Synthesis of N-acylated 7-amino-2,6,7-trideoxy-D-erythroheptopyranosides from methyl α-D-mannoside

Article abstract of DOI:10.1016/j.carres.2005.08.008

Hexopyranoside methyl α-d-mannoside (8) was homologated to yield 7-(acylamino)-2,6,7-trideoxy-heptopyranosides 19-26. A crucial reaction step is the radical cleavage of benzylidene derivative 10 to obtain bromide 11. Since nucleophilic substitution of 11

Full text of DOI:10.1016/j.carres.2005.08.008

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 2483–2493
Synthesis of N-acylated 7-amino-2,6,7-trideoxy-D-erythrohepto-
pyranosides from methyl a-D-mannoside
Kathrin Wiedemeyer and Bernhard Wunsch*
¨
Institut fu¨r Pharmazeutische und Medizinische Chemie der Westfa¨lischen Wilhelms-Universita¨t Mu¨nster,
Hittorfstraße 58-62, D-48149 Mu¨nster, Germany
Received 6 July 2005; accepted 11 August 2005
Available online 5 October 2005
Abstract—Hexopyranoside methyl a-D-mannoside (8) was homologated to yield 7-(acylamino)-2,6,7-trideoxy-heptopyranosides 19–
26. A crucial reaction step is the radical cleavage of benzylidene derivative 10 to obtain bromide 11. Since nucleophilic substitution
of 11 with KCN provided the bicyclic nitrile 13 instead of nitrile 14, ketone 11 was protected as the dimethyl acetal 15. Nucleophilic
substitution of 15 with KCN, subsequent hydrogenation with H2/Raney Ni and acylation with various carboxylic acid derivatives
yielded 7-(acylamino)heptopyranosides 19–22.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Keywords: Mannose; 7-(Acylamino)heptopyranosides; Radical cleavage of benzylidene acetal; Nucleophilic substitution; Dioxabicyclo[3.2.1]octane
1. Introduction
(1b) leads to a highly active r receptor ligand.1 (3,4-
Dichlorophenyl)acetamide 2a is also a very potent j
receptor agonist with analgesic activity.2 Formal reduc-
tion of amide 2a affords tertiary amine 2b with high
affinity toward r receptors.3
The three-dimensional arrangement of pharmacophoric
elements is crucial for the interaction of drugs with their
targets (enzymes, receptors, DNA, etc.). Monosaccha-
rides represent excellent scaffolds for the introduction
of pharmacophoric elements in a defined spatial
arrangement, since all positions of a pyranoside ring sys-
tem are substituted with functional groups. These sub-
stituents allow the stereoselective introduction of the
desired pharmacophoric groups with defined three-
dimensional orientation.
2
N
Cl
Cl
Cl
Cl
R
X
O
N
1
N
N
CH3
CH3
1a: (1S,2S) κ-agonist
1b: (1R,2S) σ-ligand
2a: X = O, R = 2-Pr κ-agonist
2b: X = H2, R = H σ-ligand
We are interested in the development of novel j recep-
tor agonists and r receptor ligands. Several of the de-
scribed high affinity j receptor agonists and r receptor
ligands comprise (3,4-dichlorophenyl)acetamide sub-
structure as the pharmacophoric element. In Figure 1
the prototypical j receptor agonist, U-50488 (1a), with
(3,4-dichlorophenyl)acetamide substructure is shown.1
Changing the stereochemistry from the trans-(1S,2S)-
configuration (1a) into the cis-(1R,2S)-configuration
Figure 1. Lead compounds with j and r affinity.
The focus of this manuscript is the synthesis of a car-
bohydrate-based scaffold for drug design. In particular,
we are interested in pyranosides bearing an aminoethyl
moiety in position 5 (compare compound 3 in Figure
2). It should be possible to introduce amino substituents
(e.g., pyrrolidin-1-yl) in position 3 and/or 4 (compound
4) to mimic j and r ligands 1 and 2. Moreover, it is
planned to connect aminoethyl side chain of 3 to the
*
Corresponding author. Tel.: +49 251 8333311; fax: +49 251
8332144; e-mail: wuensch@uni-muenster.de
0008-6215/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2005.08.008

2484
K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 340 (2005) 2483–2493
O
O
R
N
H
N
R
4
O
5
1
O
R2N
O
4
3
3
[1-5]
[3-5]
R2N
X
R
N
H
4
5
4
5
O
HO
H3CÔ
3
X
OCH3
O
[4-5]
3
O
R
N
N
R
NR2
O
4
5
O
3
4
5
3
X
X
R2N
7
6
Figure 2. Projected pharmacologically active compounds from 7-acylamino-substituted heptopyranoses.
position 1, 3, or 4 to obtain bicyclic systems 5–7. After
introduction of amino substituents (e.g., pyrrolidin-1-
yl) the bicyclic systems 5–7 represent conformationally
constrained analogues of the lead compounds 1 and 2.
Herein, we describe our studies directed to homologiza-
tion of the monosaccharide D-mannose to provide 7-
acylamino-substituted heptopyranose derivatives substi-
tuted with functional groups in pyran ring. These sub-
stituents will be used for the regio- and stereoselective
introduction of further pharmacophoric elements (see
Fig. 2).
(97%). Employing this product in the next reaction with
n-butyllithium at ꢀ40 ꢁC afforded ketone 10 in 71%
yield (Scheme 1).
It was planned to transform hexopyranoside 10 into a
heptopyranoside system. For this purpose a leaving
group should be introduced in position 6 of hexopyr-
anoside system allowing the nucleophilic substitution
with cyanide to incorporate the additional carbon atom.
Hence, benzylidene derivative 10 was reacted with N-
bromosuccinimide (NBS) and azobisisobutyronitrile
(AIBN)7,8 in a free-radical substitution reaction to pro-
vide bromobenzoate 11 in 54% yield. The desired methyl
a-D-glycoside 11 was accompanied by small amounts
(8%) of the elimination product 12, which was separated
by flash chromatography.
2. Results and discussion
The synthesis started with methyl a-D-mannopyranoside
(8), which was reacted with 2 equiv of benzaldehyde di-
methyl acetal in DMF.5 Instead of the procedure of
Evans, who used a special apparatus to remove DMF
and methanol under reduced pressure at 60 ꢁC,5 the ace-
talization of 8 was performed in a rotary evaporator at a
water bath temperature of 60–70 ꢁC under reduced pres-
sure (about 300 mbar). However, the purification of ace-
tal product 9 turned out to be difficult. In particular, the
careful removal of DMF and water was crucial for the
further transformation with n-butyllithium. Only recrys-
tallization of the crude product from 2-propanol yielded
51% of the pure product 9. In order to improve the yield
of 9,various solvents were investigated to replace DMF.
Finally, the reaction of 8 with benzaldehyde dimethyl
acetal was performed using acetonitrile as solvent at a
temperature of 60 ꢁC and at a reduced pressure of
600 mbar in a rotary evaporator to afford the acetal
product 9 (mixture of diastereomers) in very high yield
The reaction of bromoketone 11 with KCN in DMSO
resulted in a novel product without bromo substituent.
Surprisingly, instead of the expected substitution prod-
uct 14, the bicyclic compound 13 had been formed.
The structure of 13 was unambiguously proven by
NMR, IR spectroscopy, and MS. The formation of 13
may be explained by nucleophilic attack of NCꢀ at car-
bonyl moiety to yield a cyano-alcoholate, which reacted
intramolecularily with bromomethyl group to yield the
bicyclic cyanoether 13 instead of the simple substitution
product 14 (see Scheme 2).
In order to avoid the cyclization of bromoketone 11,
the carbonyl moiety of 11 was transformed into a di-
methyl acetal (!15) with methanol and trimethyl ortho-
formate. This transformation was catalyzed by p-
toluenesulfonic acid and therefore, led to epimerization
of the anomeric center. The a and b anomers 15a and
15b were formed in a ratio of 1:1 (total yield 88%) and
could be separated by flash chromatography. In a sepa-

K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 340 (2005) 2483–2493
2485
OH
OH
O
(b)
(c)
HO
HO
(a)
O
O
O
O
O
O
O
O
OCH3
O
OCH3
OCH3
8
9
10
(methyl α-D-mannoside)
O
O
Br
Br
O
O
O
O
+
O
O
OCH3
11
(d)
12
O
O
O
CN
O
OCH3
O
NC
O
O
O
OCH3
13
14
Scheme 1. Reagents and conditions: (a) PhCH(OCH3)2, TosOH, CH3CN, 60 ꢁC, 600 mbar, 97%. (b) n-BuLi, THF, ꢀ40 ꢁC, 71%. (c) NBS, AIBN,
BaCO3, CCl4, reflux, 54%; yield of 12 8%. (d) KCN, DMF, 80 ꢁC, 26%.
CN-
O
O
Br
O
OCH3
(d)
O
14
O
NC
O
O
OCH3
O
CN-
11
13
Scheme 2.
1
rate experiment, it was shown that a,b-unsaturated ke-
tone 12, the side product during the radical bromination
of the benzylidene compound 10, also reacted with
methanol and trimethyl orthoformate to give dimethyl
acetals 15a and 15b. Therefore, a mixture of 11 and 12
could be used for the synthesis of dimethyl acetals 15a
and 15b (Scheme 3).
The nucleophilic substitution of the separated ano-
meric bromo acetals 15a and 15b with KCN proceeded
to afford the anomeric cyano acetals 16a and 16b,
respectively. The cleavage of benzoates 16a and 16b
was performed with NaOH in methanol to obtain ano-
meric hydroxynitriles 17a and 17b, respectively. How-
ever, the H NMRspectra of both hydrolysis products
17a and 17b showed significant amounts of the corre-
sponding anomer. Obviously anomerization takes place
during saponification of ester moiety. Therefore, the
synthesis of substantial amounts of hydroxynitriles 17a
and 17b was usually performed with anomeric mixtures.
Catalytic hydrogenation (4.1 bar) of nitriles 17a/17b
using Raney nickel as catalyst9,10 provided the primary
amines 18a/18b. Since hydrogenation of nitriles 17a/
17b with Raney nickel requires basic reaction conditions
(4:1 methanol:NaOH (5 M)), the one-pot transforma-
tion of cyanobenzoates 16a/16b into the primary amines
18a/18b was also investigated and yielded 97% of the

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K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 340 (2005) 2483–2493
O
O
O
Br
Br
Br
(a)
O
O
O
O
O
H3CÔ
O
H3CÔ
+
OCH3
O
OCH3
OCH3
OCH3
OCH3
11 (+12)
15α
15β
O
O
CN
Br
CN
O
O
HO
H3CÔ
(d)
(c)
(b)
O
O
H3CÔ
O
H3CÔ
OCH3
OCH3
17α,β
OCH3
OCH3
OCH3
15α,β
OCH3
16α,β
X-CO-R
O
O
O
R
O
19
H3C
O
CH3
NH2
O
R
N
H
N
H
O
O
Cl
HO
H3CÔ
(e)
X-CO-R
20
O
O
HO
H3CÔ
HO
+
O
OCH3
Cl
OCH3
21,23
22,24
OCH3
OCH3
23,24α,β
O
OCH3
19-22α,β
Cl
Cl
O
18α,β
Cl
α: OCH3 axial
β: OCH3 equtaorial
Scheme 3. Reagents and conditions: (a) CH3OH, CH(OCH3)3, TosOH, reflux, 88%. (b) KCN, DMSO, 70 ꢁC, 16a 94%, 16b 67%. (c) NaOH,
CH3OH, 20 ꢁC, 17a 76%, 17b 80%. (d) H2, Raney Ni, NaOH, CH3OH, 20 ꢁC, 97% (anomeric mixture). (e) R–COX, NEt3, CH2Cl2, 20 ꢁC (19–21,
23); RCO2H, CDI, CH2Cl2, 20 ꢁC, (22); yields 19: 44%; 20: 60%; 21: –; 22: 52%; 23: 25%.
primary amines 18a/18b over two reaction steps. Be-
cause of the high degree of purity, the primary amines
18a/18b were used for the next reaction steps without
further purification.
1,10-carbonyldiimidazole to obtain amides 24a/24b in
50% yield calculated over three steps starting with cya-
nobenzoates 16a/16b. Hydrolysis of dimethyl acetal
substructure was not observed with these reaction con-
ditions (Scheme 3).
In the next step, the primary amines 18a/18b were
acylated with various acylating reagents to yield amides
and carbamates 19–24 consisting of anomeric mixtures.
Interestingly, after acylation of the primary amines 18a/
18b with benzoyl chloride and triethylamine, ketone 23,
resulting from additional hydrolysis of acetal moiety,
was isolated. The corresponding acetal 21 was only de-
tected by 1H NMRspectroscopy. With respect to devel-
oping novel j receptor agonists and r receptor ligands,
the introduction of (3,4-dichlorophenyl)acetyl residue
was of particular interest. Reaction of the primary
amines 18a/18b with (3,4-dichlorophenyl)acetyl chloride
in a two-phase system (NaOH, methanol, dichlorometh-
ane) provided amides 22a/22b. However, the yield did
not exceed 41% since the acylation was accompanied
by substantial hydrolysis of the acetal moiety to afford
the corresponding ketones 24a/24b. In an alternative
synthesis the primary amines 18a/18b were acylated
with (3,4-dichlorophenyl)acetic acid in the presence of
All attempts to synthesize morphan analogues 27 by
intramolecular N/O-acetal formation of amides and car-
bamate 19–22a/b displaying various nucleophilicity of
their nitrogen atoms failed. After heating of (dichloro-
phenyl)acetamides 22a/b with p-toluenesulfonic acid in
1,2-dichloroethane, the a/b-unsaturated ketone 26 was
isolated in 53% yield. During this transformation, the
intermediate ketones 24a/b were detected by thin-layer
chromatography. Performing the same reaction at 0 ꢁC
for 4 h led to selective hydrolysis of ketone acetal
(!24a/b), elimination of methanol did not take place.
Heating of ketone acetals 22a/b as well as ketones
24a/b with BF3ÆOEt2 or HCl as catalysts also led to
the a/b-unsaturated ketone 26 (Scheme 4).
The same reactivity was observed for benzamides
21a/b, which provided ketones 23a/b and the a/b-
unsaturated ketone 25, depending on the reaction con-
ditions.

K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 340 (2005) 2483–2493
2487
O
O
O
N
R
R
N
H
N
H
R
OCH3
O
(a)
O
HO
H3CÔ
O
HO
O
OCH3
OCH3
OCH3
19-22α,β
HO
27
25,26
R
(b)
(c)
O
21,23,25
22,24,26
R
N
H
Cl
Cl
O
HO
OCH3
O
23,24α,β
Scheme 4. Reagents and conditions: (a) TosOH, 1,2-dichloroethane, reflux, 26 53%. (b) TosOH, CH2Cl2, 0 ꢁC, 24a/b 80%. (c) TosOH, CH2Cl2,
reflux, 25 34%.
3. Conclusions
in either the electron-impact (EI), chemical ionization
(CI), electrospray ionization (LC ESI/ESI direct) or
atmospheric pressure chemical ionization (APCI/FIA
APCI/LC APCI) mode. IRspectra were recorded on a
Perkin–Elmer FTIRspectrophotometer 1605 using the
Universal ATRSampling Accessory (ATRFTIRspec-
tra). 1H NMRspectra (300 MHz) and 13C NMRspectra
(75 MHz) were determined on a Varian Unity 300 FT
NMRspectrometer (Varian); d values (in ppm) are
given relative to the internal standard tetramethylsilane;
the coupling constants J (in Hz) are given with 0.5-Hz
resolution.
Starting from methyl a-D-mannopyranoside (8) the ano-
meric nitriles 16a/b were prepared in five steps and 22–
31% overall yields. Reduction of the cyano moiety and
acylation of the resulting primary amines 17a/b with
various carboxylic acid derivatives led to 7-(acyl-
amino)heptopyranosides 19–26. Now, the development
of the (acylaminoethyl) substituted pyranosides 19–26
into novel j and r receptor ligands requires bridging
of the pyran system and introduction of amino moieties.
4. Experimental
4.2. Preparation of methyl 2,3:4,6-di-O-benzylidene-
a-D-mannopyranoside (9)4
4.1. Chemistry, general
To a solution of methyl a-D-mannopyranoside (8, 5.0 g,
25.7 mmol) in acetonitrile (30 mL) p-toluenesulfonic
acid (0.11 g, 0.6 mmol) and benzaldehyde dimethyl ace-
tal (9.1 mL, 60.4 mmol) were added. The reaction was
carried out in a rotary evaporator at 60 ꢁC water bath
temperature and a reduced pressure of 600 mbar. After
6 h, the residual mixture was concentrated in vacuo until
a colorless solid started to precipitate. For complete
precipitation of the product, the mixture was added to
NaHCO3-containing ice water (3.1 g in 100 mL) under
stirring. After filtration of the solvent–water mixture,
the colorless solid was dried in vacuo at 60 ꢁC for
24 h. Recrystallization from 2-propanol gave colorless,
spicular crystals of 9: Colorless spicules (2-propanol):
mp 179 ꢁC [R ef.4 178 ꢁC]/176–177 ꢁC (after recrystalli-
zation); yield 9.3 g (97%)/4.9 g (51%, after recrystalliza-
~
Unless otherwise noted, moisture-sensitive reactions
were conducted under dry nitrogen. Thin-layer chroma-
tography (TLC) was carried out on Silica Gel 60 F254
plates (E. Merck). Flash chromatography (FC) was per-
formed with Silica Gel 60, 40–63 lm (E. Merck).11
Parentheses include the following: (1) diameter of the
column (cm), (2) eluent, (3) fraction size (mL), and (4)
Rf. Melting points (mp) were determined on an SMP2
(Stuart Scientific) melting point apparatus and are
uncorrected. Optical rotations were measured on a Per-
kin–Elmer polarimeter model 241 using a 1.0-dm tube
with a solute concentration c (g/100 mL) at a tempera-
ture of 20 ꢁC. Elemental analyses (CHN) were deter-
mined on
a
VarioEL (Elementaranalysensysteme
GmbH) and a Perkin–Elmer Elemental Analyzer model
240. Mass spectra were recorded on MAT 44S, MAT
312, MAT 8200, and TSQ 7000 instruments (Finnigan)
tion); IR(neat): m 1082 (mC–O), 736, 696 cmꢀ1 (cCHoop
,
1
arom.); H NMR(CDCl ): d 3.42 (s, 3 · 0.5H, OCH3),
3

2488
K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 340 (2005) 2483–2493
3.44 (s, 3 · 0.5H, OCH3), 3.72–3.94 (m, 3H, 4-H, 5-H, 6-
H), 4.15 (d, J 5.8 Hz, 0.5H, 2-H), 4.30 (d, J 6.4 Hz, 0.5H,
2-H), 4.38–4.30 (m, 1H, 6-H), 4.48 (t, J 6.7 Hz, 0.5H, 3-
H), 4.64 (dd, J 7.6/5.5 Hz, 0.5H, 3-H), 5.03 (s, 0.5H, 1-
H), 5.09 (s, 0.5H, 1-H), 5.55 (s, 0.5H, PhCHO2), 5.65 (s,
0.5H, PhCHO2), 5.98 (s, 0.5H, PhCHO2), 6.30 (s, 0.5H,
PhCHO2), 7.35–7.57 (m, 10H, arom. H).
OCH3), 3.61 (dd, J 11.3/6.1 Hz, 1H, CH2Br), 3.71 (dd,
J 11.3/2.4 Hz, 1H, CH2Br), 4.36 (dddd, J 9.8/6.1/2.4/
0.6 Hz, 1H, 5-H), 5.21 (d, J 4.3 Hz, 1H, 1-Heq), 5.47
(dd, J 10.1/0.9 Hz, 1H, 4-H), 7.35 (td, J 7.3/1.3 Hz,
2H, arom. H, m-pos.), 7.59 (tt, J 7.3/1.3 Hz, 1H, arom.
H, p-pos.), 8.04–8.08 (m, 2H, arom. H, o-pos.); 13C
NMR(CDCl ): d 32.5 (1C, C-6), 46.0 (1C, C-2), 55.3
3
(1C, OCH3), 70.4 (1C, C-4), 75.8 (1C, C-5), 99.6 (1C,
C-1), 128.5 (2C, arom. C), 128.8 (1C, arom. C), 130.0
(2C, arom. C), 133.6 (1C, arom. C), 164.8 (1C, PhCOO),
196.9 (1C, CHCOCH2); EIMS: m/z [%] 105 [PhCO+,
100], 77 [Ph+, 24]; CIMS (NH3): m/z [%] 360/362
½M þ NHþ4 ; 79=78Š, 343/345 [MH+, 32/32], 328/330
[MH+ꢀCH3, 100/95], 311/313 [MH+ꢀ OCH3, 30/28],
105 [PhCO+, 25]; Anal. Calcd for C14H15BrO5 (343.2):
C, 48.99; H, 4.41. Found: C, 48.97; H, 4.37.
4.3. Preparation of methyl 4,6-O-benzylidene-2-deoxy-
a-D-erythro-hex-3-ulopyranoside (10)6
The bisacetal 9 (5.1 g, 19.3 mmol) was dissolved in THF
(100 mL). At ꢀ40 ꢁC n-butyllithium (2.4 M in n-hexane,
20 mL, 48.0 mmol), was added and the solution was stir-
red at ꢀ40 ꢁC for 3.5 h. The color of the solution chan-
ged from yellow to red. The mixture was added to
NH4Cl-containing ice water (12 g in 100 mL). Then,
THF was evaporated at 30 ꢁC water bath temperature
without separation of the layers. The aq solution was
cooled to 0 ꢁC, and the yellow crystalline product was
filtered off. Recrystallization from EtOH gave 10 as col-
orless crystals. Colorless, crystalline solid, mp 171–
172 ꢁC [Ref. 6 170–171 ꢁC]; yield after recrystallization
4.4.2. Data for 12. Rf 0.17; colorless oil; yield 0.70 g
(8%); IR(met): ~m 1730 (mO@C–O), 1690 (mC@O), 1655
(mC@C), 1597, 1491, 1451 (mC@C, arom.), 1245
(mO@C–O), 1109, 1040 (mC–O), 702, 690 cmꢀ1 (cCHoop
,
1
arom.); H NMR(CDCl ): d 3.69 (dd, J 11.9/4.9 Hz,
3
1H, CH2Br), 3.79 (dd, J 11.9/2.7 Hz, 1H, CH2Br), 4.79
(ddd, J 12.8/5.2/2.7 Hz, 1H, 2-H), 5.56 (d, J 5.8 Hz,
1H, 5-H), 5.81 (d, J 12.8 Hz, 1H, 3-H), 7.44 (d, J
6.1 Hz, 1H, 6-H), 7.45–7.51 (m, 2H, arom. H, m-pos.),
7.62 (tt, J 7.3/1.5 Hz, 1H, arom. H, p-pos.), 8.07–8.10
(m, 2H, arom. H, o-pos.); CIMS (isobutane): m/z [%]
311/313 [MH+, 100/95], 189/191 [MꢀPhCOO, 4/4],
105 [PhCO+, 7]; Anal. Calcd for C13H11BrO4 (311.1):
C, 50.19; H, 4.56. Found: C, 50.08; H, 4.20.
~
2.6 g (71%); IR(neat): m 1743 (mC@O), 1129 (mC–O),
908, 736, 650 cmꢀ1 (cCHoop, arom.); 1H NMR(CDCl 3):
d 2.66 (d, 1H, J 14.7 Hz, 2-Heq), 2.82 (dd, J 14.7/4.9 Hz
1H, 2-Hax), 3.37 (s, 3H, OCH3), 3.90 (t, J 10.1 Hz, 1H,
6-Hax), 4.14 (td, J 9.8/4.9 Hz, 1H, 5-H), 4.29 (d, J
9.8 Hz, 1H, 4-H), 4.37 (dd, J 10.1/4.9 Hz, 1H, 6-Heq),
5.13 (d, J 4.6 Hz, 1H, 1-H), 5.57 (s, 1H, PhCHO2),
7.33–7.35 (m, 3H, arom. H), 7.48–7.51 (m, 2H, arom.
H).
4.5. [(1R,3S,5S,8R)-5-Cyano-3-methoxy-2,6-dioxabi-
cyclo[3.2.1]octane-8-yl] benzoate (13)
4.4. Methyl 4-O-benzoyl-6-bromo-2,6-didedoxy-a-D-
erythro-hex-3-ulopyranoside (11) and 1,5-anhydro-
4-O-benzoyl-6-bromo-2,6-dideoxy-D-erythro-
hex-1-en-3-ulose (12)
Bromide 11 (120 mg, 0.35 mmol) was dissolved in DMF
(5 mL), and KCN (70 mg, 1.05 mmol) was added. After
stirring at 80 ꢁC for 1.5 h, H2O (5 mL) was added, and
the mixture was extracted with petroleum ether
(10 mL). Then, the aq layer was extracted with 95:5
petroleum ether–EtOAc (3 · 10 mL). The organic layer
was dried (MgSO4) and concentrated in vacuo. The res-
idue was purified by FC (1 cm, 8:2 petroleum ether–
EtOAc, fractions 2 mL, Rf 0.22). Colorless solid: mp
80 ꢁC; yield 30 mg (26%); [a]589 ꢀ62.5 (c 0.048, MeOH);
Ketone 10 (8.1 g, 30.4 mmol) was dissolved in CCl4
(360 mL) and N-bromosuccinimide (8.5 g, 47.8 mmol),
barium carbonate (13.8 g, 69.9 mmol) and AIBN
(0.44 g, 2.7 mmol) were added. At first the mixture was
carefully heated until the reaction started, then it was
heated to reflux for 3.5 h. After cooling down the mix-
ture was washed with satd aq NaHSO3 (150 mL) and
satd aq NaCl (150 mL). The organic layer was dried
(MgSO4) and concentrated in vacuo. The residue was
purified by FC (8 cm, 80:20 petroleum ether–EtAOc,
fractions 50 mL).
~
IR(neat): m 2255 (mCꢁN), 1734 (mO@C–O), 1269
(O@C–O), 1100 (mC–O), 909, 734 cmꢀ1 (cCHoop
,
1
arom.); H NMR(CDCl ): d 2.39 (dd, J 13.7/4.9 Hz,
3
1H, 4-Heq), 2.45 (dd, J 13.7/7.6 Hz, 1H, 4-Hax), 3.50
(s, 3H, OCH3), 4.27 (dd, J 10.7/2.7 Hz, 1H, 7-H), 4.32
(d, J 10.7 Hz 1H, 7-H), 4.81 (t, J 2.7 Hz, 1H, 1-H),
4.99 (dd, J 7.3/5.2 Hz, 1H, 3-H), 5.30 (d, J 3.0 Hz, 1H,
8-H), 7.50 (t, J 7.3 Hz, 2H, arom. H, m-pos.), 7.63 (tt,
J 7.3/1.7 Hz, 1H, arom. H, p-pos.), 8.08–8.12 (m, 2H,
arom. H, o-pos.); EIMS: m/z [%] 289 [M+, 1], 184
[MꢀPhCO, 3], 105 [PhCO+, 100], 77 [Ph+, 15]; CIMS
4.4.1. Data for 11. Rf 0.31; colorless solid, mp 92 ꢁC,
~
yield 5.3 g (54%); IR(neat): m 1728 (mC@O), 1599,
1492, 1451 (mC@C, arom.), 1247 (mO@C–O), 1109
(mC–O), 733, 706 cmꢀ1 (cCHoop, arom.); 1H NMR
(CDCl3): d 2.71 (dd, J 14.0/0.9 Hz, 1H, 2-Heq), 2.93
(ddd, J 14.0/4.6/0.9 Hz, 1H, 2-Hax), 3.44 (s, 3H,

K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 340 (2005) 2483–2493
2489
(NH3): m/z [%] 307 ½MþNHþ; 100Š, 105 [PhCO+, 17];
129.4 (1C, quart., arom. C), 130.0 (2C, arom. C, o-
pos.), 133.5 (1C, arom. C, p-pos.), 165.3 (1C, PhCOO);
Anal. Calcd for C16H21BrO6 (389.2): C, 49.37; H, 5.44.
Found: C, 49.11; H, 5.23.
4
HREIMS: calcd for C15H15NO5: 289.0950. Found:
289.0950.
4.6. Methyl 4-O-benzoyl-6-bromo-2,6-dideoxy-a-D-
erythro-hex-3-ulopyranoside dimethyl ketal (15a) and
methyl 4-O-benzoyl-6-bromo-2,6-dideoxy-b-D-erythro-
hex-3-ulopyranoside dimethyl ketal (15b)
In addition to the pure samples 15a and 15b, a mix-
ture of 15a/15b, was isolated as a colorless: oil, yield
2.0 g (43%); total yield 88%.
4.7. Methyl 4-O-benzoyl-6-cyano-2,6-dideoxy-a-D-
erythro-hex-3-ulopyranoside dimethyl ketal (16a)
p-Toluenesulfonic acid (0.13 g, 0.68 mmol) and tri-
methyl orthoformate (17 mL, 155 mmol) were added
to a solution of ketone 11 (4.1 g, 11.9 mmol) in MeOH
(40 mL), and the mixture was heated to reflux for
24 h. After completion of the reaction, a saturated solu-
tion of NaHCO3 (60 mL) was added, and the mixture
was extracted with CH2Cl2 (3 · 100 mL). The organic
layer was dried (MgSO4) and concentrated in vacuo,
and the residue was purified by FC (5.5 cm, 8:2 petro-
leum ether–EtOAc, fractions 20 mL).
A solution of 15a (1.5 g, 3.8 mmol) and KCN (1.5 g,
23.7 mmol) in DMSO (20 mL) was stirred at 70 ꢁC for
2.5 h. After cooling to room temperature, water
(25 mL) was added, and the aq layer was extracted with
95:5 petroleum ether–EtOAc (3 · 50 mL). The organic
layer was dried (MgSO4) and concentrated in vacuo,
and the residue was purified by FC (4 cm, 8:2 EtOAc–
petroleum ether, fractions 10 mL, Rf 0.39). Colorless
oil: yield 1.2 g (94%); [a]589 +59.0 (c 0.473, MeOH); IR
~
4.6.1. Data for 15a. Rf 0.35; colorless oil; yield 1.50 g
(neat): m 1720 (mO@C–O), 1266 (mO@C–O), 1105, 1049
1
(32%); [a]589 +55.0 (c 0.166, MeOH); IR(neat): m 1721
(mC–O), 711 cmꢀ1 (cCHoop, arom.); H NMR(CDCl ):
~
3
(mO@C–O), 1263 (mO@C–O), 1110, 1048 (mC–O),
d 2.05 (dd, J 14.6/3.9 Hz, 1H, 2-Hax), 2.27 (dd, J 14.6/
3.9 Hz, 1H, 2-Heq), 2.62 (dd, 1H, J 16.8/4.3 Hz,
CH2CN), 2.76 (dd, 1H, J 16.8/9.3 Hz, CH2CN), 3.24
(s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.48 (s, 3H,
OCH3), 4.38 (ddd, J 8.9/7.3/4.3 Hz, 1H, 5-H), 4.80 (t,
J 3.9 Hz, 1H, 1-Heq), 5.11 (d, J 7.3 Hz, 1H, 4-H), 7.46
(t, J 7.6 Hz, 2H, arom. H, m-pos.), 7.60 (tt, J 7.5/
1.5 Hz, 1H, arom. H, p-pos.), 8.06–8.09 (m, 2H, arom.
1
708 cmꢀ1 (cCHoop, arom.); H NMR(CDCl ): d 2.08
3
(ddd, J 14.3/3.9/0.9 Hz, 1H, 2-Heq), 2.23 (dd, J 14.3/
4.5 Hz, 1H, 2-Hax), 3.25 (s, 3H, OCH3), 3.32 (s, 3H,
OCH3), 3.49 (s, 3H, OCH3), 3.53–3.57 (m, 2H, CH2Br),
4.33 (td, J 6.7/5.2 Hz, 1H, 5-H), 4.80 (t, J 4.3 Hz, 1H, 1-
Heq), 5.23 (dd, J 6.7/0.9 Hz, 1H, 4-H), 7.46 (td, J 7.3/
1.5 Hz, 2H, arom. H, m-pos.), 7.59 (tt, J 7.3/1.5 Hz,
1H, arom. H, p-pos.), 8.06–8.10 (m, 2H, arom. H, o-
H, o-pos.); 13C NMR(CDCl ): d 20.7 (1C, C-6), 35.6
3
pos.); 13C NMR(CDCl ): d 31.5 (1C, C-6), 35.6 (1C,
(1C, C-2), 49.0 (1C, OCH3), 49.6 (1C, OCH3), 55.9
(1C, OCH3), 67.4 (1C, C-5 o.C-4), 73.1 (1C, C-4 o.C-
5), 97.4 (1C, C-1 o.C-3), 97.9 (1C, C-3 o.C-1), 116.8
(1C, CN), 128.5 (2C, arom. C), 129.0 (1C, arom. C),
130.0 (2C, arom. C), 133.7 (1C, arom. C), 165.6 (1C,
PhCOO); EIMS: m/z [%] 304 [MꢀOCH3, 10], 272
[MꢀHOCH3ꢀOCH3, 8], 105 [PhCO+, 100], 77 [Ph+,
24]; CIMS (NH3): m/z [%] 353 ½M þ NHþ4 ; 100Š, 304
[MꢀOCH3, 99]; Anal. Calcd for C17H21NO6 (335.4):
C, 60.89; H, 6.31; N, 4.18. Found: C, 60.84; H, 6.46;
N, 4.15.
3
C-2), 48.9 (1C, OCH3), 49.5 (1C, OCH3), 56.0 (1C,
OCH3), 73.3 (1C, C-4), 74.1 (1C, C-5), 97.2 (1C, C-1),
100.1 (1C, C-3), 128.5 (2C, arom. C, m-pos.), 128.6
(1C, quart., arom. C), 133.5 (2C, arom. C, o-pos.),
133.5 (1C, arom. C, p-pos.), 165.4 (1C, PhCOO); EIMS:
m/z [%] 357/359 [MꢀOCH3, 6/6]; CIMS (NH3): m/z [%]
406/408 ½MþNHþ4 ; 4:5=4:5Š, 357/359 [MꢀOCH3, 100/
97]; Anal. Calcd for C16H21BrO6 (389.2): C, 49.37; H,
5.44. Found: C, 49.53; H, 5.43.
4.6.2. Data for 15b. Rf 0.41; colorless solid; mp 73 ꢁC,
1
yield 0.61 g (13%)]; [a]589 ꢀ22.0 (c 0.216, MeOH); H
4.8. Methyl 4-O-benzoyl-6-cyano-2,6-dideoxy-b-D-
erythro-hex-3-ulopyranoside dimethyl ketal (16b)
NMR(CDCl ): d 1.87 (dd, J 13.4/7.3 Hz, 1H, 2-Hax),
3
2.31 (dd, J 13.4/2.7 Hz, 1H, 2-Heq), 3.24 (s, 3H,
OCH3), 3.38 (s, 3H, OCH3), 3.52 (dd, J 11.0/7.3 Hz,
1H, CH2Br), 3.54 (s, 3H, OCH3), 3.58 (dd, J 11.0/
4.0 Hz, 1H, CH2Br), 4.07 (td, J 7.8/3.9 Hz, 1H, 5-H),
4.74 (dd, J 7.6/2.7 Hz, 1H, 1-Hax), 5.27 (d, J 7.9 Hz,
1H, 4-H), 7.47 (t, J 7.6 Hz, 2H, arom. H, m-pos.), 7.59
(tt, J 7.5/1.5 Hz, 1H, arom. H, p-pos.), 8.04–8.08 (m,
A solution of 15b (810 mg, 2.1 mmol) and KCN
(843 mg, 12.9 mmol) in DMSO (25 mL) was stirred at
70 ꢁC for 2.5 h. After cooling to room temperature,
water (25 mL) was added, and the aq layer was extracted
with 95:5 petroleum ether–EtOAc (3 · 50 mL). The
organic layer was dried (MgSO4) and concentrated in
vacuo, and the residue was purified by FC (3 cm,
8:2 EtOAc–petroleum ether, fractions 10 mL, Rf 0.43).
2H, arom. H, o-pos.); 13C NMR(CDCl ): 32.4 (1C, C-
3
6), 37.5 (1C, C-2), 49.1 (1C, OCH3), 49.7 (1C, OCH3),
56.7 (1C, OCH3), 71.9 (1C, C-4), 72.1 (1C, C-5), 97.5
(1C, C-3), 98.4 (1C, C-1), 128.6 (2C, arom. C, m-pos.),
Colorless solid: mp 112 ꢁC; yield 465 mg (67%); [a]589
1
ꢀ6.0 (c 0.360, MeOH); H NMR(CDCl ): d 1.85 (dd,
3

2490
K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 340 (2005) 2483–2493
J 13.7/7.6 Hz, 1H, 2-Hax), 2.33 (dd, J 13.7/2.7 Hz, 1H,
2-Heq), 2.63 (dd, 1H, J 16.8/4.3 Hz, CH2CN), 2.79
(dd, J 16.8/8.9 Hz, 1H, CH2CN), 3.24 (s, 3H, OCH3),
3.39 (s, 3H, OCH3), 3.55 (s, 3H, OCH3), 4.13 (ddd, J
8.9/7.9/4.3 Hz, 1H, 5-H), 4.76 (dd, J 7.6/2.7 Hz, 1H,
1-Hax), 5.15 (d, J 7.9 Hz, 1H, 4-H), 7.48 (t, J 7.5 Hz,
2H, arom. H, m-pos.), 7.61 (tt, J 7.5/1.5 Hz, 1H, arom.
H, p-pos.), 8.04–8.07 (m, 2H, arom. H, o-pos.); 13C
dried (MgSO4) and concentrated in vacuo, and the res-
idue was purified by FC (3 cm, 7:3 petroleum ether–
EtOAc, fractions 10 mL, Rf 0.32). Colorless solid: mp
82 ꢁC; yield 174 mg (80%); [a]589 ꢀ35.0 (c 0.195,
1
MeOH); H NMR(CDCl ): d 1.59 (dd, J 14.0/9.5 Hz,
3
1H, 2-Hax), 2.29 (dd, J 14.0/2.1 Hz, 1H, 2-Heq), 2.64
(dd, J 16.8/7.9 Hz, 1H, CH2CN), 2.47 (s, broad, 1H,
OH), 2.89 (dd, J 16.8/3.4 Hz, 1H, CH2CN), 3.41–3.47
(m, 1H, 4-H), 3.34 (s, 3H, OCH3), 3.36 (s, 3H, OCH3),
3.50 (s, 3H, OCH3), 3.58 (ddd, J 9.3/7.8/3.6 Hz, 1H, 5-
H), 4.47 (dd, J 9.5/2.1 Hz, 1H, 1-Hax); 13C NMR
(CDCl3): d 21.2 (1C, C-6), 37.0 (1C, C-2), 48.9 (1C,
OCH3), 50.8 (1C, OCH3), 56.5 (1C, OCH3), 71.7 (1C,
C-5), 74.4 (1C, C-4), 97.3 (1C, C-1 o.C-3), 99.7 (1C, C-
3 o.C-1), 117.3 (1C, CN); Anal. Calcd for C10H17NO5
(231.3): C, 51.94; H, 7.41; N, 6.06. Found: C, 51.64;
H, 7.36; N, 5.95.
NMR(CDCl ): d 21.6 (1C, C-6), 37.4 (1C, C-2), 49.1
3
(1C, OCH3), 49.7 (1C, OCH3), 56.8 (1C, OCH3), 70.0
(1C, C-5 o.C-4), 73.9 (1C, C-4 o.C-5), 97.2 (1C, C-1
o.C-3), 100.3 (1C, C-3 o.C-1), 117.0 (1C, CN), 128.6
(2C, arom. C), 129.0 (1C, arom. C), 129.9 (2C, arom.
C), 133.7 (1C, arom. C), 165.4 (1C, PhCOO); Anal.
Calcd for C17H21NO6 (335.4): C, 60.89; H, 6.31; N,
4.18. Found: C, 60.55; H, 6.29; N, 4.05.
4.9. Methyl 6-cyano-2,6-dideoxy-a-D-erythro-hex-3-
ulopyranoside dimethyl ketal (17a)
4.11. Methyl 7-amino-2,6,7-trideoxy-a- and b-D-erythro-
hept-3-ulo-1,5-pyranoside dimethyl ketal (18a and 18b)
A mixture of 16a (0.76 g, 2.3 mmol), MeOH (40 mL),
and 3 N NaOH (10 mL) was stirred at room tempera-
ture for 9 h. After addition of H2O (10 mL), it was ex-
tracted with CH2Cl2 (4 · 50 mL). The organic layer
was dried (MgSO4) and concentrated in vacuo, and
the residue was purified by FC (3 cm, 7:3 petroleum
ether–EtOAc, fractions 10 mL, Rf 0.31). Colorless crys-
tals: mp 83 ꢁC; yield 0.4 g (76%); [a]589 +66.2 (c 0.303,
A solution of 16 (anomeric mixture, 1.0 g, 3.1 mmol) in
MeOH (60 mL) and 5 N NaOH (15 mL) was stirred at
room temperature for 2 h. After completion of the reac-
tion, Raney nickel was added to the resulting hydrolysis
product (17, anomeric mixture), and the mixture was
shaken under an H2 atmosphere (4.1 bar) at room tem-
perature for 24 h. Raney Ni was removed by filtration
through Celiteꢂ AFA. The solution was concentrated
to a volume of about 20 mL. After addition of water
(10 mL), the mixture was extracted with CH2Cl2
(4 · 50 mL). The organic layer was dried (MgSO4) and
concentrated in vacuo to yield a yellow oil (yield
0.70 g, 97%), which was pure enough for further reac-
tions. In order to characterize the primary amine 18, a
sample (103 mg) of the residue was purified by FC
[2 cm, 8:2 ethanol–acetone, 2% N-ethyl-N,N-dimethyl-
amine, fractions 5 mL, Rf 0.11, yield 17 mg (<10%)];
~
MeOH); IR(neat): m 2945 (mC–H), 2279 (mCN), 1127,
1046 cmꢀ1 (mC–O); 1H NMR(CDCl 3): d 1.74 (dd, J
15.0/4.5 Hz, 1H, 2-Hax), 2.31 (dd, J 15.2/1.2 Hz, 1H,
2-Heq), 2.60 (dd, J 16.9/7.8 Hz, 1H, CH2CN), 2.85
(dd, J 16.5/3.5 Hz, 1H, CH2CN), 3.45 (t, J 9.9 Hz, 1H,
4-H), 3.33 (s, 3H, OCH3), 3.36 (s, 3H, OCH3), 3.37 (s,
3H, OCH3), 3.82 (ddd, J 9.5/7.7/3.1 Hz, 1H, 5-H),
4.73 (dd, J 4.5/1.2 Hz, 1H, 1-Heq), a signal for the
OH-proton was not observed; 13C NMR(CDCl 3): d
20.8 (1C, C-6), 34.8 (1C, C-2), 49.1 (1C, OCH3), 51.0
(1C, OCH3), 55.4 (1C, OCH3), 67.5 (1C, C-5), 74.3
(1C, C-4), 96.5 (1C, C-1 o.C-3), 97.8 (1C, C-3 o.C-1),
117.5 (1C, CN); EIMS: m/z [%] 231 [M+, 1], 200
[MꢀOCH3, 7], 168 [MꢀHOCH3ꢀOCH3, 25],
ꢀ1
1
~
IR(neat): m 2945 (mC–H), 1128, 1053 cm (mC–O); H
NMR(CDCl 3): d 1.47 (dd, J 13.7/9.8 Hz, 0.45H, 2-
Hax, b-is.), 1.69 (dd, J 14.9/4.6 Hz, 0.55H, 2-Hax, a-
is.), 1.70–1.86 (m, 1H, CH2CH2NH2, a+b-is.), 1.92–
2.03 (m, 1H, CH2CH2NH2, a+b-is.), 2.21 (dd, J 12.8/
2.1 Hz, 0.45H, 2-Heq, b-is.), 2.23 (dd, J 14.0/2.0 Hz,
0.55H, 2-Heq, a-is.), 2.94–3.07 (m, 1H, CH2CH2NH2,
a+b-is.), 2.80–2.91 (m, 1H, CH2CH2NH2, a+b-is.),
3.29–3.53 (m, 0.45H, 5-H, b-is./1H, 4-H, a+b-is./2H,
NH2, a+b-is.), 3.28 (s, 3 · 0.55H, OCH3, a-is.), 3.30
(s, 3 · 0.55H, OCH3, a-is.), 3.31 (s, 3 · 0.45H, OCH3,
b-is.), 3.34 (s, 3 · 0.55H, OCH3, a-is.), 3.37 (s,
3 · 0.45H, OCH3, b-is.), 3.42 (s, 3 · 0.45H, OCH3, b-
is.) 3.67 (td, J 8.6/4.0 Hz, 0.55H, 5-H, a-is.), 4.39 (dd,
J 9.8/1.8 Hz, 0.45H, 1-Hax, b-is.), 4.63 (dd, J 4.4/
2.1 Hz, 0.55H, 1-Heq, a-is.), a signal for the OH-proton
was not found; the ratio of a- and b-anomers was 55:45;
EIMS: m/z [%] 204 [MꢀOCH3, 7], 173 [Mꢀ2 · OCH3,
88 ½–CðOCH3Þ –CHþ; 100Š; CIMS (NH3): m/z [%]
2
249 ½M þ NHþ4 2; 74Š; CIMS (isobutane): m/z [%] 288
½M þ C4Hþ; 13Š, 232 [MH+, 28], 168 [MꢀHOCH3ꢀ
9
OCH3, 47]; Anal. Calcd for C10H17NO5 (231.3): C,
51.94; H, 7.41; N, 6.06. Found: C, 52.13; H, 7.54; N,
5.82.
4.10. Methyl 6-cyano-2,6-dideoxy-b-D-erythro-hex-3-
ulopyranoside dimethyl ketal (17b)
A mixture of 16b (316 mg, 0.9 mmol), MeOH (15 mL),
and 3 N NaOH (6 mL) was stirred at room temperature
for 9 h. After addition of H2O (5 mL), the mixture was
extracted with CH2Cl2 (25 mL). The organic layer was

K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 340 (2005) 2483–2493
2491
3], 88 ½CðOCH3Þ –CHþ–; 100Š; CIMS (NH3): m/z [%]
14.0/9.8 Hz, 0.5H, 2-Hax, b-is.), 1.61–1.72 (m, 1H,
CH2CH2NH, a+b-is.), 1.69 (dd, J 14.9/4.6 Hz, 0.5H,
2-Hax, a-is.), 2.04–2.18 (m, 1H, m, 1H, CH2CH2NH,
a+b-is.), 2.23 (dd, J 14.0/2.1 Hz, 0.5H, 2-Heq, b-is.),
2.27 (dd, J 14.0/1.8 Hz, 0.5H, 2-Heq, a-is.), 2.28 (d, J
8.5 Hz, 0.5H, OH, b-is.), 2.44 (d, J 9.8 Hz, 0.5H, OH,
a-is.), 3.25–3.48 (m, 1H, 4-H, a+b-is./2H, CH2CH2NH,
a+b-is.), 3.28 (s, 3 · 0.5H, OCH3, a/b-is.), 3.29 (s,
3 · 0.5H, OCH3, a/b-is.), 3.31 (s, 3 · 0.5H, OCH3, a/
b-is.), 3.33 (s, 3 · 0.5H, OCH3, a/b-is.), 3.35 (s,
6 · 0.5H, OCH3, a/b-is.), 3.59 (td, J 9.2/2.4 Hz, 1H, 5-
H, a+b-is.), 4.35 (dd, J 9.8/2.1 Hz, 0.5H, 1-Hax, b-is.),
4.65 (dd, J 4.3/1.8 Hz, 0.5H, 1-Heq, a-is.), 5.07 (s, 2H,
OCH2Ph, a+b-is.), 5.13 (s, broad, 1H, NH, a+b-is.),
7.26–7.38 (m, 5H, arom. H, a+b-is.); the ratio of a-
and b-anomers was 1:1; EIMS: m/z [%] 91 [CH2Ph+,
100]. ESIMS: m/z [%] 392 [M+Na+, 100]. CIMS
(NH3): m/z [%] 287 ½M þ NHþ4 ; 3Š, 338 [MꢀOCH3, 16],
306 [M+ꢀHOCH3ꢀOCH3, 100]. HREIMS: calcd for
C17H24NO6: 338.1604. Found: 338.1611.
2
2
236 [MH+, 17], 204 [MꢀOCH3, 100]; HREIMS: calcd
for C9H18NO5: 220.1185. Found: 220.1185.
4.12. Methyl 7-(acetylamino)-2,6,7-trideoxy-a- and
b-D-erythro-hept-3-ulo-1,5-pyranoside dimethyl ketal
(19a and 19b)
Under N2 atmosphere, Et3N (0.4 mL, 2.9 mmol) and
Ac2O (0.2 mL, 2.1 mmol) were added to a solution of
crude primary amine 18 (anomeric mixture, 101 mg,
0.37 mmol) in CH2Cl2 (10 mL). After stirring the
mixture at room temperature for 2.5 h, the mixture
was concentrated in vacuo, and the residue was purified
by FC (2 cm, 9:1 EtOAc–MeOH, fractions 5 mL, Rf
0.31). Yellow oil: yield 47 mg (44% referring to nitrile
~
16); IR(neat): m 3299 (mN–H), 2943 (mC–H), 1650
(mO@C–NH, amide I), 1553 (dN–H, amide II), 1129,
1047 cmꢀ1 (mC–O); 1H NMR(CDCl 3): d 1.52 (dd, J
14.0/9.8 Hz, 0.45H, 2-Hax, b-is.), 1.61–1.76 (m, 1H,
CH2CH2NH, a+b-is.), 1.73 (dd, J 14.9/4.3 Hz, 0.55H,
2-Hax, a-is.), 1.96 (s, 3H, NHCOCH3, a+b-is.), 2.00–
2.19 (m, 1H, CH2CH2NH, a+b-is.), 2.25 (dd, J 14.9/
1.8 Hz, 0.55H, 2-Heq, a-is.), 2.30 (dd, J 14.0/1.8 Hz,
0.45H, 2-Heq, b-is.), 2.42 (d, J 7.6 Hz, 0.45H, OH, b-
is.), 2.53 (d, J 9.5 Hz, 0.55H, OH, a-is.), 3.24–3.59 (m,
1H, 4-H, a+b-is./2H, CH2CH2NH, a+b-is.), 3.32 (s,
3 · 0.55H, OCH3, a-is.), 3.33 (s, 3 · 0.55H, OCH3, a-
is.), 3.34 (s, 3 · 0.45H, OCH3, b-is.), 3.36 (s, 3 · 0.55H,
OCH3, a-is.), 3.38 (s, 3 · 0.45H, OCH3, b-is.), 3.49 (s,
3 · 0.45H, OCH3, b-is.), 3.64 (td, J 9.2/2.7 Hz, 1H, 5-
H, a+b-is.), 4.69 (dd, J 4.5/2.0 Hz, 0.55H, 1-Heq, a-
is.), 4.40 (dd, J 9.8/2.1 Hz, 0.45H, 1-Hax, b-is.), 6.00 (s,
broad, 1H, NH, a+b-is.); the ratio of a- and b-anomers
was 55:45; EIMS: m/z [%] 246 [MꢀOCH3, 2], 215
[Mꢀ2 · OCH3, 2]; ESIMS: m/z [%] 300 [M+Na+, 100],
214 [MꢀHOCH3ꢀOCH3, 31]; CIMS (NH3): m/z [%]
4.14. Methyl 7-[2-(3,4-dichlorophenyl)acetylamino]-2,6,7-
trideoxy-a- and b-D-erythro-hept-3-ulo-1,5-pyranoside
dimethyl ketal (22a and 22b)
Under N2 atmosphere, a solution of (3,4-dichlorophen-
yl)acetic acid (540 mg, 2.6 mmol) and 1,10-carbonyldiim-
idazole (420 mg, 2.6 mmol) in CH2Cl2 (15 mL) was
stirred at room temperature for 1 h. Then, the unpuri-
fied primary amine 18 (anomeric mixture, 498 mg,
2.1 mmol) dissolved in CH2Cl2 (10 mL) was added drop-
wise to the mixture under ice cooling. The mixture was
stirred at room temperature for 6 h. After completion
of the transformation the solvent was removed in vacuo,
and the residue was purified by FC (3 cm, 95:5 EtOAc–
acetone, fractions 10 mL, Rf 0.31). Pale-yellow oil: yield
~
468 mg (52%, referring to nitrile 16); IR(neat): m 3301
295 ½M þ NHþ; 3Š, 278 [MH+, 13], 246 [MꢀOCH3,
(mN–H), 2942 (mC–H), 1647 (mO@C–NH, amide I),
4
1
100], 214 [MꢀHOCH3ꢀOCH3, 83]. HREIMS: calcd
1552 (dN–H, amide II), 1129, 1048 cmꢀ1 (mC–O); H
for C11H20NO5: 246.1342. Found: 246.1338.
NMR(CDCl ): d 1.49 (dd, J 14.0/9.8 Hz, 0.5H, 2-Hax,
3
b-is.), 1.59–1.75 (m, 1H, CH2CH2NH, a+b-is.), 1.64
(dd, J 14.9/4.3 Hz, 0.5H, 2-Hax, a-is.), 2.00–2.14 (m,
1H, CH2CH2NH, a+b-is.), 2.24 (dd, J 14.9/1.5 Hz,
0.5H, 2-Heq, a-is.), 2.28 (dd, J 14.0/1.8 Hz, 0.5H, 2-
Heq, b-is.), 2.36 (d, J 8.6 Hz, 0.5H, OH, b-is.), 2.46 (d,
J 10.1 Hz, 0.5H, OH, a-is.), 3.21–3.62 (m, 1H, 4-H,
a+b-is./1H, 5-H, a+b-is./2H, CH2CH2NH, a+b-is.),
3.17 (s, 3 · 0.5H, OCH3, a/b-is.), 3.30 (s, 3 · 0.5H,
OCH3, a/b-is.), 3.33 (s, 3 · 0.5H, OCH3, a/b-is.), 3.34
(s, 3 · 0.5H, OCH3, a/b-is.), 3.36 (s, 3 · 0.5H, OCH3,
a/b-is.), 3.42 (s, 3 · 0.5H, OCH3, a/b-is.), 3.47 (s,
2 · 0.5H, COCH2Ph, a/b-is.), 3.50 (s, 2 · 0.5H,
COCH2Ph, a/b-is.), 4.33 (dd, J 9.5/2.0 Hz, 0.5H, 1-
Hax, b-is.), 4.45 (dd, J 4.3/1.5 Hz, 0.5H, 1-Heq, a-is.),
6.00 (s, broad, 0.5H, NH, a/b-is.), 6.13 (s, broad,
0.5H, NH, a/b-is.), 7.12 (dd, J 8.2/2.1 Hz, 0.5H, arom.
4.13. Methyl 7-(benzyloxycarbonylamino)-2,6,7-trideoxy-
a- and b-D-erythro-hept-3-ulo-1,5-pyranoside dimethyl
ketal (20a and 20b)
Under N2 atmosphere, Et3N (0.4 mL, 2.9 mmol) and
benzyl chloroformate (0.4 mL, 2.8 mmol) were added
to a solution of crude primary amine 18 (anomeric mix-
ture, 180 mg, 0.77 mmol) in CH2Cl2 (15 mL). After stir-
ring the reaction mixture at room temperature for 5 h, it
was concentrated in vacuo. The residue was purified by
FC (2 cm, 6:4 petroleum ether–EtOAc, fractions 5 mL,
Rf 0.22). Colorless oil: yield 177 mg (60%, referring to
~
nitrile 16); IR(neat): m 3347 (mN–H), 1702 (mO@C–
NH, amide I), 1525 (dN–H, amide II), 1250, 1128,
1051 cmꢀ1 (mC–O); 1H NMR(CDCl 3): d 50 (dd, J

2492
K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 340 (2005) 2483–2493
H, 60H, a/b-is.), 7.13 (dd, J 8.2/2.1 Hz, 0.5H, arom. H,
60-H, a/b-is.), 7.37 (d, J 2.4 Hz, 0.5H, arom. H, 20-H, a/
b-is.), 7.38 (d, J 2.4 Hz, 0.5H, arom. H, 20-H, a/b-is.),
7.39 (d, J 8.2 Hz, 0.5H, arom. H, 50-H, a/b-is.), 7.42
(d, J 8.2 Hz, 0.5H, arom. H, 50-H, a/b-is.); the ratio of
a- and b-anomers was 1:1; EIMS: m/z [%] 358/360/362
[M+ꢀHOCH3ꢀOCH3, 7.7/5.3/0.9]; CIMS (NH3): m/z
[%] 438/440/442 [M+NH3, 4.1/2.7/0.5], 422/424/426
[MH+, 17/11/2], 358/360/362 [MꢀHOCH3ꢀOCH3,
100/65/12]; Anal. Calcd for C18H25Cl2NO6 (422.3): C,
51.19; H, 5.97; N, 3.32. Found: C, 50.98; H, 6.11; N,
3.47.
(2 · 10 mL). The organic layer was dried (MgSO4) and
concentrated in vacuo, and the residue was purified by
FC (2 cm, 95:5 EtOAc–acetone, fractions 5 mL,
Rf = 0.23). Colorless solid, mp 147 ꢁC, yield 127 mg
~
(80%); IR(neat): m 3423 (mN–H), 3287 (mO-H), 2968
(mC–H), 1627 (mO@C–NH, amide I), 1566 (dN–H,
amide II), 1118 cmꢀ1 (mC–O); 1H NMR(CDCl 3): d
1.79–1.96 (m, 1H, CH2CH2NH, a+b-is.), 2.05–2.18
(m, 1H, CH2CH2NH, a+b-is.), 2.65 (dd, J 14.0/
9.2 Hz, 0.45H, 2-Hax, b-is.), 2.66 (d, J 14.0 Hz, 0.55H,
2-Heq, a-is.), 2.74 (dd, J 14.0/4.3 Hz, 0.55H, 2-Hax, a-
is.), 2.85 (dd, J 14.3/2.7 Hz, 0.45H, 2-Heq, b-is.), 3.20
(s, 2H, COCH2Ph, a+b-is.), 3.26–3.68 (m, 1H, 5-H,
a+b-is./1H, OH, a+b-is./2H, CH2CH2NH, a+b-is.),
3.48 (s, 3 · 0.45H, OCH3, b-is.), 3.51 (s, 3 · 0.55H,
OCH3, a-is.), 3.84 (d, J 9.8 Hz, 1H, 4-H, a+b-is.), 4.49
(dd, J 9.2/2.4 Hz, 0.45H, 1-Hax, b-is.), 4.90 (d, J
4.3 Hz, 0.55H, 1-Heq, a-is.), 5.81 (s, broad, 0.45H,
NH, b-is.), 5.94 (s, broad, 0.55H, NH, a-is.), 7.11 (dd,
J 8.2/2.1 Hz, 0.45H, arom. H, 60, b-is.), 7.12 (dd, J
8.2/2.4 Hz, 0.55H, arom. H, 60-H, a-is.), 7.37 (d, J
2.1 Hz, 0.55H, arom. H, 20-H, a-is.), 7.38 (d, J 1.8 Hz,
0.45H, arom. H, 20-H, b-is.), 7.41 (d, J 8.2 Hz, 0.45H,
arom. H, 50-H, b-is.), 7.42 (d, J 8.2 Hz, 0.55H, arom.
H, 50-H, a-is.); the ratio of a- and b-anomers was
55:45; EIMS: m/z [%] 343/345/347 [MꢀHOCH3, 16/
4.15. Methyl 7-(benzoylamino)-2,6,7-trideoxy-a- and b-D-
erythro-hept-3-ulo-1,5-pyranoside (23a and 23b)
Under N2 atmosphere, benzoyl chloride (0.33 mL,
2.8 mmol) and Et3N (0.54 mL, 3.9 mmol) were added
to a solution of the unpurified primary amine 18 (ano-
meric mixture, 468 mg, 2.1 mmol) in CH2Cl2 (25 mL).
The mixture was stirred at room temperature for 22 h.
The mixture was concentrated in vacuo, and the residue
was purified by FC (2 cm, EtOAc, fractions 5 mL, Rf
0.39). Pale-yellow solid: mp 154 ꢁC; yield 180 mg (25%,
~
referring to nitrile 16); IR(neat): m 3340 (mN–H), 2943
(mC–H), 1712 (mC@O), (1638 (mO@C–NH, amide I),
1536 (dN–H, amide II), 1051 (mC–O), 711, 693 cmꢀ1
11/2], 159/161/163 ½–CH2PhClþ; 100=66=11Š; CIMS
2
1
(cCHoop, arom.); H NMR(CDCl ): d 1.99–2.13 (m,
(NH3): m/z [%] 393/395 ½MþNHþ4 ; 10=7Š, 376/378/
380 [MH+, 100/63/15], 344/346/348 [MꢀHOCH3,
95/60/11]; Anal. Calcd for C16H19Cl2NO5 (376.3): C,
51.08; H, 5.09; N, 3.72. Found: C, 51.84; H, 5.58; N,
3.72.
3
1H, CH2CH2NH, a+b-is.), 2.22–2.35 (m, 1H,
CH2CH2NH, a+b-is.), 2.71 (dd, J 14.0/1.2 Hz, 0.6H,
2-Heq, a-is.), 2.70 (ddd, J 14.3/9.2/1.5 Hz, 0.4H, 2-Hax,
b-is.), 2.83 (ddd, J 14.0/4.6/1.2 Hz, 0.6H, 2-Hax, a-is.),
2.87 (dd, J 14.3/2.7 Hz, 0.4H, 2-Heq, b-is.), 3.23 (s,
3 · 0.6H, OCH3, a-is.), 3.52 (s, 3 · 0.4H, OCH3, b-is.),
3.36–3.91 (m, 2H, CH2CH2NH, a+b-is./1H, OH, a+b-
is./1H, 5-H, a+b-is.), 3.95 (dd, J 10.1/1.5 Hz, 0.4H, 4-
H, b-is.), 3.97 (dd, J 9.8/1.2 Hz, 0.6H, 4-H, a-is.), 4.58
(dd, J 9.2/2.4 Hz, 0.4H, 1-Hax, b-is.), 5.14 (d, J 4.0 Hz,
0.6H, 1-Heq, a-is.), 6.76 (s, broad, 1H, NH, a+b-is.),
7.39–7.53 (m, 3H, arom. H, a+b-is.), 7.75–7.79 (m,
2H, arom. H, a+b-is.); the ratio of a- and b-anomers
was 3:2; EIMS: m/z [%] 243 [MꢀHOCH3ꢀH2O, 9],
105 [PhCO+, 100]; CIMS (isobutane): m/z [%] 294
[MH+, 100], 262 [MꢀOCH3,85]; Anal. Calcd for
C15H19NO5 (293.3): C, 61.42; H, 6.52; N, 4.78. Found:
C, 61.71; H, 6.54; N, 4.69.
4.17. 1,5-Anhydro-7-(benzoylamino)-2,6,7-trideoxy-D-
erythro-hept-1- en-3-ulose (25)
A solution of ketone 23 (anomeric mixture, 97 mg,
0.29 mmol) and p-toluenesulfonic acid monohydrate
(62 mg, 0.32 mmol) in CH2Cl2 (15 mL) was heated to re-
flux for 30 min. Then, the mixture was washed with satd
aq NaHCO3 (10 mL). The organic layer was dried
(MgSO4) and concentrated in vacuo, and the residue
was purified by FC (2 cm, EtOAc, fractions 2 mL,
Rf = 0.42). Colorless oil: yield 25 mg (34%); IR(neat):
~
m 3346 (mN–H), 2934 (mC–H), 1721 (mC@O), 1622
(mO@C–NH, amide I), 1598 (mC@C), 1537 (dN–H,
amide II), 1256, 1113 (mC–O), 698 cmꢀ1 (cCHoop
,
4.16. Methyl 7-[2-(3,4-dichlorophenyl)acetylamino]-2,6,7-
trideoxy-a- and b-D-erythro-hept-3-ulo-1,5-pyranoside
(24a and 24b)
arom.); 1H NMR(CDCl 3): d 2.15–2.27 (m, 1H,
CH2CH2NH), 2.30–2.40 (m, 1H, CH2CH2NH), 3.68–
3.85 (m, 2H, CH2CH2NH), 4.13 (d, J 13.1 Hz, 1H, 4-
H), 4.23 (ddd, J 13.4/7.0/3.8 Hz, 1H, 5-H), 5.49 (d,
J 5.8 Hz, 1H, 2-H), 6.62 (s, broad, 1H, NH), 7.52–
7.38 (m, 3H, arom. H), 7.48 (d, J 5.5 Hz, 1H, 1-H),
7.75–7.79 (m, 2H, arom. H), a signal for the OH-
proton was not observed in the spectrum; C14H15NO4
(261.3). CIMS (isobutane): m/z [%] 262 (MH+, 100).
A solution of acetal 22 (anomeric mixture, 178 mg,
0.42 mmol) and p-toluenesulfonic acid monohydrate
(53 mg, 0.28 mmol) in CH2Cl2 (20 mL) was stirred at
0 ꢁC for 4 h. After completion of the transformation,
the mixture was washed with satd aq NaHCO3

K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 340 (2005) 2483–2493
2493
4.18. 1,5-Anhydro-7-[2-(3,4-dichlorophenyl)acetylamino]-
2,6,7-trideoxy-D-erythro-hept-1-en-3-ulose (26)
Acknowledgements
Financial support of this work by the Deutsche Fors-
chungsgemeinschaft and the Fonds der Chemischen
Industrie is gratefully acknowledged. Thanks are also
due to the Degussa AG for donation of chemicals.
A solution of acetal 22 (anomeric mixture, 152 mg,
0.36 mmol) and p-toluenesulfonic acid monohydrate
(60 mg, 0.32 mmol) in CH2Cl2 (15 mL) was heated to
reflux for 45 min. Then, the mixture was washed with
satd aq NaHCO3 (10 mL). The organic layer was dried
(MgSO4), concentrated in vacuo, and the residue was
purified by FC (2 cm, 95:5 EtOAc–acetone, fractions
2 mL, Rf 0.23). Pale-yellow solid: mp 142 ꢁC; yield
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~
65 mg (53%); IR(neat): m 3286 (mN–H), 1670 (mO@C–
NH, amide I), 1620 (mC@C), 1592 (dN–H, amide II),
1114, 1032 cmꢀ1 (mC–O); 1H NMR(CDCl 3): d 2.03
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1H, CH2CH2NH), 3.46–3.59 (m, 2H, CH2CH2NH),
3.50 (s, 2H, COCH2), 4.00 (d, J 13.1 Hz, 1H, 4-H),
4.09 (ddd, J 13.1/6.7/3.4 Hz, 1H, 5-H), 5.47 (d, J
5.8 Hz, 1H, 2-H), 5.78 (s, broad, 1H, NH), 7.12 (dd,
J 8.2/2.1 Hz, 1H, arom. H, 60-H), 7.29 (d, J 5.8 Hz,
1H, 1-H), 7.38 (d, J 1.8 Hz, 1H, arom. H, 20-H), 7.42
(d, J 8.2 Hz, 1H, arom. H, 50-H), a signal for the
OH-proton was not observed; EIMS: m/z [%] 343/
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345/347 [M+, 5.8/3.4/0.8], 159/161/163 ½–CH2PhClþ;
2
94=60=12Š; CIMS (isobutane): m/z [%] 344/346/348
[MH+, 100/65/13], 310/312 [MH+ꢀCl, 67/24], 274
[Mꢀ2 · Cl, 35]; Anal. Calcd for C15H15Cl2NO4
(344.2): C, 52.34; H, 4.39; N, 4.07. Found: C, 52.17;
H, 4.68; N, 4.02.
9. Hudlicky, M. J. Chem. Educ. 1997, 54, 100–106.
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