Synthesis of novel σ-receptor ligands from methyl α-d-mannopyranoside

Article abstract of DOI:10.1016/j.carres.2006.06.016

For the first time a monosaccharide (methyl α-d-mannopyranoside) has been used as starting material for the synthesis of novel σ-receptor ligands. The hept-3-ulopyranoside dimethyl ketals 14 and 15 were obtained from the nitrile 7 via two synthetic routes

Full text of DOI:10.1016/j.carres.2006.06.016

Carbohydrate Research 341 (2006) 2321–2334
Synthesis of novel r-receptor ligands from methyl
a-D-mannopyranoside
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 23 March 2006; received in revised form 7 June 2006; accepted 22 June 2006
Available online 18 July 2006
Abstract—For the first time a monosaccharide (methyl a-D-mannopyranoside) has been used as starting material for the synthesis of
novel r-receptor ligands. The hept-3-ulopyranoside dimethyl ketals 14 and 15 were obtained from the nitrile 7 via two synthetic
routes. After selective hydrolysis of the ketone dimethyl acetal, various amino substituents were introduced into position 3. High
r1-receptor affinity and selectivity was attained with equatorially arranged amino substituents in position 3 and a dichlorophenyl-
acetamide moiety in position 7. The anomeric mixture of dimethylamines 26a/b displayed the highest r1-receptor affinity
(Ki = 21 nM) within this small series of test compounds.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Keywords: Mannose; 3-Amino-1,5-heptopyranosides; r1-Receptor ligands; Barton–McCombie deoxygenation
1. Introduction
stitution by the amide moiety to yield bicyclic systems,
and reductive removal of the tosyloxy group with hydra-
zine/Br2 ). In all cases very rapid decomposition was
7
r Receptors are involved in several physiological and
pathophysiological events.1 In particular, ligands inter-
acting with r receptors possess a potential as antipsy-
chotics,2 antidepressants,3 anticocaine agents,4 and
antitumor agents.5 In order to find novel r-receptor
ligands, we planned to exploit the synthetic potential
of monosaccharides.
Recently, we have described the synthesis of methyl
hept-3-uloyranosides 1 from methyl a-D-mannopyrano-
side.6 Further transformations of 1, in particular intro-
duction of amino moieties into positions 3 or 4,
turned out to be difficult because of the instability of
the a-hydroxyketone substructure. For example, the
a-hydroxyketone 1 with the 3,4-dichlorophenylacetyl
moiety was transformed into the sulfonates 2 and 3.
However, all attempts to further react the sulfonates 2
and 3 failed to yield the desired products (intermolecular
substitution with NaN3 or Bu4NN3, intramolecular sub-
observed (Scheme 1).
Therefore, we decided to remove the hydroxy group in
position 4 of the mannose-derived building block 1 and
subsequently transform the carbonyl moiety in position
3 into amino substituents. In particular, removal of the
4-OH moiety should lead to the central intermediate 4,
which should give access to amino-substituted oxamor-
phanes 58 and monocyclic amines 6 (Scheme 2).
Cl
O
OH
OH
O
Cl
N
H
4
HO
HO
5
O
RO
(a)
OCH3
O
OCH3
methyl α-D-mannopyranoside
1: R = H
2: R = SO2CH3
3: R = SO2Tol
(b)
*
Scheme 1. Reagents and conditions: (a) H3CSO2Cl, NEt3, CH2Cl2, rt,
Corresponding author. Tel.: +49 251 8333311; fax: +49 251
70%; (b) TsCl, NEt3, DMAP, CH2Cl2, rt, 77%.
8332144; e-mail: wuensch@uni-muenster.de
0008-6215/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2006.06.016

2322
K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 341 (2006) 2321–2334
O
7 with H2 and Raney nickel provided the primary amine
8, which was acylated with (3,4-dichlorophenyl)acetic
acid and 1,10-carbonyldiimidazole (CDI)9 to yield the
amide 9 with the r-pharmacophoric (3,4-dichlorophen-
yl)acetyl residue.10 Deoxygenation of the hydroxy-
acetal 9 was performed according to the method of
Barton and McCombie.11 Thus, acylation of 9 with
1,10-thiocarbonyldiimidazole led to the thionocarba-
mate 10, which was reduced by Bu3SnH in a radical
chain reaction to afford the deoxygenated pyranoside
14. During this sequence (7!8!9!10!14), the ratio
of a to b anomers was about 1:1 (Scheme 3).
N
R
5
1
O
O
4
3
R
N
H
R2N
5
4
α-D-mannose
O
O
X
3
OCH3
R
N
Y
H
O
4
4
3
X,Y: OCH3 or
X/Y: = O
R2N
OCH3
In order to improve the yield of 14 and to gain flexi-
bility, that is, introduction of various acyl residues at a
late stage of the synthesis, the reaction sequence was
changed. At first the Barton–McCombie free-radical
deoxygenation11 was performed by reacting the
hydroxynitrile 7 with 1,10-thiocarbonyldiimidazole to
obtain the thionocarbamate 11. Radical reduction of
the thionocarbamate 11 with Bu3SnH afforded a mix-
ture of products, containing the desired deoxygenated
6
Scheme 2.
2. Results and Discussion
2.1. Chemistry
1
nitrile 12 and the starting hydroxynitrile 7. In the H
Starting with nitrile 7, the synthesis of deoxygenated
pyranosides 14 comprises modification of the cyano
moiety and removal of the hydroxy group in position
4. According to route A (upper reactions) reduction of
NMR spectra of both products, signals indicating Bu3Sn
impurities were observed. Therefore, instead of Bu3SnH,
the reducing agent (Me3Si)3SiH12 was used for the
Cl
O
Route A
NHR
Cl
S
N
O
HO
H
O
(a)
(c)
(d)
N
N
H3CÔ
O
H3CÔ
OCH3
OCH3
Cl
Cl
OCH3
OCH3
10α,β
O
8α,β: R = H
Cl
Cl
O
CN
(b)
N
H
9α,β: R =
O
HO
O
H3CÔ
H3CÔ
OCH3
OCH3
OCH3
OCH3
14α,β
7α,β
S
CN
CN
NH2
(e)
(h)
(i)
(f)
N
(g)
N
O
O
O
O
H3CÔ
H3CÔ
H3CÔ
OCH3
OCH3
OCH3
OCH3
11α,β
OCH3
12α,β
OCH3
13α,β
O
Route B
N
H
7-15
O
α: OCH3 axial
β: OCH3 equatorial
H3CÔ
OCH3
OCH3
15α,β
Scheme 3. Reagents and conditions: (a) H2, Raney nickel, 4.1 bar, MeOH, rt; (b) (dichlorophenyl)acetic acid, CDI, CH2Cl2, rt, 52% (from 7); (c)
S@C(Im)2, toluene, 110 ꢁC, 60%; (d) Bu3SnH, AIBN, toluene 110 ꢁC, 70%; (e) S@C(Im)2, toluene, 110 ꢁC, 90%; (f) (Me3Si)3SiH, AIBN, toluene,
110 ꢁC, 89%; (g) H2, Raney nickel, 4 bar, MeOH, rt, 81%; (h) (dichlorophenyl)acetic acid, CDI, CH2Cl2, rt, 79% (from 12); (i) PhCOCl, NEt3,
CH2Cl2, rt, 73% (from 12).

K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 341 (2006) 2321–2334
2323
O
radical deoxygenation of the thionocarbamate 11. This
reagent led to a clean transformation of 11, and the
deoxygenated nitrile 12 was isolated in 89% yield.
Hydrogenation of the nitrile 12 with H2 and Raney
nickel provided the primary amine 13, which was acyl-
ated with (3,4-dichlorophenyl)acetic acid and CDI9 to
give the deoxygenated (3,4-dichlorophenyl)acetamide
14 in 79% yield over two steps. In this reaction sequence
the ratio of a and b anomers was about 1:1. Comparison
of the synthesis of amide 14 from the hydroxynitrile 7
via route A (upper reactions) and route B (lower reac-
tions) clearly indicates route B giving higher overall
yield (64%) than route A (21%). Moreover, route B
increases the possibilities for generating chemical diver-
sity, since the acyl residue is introduced in the last reac-
tion step. This is demonstrated by acylation of the
primary amine 13 with benzoyl chloride to afford the
benzamide 15.
N
R
X
14,15
5
1
O
Y
(c)
16,17
X,Y: OCH3 or
X/Y: = O
(a)
O
O
R
R
N
H
N
H
(b)
O
O
O
OCH3
O
18α,β
19α,β
20
21
The deoxygenated amides 14 and 15 were thought to
be suitable precursors for the synthesis of bicyclic mor-
phan analogues 16 and 17. However, all attempts to
form the bicyclic N/O-acetals 16 and 17 by reacting 14
and 15 with acids failed. Reaction of the benzamide 15
with p-toluenesulfonic acid at 0 ꢁC led to the ketone
19 by cleavage of the dimethyl acetal. Performing the
same reaction at 20 ꢁC instead of 0 ꢁC provided a mix-
ture of the ketone 19 and the a,b-unsaturated ketone
21. Heating of the benzamide 15 or the ketone 19 with
BF3ÆEt2O in THF also did not yield the bicyclic com-
pound 17, but the a,b-unsaturated ketone 21 instead.
The same observations were made with the analogous
phenylacetamide 14. Treatment of 14 with p-toluenesulf-
onic acid at 0 ꢁC predominantly led to the ketone 18,
while at room temperature a mixture of ketone 18 and
a,b-unsaturated ketone 20 was formed, and heating with
BF3ÆEt2O exclusively yielded the a,b-unsaturated ketone
20. In no case was the bicyclic product 16 detected.
Attempts to deprotonate the secondary amide 20
with KHMDS and initiate an intramolecular Michael
addition also failed to give the bicyclic product 16
(Scheme 4).
The ketones 18 and 19 were used for the introduction
of amino moieties in position 3. At first the phenylacet-
amide 18 was treated with benzylamine and NaBH3CN
in MeOH at pH 6.0.13 Purification of the product by
flash chromatography yielded small amounts of dia-
stereomerically pure benzylamine 22b and a mixture of
the diastereomers 22a, 22b, and 23a. Reductive amina-
tion of the ketone 18 with methylamine and NaBH3CN
led to a mixture of anomers 24a/b and diastereomeri-
cally pure methylamine 25b. With dimethylamine and
NaBH3CN, the ketone 18 was transformed into the
anomeric mixture 26a/b bearing the amino moiety in
an equatorial position (Scheme 5).
Cl
Cl
14,16,18,20: R =
15,17,19,21: R =
α: OCH3 axial
β: OCH3 equatorial
Scheme 4. Reagents and conditions: (a) TsOH, CH2Cl2, 0 ꢁC, 18: 63%,
19: 91%; (b) BF3ÆOEt3, THF, 65 ꢁC, 21: 64%; (c) BF3ÆOEt2, THF,
65 ꢁC, 20: 86%.
NaBH3CN resulted in a mixture of products, from
which the a anomer 29a with an axially oriented benz-
ylamino group was isolated in 27% yield. After reductive
amination with dimethylamine and NaBH3CN, an ano-
meric mixture of tertiary amines 30a/b bearing an equa-
torially oriented amino moiety was isolated.
2.2. Receptor-binding studies
The affinities of the mannose-derived amines 22b, 24a/b,
25b, 26a/b, 29a, and 30a/b toward r1 and r2 receptors
were determined in receptor-binding studies using radio-
ligands with high affinity and selectivity to the corre-
sponding receptors. In the r1 assay the radioligand
[3H]-(+)-pentazocine was used. Since a selective radio-
ligand for labeling of r2 receptors is not commercially
available, the nonselective radioligand, [3H]-ditolylgua-
nidine, was employed in the presence of nontritiated
(+)-pentazocine to mask the r1 receptors. Membrane
preparations from guinea pig brains were used in the
r1 assay, and rat liver preparations served as receptor
material in the r2 assay.14 In addition to the r1 and
r2 receptor affinity, the receptor selectivity of some com-
pounds was investigated by determination of the affinity
to the phencyclidine binding site of the NMDA receptor
([3H]-(+)-MK-801]),15 to j-opioid ([3H]-U-69593), and
l-opioid receptors ([3H]-DAMGO)16 with receptor-
binding studies.
The reductive amination of benzamido ketone 19 gave
very similar results. Reaction with benzylamine and
In Table 1 the results of the receptor-binding studies
toward r1 and r2 receptors are summarized. Three of

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K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 341 (2006) 2321–2334
Cl
Cl
Cl
Cl
Cl
Cl
O
O
O
N
H
N
H
N
H
(a)
+
O
O
O
R2N
OCH3
OCH3
OCH3
O
NR2
18α,β
22α,β
24α,β
26α,β
23α,(β)
25(α),β
(27α,β)
O
O
O
N
H
N
H
N
H
(a)
+
O
O
O
R2N
OCH3
OCH3
O
OCH3
NR2
19α,β
(28α,β)
30α,β
29α,(β)
(31α,β)
22,23,28,29: NR2 = NHBn
24,25: NR2 = NHCH3
26,27,30,31: NR2 = N(CH3)2
α: OCH3 axial
β: OCH3 equatorial
˚
Scheme 5. Reagents and conditions: (a) BnNH2 or CH3NH2 or (H3C)2NH, MeOH, 3 A MS, NaBH3CN, rt.
Table 1. r-Receptor affinity
the tertiary amine 26a/b is 21 nM. The corresponding
secondary amine 24a/b is threefold less active. Exchange
of the methyl group for a benzyl moiety leads to the
secondary benzyl amine 22b (only one anomer), which
displays almost the same r1-receptor affinity as the
methylamine 24a/b.
The r2-receptor affinity (Table 1) of all test com-
pounds is very low, indicating high r1-receptor selectiv-
ity of these ligands. That means that the compounds
with high r1-receptor affinity (22b, 24a/b, 26a/b) repre-
sent selective r1-receptor ligands.
Compound
r1
r2
Ki SEM (nM)
n = 3
Ki SEM (nM)
n = 3
22b
83 32
2520 960
IC50 >10 lMb
IC50 >10 lMb
IC50 >10 lMb
6120 2760
IC50 >10 lMb
n.d.c
24a/b
25b
26a/b
29a
69
1420 281
21
250 115
5
1
a
30a/b
—
(
)-Pentazocine
3.58 0.20
2.20 0.31
n.d.c
Haloperidol
Ditolylguanidine
34.2 2.3
63.9 10.8
Since ligands for r1 receptors are often very similar to
ligands for the phencyclidine (PCP) binding site of the
NMDA receptor,17 for j-opioid receptors,17,18 and for
l-opioid receptors17 the affinity of these mannose-de-
rived r1-receptor ligands toward these receptor systems
was also investigated. At a concentration of 10 lM, all
test compounds did not significantly interact with the
PCP binding site, with j-opioid receptors and with l-
opioid receptors, indicating Ki values greater than
10 lM. Obviously the novel high-affinity mannose-de-
rived r1-receptor ligands 22b, 24a/b, and 26a/b display
high selectivity against r2 receptors, j-opioid receptors,
l-opioid receptors, and the phencyclidine binding site of
the NMDA receptor.
a At a test concentration of 100 nM, binding of the radioligand was not
significantly reduced (IC50 >100 nM).
b At a test concentration of 10 lM, binding of the radioligand was not
significantly reduced (IC50 >10 lM).
c n.d. = not determined.
the investigated compounds (22b, 24a/b, 26a/b) reveal
high affinity to r1 receptors, and the corresponding Ki
values are below 100 nM. These high-affinity ligands
are substituted with equatorially oriented amino moie-
ties. Analogues with axially arranged amino substitu-
ents, for example, 25b, display considerably lower
affinity. The data clearly indicate that the dichlorophen-
ylacetyl residue is crucial for high r1-receptor affinity,
since the corresponding benzamide derivatives 29a and
30a/b display significantly lower affinities.
3. Conclusions
The most r1-active compound in this series is the ano-
meric mixture 26a/b bearing an equatorially oriented
dimethylamino moiety in position 3. The Ki-value of
Starting with the monosaccharide, methyl a-D-manno-
pyranoside, the synthesis of a small series of 3-amino-

K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 341 (2006) 2321–2334
2325
substituted heptopyranosides with an attached r-phar-
macophoric dichlorophenylacetyl residue is described.
It was shown that some of the prepared compounds
represent highly active r1-receptor ligands, the dimeth-
ylamine 26a/b showing the highest r1-receptor affinity
(Ki = 21 nM). Within this small series of amines it was
demonstrated that the 3,4-dichlorophenylacetyl residue
and the equatorial orientation of the amino moiety in
position 3 are crucial for high r1-receptor affinity.
Compounds with tertiary amines give lower Ki values
than analogues with secondary amino groups. The
highly active compounds are very selective for r1
receptors. In this project it has been shown for the first
time that a monosaccharide (methyl a-D-mannopyr-
anoside) can be used as a building block for the synthe-
sis of novel drugs with high r1-receptor affinity and
selectivity.
ture was stirred at room temperature for 30 h. Then the
solvent was evaporated in vacuo. The residue was puri-
fied by FC (2 cm, 95:5 EtOAc–acetone, fractions 2 mL,
Rf 0.45) to give 2 (151 mg (70%)) as a colorless solid:
~
mp 115 ꢁC; IR (ATR, neat): m 3271 (mN–H), 1734
(mC@O), 1638 (mO@C–NH, amide I), 1566 (dN–H,
amide II), 1310, 1171, 1033 cmꢀ1 (mC–O); 1H NMR
(CDCl3): d 1.79–1.94 (m, 1H, CH2CH2NH, a+b-is.),
1.96–2.13 (m, 1H, CH2CH2NH, a+b-is.), 2.66 (dd, J
14.3/9.3 Hz, 0.45H, 2-Hax, b-is.), 2.75 (dd, J 14.3/
4.1 Hz, 0.55H, 2-Hax, a-is.), 2.82 (d, J 14.0 Hz, 0.55H,
2-Heq, a-is.), 2.95 (dd, J 14.3/2.6 Hz, 0.45H, 2-Heq, b-
is.), 3.14–3.77 (m, 2H, CH2CH2NH, a+b-is./5-H, b-
is.), 3.25 (s, 3 · 0.55H, OSO2CH3, a-is.), 3.26 (s,
3 · 0.45H, OSO2CH3, b-is.), 3.49 (s, 3 · 0.45H, OCH3,
b-is.), 3.50 (s, 3 · 0.55H, OCH3, a-is.), 3.51 (s,
2 · 0.45H, COCH2Ph, b-is.), 3.53 (s, 2 · 0.55H,
COCH2Ph, a-is.), 3.94–4.42 (m, 0.55H, 5-H, a-is.),
4.56 (dd, J 9.2/2.4 Hz, 0.45H, 1-Hax, b-is.), 4.65 (d, J
10.1 Hz, 0.45H, 4-H, b-is.), 4.79 (d, J 10.1 Hz, 0.55H,
4-H, a-is.), 4.93 (d, J 4.0 Hz, 0.55H, 1-Heq, a-is.), 5.65
(s, br, 0.45H, NH, b-is.), 5.78 (s, br, 0.55H, NH, a-is.),
7.12 (dd, J 8.2/2.1 Hz, 0.45H, arom. H, 60-H, b-is.),
7.13 (dd, J 8.2/2.1 Hz, 0.55H, arom. H, 60-H, a-is.),
7.38 (d, J 2.1 Hz, 0.45H, arom. H, 20-H, b-is.), 7.39 (d,
J 2.1 Hz, 0.55H, arom. H, 20-H, a-is.), 7.42 (d, J
8.2 Hz, 0.45H, arom. H, 50-H, b-is.), 7.43 (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 [%] 325/327/329
4. Experimental
4.1. Chemistry, general
Unless otherwise noted, moisture-sensitive reactions
were conducted under dry nitrogen. THF was distilled
from sodium–benzophenone ketyl prior to use. Petro-
leum ether used refers to the fraction boiling at 40–
60 ꢁC. Thin-layer chromatography (TLC): Silica Gel
60 F254 plates (E. Merck). Flash chromatography
(FC):19 Silica Gel 60, 0.040–0.063 mm (E. Merck);
parentheses include: Diameter of the column [cm], elu-
ent, fraction size [mL] and Rf. Melting points (mp’s)
were determined on a melting-point apparatus SMP2
(Stuart Scientific), and the mp’s are uncorrected. Optical
rotation: Polarimeter 241 (Perkin–Elmer); 1.0-dm tube;
concentration c [g/100 mL]; temperature 20 ꢁC. Elemen-
tal analyses: Vario EL (Elementaranalysesysteme
GmbH). MS: MAT 312, MAT 8200, MAT 44, and
TSQ 7000 (Finnigan); EI, electron impact; CI, chemical
ionization. High-resolution MS (HRMS): MAT 8200
(Finnigan). IR: 1605 FTIR spectrometer (Perkin–
[MꢀHOCH3ꢀCH3SO2OH,
11/7/1],
159/161/163
[–CH2PhCl2þ, 100/59/11], 79 [–CH3SO2þ, 33]; CIMS
(NH3): m/z [%] 454/456/458 [MH+, 53/30/6], 422/424/
426 [MꢀOCH3, 60/41/7], 328/330/332 [MꢀCH3SO2O,
100/44/11]. Anal. Calcd for C17H21Cl2N1O7S (454.3):
C, 44.94; H, 4.66; N, 3.08. Found: C, 44.47; H, 4.36;
N, 2.94.
4.3. Methyl 2,6,7-trideoxy-7-[(3,4-dichlorophenyl)acetyl-
amino]-4-O-p-toluenesulfonyl-a- and b-D-erythro-1,5-
hept-3-ulopyranoside (3)
1
Elmer), (br, broad; m, medium; s, strong). H NMR
Ketone 16 (mixture of anomers, 270 mg, 0.72 mmol) was
dissolved in CH2Cl2 (25 mL). Then p-toluenesulfonyl
chloride (953 mg, 5.0 mmol), Et3N (1.3 mL, 9.3 mmol),
and 4-(dimethylamino)pyridine (DMAP, 641 mg,
5.2 mmol) were added at 0 ꢁC (ice cooling). The mixture
was stirred at 0 ꢁC for 10 min and at room temperature
for 16 h. Then the reaction mixture was washed with N
HCl (20 mL) and satd aq NaHCO3 (20 mL). The organ-
ic layer was dried (MgSO4) and concentrated in vacuo.
The residue was purified by FC (2 cm, 80:20 EtOAc–
petroleum ether, fractions 5 mL, Rf 0.43) to give 3
(294 mg (77%) as a pale-yellow solid: mp 66 ꢁC; IR
(300 MHz), 13C NMR (75 MHz): Unity 300 FT NMR
spectrometer (Varian); d in parts per million relative to
tetramethylsilane; coupling constants are given with
0.5-Hz resolution; the assignments of 13C and of 1H
NMR signals were supported by 2D NMR techniques.
4.2. Methyl 2,6,7-trideoxy-7-[(3,4-dichlorophenyl)acetyl-
amino]-4-O-methanesulfonyl-a- and b-D-erythro-1,5-
hept-3-ulopyranoside (2)
Ketone 16 (mixture of anomers, 192 mg, 0.51 mmol) was
dissolved in CH2Cl2 (30 mL) under an N2 atmosphere.
At 0 ꢁC, methanesulfonyl chloride (0.2 mL, 2.5 mmol)
and Et3N (0.5 mL, 3.6 mmol) were added, and the mix-
~
(ATR, neat): m 3293 (mN–H), 2933 (mC–Hꢀ),1 1369 (R–
SO2–OR0), 1173, 1055 (mC–O), 811, 662 cm (cCHoop
,
arom.); 1H NMR (CDCl3): d 1.77–1.89 (m, 1H,

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K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 341 (2006) 2321–2334
CH2CH2NH, a+b-is.), 2.00–2.18 (m, 1H, CH2CH2NH,
a+b-is.), 2.45 (s, 3H, PhCH3, a+b-is.), 2.60 (d, J
14.6 Hz, 0.6H, 2-Heq, a-is.), 2.61 (dd, J 14.0/9.2 Hz,
0.4H, 2-Hax, b-is.), 2.70 (dd, J 14.3/4.3 Hz, 0.6H, 2-
Hax, a-is.), 2.77 (dd, J 14.9/2.4 Hz, 0.4H, 2-Heq, b-is.),
3.20 (s, 3 · 0.6H, OCH3, a-is.), 3.26–3.61 (m, 2H,
CH2CH2NH, a+b-is./0.4H, 5-H, b-is.), 3.49 (s,
2 · 0.4H, COCH2Ph, b-is.), 3.50 (s, 3 · 0.4H, OCH3,
b-is.), 3.52 (s, 2 · 0.6H, COCH2Ph, a-is.), 3.96 (td, J
9.2/2.7 Hz, 0.6H, 5-H, a-is.), 4.51 (dd, J 8.9/2.4 Hz,
0.4H, 1-Hax, b-is.), 4.79 (d, J 10.1 Hz, 0.4H, 4-H, b-
is.), 4.80 (d, J 10.1 Hz, 0.6H, 4-H, a-is.), 4.88 (d, J
3.7 Hz, 0.6H, 1-Heq, a-is.), 5.78 (s, br, 0.4H, NH, b-
is.), 5.88 (s, br, 0.6H, NH, a-is.), 7.11–7.15 (m, 1H,
arom. H, 60-H, a+b-is.), 7.33–7.44 (m, 2H, arom. H,
Ts–H, m-pos., a+b-is./1H, arom. H, 50-H, a+b-is./1H,
arom. H, 20-H, a+b-is.), 7.86 (d, J 8.2 Hz, 2 · 0.4H,
arom. H, Ts–H, o-pos., b-is.), 7.87 (d, J 8.2 Hz,
2 · 0.6H, arom. H, Ts–H, o-pos., a-is.); the ratio of a
and b anomers was 60:40; C23H25Cl2NO7S (530.2);
EIMS: m/z [%] 496/498/500 [MꢀHOCH3, 12/8/2],
479/481/483 [MꢀHOCH3ꢀOH, 11/7/1.5], 159/161/163
[–CH2PhCl2þ, 46/27/6], 155 [–SO2PhCH3þ, 42].
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, 3], 88
[CðOCH3Þ2–CH2þ–, 100]; CIMS (NH3): m/z [%] 236
[MH+, 17], 204 [MꢀOCH3, 100]; HREIMS: calcd for
C9H18NO5: 220.1185; found: 220.1185.
4.5. Preparation of methyl 2,6,7-trideoxy-7-[2-(3,4-
dichlorophenyl)acetylamino]-a- and b-D-erythro-1,5-hept-
3-ulopyranoside dimethyl ketal (9a/b)6
Under an N2 atmosphere, a solution of (3,4-dichloro-
phenyl)acetic acid (540 mg, 2.6 mmol) and 1,10-carbon-
yldiimidazole (420 mg, 2.6 mmol) in CH2Cl2 (15 mL)
was stirred at room temperature for 1 h. Then the unpu-
rified primary amine 8a/b (498 mg, 2.1 mmol) dissolved
in CH2Cl2 (10 mL) was added dropwise to the mixture
under ice cooling. The mixture was stirred at room tem-
perature for 6 h. After completion of the transforma-
tion, 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
~
4.4. Preparation of methyl 7-amino-2,6,7-trideoxy-a- and
(52% referring to the nitrile 7a/b) of 9a/b; IR (neat): m
b-D-erythro-1,5-hept-3-ulopyranoside dimethyl ketal (8a/
3301 (mN–H), 2942 (mC–H), 1647 (mO@C–NH, amide
I), 1552 (dN–H, amide II), 1129, 1048 cmꢀ1 (mC–O);
1H NMR (CDCl3): d 1.49 (dd, J 14.0/9.8 Hz, 0.5H, 2-
Hax, 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, br, 0.5H, NH, a/b-is.), 6.13 (s, br, 0.5H, NH,
a/b-is.), 7.12 (dd, J 8.2/2.1 Hz, 0.5H, arom. 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 50:50; 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.
b)6
To a solution of 7a/b (0.72 g, 3.1 mmol) in MeOH
(60 mL) and 5 N NaOH (15 mL), Raney nickel was
added, and the mixture was shaken under an H2 atmo-
sphere (4.1 bar) at room temperature for 24 h. The
Raney nickel was removed by filtration through
CeliteꢂAFA. 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 or-
ganic layer was dried (MgSO4) and concentrated in
vacuo to yield a yellow oil (0.70 g, 97%), which was pure
enough for further reactions. In order to characterize
the primary amine 8a/b, a sample (103 mg) of the resi-
due was purified by FC [2 cm, 80:20 ethanol–acetone,
2% N-ethyl-N,N-dimethylamine, fractions 5 mL, Rf
0.11] to yield 8a/b (17 mg, <10%): IR (neat): ~m 2945
1
(mC–H), 1128, 1053 cmꢀ1 (mC–O); H NMR (CDCl3):
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/

K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 341 (2006) 2321–2334
2327
4.6. Methyl 2,6,7-trideoxy-7-[(3,4-dichlorophenyl)acet-
ylamino]-4-O-(imidazol-1-ylthiocarbonyl)-a- and b-D-
erythro-1,5-hept-3-ulopyranoside dimethyl ketal (10a/b)
27 h. After completion of the reaction, the mixture was
extracted with N HCl (20 mL). The organic layer was
separated, and the aqueous layer was extracted with
EtOAc (50 mL). The organic layers were dried (MgSO4)
and concentrated in vacuo. The residue was purified by
FC (3 cm, EtOAc, fractions 10 mL, Rf 0.57) to give 11a/
Under N2, 1,10-thiocarbonyldiimidazole (380 mg,
2.1 mmol) was added to a solution of 9a,b (160 mg,
0.38 mmol) in toluene (15 mL). The mixture was heated
to reflux for 21 h. After completion of the reaction, the
mixture was extracted with N HCl (10 mL). The organic
layer was separated, and the aqueous layer was ex-
tracted with EtOAc (20 mL). The organic layers were
dried (MgSO4) and evaporated in vacuo. The residue
was purified by FC (2 cm, 70:30 EtOAc–acetone, frac-
tions 5 mL, Rf 0.39) to give 10a/b (121 mg, 60%) as a
~
b (931 mg, 90%) as a yellow oil: IR (ATR, film): m 2923
(mC–H), 1226 (mC@S), 1285, 1048 cmꢀ1 (mC–O); 1H
NMR (CDCl3): d 2.02–2.15 (m, 1.5H, 2-Heq, b-is./
2-Heq, a-is./2-Hax, b-is.), 2.21 (dd, J 14.3/3.7 Hz, 0.5H,
2-Hax, a-is.), 2.71 (dd, J 16.9/4.7 Hz, 0.5H, CH2CN, a/
b-is.), 2.79 (dd, J 16.8/5.2 Hz, 0.5H, CH2CN, a/b-is.),
2.87 (dd, J 16.8/9.2 Hz, 0.5H, CH2CN, a/b-is.), 3.00
(dd, J 16.8/8.9 Hz, 0.5H, CH2CN, a/b-is.), 3.24 (s,
3 · 0.5H, OCH3, a/b-is.), 3.25 (s, 3 · 0.5H, OCH3, a/
b-is.), 3.25 (s, 3 · 0.5H, OCH3, a/b-is.), 3.27 (s,
3 · 0.5H, OCH3, a/b-is.), 3.47 (s, 3 · 0.5H, OCH3, a/
b-is.), 3.51 (s, 3 · 0.5H, OCH3, a/b-is.), 4.32 (dt, J 8.9/
5.3 Hz, 0.5H, 5-H, a/b-is.), 4.48 (dt, J 9.2/5.3 Hz,
0.5H, 5-H, a/b-is.), 4.76 (dd, J 9.2/4.6 Hz, 0.5H, 1-
Hax-b), 4.80 (d, J 3.7 Hz, 0.5H, 1-Heq-a), 5.54 (d, J
5.8 Hz, 0.5H, 4-H, a/b-is.), 5.62 (dd, J 5.8/0.9 Hz,
0.5H, 4-H, a/b-is.), 7.05 (t, J 0.9 Hz, 0.5H, imidazole-
H, 20-H, a/b-is.), 7.05 (t, J 0.9 Hz 0.5H, imidazole-H,
20-H, a/b-is.), 7.61 (t, J 1.5 Hz, 0.5H, imidazole-H, 40-
H, a/b-is.), 7.63 (t, J 1.5 Hz, 0.5H, imidazole-H, 40-H,
a/b-is.), 8.31 (t, J 0.9 Hz, 0.5H, imidazole-H, 50-H, a/
b-is.), 8.34 (t, J 0.9 Hz, 0.5H, imidazole-H, 50-H, a/b-
is.); the ratio of the a and b anomers was 50:50; 13C
NMR (CDCl3): d 20.4 (0.5C, CH2CN), 21.9 (0.5C,
CH2CN), 35.0 (0.5C, C-2), 35.1 (0.5C, C-2), 48.7
(0.5C, OCH3), 49.0 (0.5C, OCH3), 49.2 (1C, OCH3),
56.1 (0.5C, OCH3), 56.9 (0.5C, OCH3), 76.7 (0.5C, C-
5), 70.0 (0.5C, C-5), 79.1 (0.5C, C-4), 79.1 (0.5C, C-4),
96.7 (0.5C, C-1-o C-3), 97.0 (0.5C, C-3-o C-1), 98.2
(0.5C, C-1-o C-3), 100.0 (0.5C, C-3-o C-1), 118.1
(0.5C, CH2CN), 118.2 (0.5C, CH2CN), 131.2 (1C, imid-
azole-C), 131.3 (1C, imidazole-C), 136.9 (0.5C, imid-
azole-C), 137.0 (0.5C, imidazole-C), 182.9 (0.5C, S@C),
183.0 (0.5C, S@C); CIMS (isobutane): m/z [%] 398
[M+C4H9þ, 11], 342 [MH+, 100], 311 [MH+ꢀOCH3,
11]; Anal. Calcd for C14H19N3O5S (341.4): C, 49.26;
H, 5.61; N, 12.31; S, 9.39. Found: C, 49.19; H, 5.51;
N, 12.82; S, 8.78.
~
pale-yellow oil: IR (ATR, film): m 3286 (mN–H), 2940
(mC–H), 1648 (mO@C–NH, amide I), 1554 (dN–H of
amide II), 1227 (mC@S), 1111, 1004 (mC–O), 734,
1
654 cmꢀ1 (cCHoop, arom.); H NMR (CDCl3): d 1.50–
1.92 (m, 2H, CH2CH2NH, a+b-is.), 1.76 (dd, J 13.7/
8.6 Hz, 0.45H, 2-Hax, b-is.), 2.09 (d,
J 4.6 Hz,
2 · 0.55H, 2-Heq, a-is.+2-Hax, a-is.), 2.33 (dd, J 13.7/
2.1 Hz, 0.45H, 2-Heq, b-is.), 3.16–3.65 (m, 2H,
CH2CH2NH, a+b-is.), 3.22 (s, 3 · 0.45H, OCH3, b-
is.), 3.22 (s, 3 · 0.55H, OCH3, a-is.), 3.23 (s, 3 · 0.55H,
OCH3, a-is.), 3.32 (s, 3 · 0.55H, OCH3, a-is.), 3.33 (s,
3 · 0.45H, OCH3, b-is.), 3.44 (s, 3 · 0.45H, OCH3, b-
is), 3.46 (s, 2 · 0.45H, COCH2Ph, b-is.), 3.47 (s,
2 · 0.55H, COCH2Ph, a-is.), 3.81–3.89 (m, 0.45H, 5-H,
b-is.), 4.14–4.20 (m, 0.55H, 5-H, a-is.), 4.58 (dd, J 8.6/
2.4 Hz, 0.45H, 1-Hax, b-is.), 4.60 (t, J 4.6 Hz, 0.55H,
1-Heq, a-is.), 4.48 (d, J 5.8 Hz, 0.45H, 4-H, b-is.), 4.63
(d, J 8.6 Hz, 0.55H, 4-H, a-is.), 5.76 (s, br, 0.45H,
NH, b-is.), 5.83 (s, br, 0.55H, NH, a-is.), 7.05–7.07
(m, 1H, imidazole-H, 200-H, a+b-is.), 7.10 (dd, J 8.2/
1.2 Hz, 1H, arom. H, 60-H, a+b-is.), 7.36 (s, br, 1H,
arom. H, 20-H, a+b-is.), 7.40 (dd, J 8.2/1.2 Hz, 1H,
arom. H, 50-H, a+b-is.), 7.60 (t, 0.45H, J 1.5 Hz, imid-
azole-H, pos. 400-H, b-is.), 7.62 (t, 0.55H, J 1.5 Hz, imid-
azole-H, pos. 400-H, a-is.), 8.33 (t, J 1.2 Hz, 0.45H,
imidazole-H, 500-H, b-is.), 8.35 (t, J 0.9 Hz, 0.55H, imid-
azole-H, 500-H, a-is.); the ratio of a and b anomers was
55:45; EIMS: m/z [%] 111 [thiocarbonyliimidazole, 20],
88 [–CðOCH3Þ2–CH2þ–, 50]; CIMS (isobutane): m/z
[%] 532/534/536 [MH+, 11.4/7.1/1.6], 342/344/346
[M+ꢀthiocarbonylimidazoleꢀ2 · OCH3,
67/37/9].
Anal. Calcd for C22H27Cl2N3O6S (532.4): C, 49.63; H,
5.11; N, 7.89; S. 6.02. Found: C, 48.99; H, 5.35; N,
8.20; S, 5.85.
4.8. Methyl 6-cyano-2,4,6-trideoxy-a- and b-D-glycero-
1,5-hex-3-ulopyranoside dimethyl ketal (12a/b)
Under N2, tris(trimethylsilyl)silane (0.9 mL, 2.9 mmol)
and AIBN (0.08 g, 0.49 mmol) were added to a solution
of 11a/b (787 mg, 2.3 mmol) in toluene (20 mL). The
mixture was heated to reflux for 7 h. Then the solvent
was concentrated in vacuo. The residue was purified
by FC (3 cm, 50:50 petroleum ether–EtOAc, fractions
10 mL, Rf 0.52) to give 12a/b (441 mg, 89%) as a yellow
4.7. Methyl 6-cyano-2,6-dideoxy-4-O-(imidazol-1-ylthio-
carbonyl)-a- and b-D-erythro-1,5-hex-3-ulopyranoside
dimethyl ketal (11a/b)
Under N2, thiocarbonyldiimidazole (2.9 g, 16.3 mmol)
was added to a solution of 7a/b (750 mg, 3.2 mmol) in
toluene (40 mL). The mixture was heated to reflux for
~
oil: IR (ATR, film): m 2942 (mC–H), 2250 (mCN), 1121,

2328
K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 341 (2006) 2321–2334
1047 cmꢀ1 (mC–O); H NMR (CDCl3): d 1.33–1.51 (m,
1H, 2-Hax, a-is.+2-Hax, b-is.), 1.69 (dd, J 14.3/4.6 Hz,
1H, 2-Heq, a-is.+2-Heq, b-is.), 2.03–2.25 (m, 2H, 4-
Hax+4-Heq, a+b-is.), 2.52–2.62 (m, 2H, CH2CN, a+b-
is.), 3.18 (s, 3 · 0.35H, OCH3, a-is.), 3.18 (s, 3 · 0.65H,
OCH3, b-is.), 3.20 (s, 3 · 0.35H, OCH3, a-is.), 3.21 (s,
3 · 0.65H, OCH3, b-is.), 3.37 (s, 3 · 0.35H, OCH3, a-
is.), 3.50 (s, 3 · 0.65H, OCH3, b-is.), 3.82 (dddd, J
11.6/6.7/6.1/2.4 Hz, 0.65H, 5-H, b-is.), 4.15 (dtd, J
11.9/6.1/2.1 Hz, 0.35H, 5-H, a-is.), 4.46 (dd, J 9.8/
2.4 Hz, 0.65H, 1-Hax, b-is.), 4.82 (d, J 4.0 Hz, 0.35H,
1-Heq, a-is.); 13C NMR (CDCl3): d 23.9 (0.65C,
CH2CN), 24.0 (0.35C, CH2CN), 35.3 (0.35C, C-2),
37.5 (0.65C, C-2), 37.8 (0.35C, C-4), 38.0 (0.65C, C-4),
47.1 (0.35C, OCH3), 47.7 (0.65C, OCH3), 47.8 (0.65C,
OCH3), 48.4 (0.35C, OCH3), 55.4 (0.35C, OCH3), 56.5
(0.65C, OCH3), 62.7 (0.35C, C-5), 67.1 (0.65C, C-5),
97.3 (0.35C, C-1-o C-3), 98.4 (0.65C, C-1-o C-3), 99.0
(0.35C, C-3-o C-1), 100.7 (0.65C, C-3-o C-1), 116.7
(0.65C, CH2CN), 116.9 (0.35C, CH2CN); the ratio of
a and b anomers was 35:65; EIMS: m/z [%] 184 [Mꢀ
OCH3, 46], 175 [MꢀCH2CN, 4], 152 [MꢀHOCH3ꢀ
OCH3, 44], 88 [–CðOCH3Þ2–CH2þ–, 60]; CIMS (NH3):
m/z [%] 233 [M+NH4þ, 32], 184 [MꢀOCH3, 8], 152
[MꢀHOCH3ꢀOCH3, 100]; Anal. Calcd for C10H17-
NO4 (215.3): C, 55.80; H, 7.96; N, 6.51. Found: C,
55.31; H, 7.99; N, 6.22.
HOCH3ꢀOCH3, 59]; CIMS (NH3): m/z [%] 220
[MH+, 100], 188 [MꢀOCH3, 50], 156 [MꢀHOCH3ꢀ
OCH3, 44].
1
4.10. Methyl 2,4,6,7-tetradeoxy-7-[(3,4-dichlorophenyl)-
acetylamino]-a- and b-D-glycero-1,5-hept-3-ulopyr-
anoside dimethyl ketal (14a/b)
4.10.1. Method A. Under N2, Bu3SnH (0.1 mL,
0.38 mmol) and AIBN (2 mg, 0.01 mmol) were added
to a cooled (ice) solution of thiocarbamate 10a/b
(52 mg, 0.10 mmol) in toluene (8 mL). The mixture
was heated under reflux for 29 h. Then the solvent was
evaporated in vacuo, and the residue was purified by
FC [2 cm, 80:20 EtOA–acetone, fractions 5 mL, Rf
0.27] to give 14a/b (28 mg, 70%).
4.10.2. Method B. Under N2, (3,4-dichlorophenyl)ace-
tic acid (788 mg, 3.8 mmol) was dissolved in CH2Cl2
(15 mL). 1,10-Carbonyldiimidazole (625 mg, 3.9 mmol)
was added, and the mixture was stirred at room temper-
ature for 1 h. Then a solution of unpurified primary
amine 13a/b (633 mg, 2.9 mmol) in CH2Cl2 (10 mL)
was added slowly under ice cooling. The mixture was
stirred at room temperature for 6 h. The solvent was
evaporated in vacuo, and the residue was purified by
FC (3 cm, 95:5 EtOAc–acetone, fractions 10 mL, Rf
0.44) to give 14a/b (1.2 g, 79% based on the nitrile
~
4.9. Methyl 7-amino-2,4,6,7-tetradeoxy-a- and b-D-
glycero-1,5-hept-3-ulopyranoside dimethyl ketal (13a/b)
12a/b) as a yellow oil: IR (ATR, film): m 2940 (mC–H),
1645 (mO@C–NH, amide I), 1552 (dN–H, amide II),
1119, 1047 cmꢀ1 (mC–O); 1H NMR (CDCl3): d 1.22–
1.41 (m, 0.45H, 2-Hax, a-is.), 1.29 (d, J 13.1 Hz,
0.45H, 2-Heq, a-is.), 1.32 (dd, J 13.4/1.8 Hz, 0.55H, 2-
Heq, b-is.), 1.37 (dd, J 13.1/9.8 Hz, 0.55H, 2-Hax, b-
is.), 1.50–1.84 (m, 2H, CH2CH2NH, a+b-is.), 1.86–
1.94 (m, 1H, 4-Hax/4-Heq, a+b-is.), 2.15–2.23 (m, 1H,
4-Hax/4-Heq, a+b-is.), 3.16 (s, 3 · 0.45H, OCH3, a-is.),
3.16 (s, 3 · 0.55H, OCH3, b-is.), 3.18 (s, 3 · 0.45H,
OCH3, a-is.), 3.18 (s, 3 · 0.45H, OCH3, a-is.), 3.20 (s,
3 · 0.55H, OCH3, b-is.), 3.23–3.37 (m, 1H,
CH2CH2NH, a+b-is.), 3.41–3.66 (m, 1H, CH2CH2NH,
a+b-is./0.55H, 5-H, b-is.), 3.43 (s, 3 · 0.55H, OCH3,
b-is.), 3.47 (s, 2 · 0.55H, COCH2Ph, b-is.), 3.50 (s,
2 · 0.45H, COCH2Ph, a-is.), 3.85–3.94 (m, 0.45H, 5-H,
a-is.), 4.37 (dd, J 9.8/2.1 Hz, 0.55H, 1-Hax, b-is.), 4.54
(d, J 4.6 Hz, 0.45H, 1-Heq, a-is.), 5.98 (s, br, 0.55H,
NH, b-is.), 6.16 (s, br, 0.45H, NH, a-is.), 7.11 (dd, J
8.2/2.1 Hz, 0.45H, arom. H, 60-H, a-is.), 7.12 (dd, J
8.2/1.8 Hz, 0.55H, arom. H, 60-H, b-is.), 7.36 (d, J
2.4 Hz, 0.45H, arom. H, 20-H, a-is.), 7.37 (d, J 2.1 Hz,
0.55H, arom. H, 20-H, b-is.), 7.41 (d, J 8.2 Hz, 0.55H,
arom. H, 50-H, b-is.), 7.42 (d, J 8.2 Hz, 0.45H, arom.
H, 50-H, a-is.); the ratio of a and b anomers was
45:55; 13C NMR (CDCl3): d 34.1 (0.55C, CH2CH2NH),
34.4 (0.45C, CH2CH2NH), 35.5 (0.55C, C-4), 37.1
(0.45C, CH2CH2NH), 37.6 (0.55C, CH2CH2NH), 37.9
A mixture of nitrile 12a/b (1.1 g, 5.3 mmol), MeOH
(40 mL), 2 N NaOH (15 mL), and Raney nickel was
shaken under an H2 atmosphere (4 bar) at room temper-
ature for 24 h. Then the Raney nickel was separated by
filtration through CeliteꢂAFA, the solvent was evapo-
rated, and after addition of water (10 mL), the mixture
was extracted with CH2Cl2 (4 · 25 mL). The organic
layer was dried (MgSO4) and concentrated in vacuo.
The resulting crude 13a/b (yellow oil, 929 mg, 81%)
was used for the next reaction without further purifica-
~
tion. C10H21NO4 (219.3); IR (ATR, film): m 3356 (mN–
H), 2926 (mC–H), 1657 (dN–H), 1342, 1172, 1042 cmꢀ1
1
(mC–O); H NMR (CDCl3): d 1.23–1.39 (m, 1H, 2-Hax,
a+b-is./0.6H, 2-Heq, b-is.), 1.41 (s, 2H, CH2CH2NH2,
a+b-is.), 1.51–1.74 (m, 2H, CH2CH2NH2, a+b-is./
0.4H, 2-Heq, a-is.), 1.85–1.95 (m, 1H, 4-Hax, a+b-is.),
2.12–2.19 (m, 1H, 4-Heq, a+b-is.), 2.75–2.85 (m, 2H,
CH2CH2NH2, a+b-is.), 3.13 (s, 3 · 0.6H, OCH3, b-is.),
3.14 (s, 3 · 0.4H, OCH3, a-is.), 3.16 (s, 3 · 0.4H,
OCH3, a-is.), 3.16 (s, 3 · 0.6H, OCH3, b-is.), 3.29 (s,
3 · 0.4H, OCH3, a-is.), 3.44 (s, 3 · 0.6H, OCH3, b-is.),
3.52–3.61 (m, 0.6H, 5-H, b-is.), 3.85–3.94 (m, 0.4H, 5-
H, a-is.), 4.38 (dd, J 9.8/2.1 Hz, 0.6H, 1-Hax, b-is.),
4.75 (d, J 4.3 Hz, 0.4H, 1-Heq, a-is.); the ratio of a
and b anomers was 40:60; EIMS: m/z [%] 156 [Mꢀ

K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 341 (2006) 2321–2334
2329
(0.45C, C-4), 38.4 (1C, C-2), 42.6 (0.45C, COCH2Ph),
42.7 (0.55C, COCH2Ph), 46.9 (0.55C, OCH3), 47.5
(0.45C, OCH3), 47.6 (0.45C, OCH3), 48.3 (0.55C,
OCH3), 55.0 (0.55C, OCH3), 56.3 (0.45C, OCH3), 66.4
(0.55C, C-5), 70.2 (0.45C, C-5), 97.3 (0.55C, C-3), 98.3
(0.55C, C-1), 99.2 (0.45C, C-3), 100.8 (0.45C, C-1),
128.5/128.8/130.6/130.6/131.0/131.3/132.7/135.2 (6C,
arom. C), 169.4 (0.55C, NHCOCH2) 169.5 (0.45C,
NHCOCH2); EIMS: m/z [%] 406 [M+, 1], 344
[Mꢀ2 · OCH3, 16]; CIMS (NH3): m/z [%] 423/425/427
[M+NH4þ, 4.5/3.1/0.5], 345/347/349 [MH+ꢀ2 · OCH3,
58/32/5], 314/316/318 [MH+ꢀ3 · OCH3, 100/64/11];
Anal. Calcd for C18H25Cl2NO5 (406.3): C, 53.21; H,
6.20; N, 3.45. Found: C, 53.17; H, 6.30; N, 3.34.
was stirred at 0 ꢁC for 4 h. The reaction mixture was ex-
tracted with satd aq NaHCO3 (2 · 20 mL). The organic
layer was dried (MgSO4) and concentrated in vacuo.
The residue was purified by FC (3 cm, 90:10 EtOAc–
acetone, fractions 10 mL, Rf 0.39) to give 18a/b
(539 mg, 63%) as a colorless solid: mp 141 ꢁC; IR
~
(ATR, neat): m 3275 (mN–H), 2929 (mC–H), 1716
(mC@O), 1641 (mO@C–NH, amide I), 1559 (dN–H,
amide II), 1114, 1033 (mC–O), 734 cmꢀ1 (cCHoop
,
arom.); 1H NMR (CDCl3): d 1.65–1.84 (m, 2H,
CH2CH2NH, a+b-is.), 2.21–2.38 (m, 2H, 4-Hax+4-
Heq, a+b-is.), 2.36–2.47 (m, 0.15H, 2-Hax, b-is.), 2.44
(dt, J 14.9/1.5 Hz, 0.85H, 2-Heq, a-is.), 2.55 (dd, J
14.8/4.4 Hz, 0.85H, 2-Hax, a-is.), 2.64 (dd, J 14.7/
2.4 Hz, 0.15H, 2-Heq, b-is.), 3.16–3.29 (m, 1H,
CH2CH2NH, a+b-is.), 3.20 (s, 3H, OCH3, a+b-is.),
3.47 (s, 2 · 0.85H, COCH2Ph, a-is.), 3.51 (s, 2 · 0.15H,
COCH2Ph, b-is.), 3.54–3.65 (m, 1H, CH2CH2NH,
a+b-is.), 4.00–4.10 (m, 1H, 5-H, a+b-is.), 4.52 (dd, J
8.6/2.7 Hz, 0.15H, 1-Hax, b-is.), 4.88 (d, J 4.3 Hz,
0.85H, 1-Heq, a-is.), 5.86 (s, br, 0.15H, NH, b-is.), 5.99
(s, br, 0.85H, NH, a-is.), 7.12 (dd, J 8.2/2.1 Hz, 1H,
arom. H, 60-H, a+b-is.), 7.38 (d, J 1.8Hz, 1H, arom.
H, 20-H, a+b-is.), 7.41 (d, J 8.2 Hz, 0.15H, arom. H,
50-H, b-is.), 7.43 (d, J 8.2 Hz, 0.85H, arom. H, 50-H,
a-is.); the ratio of a and b anomers was 85:15; EIMS:
m/z [%] 159/161/163 [–CH2PhCl2þ, 67/43/7]; CIMS
(NH3): m/z [%] 377/379/381 [M+NH4þ, 12.1/7.4/1.2],
4.11. Methyl 7-(benzoylamino)-2,4,6,7-tetradeoxy-a- and
b-D-glycero-1,5-hept-3-ulopyranoside dimethyl ketal
(15a/b)
Under N2, PhCOCl (0.4 mL, 3.5 mmol) and Et3N
(0.7 mL, 5.0 mmol) were added to a solution of unpuri-
fied primary amine 13a/b (561 mg, 2.6 mmol) in CH2Cl2
(20 mL). The mixture was stirred at room temperature
for 8 h. After concentration of the mixture in vacuo,
the residue was purified by FC (3 cm, EtOAc, fractions
10 mL, Rf 0.46) to give 15a/b (747 mg, 73% based on the
nitrile 12a/b) as a pale-yellow oil: IR (ATR, film): ~m 3323
(mN–H), 2940 (mC–H), 1638 (mO@C–NH, amide I), 1538
(dN–H, amide II), 1117, 1049 (mC–O), 710, 694 cmꢀ1
314/316/318 [MꢀCH2OCH3, 100/63/11] ; CIMS (isobu-
1
þ
(cCHoop, arom.); H NMR (CDCl3): d 1.39–1.48 (m,
tane): m/z [%] 416 [M+C4H9
,
4], 328/330/332
1H, 2-Hax, a+b-is.), 1.66–1.72 (m, 1H, 2-Heq, a+b-is.),
1.73–1.91 (m, 2H, CH2CH2NH, a+b-is.), 1.91–2.03
(m, 1H, 4-Hax, a+b-is.), 2.19–2.26 (m, 1H, 4-Heq,
a+b-is.), 3.18 (s, 3 · 0.4H, OCH3, b-is.), 3.19 (s,
3 · 0.6H, OCH3, a-is.), 3.21 (s, 3 · 0.6H, OCH3, a-is.),
3.21 (s, 3 · 0.4H, OCH3, b-is.), 3.32 (s, 3 · 0.6H,
OCH3, a-is.), 3.44 (s, 3 · 0.4H, OCH3, b-is.), 3.41–3.57
(m, 1H, CH2CH2NH, a+b-is.), 3.67–3.85 (m, 0.4H, 5-
H, b-is./1H, CH2CH2NH, a+b-is.), 4.01–4.11 (m,
0.6H, 5-H, a-is.), 4.46 (dd, J 9.8/2.1 Hz, 0.4H, 1-Hax,
b-is.), 4.86 (d, J 4.0 Hz, 0.6H, 1-Heq, a-is.), 4.92 (s, br,
1H, NH, a+b-is.), 7.38–7.51 (m, 3H, arom. H, a+b-
is.), 7.76 (tt, J 6.7/1.4 Hz, 2H, arom. H, m-pos., a+b-
is.); the ratio of a and b anomers was 60:40; EIMS:
m/z [%] 260 [MꢀHOCH3ꢀOCH3, 12], 105 [PhCO+,
100], 88 [–CðOCH3Þ2–CH2þ–, 23]; CIMS (NH3): m/z
[%] 292 [MꢀOCH3, 28], 260 [MꢀHOCH3ꢀOCH3,
100]; Anal. Calcd for C17H25NO5 (323.4): C, 63.14; H,
7.79; N, 4.33. Found: C, 62.41; H, 7.79; N, 4.45.
[MꢀOCH3, 52/35/7]; Anal. Calcd for C16H19Cl2NO4
(360.2): C, 53.35; H, 5.32; N, 3.89. Found: C, 53.21;
H, 5.55; N, 3.68.
4.13. Methyl 7-(benzoylamino)-2,4,6,7-tetradeoxy-a- and
b-D-glycero-1,5-hept-3-ulopyranoside (19a/b)
A solution of 15a/b (811 mg, 2.51 mmol) and p-tolu-
enesulfonic acid (100 mg, 0.53 mmol) in CH2Cl2
(40 mL) was stirred at 0 ꢁC for 2 h. After completion
of the reaction, the mixture was extracted with satd
aq NaHCO3 (2 · 20 mL). The organic layer was dried
(MgSO4) and concentrated in vacuo. The residual solid
was purified by recrystallization from 2-Pr2O. Rf 0.52
(80:20 TBME–acetone) to give 19a/b (636 mg, 91%)
~
as a colorless solid: mp 131 ꢁC; IR (ATR, neat): m
3318 (mN–H), 2929 (mC–H), 1730 (mC@O), 1638
(mO@C–NH, amide I), 1535 (dN–H, amide II),
1290 cmꢀ1 (mC–O); 1H NMR (CDCl3): d 1.89–1.96
(m, 2H, CH2CH2NH, a+b-is.), 2.36–2.52 (m, 2H, 4-
Heq and 4-Hax, a+b-is./0.1H, 2-Heq, b-is./0.1H, 2-Hax,
b-is), 2.49 (dd, J 14.9/1.5 Hz, 0.9H, 2-Heq, a-is.), 2.64
4.12. Methyl 2,4,6,7-tetradeoxy-7-[(3,4-dichlorophen-
yl)acetylamino]-a- and b-D-glycero-1,5-hept-3-ulo-
pyranoside (18a/b)
(dd,
J 14.9/4.7 Hz, 0.9H, 2-Hax, a-is.), 3.33 (s,
3 · 0.9H, OCH3, a-is.), 3.50 (s, 3 · 0.1H, OCH3, b-
is.), 3.46–3.65 (m, 1H, CH2CH2NH, a+b-is.) 3.73–
3.84 (m, 1H, CH2CH2NH, a+b-is.), 4.16–4.25 (m,
A solution of 14a/b (961 mg, 2.4 mmol) and p-toluene-
sulfonic acid (100 mg, 0.53 mmol) in CH2Cl2 (40 mL)

2330
K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 341 (2006) 2321–2334
1H, 5-H, a+b-is.), 4.60 (dd, J 8.7/2.9 Hz, 0.1H, 1-Hax),
5.14 (dd, J 4.6/1.5 Hz, 0.9H, 1-Heq), 6.23 (s, br, 0.1H,
NH, b-is.), 6.68 (s, br, 0.9H, NH, a-is.), 7.39–7.52
(m, 3H, arom. H, a+b-is.), 7.70–7.78 (m, 2H, arom.
H, a+b-is.); the ratio of a and b anomers was 90:10;
13C NMR (CDCl3): d 35.0 (1C, CH2CH2NH), 37.5
(1C, CH2CH2NH), 46.3 (1C, C-2), 47.2 (1C, C-4),
55.0 (1C, OCH3), 68.1 (1C, C-5), 99.7 (1C, C-1),
126.7 (1C, arom. C), 128.6 (3C, arom. C), 131.4 (2C,
arom. C), 167.7 (1C, NHCOPh), 203.7 (1H, C-3); in
the 13C NMR spectrum the intensities of the b anomer
signals were too weak; EIMS: m/z [%] 245
[MꢀHOCH3, 5], 105 [PhCO+, 100], 77 [Ph+, 40]; CIMS
(NH3): m/z [%] 295 [M+NH4þ, 100], 278 [MH+, 76],
346 [MꢀOCH3, 67]; CIMS (isobutane): m/z [%] 278
[MH+, 16], 247 [MH+ꢀOCH3, 15]; Anal. Calcd for
C15H19NO3 (277.3): C, 64.97; H, 6.91; N, 5.05. Found:
C, 64.97; H, 6.85; N, 4.85.
4.15. 1,5-Anhydro-7-benzoylamino-2,4,6,7-tetradeoxy-
D-glycero-hept-1-en-3-ulose (20) {N-{2-[(2R)-4-oxo-2,3-
dihydropyran-2-yl]ethyl}benzamide (21)}
Under N2, a solution of 19a/b (100 mg, 0.36 mmol) and
BF3ÆEt2O (12 drops) in THF (12 mL) was heated to re-
flux for 28 h. Then H2O (8 mL) and Et2O (15 mL) were
added. After separation of the organic layer, the aque-
ous layer was extracted with Et2O (15 mL). The organic
layers were dried (MgSO4) and concentrated in vacuo.
The residue was purified by FC (2 cm, 90:10 EtOAc–
petroleum ether, fractions 2 mL, Rf 0.29) to give 21
~
(57 mg, 64%) as an orange oil: IR (ATR, film): m 3321
(mN–H), 2924 (mC–H), 1717 (mC@O), 1637 (mO@C–
NH, amide I), 1591 (mC@C), 1537 (dN–H, amide II),
1275 (mC–O), 697 cmꢀ1 (cCHoop, arom.); 1H NMR
(CDCl3): d 2.02–2.15 (m, 2H, CH2CH2NH), 2.47 (ddd,
J 16.8/4.0/1.0 Hz, 1H, 3-Heq), 2.59 (dd, J 16.8/13.1 Hz,
1H, 3-Hax), 3.59–3.72 (m, 2H, CH2CH2NH), 4.50–4.60
(m, 1H, 2-H), 5.43 (dd, J 6.0/0.9 Hz, 1H, 5-H), 6.46 (s,
br, 1H, NH), 7.36 (d, J 5.8 Hz, 1H, 6-H), 7.40–7.54
(m, 3H, arom. H), 7.74–7.77 (m, 2H, arom. H); EIMS:
m/z [%] 245 [M+, 1], 140 [MꢀPhCO, 6], 105 [PhCO+,
100], 77 [Ph+, 40]; Anal. Calcd for C14H15NO3 (245.3):
C, 68.56; H, 6.16; N, 5.71. Found: C, 68.02; H, 6.23;
N, 5.21.
4.14. 1,5-Anhydro-2,4,6,7-tetradeoxy-7-(3,4-dichloro-
phenyl)acetylamino-D-glycero-hept-1-en-3-ulose (20)
{2-(3,4-dichlorophenyl)-N-{2-[(2R)-4-oxo-2,3-dihydro-
pyran-2-yl]ethyl}-acetamide (20)}
Under N2, a solution of 14a/b (77 mg, 0.19 mmol) and
BF3ÆEt2O (seven drops) in THF (10 mL) was heated to
reflux for 3 days. Then H2O (10 mL) and Et2O
(10 mL) were added. After separation of the organic
layer, the aqueous layer was extracted with Et2O
(2 · 20 mL). The organic layers were dried (MgSO4)
and concentrated in vacuo. The residue was purified
by FC (1 cm, 80:20 EtOAc–acetone, fractions 2 mL, Rf
0.31) to give 20 (53 mg, 86%) as a colorless solid: mp
4.16. Methyl 3-(benzylamino)-2,3,4,6,7-pentadeoxy-7-
[(3,4-dichlorophenyl)acetylamino]-b-D-threo-1,5-hepto-
pyranoside (22b), methyl 3-(benzylamino)-2,3,4,6,7-penta-
deoxy-7-[(3,4-dichlorophenyl)acetylamino]-a-D-threo-
1,5-heptopyranoside (22a) and methyl 3-(benzylamino)-
2,3,4,6,7-pentadeoxy-7-[(3,4-dichlorophenyl)acetyl-
amino]-a-D-erythro-1,5-heptopyranoside (23a)
~
126 ꢁC; IR (ATR, neat): m 3283 (mN–H), 1663 (mC@O),
1638 (mO@C–NH, amide I), 1557 (dN–H, amide II),
1
1270, 1031 cmꢀ1 (mC–O); H NMR (CDCl3): d 1.87–
Benzylamine (0.3 mL, 2.8 mmol) was dissolved in a
small amount of abs MeOH and the solution was
brought to pH 6 with 5 N HCl in MeOH. Then a small
1.97 (m, 2H, CH2CH2NH), 2.40 (ddd, J 16.8/4.0/
1.2 Hz, 1H, 3-Heq), 2.53 (dd, J 16.8/13.4 Hz, 1H, 3-
Hax), 3.33–3.48 (m, 2H, CH2CH2NH), 3.51 (s, 2H,
COCH2), 4.42 (ddt, J 13.4/8.0/4.3 Hz, 1H, 2-H), 5.41
(dd, J 6.1/1.2 Hz, 1H, 5-H), 5.68 (s, br, 1H, NH), 7.12
(dd, J 8.2/2.1 Hz, 1H, arom. H, 60-H), 7.23 (d, J
6.1 Hz, 1H, 6-H), 7.37 (d, J 2.1 Hz, 1H, arom. H, 20-
H), 7.43 (d, J 8.2 Hz, 1H, arom. H, 50-H); 13C NMR
˚
amount of 3 A molecular sieves was added to a solution
of the ketone 18a/b (103 mg, 0.29 mmol) in abs MeOH
(10 mL), and afterwards the benzylamine solution was
added. Under N2, NaBH3CN (35 mg, 0.56 mmol) was
added, and the mixture was stirred at room temperature
for 5 days. After completion of the reaction, satd aq
NaHCO3 (5 mL) was added, and the aqueous layer
was extracted with Et2O (3 · 15 mL). The organic layer
was dried (MgSO4) and concentrated in vacuo. Purifica-
tion of the residue by FC (2 cm, 90:10 CH2Cl2–MeOH,
fractions 2 mL) gave the isomerically pure secondary
amine 22b and a mixture of 22b, 22a, and 23a.
(CDCl3):
d
33.9 (1C, CH2CH2NH), 36.3 (1C,
CH2CH2NH), 41.8 (1C, C-3), 42.6 (1C, COCH2Ph),
78.0 (1C, C-2), 107.4 (1C, C-5), 28.7/130.8/131.3/
131.6/132.9/134.9 (6C, arom. C), 162.4 (1C, C-6),
169.7 (1C, COCH2Ph), 191.7 (1H, C-4); EIMS: m/z
[%]
327/329/331
[M+,
24/16/3],
159/161/163
[–CH2PhCl2þ, 56/38/7]. CIMS (NH3): m/z [%] 345/
347/349 [M+NH4þ, 100/66/12], 328/330/332 [MH+,
97/66/13], 294/296 [MH+ꢀCl, 97/35]. APCIMS: m/z
[%] 328/330/332 [MH+, 100/57/7]; Anal. Calcd for
C15H15Cl2NO3 (328.2): C, 54.90; H, 4.61; N, 4.27.
Found: C, 54.60; H, 4.75; N, 4.11.
4.16.1. Data for 22b. Colorless oil; yield 6.0 mg (6%);
Rf 0.31; [a]589 +18.9 (c 0.018, MeOH); IR (ATR, film):
~
m 3289 (mN–H), 2928 (mC–H), 1646 (mO@C–NH, amide
I), 1555 (dN–H, amide II), 1470 (dC–H), 1122, 1032
1
(mC–O), 733 cmꢀ1 (cCHoop, arom.); H NMR (CDCl3):

K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 341 (2006) 2321–2334
2331
d 1.15 (q, J 12.2H, 1H, 2-Hax-o 4-Hax), 2.20 (q, J
11.9 Hz, 1H, 2-Hax-o 4-Hax), 1.58–1.87 (m, 1H, 2-Heq-o
4-Heq/2H, CH2CH2NH/1H, benzyl-NH), 2.09–2.15
(m, 1H, 2-Heq-o 4-Heq), 2.78 (tt, J 11.6/4.0 Hz, 1H, 3-
H), 3.28 (td, J 12.5/6.1 Hz, 1H, 5-H), 3.42 (s, 3H,
OCH3), 3.46 (s, 2H, COCH2Ph), 3.36–3.59 (m, 2H,
CH2CH2NH), 3.82 (s, 2H, NHCH2Ph), 4.23 (dd, J
9.8/2.1 Hz, 1H, 1-Hax), 5.96 (s, br, 1H, NHCO), 7.11
(dd, J 8.2/2.1 Hz, 1H, arom. H, 60-H), 7.23–7.43 (m,
5H, arom. H, phenyl), 7.38 (d, J 2.1 Hz, 1H, arom. H,
20-H), 7.40 (d, J 8.2 Hz, 1H, arom. H, 50-H); EIMS:
m/z [%] 392/394/396 [MꢀCH2CH(OCH3)–, 9.5/5.8/
IMS: m/z [%] 451/453/455 [MH+, 100/60/10], 419/421/
423 [MꢀOCH3, 12.4/6.6/0.9]; CIMS (isobutane): m/z
[%] 451/453/455 [MH+, 100/66/11], 419/421/423
[MꢀOCH3, 55/33/6.7]; Anal. Calcd for C23H28Cl2N2O3
(451.4): C, 61.20; H, 6.25; N, 6.21. Found: C, 61.35; H,
6.05; N, 6.47.
sieves and abs MeOH (10 mL). Under N2, NaBH3CN
(40 mg, 0.64 mmol) was added, and the mixture was stir-
red at room temperature for 5 days. After completion of
the reaction, satd aq NaHCO3 (10 mL) was added, and
the aqueous layer was extracted with Et2O (3 · 20 mL).
The organic layer was dried (MgSO4) and concentrated
in vacuo. Purification of the residue by FC (2 cm, 80:20
CH2Cl2–MeOH, fractions 5 mL) gave the isomerically
pure amine 25b, a mixture of 24a, 24b, and 25b [colorless
oil, yield 11 mg (5%)] and an anomeric mixture of 24a
and 24b.
1.1], 106 [PhCH2NH+, 89], 91 [PhCH þ, 100]; LC–APC-
4.17.1. Data for 24a/24b. Colorless oil; yield 55 mg
(25%); Rf 0.07; [a]589 +11.5 (c 0.013, MeOH); IR
2
~
(ATR, film): m 3297 (mN–H), 2943 (mC–H), 1638
(mO@C–NH, amide I), 1554 (dN–H, amide II), 1471
(dC–H), 1125, 1066, 1032 cmꢀ1 (mC–O). 1H NMR
(CDCl3): d 1.21–1.80 (m, 2H, 4-Hax+2-Hax, a+b-is./
2H, CH2CH2NH, a+b-is.), 1.90–2.19 (m, 2H, 4-
Heq+2-Heq, a+b-is.), 2.48 (s, 3H, NHCH3, a+b-is.),
2.86–2.96 (m, 1H, 3-H, a+b-is.), 3.13–3.59 (m, 0.65H,
5-H, b-is.), 3.16 (s, 3 · 0.35H, OCH3, a-is.), 3.26 (dt, J
18.9/6.1 Hz, 2H, CH2CH2NH, a+b-is.), 3.42 (s,
3 · 0.65H, OCH3, b-is.), 3.47 (s, 2 · 0.65H, COCH2Ph,
b-is.), 3.49 (s, 2 · 0.35H, COCH2Ph, a-is.), 3.70–3.78
(m, 0.35H, 5-H, a-is.), 4.25 (d, J 8.2 Hz, 0.65H, 1-Hax,
b-is.), 4.61 (d, J 1.8 Hz, 0.35H, 1-Heq, a-is.), 6.24 (s,
br, 0.65H, NHCO, b-is.), 6.51 (s, br, 0.35H, NHCO,
a-is.), 7.11 (dd, J 8.2/1.8 Hz, 0.35H, arom. H, 60-H, a-
is.), 7.12 (dd, J 8.2/1.5 Hz, 0.65H, arom. H, 60-H, b-
is.), 7.37 (d, J 2.1 Hz, 0.65H, arom. H, 20-H, b-is.),
7.38 (d, J 2.4 Hz, 0.35H, arom. H, 20-H, a-is.), 7.39 (d,
J 8.5 Hz, 0.65H, arom. H, 50-H, b-is.), 7.41 (d, J
8.2 Hz, 0.35H, arom. H, 50-H, a-is.); a signal for the
NH-proton was not seen in the spectrum; the ratio of
a and b anomers was 35:65; EIMS: m/z [%] 315/317/
319 [M+ꢀOCH3ꢀNHCH3, 5/3/0.5], 159/161/163
[–CH2PhCl2þ, 25/18/3]; CIMS (NH3): m/z [%] 375/
377/379 [MH+, 100/56/9], 343/345/347 [M+ꢀOCH3,
27/13/2]; Anal. Calcd for C17H24Cl2N2O3 (375.3): C,
54.41; H, 6.45; N, 7.46. Found: C, 54.30; H, 7.03; N,
7.10.
4.16.2. Data for a mixture of 22b, 22a, and 23a. Pale-
yellow oil; yield 39 mg (31%); Rf 0.28; 1H NMR
(CDCl3): d 1.04–2.15 (m, 2H, 4-Heq+4-Hax, isomer 1,
2, and 3/2H, 4-Heq+4-Hax, isomer 1, 2, and 3/2H,
CH2CH2NH, isomer 1, 2, and 3/benzyl-NH, isomer 1,
2, and 3), 2.75 (tt, J 11.6/4.0 Hz, 0.33H, 3-Hax, isomer
1), 2.96–3.07 (m, 0.40H, 3-Hax, isomer 2/0.27H, 3-Heq,
isomer 3), 3.09–3.97 (m, 2H, CH2CH2NH, isomer 1, 2,
and 3/1H, 5-H, isomer 1, 2, and 3), 3.15 (s, 3 · 0.27H,
OCH3, isomer 3), 3.17 (s, 3 · 0.40H, OCH3, isomer 2),
3.42 (s, 3 · 0.33H, OCH3, isomer 1), 3.46 (s, 2 · 0.33H,
COCH2Ph, isomer 1), 3.49 (s, 2 · 0.27H, COCH2Ph,
isomer 3), 3.50 (s, 2 · 0.40H, COCH2Ph, isomer 2),
3.78 (s, 2 · 0.40H, NHCH2Ph, isomer 2), 3.81 (s,
2 · 0.33H, NHCH2Ph, isomer 1, 2 · 0.27H, NHCH2Ph,
isomer 3), 4.24 (dd, J 9.8/1.8 Hz, 0.33H, 1-Hax, isomer
1), 4.56 (d, J 3.4 Hz, 0.27H, 1-Heq, isomer 3), 4.57 (d,
J 3.9 Hz, 0.40H, 1-Heq, isomer 2), 5.95 (s, br, 0.33H,
NHCO, isomer 1), 6.15 (s, br, 0.27H, NHCO, isomer
3), 6.47 (s, br, 0.40H, NHCO, isomer 2), 7.09–7.15 (m,
1H, arom. H, isomer 1, 2, and 3), 7.28–7.43 (m, 7H,
arom. H, isomer 1, 2, and 3); the ratio of the isomers
1 (22b), 2 (22a), and 3 (23a) was 33:40:27; C23H28Cl2-
N2O3 (451.4).
4.17.2. Data for 25b. Colorless oil; yield 24 mg (11%);
Rf 0.19; [a]589 +10.8 (c 0.011, MeOH); IR (ATR, film):
~
4.17. Methyl 2,3,4,6,7-pentadeoxy-7-[(3,4-dichlorophen-
yl)acetylamino]-3-(methylamino)-a- and b-D-threo-1,5-
heptopyranoside (24a/b) and methyl 2,3,4,6,7-pentade-
oxy-7-[(3,4-dichlorophenyl)acetylamino]-3-(methylamino)-
pentadeoxy-a-D-erythro-1,5-heptopyranoside (25b)
m 3288 (mN–H), 2928 (mC–H), 1645 (mO@C–NH, amide
I), 1554 (dN–H, amide II), 1471 (dC–H), 1132, 1032
(mC–O), 682 cmꢀ1 (cCHoop, arom.); H NMR (CDCl3):
1
d 1.66–2.15 (m, 2H, CH2CH2NH/2H, 2-Hax+2-Heq/2H,
4-Hax+4-Heq), 2.49 (s, 3H, NHCH3), 3.14 (quint., br, J
3.5 Hz, 1H, 3-H), 3.27–3.51 (m, 2H, CH2CH2NH), 3.43
(s, 3H, OCH3), 3.51 (s, 2H, COCH2Ph), 3.96–4.05 (m,
1H, 5-H), 4.75 (dd, J 9.3/2.0 Hz, 1H, 1-Hax), 6.16 (s,
br, 1H, NH), 7.15 (dd, J 8.2/1.8 Hz, 1H, arom. H, o-
pos.-60), 7.40 (d, J 8.5 Hz, 1H, arom. H, m-pos.-50),
7.41 (d, J 1.5 Hz, 1H, arom. H, o-pos.-20); Anal. Calcd
An ethanolic solution of methylamine (8 M, 0.45 mL,
3.6 mmol) was dissolved in a small amount of abs
MeOH. The solution was brought to pH 6 with 5 N
HCl in MeOH. This solution was added to a mixture
˚
of ketone 18a/b (210 mg, 0.58 mmol), 3 A molecular

2332
K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 341 (2006) 2321–2334
for C17H24Cl2N2O3 (375.3): C, 54.41; H, 6.45; N, 7.46.
Found: C, 54.02; H, 6.18; N, 7.20.
128.9 (0.65C, arom. C, o-pos.60), 130.7 (1C, arom. C,
o-pos.20), 131.1, 131.4, 132.8 (3C, arom. C, m-pos.30
and 50, p-pos.40), 135.2 (0.35C, arom. C, pos.10), 135.3
(0.65C, arom. C, pos.10), 169.4 (0.65C, NHCOCH2),
169.5 (0.35C, NHCOCH2); the ratio of a and b
anomers was 65:35; C18H26Cl2N2O3 (389.3); EIMS: m/
z [%] 159/161/163 [–CH2PhCl2þ, 37/21/4]; CIMS (iso-
butane): m/z [%] 389/391/393 [MH+, 100/64/11], 358/
360/362 [MH+ꢀOCH3, 13.2/9.6/1.5]; HREIMS: Calcd
for C18H26Cl2N2O3 m/z 388.1321; found 388.1322.
4.18. Methyl 2,3,4,6,7-pentadeoxy-7-[(3,4-dichlorophen-
yl)acetylamino]-3-(dimethylamino)-a- and b-D-threo-1,5-
heptopyranoside (26a/b)
A methanolic solution of dimethylamine (2 M, 0.6 mL,
1.2 mmol) was dissolved in a small amount of abs
MeOH. The solution was brought to pH 6 with 5 N
HCl in MeOH. This solution was added to a mixture
of ketone 18a/b (89 mg, 0.25 mmol), a small amount
4.19. Methyl 7-(benzoylamino)-3-(benzylamino)-
2,3,4,6,7-pentadeoxy-a-D-erythro-1,5-heptopyranoside
(29a)
˚
of 4 A molecular sieves and abs MeOH (10 mL). Under
N2, NaBH3CN (32 mg, 0.50 mmol) was added, and the
mixture was stirred at room temperature for 4 days.
Then satd aq NaHCO3 (10 mL) was added, and the mix-
ture was extracted with Et2O (3 · 20 mL). The organic
layer was dried (MgSO4) and concentrated in vacuo.
The residue was purified by FC (2 cm, 80:20 CH2Cl2–
MeOH, fractions 2 mL, Rf 0.14) to give 26a/b as a yel-
low oil (30 mg, 31%): [a]589 +14.4 (c 0.013, MeOH);
Benzylamine (0.8 mL, 7.3 mmol) was dissolved in a
small amount of abs MeOH. The solution was brought
to pH 6 with 5 N HCl in MeOH. This solution was
added to a mixture of ketone 19a/b (277 mg, 1.0 mmol),
˚
a small amount of 4 A molecular sieves and abs MeOH
(10 mL). Under N2, NaBH3CN (64 mg, 1.02 mmol) was
added, and the mixture was stirred at room temperature
for 6 days. After completion of the reaction, 2 N NaOH
(5 mL) was added and the aqueous layer was extracted
with Et2O (3 · 15 mL). The organic layers were dried
(MgSO4) and concentrated in vacuo. The residue was
purified by FC (2 cm, 80:20 CH2Cl2–MeOH, fractions
2 mL, Rf 0.45) to give 29a as a yellow oil (99 mg,
~
IR (film): m 3293 (mN–H), 2938 (mC–H), 1647 (mO@C–
NH, amide I), 1555 (dN–H, amide II), 1470 (dC–H),
1
1123, 1046 cmꢀ1 (mC–O); H NMR (CDCl3): d 1.18–
1.37 (m, 0.35H, 2-Hax, b-is.), 1.22 (q, J 11.9H, 1H, 4-
Hax, a+b-is.), 1.42 (td, J 12.5/3.7H, 0.65H, 2-Hax, a-
is.), 1.53–1.87 (m, 2H, CH2CH2NH, a+b-is.), 1.89–
1.96 (m, 1H, 2-Heq, a+b-is.), 1.98–2.06 (m, 1H, 4-Heq,
a+b-is.), 2.27 (s, 3 · 0.35H, N(CH3)2, b-is.), 2.28 (s,
3 · 0.65H, N(CH3)2, a-is.), 2.46 (tt, J 11.9/4.0 Hz,
0.35H, 3-H, b-is.), 2.76 (tt, J 12.1/3.8 Hz, 0.65H, 3-H,
a-is.), 3.11–3.22 (m, 1H, CH2CH2NH, a+b-is.), 3.16
(s, 3 · 0.65H, OCH3, a-is.), 3.35–3.45 (m, 0.35H, 5-H,
b-is.), 3.43 (s, 3 · 0.35H, OCH3, b-is.), 3.47 (s,
2 · 0.35H, COCH2Ph, b-is.), 3.50 (s, 2 · 0.65H,
~
27%): [a]589 +60.0 (c 0.014, MeOH); IR (ATR, film): m
3314 (mN–H), 2927 (mC–H), 1637 (mO@C–NH, amide
I), 1539 (dN–H, amide II), 1119, 1039 (mC–O),
1
693 cmꢀ1 (cCHoop, arom.); H NMR (CDCl3): d 1.57
(ddd, J 13.7/11.6/4.0 Hz, 1H, 4-Hax), 1.77–1.99 (m,
1H, 4-Heq/2H, 2-Hax+2-Heq/2H, CH2CH2NH), 3.01–
3.06 (m, 1H, 3-H), 3.23 (s, 3H, OCH3), 3.38–3.47 (m,
1H, CH2CH2NH), 3.77–3.89 (m, 1H, CH2CH2NH),
3.88 (s, 2H, NHCH2Ph), 4.07–4.16 (m, 1H, 5-H), 4.84
(d, J 3.1 Hz, 1H, 1-Heq), 7.12 (s, br, 1H, NHCO),
7.28–7.49 (m, 8H, arom. H), 7.77–7.81 (m, 2H, arom.
H); the signal for the Bn–NH-proton was not observed
in the spectrum; 13C NMR (CDCl3): d 32.0, 34.7, 34.8
(3C, C-2, C-4, C-6), 37.9 (1C, CH2CH2NH), 48.5 (1C,
C-3), 50.9 (1C, NHCH2Ph), 55.3 (1C, OCH3), 63.8
(1C, C-5), 99.3 (1C, C-1), 126.7, 126.8, 127.2, 128.1,
128.3, 128.4, 128.5, 131.2, 134.7 (12C, arom. C), 167.1
(1C, NHCOPh); C22H28N2O3 (368.5); EIMS: m/z [%]
105 [PhCO+, 91], 91 [PhCH2þ, 100], 77 [Ph+, 22]; CIMS
(NH3): m/z [%] 369 [MH+, 100], 337 [MH+ꢀHOCH3,
4].
COCH2Ph, a-is.), 3.58 (td,
J
13.5/6.5 Hz, 1H,
CH2CH2NH, a+b-is.), 3.74 (ddt, J 11.7/8.7/2.6 Hz,
0.65H, 5-H, a-is.), 4.25 (dd, J 9.6/2.0 Hz, 0.35H, 1-
Hax, b-is.), 4.59 (d, J 2.7 Hz, 0.65H, 1-Heq, a-is.), 5.99
(s, br, 0.35H, NH, b-is.), 6.16 (s, br, 0.65H, NH, a-is.),
7.11 (dd, J 8.2/2.0 Hz, 0.65H, arom. H, 60-H, a-is.),
7.12 (dd, J 8.2/2.1 Hz, 0.35H, arom. H, 60-H, b-is.),
7.37 (d, J 2.1 Hz, 0.35H, arom. H, 20-H, b-is.), 7.38 (d,
J 2.1 Hz, 0.65H, arom. H, 20-H, a-is.), 7.41 (d, J
7.9 Hz, 0.35H, arom. H, 50-H, b-is.), 7.42 (d, J 7.9 Hz,
0.65H, arom. H, 50-H, a-is.); the ratio of the a and b
anomers was 65:35; 13C NMR (CDCl3): d 32.0 (0.65C,
C-2), 33.6 (0.35C, C-2), 33.8 (0.35C, C-4), 34.1 (0.65C,
C-4), 34.6 (0.65C, CH2CH2NH), 34.8 (0.35C,
CH2CH2NH), 37.3 (0.35C, CH2CH2NH), 37.8 (0.65C,
CH2CH2NH), 41.0 (2 · 0.65C, N(CH3)2), 41.3
(2 · 0.35C, N(CH3)2), 42.8 (0.35C, COCH2Ph), 42.8
(0.65C, COCH2Ph), 54.4 (0.65C, OCH3), 55.8 (0.65C,
C-3), 56.3 (0.35C, OCH3), 59.8 (0.35C, C-3), 68.3
(0.65C, C-5), 72.5 (0.35C, C-5), 98.7 (0.65C, C-1),
102.5 (0.35C, C-1), 128.6 (0.35C, arom. C, o-pos.60),
4.20. Methyl 7-(benzoylamino)-2,3,4,6,7-pentadeoxy-3-
(dimethylamino)-a- and b-D-threo-1,5-heptopyranoside
(30a/b)
An ethanolic solution of dimethylamine (5 M, 0.85 mL,
4.9 mmol) was dissolved in a small amount of abs

K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 341 (2006) 2321–2334
2333
MeOH. The solution was brought to pH 6 with 5 N HCl
in MeOH. This solution was added to a mixture of
ketone 19a/b (270 mg, 0.97 mmol), a small amount of
(Roth). Liquid scintillation analyzer was a TriCarb
2100 TR (Canberra–Packard), with a counting efficiency
of 66%. All experiments were carried out in triplicate.
IC50-values were determined from competition experi-
ments with at least six concentrations of test compounds
and were calculated with the program, GraphPad
Prismꢂ 3.0 (GraphPad Software) by nonlinear regression
analysis. Ki-values were calculated according to Cheng
and Prusoff.20 The Ki-values are given as the mean
value SEM from three independent experiments.
˚
4 A molecular sieves and abs MeOH (15 mL). Under
N2, NaBH3CN (61 mg, 0.97 mmol) was added, and the
mixture was stirred at room temperature for 6 days.
After completion of the reaction, 2 N NaOH (10 mL)
was added and the mixture was extracted with Et2O
(3 · 15 mL). The organic layer was dried (MgSO4) and
concentrated in vacuo. The residue was purified by FC
(2 cm, 80:20 CH2Cl2–MeOH, fractions 5 mL, Rf 0.23)
to give 30a/b as a yellow oil (107 mg, 36%): [a]589
5.2. r1 Assay procedures14c
~
+44.3 (c 0.016, MeOH); IR (ATR, film): m 3312 (mN–
H), 2936 (mC–H), 1637 (mO@C–NH, amide I), 1541
For the r1 assay, guinea pig-brain membranes were pre-
pared as described in the literature.14c The test was per-
formed with the radioligand [3H]-pentazocine (1036
GBq/mmol; NENTM Life Science Products). The thawed
membrane preparation (about 150 lg of protein) was
incubated with various concentrations of the test com-
pound, 3 nM [3H]-pentazocine, and buffer (50 mM
Tris–HCl, pH 7.4) in a total volume of 500 lL for
120 min at 37 ꢁC. The incubation was terminated by ra-
pid filtration through presoaked Whatman GF/B filters
(0.5% polyethylenimine in water for 2 h at 4 ꢁC) using a
cell harvester. After washing four times with 2 mL of cold
buffer, 3 mL of scintillation cocktail was added to the fil-
ters. After at least 8 h, bound radioactivity trapped on the
filters was counted in a liquid scintillation analyzer. Non-
specific binding was determined with 10 lM haloperidol.
(dN–H, amide II), 1122, 1045 (mC–O), 696 cmꢀ1
1
(cCHoop, arom.); H NMR (CDCl3): d 1.24–1.42 (m,
0.2H, 2-Hax, b-is./0.2H, 4-Hax, b-is.), 1.35 (q, J
12.2 Hz, 0.8H, 4-Hax, a-is.), 1.57 (td, J 12.5/3.7 Hz,
0.8H, 2-Hax, a-is.), 1.76–2.03 (m, 2H, CH2CH2NH,
a+b-is./1H, 2-Heq, a+b-is./1H, 4-Heq, a+b-is.), 2.29
(s, 6 · 0.2H, N(CH3)2, b-is.), 2.32 (s, 6 · 0.8H,
N(CH3)2, a-is.), 2.86 (tt, J 12.2/4.0 Hz, 1H, 3-H, a+b-
is.), 3.31 (s, 3 · 0.8H, OCH3, a-is.), 3.40–3.50 (m, 1H,
CH2CH2NH, a+b-is.), 3.46 (s, 3 · 0.2H, OCH3, b-is.),
3.80 (ddd, J 13.7/11.9/6.4 Hz, 1H, CH2CH2NH, a+b-
is.), 3.92 (ddt, J 11.4/9.2/2.7 Hz, 1H, 5-H, a+b-is.),
4.35 (dd, J 9.5/2.1 Hz, 0.2H, 1-Hax, b-is.), 4.91 (d, J
3.4 Hz, 0.8H, 1-Heq, a-is.), 6.90 (s, br, 1H, NH, a+b-
is.), 7.39–7.52 (m, 3H, arom. H, a+b-is.), 7.74–7.80
(m, 2H, arom. H, a+b-is.); the ratio of a and b anomers
was 80:20; 13C NMR (CDCl3): d 32.2 (0.8C, C-2),
33.4 (0.2C, C-2), 33.9 (0.2C, C-4), 34.3 (0.8C, C-4),
34.6 (0.2C, CH2CH2NH), 34.8 (0.8C, CH2CH2NH),
37.8 (0.2C, CH2CH2NH), 38.1 (0.8C, CH2CH2NH),
41.0 (2 · 0.8C, N(CH3)2), 41.3 (2 · 0.2C, N(CH3)2),
54.7 (0.8C, OCH3), 55.9 (1C, C-3), 56.4 (0.2C, OCH3),
68.4 (1C, C-5), 98.9 (0.8C, C-1), 102.5 (0.2C, C-1),
126.7, 126.8, 128.4, 128.5, 131.2, 134.7 (6C, arom. C),
167.1 (0.8C, NHCOCH2), 167.2 (0.2C, NHCOCH2);
C17H26N2O3 (306.4); EIMS: m/z [%] 306 [M+, 7], 105
[PhCO+, 92], 77 [Ph+, 31]; CIMS (NH3): m/z [%] 307
[MH+, 100], 275 [MH+ꢀHOCH3, 20].
5.3. r2 Assay procedures14c
For the r2-assay, rat-liver membranes were prepared as
described in the literature.14c The membrane prepara-
tion (about 60 lg of protein) was incubated with 3 nM
[3H]-ditolylguanidine
(2220 GBq/mmol,
American
Radiolabeled Chemicals, Inc.), and different concentra-
tions of test compounds in buffer (50 mM Tris–HCl,
pH 8.0) in the presence of 100 nM (+)-pentazocine.
The total volume was 250 lL. The incubation
(120 min, 25 ꢁC) was stopped by addition of 2 mL of
ice-cold buffer (10 mM Tris–HCl, pH 8.0), followed by
rapid filtration through presoaked Whatman GF/B fil-
ters using a cell harvester. After the sample was washed
three times with 2 mL of cold buffer, a total volume of
3 mL of scintillation cocktail was added to the filters.
After at least 8 h, bound radioactivity trapped on the
filters was counted in a liquid scintillation analyzer.
Nonspecific binding was determined with 10 lM
nonradiolabeled ditolylguanidine.
5. Receptor-binding studies
5.1. General information
The following equipment was used: Homogenizer, Pot-
terꢂS (B. Braun Biotech International); Ultraturrax,
Euroturraxꢂ T20 (Ika Labortechnik); centrifuge, high-
speed cooling centrifuge model J2-HS (Beckman); filter,
Whatman glass fiber filters GF/B, presoaked in 0.5%
polyethylenimine in water for 2 h at 4 ꢁC before use. Fil-
tration was performed with a Brandel 24-well cell har-
vester. The scintillation cocktail was Rotiscint Eco Plus
5.4. NMDA, j-opioid, and l-opioid receptor-assay
procedures
These were conducted according to the published
method.14c

2334
K. Wiedemeyer, B. Wu¨nsch / Carbohydrate Research 341 (2006) 2321–2334
Scopes, D. I. C.; Hayes, A. G.; Birch, P. J. J. Med. Chem.
Acknowledgments
1993, 36, 2075–2083.
10. deCosta, B. R.; Rice, K. C.; Bowen, W. D.; Thurkauf, A.;
Rothman, R. B.; Band, L.; Jacobson, A. E.; Radesca, L.;
Contreras, P. C.; Gray, N. M.; Daly, I.; Iyengar, S.; Finn,
D. T.; Vazirani, S.; Waler, J. M. J. Med. Chem. 1990, 33,
3100–3110.
Thanks are also due to the Degussa AG, Janssen-Cilag
GmbH, and Bristol–Myers Squibb for donation of
chemicals and reference compounds.
11. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574–1585.
12. (a) Studer, A.; Amrein, S. Synthesis 2002, 7, 835–849; (b)
Mathe, C.; Imbach, J.-L.; Gosselin, G. Carbohydr. Res.
2000, 323, 226–229.
13. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem.
Soc. 1971, 2897–2904.
14. (a) DeHaven-Hudkins, D. L.; Fleissner, L. C.; Ford-Rice,
F. Y. Eur. J. Pharmacol. 1992, 227, 371–378; (b) Mach, R.
H.; Smith, C. R.; Childers, S. R. Life Sci. 1995, 57, PL57–
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