Ring transformations of pentose glycals with push-pull butadiene functionality

Article abstract of DOI:10.1055/s-2005-872095

2-Formyl-D-xylal (1a) and 2-formyl-L-arabinal (1b) were reacted with alkyl cyanoacetates to furnish the 1,5-anhydro-3,4-di-O-benzyl-2-[(E)-2-cyano-2- alkoxycarbonylvinyl]-2-deoxy-D(L)-hex-1-enitols 2a and 2b, respectively. Treatment of 2a, 2b with aromati

Full text of DOI:10.1055/s-2005-872095

2758
PAPER
Ring Transformations of Pentose Glycals with Push-Pull Butadiene
Functionality
Pentose
Glycals
w
h
ithPush-Pul
mButadiene Functioe
nality d Bari,a Selena Milicevic,a Holger Feist,a Dirk Michalik,b Manfred Michalik,*b Klaus Peseke*a
a
Universität Rostock, Institut für Chemie, Albert-Einstein-Str. 3a, 18051 Rostock, Germany
Fax +49(381)4986412; E-mail: klaus.peseke@uni-rostock.de
b
Leibniz-Institut für Organische Katalyse, Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 17 March 2005; revised 26 April 2005
Dedicated to Prof. Dr. Ralf Miethchen on the occasion of his 65th birthday
We have previously reported the ring transformation reac-
tions of 2-formyl glycals in the hexose series.6–12 Recent-
ly, the first reactions of pentose glycals with nitrogen
nucleophiles to yield acyclo-C-nucleoside analogues were
Abstract: 2-Formyl-D-xylal (1a) and 2-formyl-L-arabinal (1b)
were reacted with alkyl cyanoacetates to furnish the 1,5-anhydro-
3,4-di-O-benzyl-2-[(E)-2-cyano-2-alkoxycarbonylvinyl]-2-deoxy-
D(L)-hex-1-enitols 2a and 2b, respectively. Treatment of 2a, 2b
with aromatic amines afforded the 1-aryl-5-[1,2-bis(benzyloxy)-3- described.13 The double bond of these branched chain ene-
hydroxypropyl]-1,2-dihydro-2-oxopyridine-3-carbonitriles 3a–c.
Ring transformation of 1a, 1b with N-substituted oxobutyramides,
dialkyl 3-oxopentanedioate and benzimidazol-2-ylacetonitrile
yielded the 3-acetyl-1-aryl-5-[1,2-bis(benzyloxy)-3-hydroxypro-
pyl]-1,2-dihydropyridin-2-ones 6a–d, alkyl 5-[1,2-bis(benzyloxy)-
3-hydroxypropyl]-2-hydroxyisophthalates 8a–d and 2-[1,2-
bis(benzyloxy)-3-hydroxypropyl]benzo[4,5]imidazo-[1,2-a]-pyri-
dine-4-carbonitriles 11a, 11b, respectively.
sugars was push-pull activated and, therefore, susceptible
to nucleophilic attack by different N-nucleophiles. Here-
in, we report the syntheses of C-2 branched-chain pentose
glycals with an integrated push-pull butadiene unit that af-
ter reacting with different nucleophiles should give differ-
ent acyclo-C-nucleoside analogues and acyclo-C-
glycosides, respectively.
Key words: carbohydrates, heterocycles, nucleosides, ring open-
ing, ring closure
Treatment of 1,5-anhydro-3,4-di-O-benzyl-2-deoxy-2-
formyl-D-threo-hex-1-enitol (1a)13 with ethyl cyanoace-
tate and 1,5-anhydro-3,4-di-O-benzyl-2-deoxy-2-formyl-
L-erythro-hex-1-enitol (1b)13 with methyl cyanoacetate
under Knoevenagel conditions gave the monosaccharide
push-pull butadienes 2a and 2b, respectively, in moderate
to high yields (Scheme 1). The reactions were performed
by using piperidinium acetate as the most efficient cata-
Analogues of nucleosides in which an open-chain mono-
saccharide unit is linked via a C–C single bond to the het-
erocyclic part have received considerable attention in
recent years due to their diverse biological properties.1–5
BnO
OBn
BnO
CH2(CN)COOR3
5
O
3'
4
O
R1
CN
O
1
R4NH2
(ii)
5
R1
2'
1'
R2 R1
3
HO
2
4
(i)
3
1'
2'
COOR3
R2
NC
CHO
R3 = Me
R2
6
R4 = Ph
2
N
1
3 = Et
R4
R
R
4 = p-MeOC6H4
1a: R1 = H, R2 = OBn
1b: R1 = OBn, R2 = H
2a: R1 = H, R2 = BnO, R3 = Et (92%)
2b: R1 = BnO, R2 = H, R3 = Me (56%)
3a: R1 = H, R2 = BnO, R4 = p-MeOC6H4 (2a, ii: 62%; 1a, iii: 95%)
3b: R1 = BnO, R2 = H, R4 = Ph (2b, ii: 41%)
3c: R1 = BnO, R2 = H, R4 = p-MeOC6H4 (2b, ii: 65%; 1b, iii: 63%)
3d: R1 = BnO, R2 = H, R4 = H (1b, iii: 57%)
BnO
O
R1
CH2(CN)CONHR4
1a, 1b
R2
(iii)
NC
R4 = H
R
NHR4
4 = p-MeOC6H4
O
4
Scheme 1 Reagents and conditions: (i) piperidine, AcOH, toluene, reflux (ii) EtOH, reflux; (iii) piperidine, AcOH, chlorobenzene, reflux
SYNTHESIS 2005, No. 16, pp 2758–2764
x
x.
x
x
.
2
0
0
5
Advanced online publication: 22.07.2005
DOI: 10.1055/s-2005-872095; Art ID: T03705SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Pentose Glycals with Push-Pull Butadiene Functionality
2759
lyst in boiling toluene and were completed within one
hour.
BnO
BnO
CH2(Ac)CONHR5
O
R1
O
R1
(i)
The structures were established by IR and NMR spectros-
copy. The IR spectra showed the expected carbonyl and
nitrile bands at 1715 and 2217 cm–1 for compound 2a and
at 1723 and 2219 cm–1 for compound 2b. The 13C NMR
spectra shows a strong p-interaction between the donor
(ring O-atom) and acceptor groups (CN and CO2R3) and
the butadiene double bonds. Thus, in accordance with this
typical push-pull butadiene behavior,14,15 the signals of C-
2 (d = 111.7, 113.1) and exocyclic C-2¢ (d = 95.1, 94.8)
were shifted upfield. On the other hand, the signals for the
C-1 (d = 162.6, 162.2) and C-1¢ (d = 154.8, 153.7)
showed the expected downfield shift. The NMR spectra of
2a, 2b exhibited the existence of only one diastereomer
for each product. In both cases the E-isomer obtained was
confirmed by recording the gated-decoupling spectra.
Vicinal couplings of 13.3 Hz for 2a and 2b were found be-
tween the C atom of the nitrile group and the H-1¢ proton.
On the other hand, coupling constants of 3.7 Hz between
the C-atom of the CO2R3 group and H-1¢ were found.
These coupling constants prove the E-arrangement of CN
and H-1¢.
CHO
R2
R5 = Ph
R2
R5 = p-MeOC6H4
1a: R1 = H, R2 = BnO
1b: R1 = BnO, R2 = H
Ac
NHR5
O
5
OBn
1'
3'
4
3
5
Ac
O
2'
HO
R2 R1
2
6
1 N
R5
6a: R1 = H, R2 = BnO, R5 = Ph (68%)
6b: R1 = BnO, R2 = H, R5 = Ph (64%)
6c: R1 = H, R2 = BnO, R5 = p-MeOC6H4 (95%)
6d: R1 = BnO, R2 = H, R5 = p-MeOC6H4 (59%)
Scheme 2 Reagents and conditions: (i) piperidine, AcOH, chloro-
benzene, reflux
nucleosides 6a–d could be isolated in acceptable yields.
In the IR and NMR spectra of compounds 6a–d, signals
for a formyl group were absent. H-4 and H-6 appeared as
two doublets and gave the characteristic coupling in the
1H NMR spectra. Furthermore, broad bands at 3427–3445
cm–1 in the IR spectra confirmed the presence of an OH
group (Scheme 2).
The push-pull functionality of 2a, 2b should allow reac-
tions with nitrogen nucleophiles like aniline and 4-meth-
oxyaniline. In analogy to similar butadienes16 the
nucleophilic attack was most likely be initiated at C-1 fol-
lowed by cyclization under participation of the alkoxycar-
bonyl group to furnish the corresponding pyridine-C-
nucleoside analogues 3a–c in reasonable yields. The cor-
responding reaction of 2a, 2b with ammonia failed. But,
the condensation of compounds 1b with cyanoacetamide
under Knoevenagel–Cope conditions in chlorobenzene as
solvent resulted in the formation of 3d. Similar treatment
of compounds 1a, 1b with 2-cyano-N-(4-methoxyphe-
nyl)acetamide yielded dihydropyridinecarbonitriles 3a,
3c. It was, however, impossible to isolate the correspond-
ing push-pull butadienes 4. Compounds 3a–d have a spe-
cial relevance to the potential biological activity of other
2-pyridone-C-nucleosides.17,18
The inhibition of glutamate dehydrogenase by derivatives
of isophthalic acid has been investigated.19,20 Therefore, it
seemed interesting to synthesize the alkyl 5-[1,2-bis(ben-
zyloxy)-3-hydroxypropyl]-2-hydroxyisophthalates 8 by
conversion of 1a, 1b with dialkyl 3-oxopentanedioate us-
ing a similar strategy as described for the preparation of 3
and 6. The reactions of 1a, 1b with dialkyl 3-oxopen-
tanedioate were carried out in THF under reflux in the
presence of K2CO3 and 18-crown-6. The Knoevenagel
BnO
O
The IR spectra of compounds 3a–d proved the existence
of a cyano group. Furthermore, there were also absorp-
tions which are typical for the OH group in the sugar
chain. The corresponding mass spectra showed the ex-
pected molecular peaks for 3a–d. In the 1H NMR spectra
the typical long-range coupling constant of pyridine pro-
tons H-4 and H-6 (4J = 2.5 Hz) confirmed the success of
the ring transformation.
R1
O=C(CH2COOR6)2
(i)
1a, 1b
R2
R6OOC
R6 = Me
R6 = Et
O
COOR6
7
OBn
1'
3'
6
1 COOR6
2'
R2 R1
5
Similarly, N-substituted oxobutyramides under Knoeve-
nagel–Cope conditions in the presence of piperidinium
acetate could allow the synthesis of corresponding
branched-chain pentose glycals 5 with a push-pull butadi-
ene unit. These compounds should afford with ammonia
and primary amines in a ring transformation reaction the
corresponding pyridine derivatives. Actually, the interme-
diates 5 were not isolable because of their spontaneous
ring opening and ring closure reaction. The pyridone-C-
HO
2
4
OH
3
COOR6
8a: R1 = H, R2 = BnO, R6 = Me (83%)
8b: R1 = H, R2 = BnO, R6 = Et (83%)
8c: R1 = BnO, R2 = H, R6 = Me (83%)
8d: R1 = BnO, R2 = H, R6 = Et (57%)
Scheme 3 Reagents and conditions: (i) THF, K2CO3, 18-crown-6,
reflux
Synthesis 2005, No. 16, 2758–2764 © Thieme Stuttgart · New York

2760
A. Bari et al.
PAPER
condensation and the following ring transformation pro- ring resulting in the ring transformation reaction. Howev-
cess of the unisolable monosaccharidic push-pull buta- er, the primary addition of ring NH of benzimidazol-2-
dienes 7 yielded the expected compounds 8 in good yields ylacetonitrile to the formyl group to furnish the glycal de-
(Scheme 3).
rivatives 10 followed by the sugar ring opening, ring clo-
sure reaction and the cleavage of H2O should afford the
same target compounds 11a, 11b.
The IR spectra of 5-[1,2-bis(benzyloxy)-3-hydroxypro-
pyl]-2-hydroxyisophthalates 8 showed two absorption
bands for the ester groups, one for the free ester group, and The successful ring transformation was proved by the typ-
the other one representing the association with the phenol- ical couplings between H-1 and H-3 (4J = 1.5 Hz). Fur-
ic OH group. Likewise, the NMR spectra of these com- thermore, the polycyclic structure was confirmed by
pounds proved the absence of a formyl group and the correlations found between the protons H-1 and H-9 ob-
presence of hydroxy and two alkoxycarbonyl groups, served in a two-dimensional 1H,1H NOESY spectrum re-
each. The NMR signals of the C and H atoms could unam- corded for 11a. Cross peaks between H-1 of the
biguously be assigned with 13C,1H correlation experi- heterocyclic part and H-1¢ of the attached acyclic sugar
ments confirming the postulated structures. For the two moiety were also observed, which proved that a confor-
aromatic protons H-4 and H-6 only one singlet appeared mation with respect to C-1¢–C-2-bond should be preferred
1
in the H NMR spectra and, the signals for the phenolic in which both protons are arranged in a neighboring fash-
OH protons were observed at about d = 11.80–11.90.
ion.
From the literature, nucleoside analogues synthesized
with an imidazo[1,2-a]pyridine skeleton are known and
showed antiviral activity.21,22 Starting with the formylated
pentose glycals 1a, 1b we planned to prepare similar acy-
clo-C-nucleosides. Following the Knoevenagel–Cope re-
action conditions with piperidinium acetate as catalyst, we
synthesized the corresponding polycyclic C-nucleoside
analogues by treating compounds 1a, 1b with benzimida-
The chemical reagents used were obtained from Fluka, Sigma-Ald-
rich and Merck and were applied without further purifications. Sol-
vents were distilled and if necessary dried using standard
procedures. For the reactions carried out under anhydrous condi-
tions, the glassware was dried in an oven thermostated at 100 °C.
The inert gas utilized for all reactions was argon. Silica gel column
chromatography was performed on silica gel 60 (Merck) having 70–
230 mesh and was used as received. Merck silica gel 60 GF254 was
zol-2-ylacetonitrile. The reactions were completed within applied for TLC with detection by UV light and/or by charring with
5% H2SO4 in MeOH.
three hours under reflux using a Dean–Stark trap to give
the 2-[1,2-bis(benzyloxy)-3-hydroxypropyl]benzo[4,5]imi-
dazo[1,2-a]pyridine-4-carbonitriles 11a, 11b in a ring
opening and ring closure reaction in yields of 67% and
56%, respectively (Scheme 4).
IR spectra were analyzed with a Nicolet 205 FT-IR spectrometer.
Specific rotations were determined with a Gyromat HP (Dr.
1
Kernchen). H NMR spectra (250.13 MHz and 300.13 MHz) and
13C NMR spectra (62.9 MHz and 75.5 MHz) were recorded on
Bruker instruments AC 250 and ARX 300 with CDCl3 and DMSO-
d6, respectively, as solvent. The calibration of spectra was carried
out on solvent signals [CDCl3:d(1H) = 7.25; d(13C) = 77.0; DMSO-
d6: d(1H) = 2.50; d(13C) = 39.7]. The 1H and 13C NMR signals were
Knoevenagel–Cope condensation of benzimidazol-2-yl-
acetonitrile with the formyl group should at first afford the
branched-chain glycals 9 possessing a push-pull butadi-
ene functionality. But, these compounds were not isolable
because of the immediately following nucleophilic substi-
tution by attack of the free NH group at C-1 of the sugar
1
1
assigned by DEPT and two-dimensional H,1H COSY and H,13C
correlation spectra (HETCOR, HMBC). The mass spectra were re-
corded on an AMD 402/3 spectrometer (AMD Intectra GmbH). El-
BnO
O
R1
R2
NC
NH
N
8
9
OBn
1'
3'
1
9a
7
10
N
2'
N
– H2O
(i)
HO
9
2
R2 R1
+
6
1a, 1b
5a
3
N
5
NH
4a
CN
NC
4
BnO
11a: R1 = H, R2 = OBn (67%)
11b: R1 = OBn, R2 = H (56%)
O
– H2O
R1
R2
HO
CN
N
N
10
Scheme 4 Reagents and conditions: (i) piperidine, AcOH, chlorobenzene, reflux
Synthesis 2005, No. 16, 2758–2764 © Thieme Stuttgart · New York

PAPER
Pentose Glycals with Push-Pull Butadiene Functionality
2761
emental analyses were performed on a CHNS automatic elemental
analyser Flash EA 1112 (ThermoQuest).
was purified by column chromatography (CHCl3–MeOH, 9:1) to
give 3a; yield: 142 mg (62%); yellow syrup.
Method B: To a stirred solution of 1a (100 mg, 0.30 mmol) in chlo-
robenzene (5 mL) was added 2-cyano-N-(4-methoxyphenyl)acet-
amide (116 mg, 0.61 mmol), followed by piperidine (0.013 mL,
0.13 mmol) and AcOH (0.031 mL, 0.54 mmol). The mixture was re-
fluxed using a Dean–Stark trap for 2 h. After removal of the solvent
under reduced pressure, the residue obtained was purified by col-
umn chromatography (CHCl3–MeOH, 9:1) to give 3a; yield: 145
mg (95%); yellow syrup; Rf 0.45 (CHCl3–MeOH, 9:1); [a]D21 –16.5
(c = 0.5, CHCl3).
1,5-Anhydro-3,4-di-O-benzyl-2-[(E)-2-cyano-2-ethoxycarbon-
ylvinyl]-2-deoxy-D-threo-hex-1-enitol (2a)
To a stirred solution of 1a (250 mg, 0.77 mmol) in toluene (10 mL)
was added ethyl cyanoacetate (0.165 mL, 1.55 mmol), followed by
piperidine (0.032 mL, 0.32 mmol) and AcOH (0.077 mL, 1.34
mmol). The mixture was heated under reflux using a Dean–Stark
trap for 1 h. After removal of the solvent under reduced pressure, the
residue obtained was purified by column chromatography (toluene–
EtOAc 10:1) to give 2a as yellow syrup; yield: 300 mg (92%); yel-
low syrup; Rf 0.40 (toluene–EtOAc, 9.5:0.5); [a]D23 –17.8 (c = 0.5,
CHCl3).
IR (capillary): 3443 (OH), 2227 cm–1 (C≡N).
1NMR (250 MHz, CDCl3): d = 2.05 (br s, 1 H, OH), 3.53–3.60 (m,
2 H, H-2¢, H-3¢a), 3.72–3.80 (m, 1 H, H-3¢b), 3.83 (s, 3 H, OCH3),
4.38 (d, 2 H, 3J1¢,2¢ = 4.5 Hz, H-1¢), 4.41 (d, 1 H, 2J = 12.0 Hz, CHH-
Ph), 4.55 (d, 1 H, 2J = 11.8 Hz, CHHPh), 4.58 (d, 1 H, 2J = 12.0 Hz,
IR (capillary): 1715 (C=O), 2217 cm–1 (C≡N).
1H NMR (250 MHz, CDCl3): d = 1.36 (t, 3 H, J = 7.0 Hz, CH3),
3
3.88 (m, 1 H, H-4), 4.20 (br d, 1 H, 2J5ax,5eq = 12.0 Hz, H-5ax), 4.32
2
CHHPh), 4.70 (d, 1 H, J = 11.8 Hz, CHHPh), 6.95 (m, 2 H, m-
3
3
(q, 2 H, J = 7.0 Hz, CH2CH3), 4.39 (dt, 1 H, J4,5eq = 4J3,5eq = 2.0
Hz, H-5eq), 4.52 (d, 1 H, 2J = 10.8 Hz, CHHPh), 4.64 [q(AB), 2 H,
2J = 12.5 Hz, CH2Ph], 4.89 (dd, 1 H, 3J3,4 = 2.5 Hz, 4J3,5eq = 2.0 Hz,
CHarom, C6H4), 7.17 (m, 2 H, o-CHarom, C6H4), 7.21–7.36 (m, 10 H,
2 C6H5), 7.50 (d, 1 H, 4J4,6 = 2.5 Hz, H-6), 7.82 (d, 1 H, 4J4,6 = 2.5
Hz, H-4).
13C NMR (62.9 MHz, CDCl3): d = 55.5 (OCH3), 61.0 (C-3¢), 71.9
(CH2Ph), 73.2 (CH2Ph), 77.3 (C-1¢), 80.7 (C-2¢), 105.5 (C-3), 114.5
(m-CHarom, C6H4), 115.5 (CN), 116.5 (C-5), 128.0–129.0 (o-, m-, p-
CHarom, C6H5), 127.0 (o-CHarom, C6H4), 132.1 (i-Carom, C6H4), 136.9
(i-Carom, C6H5), 137.5 (i-Carom, C6H5), 142.0 (C-6), 147.0 (C-4),
159.9 (C=O).
2
H-3), 4.99 (d, 1 H, J = 10.8 Hz, CHHPh), 7.18–7.38 (m, 11 H,
H-1, 2 C6H5), 7.72 (s, 1 H, H-1¢).
13C NMR (62.9 MHz, CDCl3): d = 14.3 (CH3), 62.0 (CH2), 65.1 (C-
5), 66.6 (C-3), 68.1 (C-4), 69.7 (CH2Ph), 71.2 (CH2Ph), 95.1 (C-2¢),
111.7 (C-2), 116.7 (CN), 127.8–129.0 (o-, m-, p-CHarom), 137.1 (i-
Carom), 137.8 (i-Carom), 154.8 (C-1¢), 162.6 (C-1), 163.8 (C=O).
MS (CI, isobutane): m/z (%) = 420 (27, MH+), 313 (90, MH –
MS (CI, isobutane): m/z (%) = 497 (78, MH+), 91 (100).
OBn+), 91 (100).
Anal. Calcd for C30H28N2O5: C, 72.56; H, 5.68; N, 5.64. Found: C,
72.82; H, 5.90; N, 5.36.
Anal. Calcd for C25H25NO5: C, 71.58; H, 6.01; N, 3.34. Found: C,
71.86; H, 6.06; N, 3.39.
5-[1R,2S-1,2-Bis(benzyloxy)-3-hydroxypropyl]-2-oxo-1-phenyl-
1,2-dihydropyridine-3-carbonitrile (3b)
Compound 2b (200 mg, 0.49 mmol) was reacted with aniline (0.091
mL, 0.99 mmol) as described above under Method A; yield: 93 mg
(41%); yellow syrup; Rf = 0.40 (toluene–EtOAc, 9:1); [a]D21 –9.53
(c = 1, CHCl3).
1,5-Anhydro-3,4-di-O-benzyl-2-[(E)-2-cyano-2-methoxycarbo-
nylvinyl]-2-deoxy-L-erythro-hex-1-enitol (2b)
The reaction of 1b (100 mg, 0.30 mmol) with methyl cyanoacetate
(0.030 mL, 0.33 mmol), piperidine (0.013 mL, 0.13 mmol) and
AcOH (0.031 mL, 0.54 mmol) in toluene (10 mL) was carried out
by a procedure similar to that described for 1a; yield: 70 mg (56%);
yellow syrup; Rf 0.50 (toluene–EtOAc, 10:1); [a]D24 –9.8 (c = 0.5,
CHCl3).
IR (capillary): 3448 (OH), 2227 cm–1 (C≡N).
1H NMR (250 MHz, CDCl3): d = 2.03 (t, 1 H, 3J3¢,OH = 6.0 Hz, OH),
3
3
IR (capillary): 1723 (C=O), 2219 cm–1 (C≡N).
3.49 (dt, 1 H, J1¢,2¢ = 8.0 Hz, J2¢,3¢ = 4.0 Hz, H-2¢), 3.83 (dd, 2 H,
3J3¢,OH = 6.0 Hz, 3J2¢,3¢ = 4.0 Hz, H-3¢a,b), 4.22 (d, 1 H, J1¢,2¢ = 8.0
3
1H NMR (300 MHz, CDCl3): d = 3.86 (s, 3 H, CH3), 3.89 (ddd, 1 H,
Hz, H-1¢), 4.34 (d, 1 H, 2J = 11.6 Hz, CHHPh), 4.46 [q(AB), 2 H,
3
3J4,5ax = 11.0 Hz, J4,5eq = 4.5 Hz, 3J3,4 = 2.5 Hz, H-4), 4.24 (ddd, 1
2J = 11.6 Hz, CH2Ph], 4.62 (d, 1 H, J = 11.6 Hz, CHHPh), 7.10–
2
H, 2J5ax,5eq = 10.5 Hz, 3J4,5eq = 4.5 Hz, 4J3,5eq = 1.5 Hz, H-5eq), 4.41
(dd, 1 H, 2J4,5ax = 11.0 Hz, 2J5ax,5eq = 10.5 Hz, H-5ax), 4.75 [q(AB),
2 H, 2J = 11.8 Hz, CH2Ph], 5.10 [q(AB), 2 H, 2J = 10.5 Hz,
CH2Ph], 5.24 (dd, 1 H, 3J3,4 = 2.5 Hz, 4J3,5eq = 1.5 Hz, H-3), 7.20 (s,
1 H, H-1), 7.23–7.43 (m, 10 H, 2 C6H5), 7.66 (s, 1 H, H-1¢).
7.13 (m, 2 H, NC6H5), 7.23–7.35 (m, 10 H, 2 C6H5), 7.43 (d, 1 H,
4J4,6 = 2.5 Hz, H-6), 7.44–7.49 (m, 3 H, NC6H5), 7.74 (d, 1 H,
4J4,6 = 2.5 Hz, H-4).
13C NMR (62.9 MHz, CDCl3): d = 60.8 (C-3¢), 71.7 (CH2Ph), 72.5
(CH2Ph), 76.9 (C-1¢), 80.0 (C-2¢), 106.3 (C-3), 115.3 (CN), 117.0
13C NMR (75.5 MHz, CDCl3): d = 53.0 (CH3), 64.1 (C-5), 66.5 (C-
3), 71.8 (CH2Ph), 72.3 (CH2Ph), 74.0 (C-4), 94.8 (C-2¢), 113.1 (C-
2), 116.7 (CN), 127.6-128.7 (o-, m-, p-CHarom), 137.2 (i-Carom),
138.6 (i-Carom), 153.7 (C-1¢), 162.2 (C-1), 164.0 (C=O).
(C-5), 126.0–129.5 (o-, m-, p-CH, C6H5 and NC6H5), 136.7 (i-Carom
,
C6H5), 136.8 (i-Carom, C6H5), 139.4 (i-Carom, NC6H5), 141.8 (C-6),
146.6 (C-4), 158.9 (C=O).
MS (CI, isobutane): m/z (%) = 467 (100, MH+), 359 (19) (MH –
MS (EI, 70 eV): m/z (%) = 405 (10, M+), 91 (100).
OBn+), 91 (25).
Anal. Calcd for C24H23NO5: C, 71.10; H, 5.72; N, 3.45. Found: C,
70.89; H, 6.02; N, 3.36.
Anal. Calcd for C29H26N2O4: C, 74.66; H, 5.62; N, 6.00. Found: C,
74.42; H, 5.59; N, 5.69.
5-[1R,2R-1,2-Bis(benzyloxy)-3-hydroxypropyl]-1-(4-methoxy-
phenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (3a); Typical
Procedures
Method A: To a stirred solution of 2a (150 mg, 0.35 mmol) in anhyd
EtOH (10 mL) was added 4-methoxyaniline (0.088 mL, 0.77 mmol)
at r.t. The resulting mixture was then refluxed for 1.5 h. After re-
moval of the solvent under reduced pressure, the residue obtained
5-[1R,2S-1,2-Bis(benzyloxy)-3-hydroxypropyl]-1-(4-methoxy-
phenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (3c)
Method A: Compound 2b (225 mg, 0.55 mmol) was reacted with 4-
methoxyaniline (0.13 mL, 1.1 mmol) in anhyd EtOH (10 mL) as de-
scribed above for 3a; yield: 179 mg (65%); yellow syrup.
Method B: Compound 1b, (150 mg, 0.46 mmol) 2-cyano-N-(4-
methoxyphenyl)acetamide (175 mg, 0.92 mmol), piperidine (0.021
mL, 0.21 mmol) and AcOH (0.049 mL, 0.85 mmol) were reacted in
Synthesis 2005, No. 16, 2758–2764 © Thieme Stuttgart · New York

2762
A. Bari et al.
PAPER
2
chlorobenzene (6 mL) as described above for 3a; yield: 145 mg
(63%); yellow syrup; Rf 0.30 (CHCl3–MeOH, 9:1); [a]D –11.2
(c = 1, CHCl3).
IR (capillary): 3446 (OH), 2226 cm–1 (C≡N).
3J1¢,2¢ = 5.5 Hz, H-1¢), 4.60 (d, 1 H, J = 12.0 Hz, CHHPh), 4.66
24
2
[q(AB), 2 H, J = 11.6 Hz, CH2Ph], 7.23–7.35 (m, 12 H, C6H5,
NC6H5), 7.43–7.50 (m, 3 H, C6H5), 7.60 (d, 1 H, 4J4,6 = 2.8 Hz, H-
6), 8.18 (d, 1 H, 4J4,6 = 2.8 Hz, H-4).
13C NMR (62.9 MHz, CDCl3): d = 31.1 (CH3), 61.5 (C-3¢), 71.6
(CH2Ph), 73.5 (CH2Ph), 78.3 (C-1¢), 81.0 (C-2¢), 115.9 (C-5),
126.4–129.4 (o-, m-, p-CHarom, C6H5, NC6H5, C-3), 137.2 (i-Carom
C6H5), 137.7 (i-Carom, C6H5), 140.3 (i-Carom, NC6H5), 142.0 (C-6),
143.2 (C-4), 160.7 (C=O), 197.4 (MeCO).
MS (CI, isobutane): m/z (%) = 484 (90, M + H+), 332 (35, M –
1H NMR (250 MHz, CDCl3): d = 2.07 (br s, 1H, OH), 3.47 (dt, 1 H,
3J1¢,2¢ = 8.0 Hz, 3J2¢,3¢ = 4.0 Hz, H-2¢), 3.83 (br s, 2 H, H-3¢a,b), 3.84
,
3
(s, 3 H, OCH3), 4.22 (d, 1 H, J1¢,2¢ = 8.0 Hz, H-1¢), 4.33 (d, 1 H,
2
2J = 11.8 Hz, CHHPh), 4.45 [q(AB), 2 H, J = 11.5 Hz, CH2Ph],
4.62 (d, 1 H, 2J = 11.8 Hz, CHHPh), 6.95 (m, 2 H,m- CHarom, C6H4),
7.09–7.13 (m, 2 H, C6H5), 7.15 (m, 2 H, o-CHarom, C6H4), 7.22–7.35
4
(m, 8 H, C6H5), 7.42 (d, 1 H, J4,6 = 2.5 Hz, H-6), 7.72 (d, 1 H,
HOCH2CHOBn+), 91 (84).
4J4,6 = 2.5 Hz, H-4).
HRMS: m/z calcd for C30H29NO5: 483.2046; found: 483.2045.
13C NMR (62.9 MHz, CDCl3): d = 55.6 (OMe), 60.8 (C-3¢), 71.7
(CH2Ph), 72.5 (CH2Ph), 76.9 (C-1¢), 80.0 (C-2¢), 106.0 (C-3), 114.6
(m-CHarom, C6H4), 115.4 (CN), 116.8 (C-5), 127.1–128.7 (o-, m-, p-
3-Acetyl-5-[1R,2S-1,2-bis(benzyloxy)-3-hydroxypropyl]-1-phe-
nyl-1,2-dihydropyridin-2-one (6b)
CHarom, C6H5, o-CHarom, C6H4), 132.2 (i-Carom, C6H4), 136.9 (i-Carom
C6H5), 136.9 (i-Carom, C6H5), 142.3 (C-6), 146.5 (C-4), 159.3 (p-
CHarom, C6H4), 159.9 (C=O).
,
The reaction of 1b (250 mg, 0.77 mmol) with acetoacetanilide (275
mg, 1.55 mmol), piperidine (0.035 mL, 0.35 mmol) and AcOH
(0.08 mL, 1.39 mmol) in chlorobenzene (5 mL) was carried out as
described for 6a; yield: 240 mg (64%); yellow syrup; Rf 0.35 (tolu-
ene–EtOAc, 6:4); [a]D21 –10.7 (c = 1, CHCl3).
MS (EI, 70 eV): m/z (%) = 496 (5, M+), 345 (100, M –
HOCH2CHOBn+), 91 (84).
IR (capillary): 3434 (OH), 1680 cm–1 (C=O).
HRMS: m/z calcd for C30H28N2O5: 496.1998; found: 496.1998.
1H NMR (250 MHz, CDCl3): d = 2.27 (br s, 1 H, OH), 2.69 (s, 3 H,
CH3), 3.56 (dt, 1 H, 3J1¢,2¢ = 8.0 Hz, 3J2¢,3¢ = 4.0 Hz, H-2¢), 3.82 (d, 2
H, 3J2¢,3¢ = 4.0 Hz, H-3¢a,b), 4.26 (d, 1 H, 3J1¢,2¢ = 8.0 Hz, H-1¢), 4.34
(d, 1 H, 2J = 11.6 Hz, CHHPh), 4.38 (d, 1 H, 2J = 11.6 Hz, CHHPh),
5-[1R,2S-1,2-Bis(benzyloxy)-3-hydroxypropyl]-2-oxo-1,2-dihy-
dropyridine-3-carbonitrile (3d)
To a stirred solution of 1b (300 mg, 0.92 mmol) in chlorobenzene
(10 mL) was added cyanoacetamide (199 mg, 2.3 mmol), followed
by piperidine (0.042 mL, 0.42 mmol) and AcOH (0.098 mL, 1.71
mmol). The mixture was refluxed using a Dean–Stark trap for 3 h.
After removal of the solvent under reduced pressure, the residue ob-
tained was purified by column chromatography (CHCl3–MeOH,
9:1) to give 3d; yield: 205 mg (57%); yellow syrup; Rf 0.45
(CHCl3–MeOH, 9:1); [a]D21 –28.7 (c = 1, CHCl3).
2
2
4.54 (d, 1 H, J = 11.6 Hz, CHHPh), 4.58 (d, 1 H, J = 11.6 Hz,
CHHPh), 7.07–7.33 (m, 12 H, 2 C6H5, NC6H5), 7.43–7.51 (m, 4 H,
NC6H5, H-6), 8.21 (d, 1 H, 4J4,6 = 2.8 Hz, H-4).
13C NMR (62.9 MHz, CDCl3): d = 31.1 (CH3), 61.3 (C-3¢), 71.4
(CH2Ph), 72.7 (CH2Ph), 77.7 (C-1¢), 80.7 (C-2¢), 116.6 (C-5),
126.4–129.5 (o-, m-, p-CHarom, C6H5, NC6H5, C-3), 137.1 (i-Carom
,
C6H5), 137.2 (i-C6H5), 140.2 (i-Carom, NC6H5), 142.1 (C-6), 143.1
(C-4), 160.8 (C=O), 197.3 (MeCO).
IR (capillary): 3445 (OH), 2230 cm–1 (C≡N).
1H NMR (250 MHz, DMSO-d6): d = 3.50–3.55 (br m, 2 H, H-3¢a,b),
3.67 (q, 1 H, 3J1¢,2¢ = 3J2¢,3¢ = 5.8 Hz, H-2¢), 4.39 [q(AB), 2 H,
2J = 12.0 Hz, CH2Ph], 4.39 (d, 1 H, 3J1¢,2¢ = 5.8 Hz, H-1¢), 4.50 (d, 1
MS (CI, isobutane): m/z (%) = 484 (60, M + H+), 332 (30, M –
HOCH2CHOBn+), 91 (100).
Anal. Calcd for C30H29NO5: C, 74.52; H, 6.04; N, 2.90. Found: C,
74.26; H, 5.86; N, 2.71.
2
2
H, J = 12.0 Hz, CHHPh), 4.66 (d, 1 H, J = 12.0 Hz, CHHPh),
4.78 (t, 1 H, J = 5.5 Hz, OH), 7.15–7.35 (m, 10 H, 2 C6H5), 7.68 (d,
1 H, 4J4,6 = 2.5 Hz, H-6), 8.03 (d, 1 H, J4,6 = 2.5 Hz, H-4), 12.50
4
3-Acetyl-5-[1R,2R-1,2-bis(benzyloxy)-3-hydroxypropyl]-1-(4-
methoxyphenyl)-2-oxo-1,2-dihydropyridine-2-one (6c)
(br s, NH).
13C NMR (75.4 MHz, DMSO-d6): d = 60.5 (C-3¢), 70.3 (CH2Ph),
72.2 (CH2Ph), 77.0 (C-1¢), 81.3 (C-2¢), 103.3 (C-3), 116.3, 116.6
(C-5, CN), 127.5–128.4 (o-, m-, p-CHarom), 138.3 (i-Carom), 138.7 (i-
The reaction of 1a (100 mg, 0.30 mmol) with N-(4-methoxyphe-
nyl)-3-oxobutyramide (127 mg, 0.61 mmol), piperidine (0.013 mL,
0.13 mmol) and AcOH (0.031 mL, 0.54 mmol) in chlorobenzene (5
mL) was carried out as described for 6a; yield: 151 mg (95%); yel-
Carom), 140.7 (C-6), 149.0 (C-4), 160.0 (C=O).
21
low syrup; Rf 0.4 (toluene–EtOAc, 6:4); [a]D –55.2 (c = 0.5,
MS (CI, isobutane): m/z (%) = 391 (82, MH+), 91 (100).
CHCl3).
Anal. Calcd for C23H22N2O4: C, 70.75; H, 5.68; N, 7.17. Found: C,
70.48; H, 5.77; N, 6.90.
IR (capillary): 3438 (OH), 1678 cm–1 (C=O).
1H NMR (250 MHz, CDCl3): d = 2.07 (br s, 1 H, OH), 2.69 (s, 3 H,
3-Acetyl-5-[1R,2R-1,2-bis(benzyloxy)-3-hydroxypropyl]-1-phe-
nyl-1,2-dihydropyridin-2-one (6a); Typical Procedure
CH3), 3.52 (m, 1 H, H-3¢a), 3.71 (dt, 1 H, 3J1¢,2¢ = 5.5 Hz,
2
3J2¢,3¢a = 3J2¢,3¢b = 4.2 Hz, H-2¢), 3.73 (dd, 1 H, J3¢a,b = 11.0 Hz,
To a stirred solution of 1a (100 mg, 0.30 mmol) in chlorobenzene
(5 mL) was added acetoacetanilide (110 mg, 0.62 mmol), followed
by piperidine (0.013 mL, 0.13 mmol) and AcOH (0.031 mL, 0.54
mmol). The mixture was refluxed using a Dean–Stark trap for 3 h.
After removal of the solvent under reduced pressure, the residue ob-
tained was purified by column chromatography (toluene–EtOAc,
6:4) to give 6a; yield: 101 mg (68%); yellow syrup; Rf 0.45 (tolu-
ene–EtOAc, 6:4); [a]D21 –50.1 (c = 0.5 CHCl3).
3J2¢,3¢b = 4.2 Hz, H-3¢b), 3.85 (s, 3 H, OCH3), 4.40 (d, 1 H, 2J = 12.0
3
Hz, CHHPh), 4.43 (d, 1 H, J1¢,2¢ = 5.2 Hz, H-1¢), 4.60 (d, 1 H,
2
2J = 12.0 Hz, CHHPh), 4.66 [q(AB), 2 H, J = 11.6 Hz, CH2Ph],
6.98 (m, 2 H, m-CHarom, C6H4), 7.17–7.32 (m, 12 H, 2 C6H5, o-
4
CHarom, C6H4), 7.59 (d, 1 H, J4¢,6¢ = 2.8 Hz, H-6), 8.17 (d, 1 H,
4J4¢,6¢ = 2.8 Hz, H-4).
13C NMR (62.9 MHz, CDCl3): d = 31.0 (CH3), 55.6 (OCH3), 61.5
(C-3¢), 71.6 (CH2Ph), 73.5 (CH2Ph), 78.3 (C-1¢), 81.0 (C-2¢), 114.6
(m-CHarom, C6H4), 115.7 (C-5), 127.5–129.0 (o-, m-, p-CHarom,
IR (capillary): 3427 (OH), 1680 cm–1 (C=O).
C6H4, and C-3), 133.0 (i-Carom, C6H4), 137.2 (i-Carom, C6H5), 137.8
(i-Carom, C6H5), 142.4 (C-6), 143.1 (C-4), 159.7 (p-CHarom, C6H4),
161.0 (C=O), 197.5 (MeCO).
1H NMR (250 MHz, CDCl3): d = 2.07 (br s, 1 H, OH), 2.68 (s, 3 H,
CH3), 3.55 (dd, 1 H, 2J3¢a,b = 11.5 Hz, 3J2¢,3¢ = 4.8 Hz, H-3¢a), 3.63 (q,
1 H, 3J2¢,3¢ = 4.8 Hz, H-2¢), 3.73 (dd, 1 H, 2J3¢a,b = 11.5 Hz,3J2¢,3¢ = 4.8
2
Hz, H-3¢b), 4.40 (d, 1 H, J = 12.0 Hz, CHHPh), 4.43 (d, 1 H,
Synthesis 2005, No. 16, 2758–2764 © Thieme Stuttgart · New York

PAPER
Pentose Glycals with Push-Pull Butadiene Functionality
2763
MS (CI, isobutane): m/z (%) = 513 (10, M + H+), 362 (28, M –
and K2CO3 (57 mg, 0.41 mmol) in anhyd THF (10 mL) was carried
as described for 8a; yield: 133 mg (83%); yellow syrup; Rf 0.35 (tol-
uene–EtOAc, 9:1); [a]D21 –49.6 (c = 1, CHCl3).
IR (capillary): 3516 (OH), 1730, 1672 cm–1 (C=O).
HOCH2CHOBn+), 91 (100).
HRMS: m/z calcd for C31H31NO6: 513.2151; found: 513.2154.
3-Acetyl-5-[1R,2S-1,2-bis(benzyloxy)-3-hydroxypropyl]-1-(4-
methoxyphenyl)-1,2-dihydropyridine-2-one (6d)
1H NMR (250 MHz, CDCl3): d = 1.40 (t, 6 H, 3J = 7.0 Hz, 2 CH3),
2.09 (br s, 1 H, OH), 3.44 (dd, 1 H, 2J3¢a,b = 11.7 Hz, 3J2¢,3¢a = 5.8 Hz,
H-3¢a), 3.60 (dd, 1 H, 2J3¢a,b = 11.7 Hz, 3J2¢,3¢b = 4.5 Hz, H-3¢b), 3.66
(m, 2 H, H-2¢), 4.30 (d, 1 H, 2J = 12.0 Hz, CHHPh), 4.41 (q, 4 H,
3J = 7.0 Hz, 2 CH2CH3), 4.54 (d, 1 H, 2J = 12.0 Hz, CHHPh), 4.55
(d, 1 H, J1,2¢ = 5.5 Hz, H-1¢), 4.64 [q(AB), 2 H, J = 11.8 Hz,
CH2Ph], 7.20–7.35 (m, 10 H, 2 C6H5), 8.04 (s, 2 H, H-4, H-6), 11.80
(s, 1 H, OH).
The reaction of 1b (250 mg, 0.30 mmol) with N-(4-methoxyphe-
nyl)-3-oxobutyramide (320 mg, 1.5 mmol), piperidine (0.035 mL,
0.35 mmol) and AcOH (0.08 mL, 1.39 mmol) in chlorobenzene (5
mL) was carried out as described for 6a; yield: 235 mg (59%); yel-
low syrup; Rf 0.4 (toluene–EtOAc, 6:4); [a]D21 –53.5 (c = 1, CHCl3).
3
2
IR (capillary): 3445 (OH), 1676 cm–1 (C=O).
1H NMR (250 MHz, CDCl3): d = 2.33 (br s, 1 H, OH), 2.69 (s, 3 H,
13C NMR (62.9 MHz, CDCl3): d = 14.2 (2 CH3), 61.6 (2 CH2CH3),
61.8 (C-3¢), 71.0 (CH2Ph), 73.8 (CH2Ph), 80.5 (C-1¢), 82.0 (C-2¢),
116.8 (C-1, C-3), 127.7–128.5 (o-, m-, p-CHarom), 128.9 (C-5),
134.9 (C-4, C-6), 137.6 (i-Carom), 138.0 (i-Carom), 161.3 (C-2), 167.4
(C=O).
MS (EI, 70 eV): m/z (%) = 463 (10, M – OC2H5)+, 91 (100).
HRMS: m/z calcd for C29H32O8 (M – C2H5O)+: 463.1757; found:
CH3), 3.56 (dt, 1 H, 3J1¢,2¢ = 7.8 Hz, 3J2¢,3¢ = 4.0 Hz, H-2¢), 3.81 (d, 2
3
H, J2¢,3¢ = 4.0 Hz, H-3¢a,b), 3.84 (s, 3 H, CH3O), 4.26 (d, 1 H,
3J1¢,2¢ = 7.8 Hz, H-1¢), 4.35 (d, 1 H, 2J = 11.6 Hz, CHHPh), 4.37 (d,
2
2
1 H, J = 11.6 Hz, CHHPh), 4.53 (d, 1 H, J = 11.6 Hz, CHHPh),
4.58 (d, 1 H, 2J = 11.6 Hz, CHHPh), 6.97 (m, 2 H, m-CHarom, C6H4),
7.09–7.32 (m, 12 H, 2 C6H5, o-CHarom, C6H4), 7.50 (d, 1 H,
4J4,6 = 2.8 Hz, H-6), 8.20 (d, 1 H, 4J4,6 = 2.8 Hz, H-4).
463.1756.
13C NMR (62.9 MHz, CDCl3): d = 31.0 (CH3), 55.5 (OCH3), 61.3
(C-3¢), 71.2 (CH2Ph), 72.6 (CH2Ph), 77.6 (C-1¢), 80.7 (C-2¢), 114.5
Dimethyl 5-[1R,2S-1,2-Bis(benzyloxy)-3-hydroxypropyl]-2-hy-
droxyisophthalate (8c)
(m-CHarom, C6H4), 116.4 (C-5), 127.5–128.6 (o-, m-, p-CHarom
,
C6H4, and C-3), 132.9 (i-CHarom, C6H4), 137.1 (i-Carom, C6H5), 137.2
(i-Carom, C6H5), 142.4, 142.9 (C-4, C-6), 159.6 (p-CHarom, C6H4),
160.0 (C=O), 197.3 (MeCO).
The reaction of 1b (100 mg, 0.30 mmol) with dimethyl 3-oxopen-
tanedioate (0.05 mL, 0.34 mmol), 18-crown-6 (57 mg, 0.21 mmol)
and K2CO3 (57 mg, 0.41 mmol) in anhyd THF (10 mL) was carried
out as described for 8a; yield: 92 mg (62%); yellow syrup; Rf 0.35
(toluene–EtOAc, 9:1); [a]D21 –16.5 (c = 0.25, CHCl3).
MS (CI, isobutane): m/z (%) = 514 (100, M + H+), 362 (40, M –
HOCH2CHOBn+), 91 (100).
Anal. Calcd for C31H31NO6: C, 72.50; H, 6.08; N, 2.73. Found: C,
72.21; H, 6.30; N, 3.02.
IR (capillary): 3507 (OH), 1731, 1678 cm–1 (C=O).
1H NMR (250 MHz, CDCl3): d = 2.22 (br s, 1 H, OH), 3.55 (dt, 1 H,
3J1¢,2¢ = 8.0 Hz, 3J2¢,3¢ = 4.2 Hz, H-2¢), 3.83 (br d, 2 H, H-3¢a,b), 3.94
(s, 6 H, 2 CH3), 4.18 (d, 1 H, 2J = 11.6 Hz, CHHPh), 4.28 (d, 1 H,
2J = 11.6 Hz, CHHPh), 4.41 (d, 1 H, 3J1¢,2¢ = 8.0 Hz, H-1¢), 4.42 (d,
1 H, 2J = 11.6 Hz, CHHPh), 4.47 (d, 1 H, 2J = 11.6 Hz, CHHPh),
6.97–7.02 (m, 2 H, 2 C6H5), 7.16–7.36 (m, 8 H, 2 C6H5), 8.02 (s, 2
H, H-4, H-6), 11.80 (s, 1 H, OH).
13C NMR (62.9 MHz, CDCl3): d = 52.4 (2 CH3), 61.9 (C-3¢), 71.0
(CH2Ph), 72.8 (CH2Ph), 80.2 (C-1¢), 81.6 (C-2¢), 116.3 (C-1, C-3),
127.7–128.5 (o-, m-, p-CHarom), 129.5 (C-5), 135.5 (C-4, C-6),
137.2 (i-Carom), 137.3 (i-Carom), 161.3 (C-2), 167.8 (C=O).
Dimethyl 5-[1R,2R-1,2-Bis(benzyloxy)-3-hydroxypropyl]-2-hy-
droxyisophthalate (8a)
To a vigorously stirred solution of 1a (100 mg, 0.30 mmol) in anhyd
THF (10 mL) was added 18-crown-6 (57 mg, 0.21 mmol), followed
by dimethyl 3-oxopentanedioate (0.050 mL, 0.34 mmol) and K2CO3
(57 mg, 0.41 mmol). The mixture was then refluxed for 2 h. After
this time, an additional amount of dimethyl 3-oxopentanedioate
(0.050, 0.34 mmol) was added and the mixture was refluxed again
for 1 h. After removal of the solvent under reduced pressure, the res-
idue obtained was purified by column chromatography (toluene–
EtOAc, 9:1) to give 8a; yield: 123 mg (83%); yellow syrup; Rf 0.40
(toluene–EtOAc, 9:1); [a]D23 –60.1 (c = 1, CHCl3).
MS (FAB+, NaCl): m/z (%) = 503 (90, M + Na)+, 91 (100).
Anal. Calcd for C27H28O8: C, 67.49; H, 5.87. Found: C, 67.32; H,
6.12.
IR (capillary): 3488 (OH), 1730 cm–1 (C=O).
1H NMR (250 MHz, CDCl3): d = 2.06 (br s, 1 H, OH), 3.40 (dd, 1
2
3
Diethyl 5-[1R,2S-1,2-Bis(benzyloxy)-3-hydroxypropyl]-2-hy-
droxyisophthalate (8d)
H, J3¢a,b = 11.5 Hz, J2¢,3¢a = 5.8 Hz, H-3¢a), 3.59 (dd, 1 H,
3
2J3¢a,b = 11.5 Hz, J2¢,3¢b = 4.2 Hz, H-3¢b), 3.66 (m, 1 H, H-2¢), 3.94
(s, 6 H, 2 CH3), 4.30 (d, 1 H, 2J = 12.0 Hz, CHHPh), 4.54 (d, 1 H,
To a vigorously stirred solution of 1b (100 mg, 0.30 mmol) in anhyd
THF (10 mL) was added 18-crown-6 (57 mg, 0.21 mmol), followed
by diethyl 3-oxopentanedioate (0.062 mL, 0.34 mmol) and K2CO3
(57 mg, 0.41 mmol). The mixture was then refluxed for 1.5 h. After
this time an additional amount of diethyl 3-oxopentanedioate (0.062
mL, 0.34 mmol) was added and the mixture was refluxed again for
1 h. After removal of the solvent under reduced pressure, the residue
obtained was purified by column chromatography (toluene–EtOAc,
9:1) to give 8d; yield: 130 mg (83%); yellow syrup; Rf 0.35 (tolu-
ene–EtOAc, 9:1); [a]D21 –56.5 (c = 1, CHCl3).
3
2J = 12.0 Hz, CHHPh), 4.55 (d, 1 H, J1¢,2¢ = 5.8 Hz, H-1¢), 4.66
[q(AB), 2 H, 2J = 11.6 Hz, CH2Ph], 7.22–7.35 (m, 10 H, 2 C6H5),
8.06 (s, 2 H, H-4, H-6), 11.85 (s, 1 H, OH).
13C NMR (62.9 MHz, CDCl3): d = 52.4 (2 CH3), 61.8 (C-3¢), 71.1
(CH2Ph), 73.8 (CH2Ph), 80.6 (C-1¢), 82.0 (C-2¢), 116.5 (C-1, C-3),
127.8–128.4 (o-, m-, p-CHarom), 128.6 (C-5), 135.3 (C-4, C-6),
136.6 (i-Carom), 137.9 (i-Carom), 161.2 (C-2), 167.8 (C=O).
MS (FAB+, NaCl): m/z (%) = 503 (20, M + Na)+, 91 (100).
Anal. Calcd for C27H28O8: C, 67.49; H, 5.87. Found: C, 67.23; H,
5.97.
IR (capillary): 3488 (OH), 1730, 1672 cm–1 (C=O).
3
1H NMR (250 MHz, CDCl3): d = 1.41 (t, 6 H, J (CH2,CH3)= 7.0
3
Hz, 2 CH3), 2.28 (br s, 1 H, OH), 3.56 (dt, 1 H, J1¢,2¢ = 8.0 Hz,
Diethyl 5-[1R,2R-1,2-Bis(benzyloxy)-3-hydroxypropyl]-2-hy-
droxyisophthalate (8b)
The reaction of 1a (100 mg, 0.30 mmol) with diethyl 3-oxopen-
3J2¢,3¢ = 4.2 Hz, H-2¢), 3.86 (br d, 2 H, H-3¢a,b), 4.19 (d, 1 H,
2J = 11.8 Hz, CHHPh), 4.31 (d, 1 H, 2J = 11.5 Hz, CHHPh), 4.38–
4.50 (m, 7 H, 3J1¢,2¢ = 8.0 Hz, 2 CH2CH3, H-1¢, 2 CHHPh), 6.98–
tanedioate (0.124 mL, 0.68 mmol), 18-crown-6 (57 mg, 0.21 mmol)
Synthesis 2005, No. 16, 2758–2764 © Thieme Stuttgart · New York

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A. Bari et al.
PAPER
7.02 (m, 2 H, C6H5), 7.18–7.36 (m, 8 H, C6H5), 8.04 (s, 2 H, H-4, H-
6), 11.90 (s, 1 H, OH).
13C NMR (62.9 MHz, CDCl3): d = 60.8 (C-3¢), 71.8 (CH2Ph), 72.5
(CH2Ph), 77.4 (C-1¢), 80.2 (C-2¢), 101.8 (C-4), 110.8 (C-9), 114.8
(CN), 120.6 (C-6), 121.6 (C-2), 122.5 (C-8), 126.9 (C-7), 127.9–
128.9 (o-, m-, p-CHarom, C-1, C-9a), 136.3 (C-3), 136.5 (i-Carom),
136.7 (i-Carom), 144.5 (C-5a), 145.1 (C-4a).
13C NMR (62.9 MHz, CDCl3): d = 14.2 (2 CH3), 61.6 (2 CH2CH3),
61.9 (C-3¢), 71.1 (CH2Ph), 72.8 (CH2Ph), 80.2 (C-1¢), 81.6 (C-2¢),
116.6 (C-1, C-3), 127.9–128.5 (o-, m-, p-CHarom), 129.4 (C-5),
135.2 (C-4, C-6), 137.2 (i-Carom), 137.3 (i-Carom), 161.4 (C-2), 167.4
(C=O).
MS (CI, isobutane): m/z (%) = 464 (100, M + H+), 356 (20, M –
OBn)+, 91 (85).
MS (CI, isobutane): m/z (%) = 509 (10, MH+), 91 (100).
Anal. Calcd for C29H25N3O3: C, 75.14; H, 5.44; N, 9.07. Found: C,
74.99; H, 5.55; N, 8.86.
+
HRMS: m/z calcd for C29H32O8 (M – C2H5O1 ): 463.1757; found:
463.1756.
Acknowledgment
2-[1R,2R-1,2-Bis(benzyloxy)-3-hydroxypropyl]benzo[4,5]imi-
dazo[1,2-a]pyridine-4-carbonitrile (11a)
We thank the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie for financial support.
To a stirred solution of 1a (100 mg, 0.30 mmol) in chlorobenzene
(10 mL) was added benzimidazol-2-ylacetonitrile (75 mg, 0.47
mmol), followed by piperidine (0.012 mL, 0.12 mmol) and AcOH
(0.03 mL, 0.52 mmol). The mixture was refluxed using a Dean–
Stark trap for 3 h. After removal of solvent under reduced pressure
the residue obtained was purified by column chromatography (tolu-
ene–EtOAc, 6:4) to give 11a; yield: 95 mg (67%); Rf 0.40 (toluene–
EtOAc, 6:4); yellow syrup; [a]D24 –24.3 (c = 1, CHCl3).
References
(1) Chen, J.; Sambaiah, T.; Illarionov, B.; Fischer, M.; Bacher,
A.; Cushman, M. J. Org. Chem. 2004, 69, 6996.
(2) Alahiane, A.; Rochdi, A.; Taourirte, M.; Redwane, N.; Sebti,
S.; Lazrek, H. B. Tetrahedron Lett. 2001, 42, 3579.
(3) Shaban, M. A. E.; Nasr, A. Z.; Morgaan, A. E. A. Pharmazie
2000, 55, 87.
IR (capillary): 3394 (OH), 2232 cm–1 (C≡N).
1H NMR (250 MHz, CDCl3): d = 2.64 (br s, 1 H, OH), 3.62–3.72
(m, 2 H, H-2¢, H-3¢a), 3.82–3.90 (m, 1 H, H-3¢b), 4.46 (d, 1 H,
2J = 12.0 Hz, CHHPh), 4.51 (d, 1 H,2J = 11.8 Hz, CHHPh), 4.65 (d,
(4) Kim, D.-K.; Kim, Y.-W.; Lee, N. J. Heterocycl. Chem. 2001,
38, 45.
2
1 H, J = 12.0 Hz, CHHPh), 4.70 (d, 1 H, 2J = 11.8 Hz, CHHPh),
(5) Nasr, A. Z. Nucleosides, Nucleotides Nucleic Acids 2004,
23, 1825.
(6) Rudloff, I.; Peseke, K.; Reinke, H. J. Prakt. Chem. 1998,
340, 334.
(7) Rudloff, I.; Michalik, M.; Montero, A.; Peseke, K. Synthesis
2001, 1686.
(8) Montero, A.; Feist, H.; Michalik, M.; Quincoces, J.; Peseke,
K. Synthesis 2002, 664.
3
4.73 (d, 1 H, J1¢,2¢ = 4.5 Hz, H-1¢), 7.05–7.32 (m, 10 H, 2 C6H5),
3
3
4
7.44 (ddd, 1 H, J8,9 = 8.3 Hz, J7,8 = 7.2 Hz, J6,8 = 1.0 Hz, H-8),
3
3
4
7.59 (ddd, 1 H, J6,7 = 8.2 Hz, J7,8 = 7.2 Hz, J7,9 = 1.0 Hz, H-7),
4
3
7.80 (d, 1 H, J1,3 = 1.5 Hz, H-3), 7.82 (dt, 1 H, J8,9 = 8.3 Hz,
4J7,9 = 5J6,9 = 1.0 Hz, H-9), 8.02 (dt, 1 H, J6,7 = 8.2 Hz,
3
4J6,8 = 5J6,9 = 1.0 Hz, H-6), 8.57 (d, 1 H, H-1).
13C NMR (62.9 MHz, CDCl3): d = 61.1 (C-3¢), 72.1 (CH2Ph), 73.5
(CH2Ph), 77.9 (C-1¢), 81.0 (C-2¢), 101.7 (C-4), 110.9 (C-9), 114.8
(CN), 120.5 (C-6), 121.2 (C-2), 122.6 (C-8), 127.0 (C-7), 127.9–
129.0 (o-, m-, p-CHarom, C-1, C-9a), 136.5 (C-3), 136.9 (i-Carom),
137.3 (i-Carom), 144.5 (C-5a), 145.1 (C-4a).
(9) Montero, A.; Feist, H.; Michalik, M.; Quincoces, J.; Peseke,
K. J. Carbohydr. Chem. 2002, 21, 305.
(10) Rudloff, I.; Bari, A.; Feist, H.; Michalik, M.; Reinke, H.;
Peseke, K. Z. Naturforsch. 2004, 59b, 398.
(11) Montero, A.; Michalik, M.; Feist, H.; Reinke, H.; Rudloff, I.;
Peseke, K. J. Carbohydr. Chem. 2004, 23, 317.
(12) Ramesh, N. G.; Balasubramanian, K. K. Eur. J. Org. Chem.
2003, 4477.
(13) Bari, A.; Feist, H.; Michalik, D.; Michalik, M.; Peseke, K.
Synthesis 2004, 2863.
(14) Michalik, M.; Freier, T.; Zahn, K.; Peseke, K. Magn. Reson.
Chem. 1997, 35, 859.
MS (EI, 70 eV): m/z (%) = 463 (20, M+), 312 (24, M –
HOCH2CHOBn+), 91 (100).
Anal. Calcd for C29H25N3O3: C, 75.14; H, 5.44; N, 9.07. Found: C,
75.22; H, 5.78; N, 9.25.
HRMS: m/z calcd for C29H25N3O3: 463.1896; found: 463.1896.
2-[1R,2S-1,2-Bis(benzyloxy)-3-hydroxypropyl]benzo[4,5]imi-
dazo[1,2-a]pyridine-4-carbonitrile (11b)
(15) Michalik, M.; Peseke, K.; Radeglia, R. J. Prakt. Chem. 1981,
323, 506.
The reaction of 1b (310 mg, 0.95 mmol) with benzimidazol-2-yl-
acetonitrile (230 mg, 0.146 mmol), piperidine (0.038 mL, 0.38
mmol) and AcOH (0.093 mL, 1.62 mmol) in chlorobenzene (10
mL) was carried as described for 11a; yield: 250 mg (56%); yellow
syrup; Rf 0.45 (toluene–EtOAc, 6:4); [a]D22 –38.2 (c = 1, CHCl3).
(16) Ege, G.; Frey, H. O.; Schuck, E. Synthesis 1979, 376.
(17) Knutsen, S. J. Nucleosides, Nucleotides Nucleic Acids 1992,
11, 961.
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Lepoivre, J. A.; Alderweireldt, F. C.; Balzarini, J.; De
Clercq, E. Nucleosides, Nucleotides Nucleic Acids 1991, 10,
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(19) Cunliffe, D.; Leason, M.; Parkin, D.; Lea, P. J.
Phytochemistry 1983, 22, 1357.
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Lipsitz, C.; Boots, M. R.; Rogers, K. S. Proc. Soc. Exp. Biol.
Med. 1976, 151, 316.
IR (capillary): 3427 (OH), 2232 cm–1 (C≡N).
1H NMR (250 MHz, CDCl3): d = 2.60 (br, 1 H, OH), 3.61 (dt, 1 H,
3J1¢,2¢ = 8.0 Hz, 3J2¢,3¢ = 4.0 Hz, H-2¢), 3.94 [dq (AB part of an ABX
system), 2 H, H-3¢a,b], 4.25 (d, 1 H, 2J = 11.8 Hz, CHHPh), 4.43 (d,
2
2
1 H, J = 11.6 Hz, CHHPh), 4.54 (d, 1 H, J = 11.6 Hz, CHHPh),
4.55 (d, 1 H, 2J = 11.8 Hz, CHHPh), 4.56 (d, 1 H, 3J1¢,2¢ = 8.0 Hz, H-
1¢), 6.90–7.35 (m, 10 H, 2 C6H5), 7.46 (ddd, 1 H, 3J8,9 = 8.3 Hz,
(21) Williams, J. D.; Mourad, A. E.; Drach, J. C.; Townsend, L.
B. Nucleosides, Nucleotides Nucleic Acids 2003, 22, 1907.
(22) Gudmundsson, K. S.; Williams, J. D.; Drach, J. C.;
Townsend, L. B. J. Med. Chem. 2003, 46, 1449.
3J7,8 = 7.2 Hz, J6,8 = 1.0 Hz, H-8), 7.62 (ddd, 1 H, J6,7 = 8.3 Hz,
4
3
3J7,8 = 7.2 Hz, J7,9 = 1.0 Hz, H-7), 7.75 (d, 1 H, 4J1,3 = 1.5 Hz, H-
4
3), 7.82 (dt, 1 H, 3J8,9 = 8.3 Hz, 4J7,9 = 5J6,9 = 1.0 Hz, H-9), 8.05 (dt,
1 H, 3J6,7 = 8.3 Hz, 4J6,8 = 5J6,9 = 1.0 Hz, H-6), 8.46 (d, 1 H, H-1).
Synthesis 2005, No. 16, 2758–2764 © Thieme Stuttgart · New York