7): 1H
NMR (300 MHz, CDCl3), d ppm: 1.38 (d, J = 6.3 Hz, 3H, H-9), 1.66
(m, 1H, H-20), 2.45 (ddd, J = 12.0, 12.0, 11.8 Hz, 1H, H-200), 3.26 (d,
J = 3.6 Hz, 1H, H-7), 3.49–3.70 (m, 4H, CH, H-60, H-600), 3.90 (m,
1H, CH), 4.04 (q, J = 6.3 Hz, 1H, H-8), 4.40–5.00 (m, 6H, PhCH2),
7.19–7.39 (m, 20H, Ph); 13C NMR (75 MHz, CDCl3), d ppm: 25.2
(C-9), 28.5 (C-2), 52.5 (C-7), 56.4 (C-8), 69.2 (C-6), 70.5 (PhCH2),
72.3 (CH), 73.7 (PhCH2), 74.3 (PhCH2), 75.8 (CH), 78.1 (CH), 78.3
(CH), 118.8 (CN), 127.2, 127.6, 127.8, 127.9, 128.1, 128.4, 128.7,
129.0 (Ph-CH), 138.2, 138.4, 139.3, 143.6 (Ph-Cq). Minor diastero-
mer (S at C-7): 1H NMR (300 MHz, CDCl3), d ppm: 1.33 (d,
J = 6.6 Hz, 3H, H-9), 1.99 (m, 1H, H-2), 2.15 (ddd, J = 12.0, 12.0,
11.8 Hz, 1H, H-20), 3.63 (m, 1H, H-7), 3.49–3.71 (m, 4H, CH, H-60,
H-600), 3.90 (m, 1H, CH), 4.06 (q, J = 6.6 Hz, 1H, H-8), 4.40–4.97
(m, 6H, PhCH2), 7.20–7.40 (m, 20H, Ph); 13C NMR (75 MHz, CDCl3),
d ppm: 22.3 (C-9), 29.9 (C-2), 53.3 (C-7), 56.2 (C-8), 69.2 (C-6), 70.5
(PhCH2), 72.6 (CH), 73.7 (PhCH2), 74.3 (PhCH2), 75.6 (CH), 77.3
(CH), 78.4 (CH), 118.8 (CN), 127.1, 127.6, 127.8, 127.9, 128.1,
128.4, 128.7, 128.7, 128.9 (Ph-CH), 138.2, 138.4, 139.1, 144.7 (Ph-
Cq); MS (ESI): m/z = 577.1 [M+H]+. Anal. Calcd for C36H38N2O4: C,
76.84; H, 6.81; N, 4.98. Found: C, 76.93; H, 6.72; N, 4.91.
4.3.5. (S/R)-2-(Benzylamino)-2-C-(3,4,6-tri-O-benzyl-2-deoxy-
D-
lyxo-hex-1-enopyranosyl) acetonitrile (5b-3)
Compound 5b-3 was obtained as colorless from 2b syrup by
Method (in CH2Cl2 69%, dr = 2.78) or (72%, dr = 3.36).
A
B
Rf = 0.27 (hexanes–EtOAc, 7:3) for both diastereomers. Major dia-
stereomer (assigned R at C-7): 1H NMR (300 MHz, CDCl3), d ppm:
3.76 (m, 2H, H-60, H-600), 3.82 (m, 1H, H-80), 3.87 (s, 1H, H-7), 3.98
(m, 1H, CH), 4.06 (m, 1H, H-800), 4.18 (m, 1H, CH), 4.25 (t,
J = 6.0 Hz, 1H, CH), 4.40–4.89 (m, 6H, PhCH2), 5.10 (d, J = 2.4 Hz,
1H, H-2), 7.19–7.41 (m, 20H, Ph); 13C NMR (75 MHz, CDCl3), d
(ppm) 50.6 (C-8), 51.6 (C-7), 67.7 (C-6), 70.6 (CH), 71.1 (CH),
71.2 (PhCH2), 73.4 (PhCH2), 73.5 (PhCH2), 76.6 (CH), 100.1 (C-2),
117.1 (CN), 127.4, 127.7, 127.8, 127.9, 127.94, 127.98, 128.1,
128.3, 128.4, 128.42, 128.47, 128.5, 128.7 (Ph-CH), 137.8, 138.0,
138.1, 138.2 (Ph-Cq), 147.0 (C-1). Minor diasteromer (assigned S
4.3.8. (S/R)-2-((S)-Phenylethylamino)-2-C-(2,3,4,6-tetra-O-benzyl-
1
at C-7): H NMR (300 MHz, CDCl3), d (ppm) 3.76 (m, 2H, H-60,
a-
D
-glucopyranosyl)acetonitrile (
a-8a)
H-600), 3.80 (m, 1H, H-80), 3.91 (s, 1H, H-7), 3.95 (m, 1H, CH),
4.09 (m, 1H, H-800), 4.20 (m, 1H, CH), 4.28 (m, 1H, CH), 4.40–
4.94 (m, 6H, PhCH2), 5.19 (d, J = 2.4 Hz, 1H, H-2), 7.19–7.41 (m,
20H, Ph); 13C NMR (75 MHz, CDCl3), d (ppm) 50.6 (PhCH2N),
51.7 (C-7), 67.8 (C-6), 70.8 (CH), 71.2 (CH), 71.3 (PhCH2), 73.34
(PhCH2), 73.5 (PhCH2), 76.7 (CH), 99.5 (C-2), 117.1(CN), 127.4,
127.7, 127.77, 127.9, 127.94, 127.98, 128.1, 128.3, 128.4, 128.42,
128.47, 128.5, 128.7 (Ph-CH),137.8, 138.0, 138.1, 138.2, (Ph-Cq),
147.2 (C-1); MS (ESI): m/z = 561.8 [M+H]+. Anal. Calcd for
Compound -8a was obtained from a-8a as colorless syrup by
a
Method A; in CH3CN yield 42%; dr = 1.35. Major diastereomer (S
at C-7): ½a 2D0
ꢁ
+12.6 (c 0.95, CHCl3); Rf = 0.18 (hexanes–EtOAc,
8:2); 1H NMR (300 MHz, CDCl3), d (ppm): 1.30 (d, J = 6.3 Hz, 3H,
H-9), 3.56 (m, 1H, CH), 3.63 (m, 2H, H-60, H-600), 3.88 (m, 3H, CH),
4.02 (q, J = 6.3 Hz, 1H, H-8), 4.03 (d, J = 8.4 Hz, 1H, H-7), 4.22 (dd,
J = 8.4, 3.0 Hz, 1H, H-1), 4.42–4.76 (m, 8H, PhCH2), 7.08–7.40 (m,
25H, Ph); 13C NMR (75 MHz, CDCl3), d (ppm) 22.7 (C-9), 48.2 (C-
7), 57.2 (C-8), 69.1 (C-6), 73.1 (C-1), 73.7 (PhCH2), 73.9 (PhCH2),
74.0 (CH), 74.1 (PhCH2), 74.3 (PhCH2), 76.5 (CH), 77.1 (CH), 79.1
(CH), 119.2 (CN), 127.1, 127.7, 128.1, 128.2, 128.3, 128.5, 128.7,
128.9 (Ph-CH), 137.5, 138.1, 138.3, 138.5, 144.7 (Ph-Cq); MS
(ESI): m/z = 683.6 [M+H]+. Anal. Calcd for C44H46N2O5: C, 77.39;
H, 6.79; N, 4.10. Found: C, 77.58; H, 6.68; N, 4.08. Minor diastereo-
mer (R at C-7): Rf = 0.20 (hexanes–EtOAc, 8:2).1H NMR (300 MHz,
CDCl3), d (ppm): 1.32 (d, 3H, J = 6.6 Hz, H-9), 3.58 (m, 1H, H-7),
3.63 (m, 3H, CH, H-60, H-600), 3.81 (m, 1H, CH), 4.01–4.08 (m, 3H,
CH), 4.06 (q, J = 6.6 Hz, 1H, H-8) 4.42–4.76 (m, 8H, PhCH2), 7.09–
7.38 (m, 25H, Ph); 13C NMR (75 MHz, CDCl3), d (ppm): 24.8 (C-9),
48.5 (C-7), 56.4 (C-8), 69.2 (C-6), 73.1 (C-1), 73.7 (PhCH2), 73.8
(PhCH2), 74.1 (CH), 74.2 (PhCH2), 74.24 (PhCH2), 76.3 (CH), 77.5
(CH), 81.1 (CH), 119.5 (CN), 127.0, 127.4, 127.46, 127.6, 127.7,
127.8, 127.9, 128.1, 128.3, 128.4, 128.7 (Ph-CH), 137.5, 137.9,
138.1, 138.3, 146.6 (Ph-Cq); MS (ESI): m/z = 683.6 [M+H]+. Anal.
Calcd for C44H46N2O5: C, 77.39; H, 6.79; N, 4.10. Found: C, 77.53;
H, 6.72; N, 3.97.
C36H36N2O4: C, 77.12; H, 6.47; N, 5.00. Found: C, 77.31; H, 6.55;
N, 4.93.
4.3.6. (S/R)-2-[(S)-Phenylethylamino]-2-C-(3,4,6-tri-O-benzyl-2-
deoxy-b-D-glucopyranosyl) acetonitrile (6a)
Compound 6a was obtained from 4a as colorless syrup by
Method B; yield 65%; dr = 8.25. Rf = 0.60 (hexanes–EtOAc, 1:1)
for both diastereomers. Major diastereomer (R at C-7): 1H NMR
(400 MHz, CDCl3), d (ppm) 1.38 (d, J = 6.6 Hz, 3H, H-9), 1.80 (br
s, 1H, NH), 1.93 (ddd, J = 12.6, 11.5, 10.9 Hz, 1H, H20), 2.02 (ddd,
J = 12.6, 5.2, 2.7 Hz, 1H, H200), 3.29 (d, J = 3.3 Hz, 1H, H-7), 3.43
(dt, J = 9.3, 3.0 Hz, 1H, H-5), 3.48–3.70 (m, 3H, H-1, H-3, H-4),
3.74 (m, 2H, H-60, H-600), 4.05 (q, J = 6.6 Hz, 1H, H-8), 4.50–4.92
(m, 6H, PhCH2), 7.18–7.38 (m, 20H, Ph); 13C NMR (100 MHz,
CDCl3), d (ppm): 24.9 (C-9), 32.3 (C-2), 52.0 (C-7), 56.3 (CH, C-
8), 69.2 (C-6), 71.7 (PhCH2), 73.4 (PhCH2), 74.7 (CH), 75.1 (PhCH2),
77.9 (CH), 79.3 (C-5), 80.3 (CH), 118.5 (CN), 126.9, 127.5, 127.7,
128.3, 128.4, 128.8 (Ph-CH), 138.3, 138.4, 143.1 (Ph-Cq). Minor
diasteromer (S at C-7): 1H NMR (400 MHz, CDCl3), d (ppm): 1.34
(d, J = 6.6 Hz, 3H, H-9), 1.71 (m, 1H, H-20), 2.22 (m, 1H, H-200),
3.38–3.82 (m, 6H, CH), 3.69 (m,1H, H7), 4.06 (q, J = 6.6 Hz, 1H,
H-8), 4.50–4.92 (m, 6H, PhCH2), 7.18–7.38 (m, 20H, Ph); 13C
NMR (100 MHz, CDCl3), d ppm: 22.1 (C-9), 33.9 (C-2), 53.0 (C-
7), 55.9 (C-8), 68.9 (C-6), 71.8 (PhCH2), 73.1 (PhCH2), 74.8 (CH),
75.2 (PhCH2), 77.9 (CH), 79.3 (CH), 80.4 (CH), 117.6 (CN), 126.6,
126.7, 127.2, 127.8, 128.1, 128.7 (Ph-CH), 138.1, 138.3, 144.4
(Ph-Cq); MS (ESI): m/z = 577.5 [M+H]+. Anal. Calcd for
4.3.9. (S/R)-2-((S)-Phenylethylamino)-2-C-(2,3,4,6-tetra-O-
benzyl-b-D-galactopyranosyl) acetonitrile (b-8b-1)
Compound b-8b-1 was obtained from b-7b as colorless syrup by
Method B; yield 29%; dr = 3.3. Major diastereomer (R at C-7):
Rf = 0.23 (hexanes–EtOAc, 8:2); 1H NMR (300 MHz, CDCl3), d
(ppm): 1.39 (d, J = 6.6 Hz, 3H, H-9), 2.12 (br s, 1H, NH), 3.49 (dd,
J = 9.3, 1.5 Hz, 1H, CH), 3.58 (dd, J = 9.3, 2.7 Hz, 1H, CH), 3.60 (m,
1H, CH), 3.62 (m, 2H, H-60, H-600), 3.64 (m, 1H, H-7), 4.03 (m, 1H,
CH), 4.04 (q, J = 6.6 Hz, 1H, H-8), 4.27 (dd, J = 9.3, 9.3 Hz, 1H, CH),
4.22–5.02 (m, 8H, PhCH2), 6.81–6.85 (m, 2H, Ph), 7.13–7.37 (m,
23H, Ph); 13C NMR (75 MHz, CDCl3), d ppm: 24.6 (C-9), 49.4 (C-7),
C36H38N2O4: C, 76.84; H, 6.81; N, 4.98. Found: C, 77.01; H, 6.75;
N, 4.87.

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S. Sipos et al. / Carbohydrate Research 346 (2011) 2862–2871
56.3 (C-8), 68.4 (C-6), 72.3 (PhCH2), 73.4 (CH), 73.8 (PhCH2), 74.2
(CH), 74.4 (PhCH2), 75.4 (PhCH2), 77.4 (CH), 79.1 (CH), 85.0 (CH),
119.3 (CN), 127.6, 127.62, 127.67, 127.8, 127.9, 128.0, 128.04,
128.1, 128.2, 128.5, 128.69, 128.7, 129.9 (Ph-CH), 138.1, 138.12,
138.23, 139.26, 143.3 (Ph-Cq); MS (ESI): m/z = 683.5 [M+H]+. Anal.
Calcd for C44H46N2O5: C, 77.39; H, 6.79; N, 4.10. Found: C, 77.50;
H, 6.69; N, 4.13. Minor diastereomer (S at C-7): Rf = 0.17 (hex-
anes–EtOAc, 8:2). 1H NMR (300 MHz, CDCl3), d (ppm): 1.25 (d,
J = 6.3 Hz, 3H, H-9), 1.87 (br s, 1H, NH), 3.51 (m, 1H, CH), 3.55 (m,
2H, H-60, H-600), 3.59 (m, 1H, CH), 3.62 (dd, J = 9.3, 2.7 Hz, 1H, CH),
3.99 (q, J = 6.3 Hz, 1H, H-8), 4.00 (m, 1H, CH), 4.02 (m, 1H, H-7),
4.10 (dd, J = 9.3, 9.3 Hz, 1H, CH), 4.36–5.01 (m, 8H, PhCH2), 7.17–
7.35 (m, 25H, Ph); 13C NMR (75 MHz, CDCl3), d ppm : 21.9 (C-9),
49.8 (C-7), 55.9 (C-8), 68.7 (C-6), 72.7 (PhCH2), 73.4 (CH), 73.7
(PhCH2), 75.4 (PhCH2), 75.9 (PhCH2), 76.1 (CH), 77.6 (CH), 78.8
(CH), 84.7 (CH), 117.4 (CN), 127.1, 127.2, 127.5, 127.6, 127.8,
128.0, 128.0, 128.1, 128.2, 128.4, 128.5, 128.6, 129.6, 128.7, 128.9
(Ph-CH), 138.0, 138.2, 138.3, 139.1, 144.7 (Ph-Cq); MS (ESI): m/
z = 683.5 [M+H]+. Anal. Calcd for C44H46N2O5: C, 77.39; H, 6.79; N,
4.10. Found: C, 77.57; H, 6.62; N, 4.05.
3H, H-9), 2.11 (br s, 1H, NH), 3.38 (s, 3H, OCH3), 3.40 (s, 3H, OCH3),
3.48 (s, 3H, OCH3) 3.51 (s, 3H, OCH3), 3.52 (m, 1H, CH), 3.67 (m, 2H,
H-60, H-600), 3.79 (m, 1H, CH), 3.82 (m, 1H, CH), 4.04 (m, 4H, CH, H-
7, H-8), 7.21–7.38 (m, 5H, Ph); 13C NMR (75 MHz, CDCl3), d (ppm):
21.8 (C-9), 49.2 (C-7), 56.1 (C-8), 57.3 (OCH3), 57.9 (OCH3), 59.0
(OCH3), 59.4 (OCH3), 70.2 (CH), 70.2 (C-6), 74.2 (CH), 74.3 (CH),
75.6 (CH), 75.9 (CH), 119.1 (CN), 127.1, 127.7, 128.8 (Ph-CH),
145.0 (Ph-Cq); MS (ESI): m/z = 379.1 [M+H]+. Anal. Calcd for
C20H30N2O5: C, 63.47; H, 7.99; N, 7.40. Found: C, 63.56; H, 7.82;
N, 7.28.
4.4. General procedure for the preparation of galactal imines 9b
1-Formyl-3,4,6-tri-O-benzyl-D-galactal (2b) (1 mmol, 45 mg)
was dissolved in dry CH2Cl2 (3 ml) and molecular sieves 4 Å
(100 mg) then S-or R-PEA or benzylamine (1.02 mmol) were added
during stirring. After 2 h the mixture was filtered and the filtrate
was evaporated in vacuo and imines formed were used without
purification for C-glycosyl aminoacetonitrile preparation in the
presence of catalysts 11 and 12 as described in Method B.
4.3.10. (S/R)-2-(Benzhydrylamino)-2-C-(2,3,4,6-tetra-O-benzyl-
4.4.1. N-((S)-1-Phenylethyl)-(3,4,6-tri-O-benzyl-2-deoxy-D-lyxo-
b-D
-galactopyranosyl)acetonitrile (b-8b-2)
hex-2-enopyranosyl)formaldimine (9b-1)
Compound b-8b-2 was obtained from b-7b as colorless syrup
Compound 9b-1 was obtained as colorless syrup; yield 99%.
Rf = 0.37 (hexanes–EtOAc, 6:4); 1H NMR (300 MHz, CDCl3), d
(ppm): 1.54 (d, J = 6.6 Hz, 3H, H-9), 3.80 (m, 2H, H-60, H-600), 4.02
(m, 1H, CH), 4.22–4.26 (m, 2H, CH), 4.42 (q, J = 6.6 Hz, 1H, H-8),
4.44–4.91 (m, 6H, PhCH2), 5.37 (d, J = 2.1 Hz, 1H, H-2), 7.18–7.39
(m, 20H, Ph), 7.60 (s, 1H, CH@N); 13C NMR (75 MHz, CDCl3), d
(ppm): 24.4 (C-9), 67.7 (C-6), 69.6 (C-8), 70.9 (CH), 71.5 (CH),
71.8 (PhCH2), 73.6 (PhCH2), 73.8 (PhCH2), 76.6 (CH), 108.2 (C-2),
127.1, 127.2, 127.7, 127.9, 128.1, 128.4, 128.5, 128.6, 128.7 (Ph-
CH), 138.3, 138.4, 138.5, 144.4 (Ph-Cq), 150.5 (C-1), 155.4 (CH@N);
MS (ESI): m/z = 656.3 [M+H]+. Anal. Calcd for C43H45NO5: C, 78.75;
H, 6.92; N, 2.14. Found: C, 78.96; H, 6.82; N, 2.28.
by Method C; yield 38%; dr = 2.79. Rf = 0.30 (hexanes–EtOAc, 8:2)
for both diastereomers. Major diastereomer (assigned R at C-7):
1H NMR (300 MHz, CDCl3), dppm: 2.63 d, J = 12.9 Hz, 1H, NH,
3.44–3.70 (m, 5H, CH, H-60, H-600), 3.79 (d, J = 12.9 Hz, 1H, H-7),
3.92 (d, J = 2.4 Hz, 1H, CH), 4.01 (m, 1H, CH), 5.11 (s, 1H, H-8),
4.34–5.06 (m, 8H, PhCH2), 6.80 (m, 2H, Ph), 7.17–7.54 (m, 28H,
Ph); 13C NMR (75 MHz, CDCl3), d ppm: 49.3 (C-7), 65.1 (C-8),
68.3 (C-6), 73.5 (PhCH2), 73.9 (CH), 74.5 (PhCH2), 74.6 (PhCH2),
76.5 (PhCH2), 77.3 (CH), 78.9 (CH), 84.9 (CH), 119.0 (CN), 126.9,
127.3, 127.6, 127.9, 128.2, 128.4, 128.5, 128.7, 128.8 (Ph-CH),
138.1, 138.2, 138.4, 139.3, 141.5, 143.6 (Ph-Cq). Minor diasteromer
(assigned S at C-7): 1H NMR (300 MHz, CDCl3), d ppm: 2.48 (d,
J = 11.6 Hz, 1H, NH), 3.57–3.68 (m, 5H, CH, H-60, H-600), 3.86 (d,
J = 11.6 Hz, 1H, H-7), 3.92 (d, J = 2.4 Hz, 1H, CH), 4.01 (m, 1H,
CH), 5.11 (s, 1H, H-8), 4.34–5.06 (m, 8H, PhCH2), 6.80 (m, 2H,
Ph), 7.17–7.54 (m, 28H, Ph). 13C NMR (75 MHz, CDCl3), d (ppm):
50.3 (C-7), 65.6 (C-8), 68.6 (C-6), 73.6 (PhCH2), 74.2 (CH), 74.5
(PhCH2), 74.6 (PhCH2), 76.3 (PhCH2), 77.7 (CH), 79.5 (CH), 84.6
(CH), 118.4 (CN), 126.9, 127.3, 127.6, 127.9, 128.2, 128.4, 128.5,
128.8, (Ph-CH), 137.6, 137.9, 138.1, 139.3, 141.3, 143.4 (Ph-Cq);
MS (ESI): m/z = 745.5 [M+H]+. Anal. Calcd for C49H48N2O5: C,
79.01; H, 6.49; N, 3.76. Found: C, 79.16; H, 6.42; N, 3.68.
4.4.2. N-((R)-1-Phenylethyl)-(3,4,6-tri-O-benzyl-2-deoxy-D-lyxo-
hex-2-enopyranosyl)formaldimine (9b-2)
Compound 9b-2 was obtained as colorless syrup; yield 99%.
Rf = 0.37 (hexanes–EtOAc, 6:4); 1H NMR (300 MHz, CDCl3), d
(ppm): 1.54 (t, J = 6.9 Hz, 3H, H-9), 3.80 (m, 2H, H-60, H-600), 4.02
(m, 1H, CH), 4.24 (m, 1H, CH), 4.29 (m, 1H, CH), 4.41 (q,
J = 6.9 Hz, 1H, H-8), 4.44–4.91 (m, 6H, PhCH2), 5.37 (m, 1H, H-2),
7.18–7.38 (m, 20H, Ph), 7.59 (s, 1H, CH@N); 13C NMR (75 MHz,
CDCl3), d (ppm) 24.3 (C-9), 68.0 (C-6), 69.5 (C-8), 70.5 (CH), 71.4
(PhCH2), 72.3 (CH), 73.7 (PhCH2), 74.1 (PhCH2), 76.5 (C-3), 108.2
(C-2), 127.2, 127.7, 127.9, 128.0, 128.2, 128.5, 128.6, 128.7(Ph),
138.2, 138.4, 138.6, 144.4 (Cq), 150.7 (C-1), 155.6 (CH@N); MS
(ESI): m/z = 656.3 [M+H]+. Anal. Calcd for C43H45NO5: C, 78.75; H,
6.92; N, 2.14. Found: C, 78.90; H, 6.80; N, 2.26.
4.3.11. (S/R)-2-((S)-Phenylethylamino)-2-C-(2,3,4,6-tetra-O-
benzyl-a-
D
-mannopyranosyl) acetonitrile (
a-8c)
Compound
a
-8c was obtained from -7c as colorless syrup by
a
Method A; in CH2Cl2 yield 21%; dr = 2.0. Major diastereomer (R at
C-7): Mp 105–107 °C; ½a D20
ꢁ
ꢀ36.2 (c 0.94, CHCl3); Rf = 0.24 (hex-
4.4.3. N-Benzyl-(3,4,6-tri-O-benzyl-2-deoxy-D-lyxo-hex-2-eno-
pyranosyl)formaldimine (9b-3)
anes–EtOAc, 1:1); 1H NMR (400 MHz, CDCl3), d (ppm): 1.35 (d,
J = 6.6 Hz, 3H, H-9), 2.08 (d, J = 12.9 Hz, 1H, NH), 3.31 (s, 3H,
OCH3), 3.40 (s, 3H, OCH3), 3.42 (s, 3H, OCH3), 3.47 (s, 3H, OCH3),
3.53 (dd, J = 3.6, 2.4 Hz, 1H, H-2), 3.59 (m, 1H, H-7), 3.60 (1H, m,
H-4), 3.64 (m, 2H, H-60, H-600), 3.67 (m, 1H, H-3), 3.89 (dd, J = 9.1,
3.6 Hz, 1H, H-1), 4.05 (1H, m, H-5), 4.06 (q, J = 6.6 Hz, 1H, H-8),
7.24–7.37 (m, 5H, Ph). 13C NMR (100 MHz, CDCl3), d (ppm): 25.1
(C-9), 50.0 (C-7), 56.1 (C-8), 56.7 (OCH3), 57.7 (OCH3), 58.4
(OCH3), 59.1 (OCH3), 69.9 (C-1), 70.1 (C-6), 73.5 (C-5), 75.0 (C-2),
75.1 (C-4), 75.2 (C-3), 117.7 (CN), 126.9, 127.5, 128.7(Ph), 143.2
(Cq); MS (ESI): m/z = 379.1 [M+H]+. Anal. Calcd for C20H30N2O5: C,
63.47; H, 7.99; N, 7.40. Found: C, 63.53; H, 7.87; N, 7.31. Minor dia-
Compound 9b-3 was obtained as colorless syrup; yield 99%.
Rf = 0.36 (hexanes–EtOAc, 6:4); 1H NMR (300 MHz, CDCl3), d
(ppm): 3.79 (d, J = 6.6 Hz, 2H, H-60, H-600), 4.07 (m, 1H, H-4), 4.23
(dd, J = 6.9, 6.6 Hz, 1H, H-5), 4.32 (m, 1H, H-3), 4.42 (m, 2H, PhCH2),
4.64 (m, 2H, PhCH2), 4.66 (d, J = 12.0 Hz, 1H, H80), 4.71 (m, 2H,
PhCH2), 4.90 (d, J = 12.0 Hz, 1H, H800), 5.35 (s, 1H, H-2), 7.20–7.37
(m, 20H, Ph), 7.59 (s, 1H, CH@N); 13C NMR (75 MHz, CDCl3), d
(ppm): 64.8 (C-8), 67.8 (C-6), 70.2 (CH), 71.3 (PhCH2), 72.5 (CH),
73.6 (PhCH2), 74.2 (PhCH2), 76.4 (CH), 109.3 (C-2), 127.3, 127.7,
127.8, 127.9, 128.2, 128.4, 128.5, 128.6, 128.7 (Ph-CH), 137.1,
138.4, 138.6, 138.7 (Ph-Cq), 150.6 (C-1), 157.3 (CH@N) ; MS (ESI):
m/z = 642.3 [M+H]+. Anal. Calcd for C42H43NO5: C, 78.60; H, 6.75;
N, 2.18. Found: C, 78.79; H, 6.68; N, 2.27.
stereomer (S at C-7): ½a D20
ꢁ
+31.2 (c 0.94, CHCl3); Rf = 0.26 (hexanes–
EtOAc, 1:1); 1H NMR (300 MHz, CDCl3), d (ppm): 1.33 (d, J = 6.4 Hz,

S. Sipos et al. / Carbohydrate Research 346 (2011) 2862–2871
2871
4.5. Crystal structure determination of a-8c
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(3.09 6 h 6 27.52°) reflections. Intensity data were collected on a
R-Axis RAPID diffractometer (graphite monochromator; Mo-K
a
radiation, k = 0.71075 Å) at 294(2) K in the range 3.09 6 h 6 26.37°
using oscillations. A total of 28641 reflections were collected of
which 4359 were unique [R(int) = 0.0243, R( ) = 0.0201]; intensities
of 3174 reflections were greater than 2 (I). Completeness to
x
r
r
h = 0.998. An empirical absorption correction was applied to the
data, minimum and maximum transmission factors were 0.947
and 0.975. The structure was solved by direct methods. Anisotropic
full-matrix least-squares refinement on F2 for all non-hydrogen
atoms yielded R1 = 0.0413 and wR2 = 0.1056 for 3174 [I > 2r(I)]
and R1 = 0.0573 and wR2 = 0.1148 for all (4359) intensity data,
(number of parameters = 249, goodness-of-fit = 1.088, Flack abso-
lute structure parameter x = 1.1(11), Hooft absolute structure
parameter y = 0.0(3). The maximum and minimum residual electron
densities in the final difference map were 0.15 and ꢀ0.13 e Åꢀ3
.
Hydrogen atomic positions were calculated from assumed geome-
tries and were included in structural factor calculations but they
were not refined.
Acknowledgements
The authors thank Dr. Pal Szabo for the mass spectrometry anal-
yses. Excellent technical assistance by Janosne Keri and Eva Peter
are gratefully acknowledged.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2011.10.023.