Facile one-pot method for the synthesis of novel glycosylidene-based quinolines

Article abstract of DOI:10.1016/j.tetlet.2009.10.129

A one-pot approach to the synthesis of novel glycosylidene-based quinolines is described. The reaction involves a Lewis acid catalyzed Povarov addition followed by oxidation of the resulting spiroanellated tetrahydroquinoline intermediates to yield the open-ring glycosylidene-derived quinoline.

Full text of DOI:10.1016/j.tetlet.2009.10.129

Tetrahedron Letters 51 (2010) 201–204
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile one-pot method for the synthesis of novel glycosylidene-based quinolines
*
Peter H. Dobbelaar, Cecilia H. Marzabadi
Department of Chemistry and Biochemistry, Seton Hall University, South Orange, NJ 07079, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot approach to the synthesis of novel glycosylidene-based quinolines is described. The reaction
involves a Lewis acid catalyzed Povarov addition followed by oxidation of the resulting spiroanellated
tetrahydroquinoline intermediates to yield the open-ring glycosylidene-derived quinoline.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 27 September 2009
Revised 26 October 2009
Accepted 27 October 2009
Available online 30 October 2009
The importance of cell-surface carbohydrates in biological pro-
cesses such as recognition, fertilization, and signal transduction
cannot be overstated.1 In addition to these surface interactions,
hexoses such as glucose are readily transported across a range of
cellular membranes via glucose transporter proteins and are thus
also able to act within the cell.2 The biological prevalence and bio-
availability of carbohydrates make stable sugar derivatives attrac-
tive scaffolds for drug design.3
Quinolines are another group of compounds that are of interest
from a therapeutic point of view.4 This structural class includes
fluoroquinolone antibiotics such as ciprofloxacin5 1 and antitumor
alkaloids related to streptonigrin6 2 (Fig. 1). Other therapeutic
areas in which quinoline derivatives have shown promising activ-
ity include asthma,7 Alzheimers’ disease,8 and AIDS.9
Due to the medicinal importance of quinolines, we became
interested in the synthesis of molecules that contained carbohy-
drates conjugated to these heterocycles. We hypothesized that
incorporation of a sugar would not only facilitate drug delivery,
but may also aid in the DNA intercalation of the quinoline ring.
The sugar moiety could help to stabilize DNA binding by interact-
ing with the sugar–phosphate backbone once the quinoline is in
contact with the DNA.10 Furthermore, if the quinoline and sugar
were appended via carbon–carbon bonds, (rather than carbon–
oxygen bonds) this would impart an additional measure of stability
to the molecule from endogenous glycosidases in the body.
In order to synthesize these interesting target molecules, we
surmised that a variation of the Povarov reaction could allow us
access to glycosylidene-spiroanellated quinolines. In the 1960s,
Povarov et al. described a [4+2] cycloaddition reaction between
an aromatic Schiff base and activated alkene to give tetrahydro-
quinolines.11 They also reported that these products could be read-
ily oxidized to the corresponding dihydroquinolines. Subsequent
studies by other researchers showed that this reaction actually in-
volved a polar addition to a vinyl ether, and intermediates from
this process were trapped and characterized.12 Recent publications
have documented the utility of the Povarov reaction,13 and new
catalysts, including lanthanide triflates, have led to improved reac-
tion conditions.14
Povarov additions have recently been described in which Lewis
acid catalyzed multicomponent reactions were carried out with
protected glycals.15 However, to the best of our knowledge, an
application with exo-glycals has not yet been reported. We have
developed a one-pot methodology utilizing a substituted benzani-
line, scandium triflate, and manganese dioxide to convert an exo-
glycal directly into a novel C-linked, glycosylidene-based quino-
line. In this Letter, we herein demonstrate the utility of this one-
pot reaction.
In order to investigate Povarov reaction conditions, we screened
several rare earth metal triflates as Lewis acid catalysts for the
reaction between exo-glycal16 3 and benzaniline 4a (Table 1). With
all three catalysts (entries 1–3), we observed the complete conver-
sion of 3 to a mixture of products. Isolation and structural charac-
terization of the resulting compounds indicated the formation of
spiroanellated tetrahydroquinoline17 5 as a 4:1 mixture of diaste-
reomers in addition to the open-ring glycosylidene-based quino-
line18 6a. The spiro-compounds 5 are also interesting due to their
structural resemblance to (+)-hydantocidin19 and its glucose-based
analogues,20 all of which are potent glycosidase inhibitors.
O
HN
H3CO
H2N
N
F
N
O
N
COOH
N
COOH
O
H2N
CH3
OH
1
2
OCH3
OCH3
* Corresponding author.
E-mail address: marzabce@shu.edu (C.H. Marzabadi).
Figure 1. Biologically active quinoline derivatives.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.129

202
P. H. Dobbelaar, C. H. Marzabadi / Tetrahedron Letters 51 (2010) 201–204
Table 1
Catalyst and reaction conditions screeninga
OBn
6
5
BnO
OBn
6
OH
OBn
4
5
h
O
a
H
3
2
BnO
i
4
3
1
k
BnO
b
BnO
2
g
N
j
1
BnO
b
f
k
l
OBn
l
NH
a
c
+
j
O
4a
c
i
BnO
d
e
N
BnO
e
d
BnO
CH2
f
h
5Major
6a
g
3
c
OBn
6
b
d
5
O
BnO
1
4
3
BnO
e
k
j
2
l
BnO
a
NH
H
i
f
g
h
5Minor
Entry
Catalyst
Reaction conditions
Ratio of 6a:b (5Major + 5Minor)
1
2
3
4
5
Sc(OTf)3
Yb(OTf)3
Tb(OTf)3
Sc(OTf)3
Sc(OTf)3
Room temperature, overnight
Room temperature, overnight
Room temperature, overnight
Reflux, overnight
2.67:1
0.92:1
0.96:1
2.51:1
1:0
Room temperature, MnO2,c overnight
a
b
c
Compounds 3 (1.0 equiv), 4a (1.0 equiv), and catalyst (0.2 equiv) were dissolved in MeCN and allowed to react under the specified conditions.
Determined by HPLC/MS analysis.
Two equivalents added after 2 h.
The regiochemistry of addition to the glycal to produce the spiro
The aromatization of the tetrahydroquinoline portion of 5 likely
products is as what would be anticipated; attack of the imine car-
bon by the more nucleophilic C2 carbon of the vinyl ether followed
by electrophilic attack of the resulting oxonium ion by the ortho
carbon of the aniline ring. This two-step process, as has been de-
scribed by others,12 was further supported by our isolation of an
intermediate addition product in which the imine carbon of the
benzaniline was added to C2, and water was added to the C1 carbon
of the vinyl ether. The observed axial facial preference for addition
to the exo-glycal leading to the b-substituted methylene group at
the anomeric carbon most likely arises because of steric effects
experienced by the bicyclic component in the equatorial plane.21
drives the opening of the glucopyranose ring. Although the spiro-
compound mixture 5 is stable while refrigerated, we observed
the slow, partial oxidation to 6a at room temperature.
In consideration of these initial results, it was therefore our de-
sire to exclusively obtain the oxidized product 6a, preferably from
a one-pot reaction. Of the screened catalysts, Sc(OTf)3 gave the
highest ratio of 6a to 5Major + 5Minor as well as the cleanest reac-
tion. Heating the Sc(OTf)3 mixture to reflux overnight did not have
an effect on the ratio of products compared to the reaction main-
tained at room temperature (entries 1 and 4). We then turned
our attention to the addition of oxidizing agents, and quickly
Table 2
One-pot synthesis of glycosylidene-based quinolines22
Entry
Benzaniline R-group23
Product
Isolated yield (%)
1
2
3
4
5
6
H
F
Br
CN
CF3
OCH3
6a
6b
6c
6d
6e
6f
65
60
64
43
46
45

P. H. Dobbelaar, C. H. Marzabadi / Tetrahedron Letters 51 (2010) 201–204
203
6. Shaikh, I. A.; Johnson, F.; Grollman, A. P. J. Med. Chem. 1986, 29, 1329.
7. Paris, D.; Cottin, M.; Demonchaux, P.; Augert, G.; Dupassieux, P.; Lenoir, P.;
Peck, M. J.; Jasserand, D. J. Med. Chem. 1995, 38, 669.
8. Normand-Bayle, M.; Benard, C.; Zouhiri, F.; Mouscadet, J.-F.; Leh, H.; Thomas,
C.-M.; Mbemba, G.; Desmaele, D.; d’Angelo, J. Bioorg. Med. Chem. Lett. 2005, 15,
4019.
OBn
OH
BnO
BnO
HO
HO
OH
OH
OH
BCl3
OBn
9. Polanski, J.; Zouhiri, F.; Jeanson, L.; Desmaele, D.; d’Angelo, J.; Mouscadet, J.-F.;
Gieleciak, R.; Gasteiger, J.; Le Bret, M. J. Med. Chem. 2002, 45, 4647.
10. Li, W.; Zhang, Z.-W.; Wang, S.-X.; Ren, S.-M.; Jiang, T. Chem. Biol. Drug Des.
2009, 74, 80.
11. (a) Povarov, L. S.; Grigos, V. I.; Karakhanov, R. A.; Mikhailov, B. M. Russ. Chem.
Bull., Int. Ed. (Engl. Transl.) 1965, 344; (b) Povarov, L. S.; Grigos, V. I.; Mikhailov,
B. M. Russ. Chem. Bull., Int. Ed. (Engl. Transl.) 1966, 120.
CH2Cl2, -78 °C
N
N
6a
7a
12. (a) Hermitage, S.; Jay, D. A.; Whiting, A. Tetrahedron Lett. 2002, 43, 9633; (b)
Hermitage, S.; Howard, J. A. K.; Jay, D. A.; Pritchard, R. G.; Probert, M. R.;
Whiting, A. Org. Biomol. Chem. 2004, 2, 2451; (c) Beifuss, U.; Ledderhose, S.;
Ondrus, V. Arkivoc 2005, v, 147; (d) Alves, M. J.; Azoia, N. G.; Fortes, A. G.
Tetrahedron 2007, 63, 727; (e) Mayr, H.; Ofial, A. R.; Sauer, J.; Schmied, B. Eur. J.
Org. Chem. 2000, 2013.
Scheme 1. Deprotection of perbenzylated quinolone 6a.
discovered that complete conversion to 6a could be obtained with
2 equiv of MnO2 (entry 5).
13. For reviews, see: (a) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656; (b) Glushkov,
V. A.; Tolstikov, A. G. Russ. Chem. Rev. 2008, 77, 137; (c) Koutznetsov, V. V.
Tetrahedron 2009, 65, 2721.
14. (a) Makioka, Y.; Shindo, T.; Taniguchi, Y.; Takaki, K.; Fujiwara, Y. Synthesis 1995,
801; (b) Cheng, D.; Zhou, J.; Saiah, E.; Beaton, G. Org. Lett. 2002, 4, 4411.
15. Jimenez, O.; de la Rosa, G.; Lavilla, R. Angew. Chem., Int. Ed. 2005, 44, 6521.
We next applied this one-pot reaction to a series of para-substi-
tuted benzanilines in order to evaluate the electronic effect of sub-
stituents on this reaction (Table 2). In general, the halogen
substituted benzanilines (entries 2 and 3) reacted efficiently to
produce the corresponding open-ring glycosylidene-based quino-
lines. The yields, which exceeded 60%, were very similar when
compared to the non-substituted phenyl ring (entry 1). However,
reactions that involved a benzaniline with an electron-withdraw-
ing group, such as a cyano- or trifluoromethyl-substituent, resulted
in lower yields of the desired product (entries 4 and 5). The reac-
tion yields also suffered when benzaniline was substituted with
an electron-donating methoxy group (entry 6). These observations
suggest that benzanilines containing strongly electron-donating or
withdrawing moieties in the para position resulted in diminished
reaction yields in comparison to halogen substituents. Nonethe-
less, this procedure represents an effective way to access unique
carbohydrate-based quinolines.
Deprotection of perbenzylated intermediate 6a was carried out
utilizing BCl3 (Scheme 1).24 Successful removal of the protective
groups validates this sequence as an expeditious approach toward
sugar-derived quinolines. Biological evaluation of these novel com-
pounds is underway and will be reported in due course.
In conclusion, we have demonstrated that carbon-linked glu-
cose-derived quinolines can be obtained from a one-pot, scandium
triflate-catalyzed Povarov reaction followed by oxidation with
manganese dioxide. We have also shown that the reaction pro-
ceeds through the glucose–spiroanellated tetrahydroquinoline
intermediates. The utility of this procedure has been effectively
employed with different para-substituted benzanilines to access
several novel open-ring glycosylidene quinolines. Facile deprotec-
tion of the sugar benzyl ether groups is realized by using boron tri-
chloride. Novel C-glycosylated quinolines have been obtained that
are currently being evaluated in cancer cell line screenings.
16. Tetra-O-benzyl-D-glucopyranose oxidation with Dess–Martin periodinane
followed by lactone olefination with Tebbe reagent gave exo-glycal 3 in two
steps. For the lactone synthesis experimental procedure, see: Csuk, R.; Dorr, P.
J. Carbohydr. Chem. 1995, 14, 35; for the olefin synthesis experimental
procedure, see: RajanBabu, T. V.; Reddy, G. S. J. Org. Chem. 1986, 51, 5458.
17. 5Major and 5Minor were isolated in 65% yield as
a
ꢀ4:1 mixture of
diastereomers by stopping the room temperature reactions after 3 h. NOE
experiments have confirmed the stereochemistry of both isomers of 5. For
5Major, NOEs were observed between the hydrogens attached to the following
carbon atoms (for atom labels, see structure in Table 1): 2 with both j and a, b
with both 3 and 5, and 4 with a. For 5Minor, NOEs were observed between the
hydrogens attached to the following carbon atoms: b with both 2 and 4, 3 with
a, and 5 with j.
18. Both 1D and 2D NMR experiments, conducted in CD3CN, were required to
confirm the open-ring structure of 6a (for atom labels, see structure in Table 1).
Evidence includes the 13C shift of C-1 (146 ppm) and the coupling constant for
the hydrogen attached to C-2 (3.1 Hz). The broad 13C resonance of 2 sharpens
upon increased temperature and indicates restricted rotation about the C1–C2
bond. NOEs were observed between the hydrogens attached to the following
carbon atoms: 2 with both a and b. COSY and NOESY signals were also
observed between the hydrogen and hydroxyl group attached to 5.
19. (a) Nakajima, M.; Itoi, K.; Takamatsu, Y.; Kinoshita, T.; Okazaki, T.; Kawakubo,
K.; Shindo, M.; Honma, T.; Tohjigamori, M.; Haneishi, T. J. Antibiot. 1991, 44,
293; (b) Haruyama, H.; Takayama, T.; Kinoshita, T.; Kondo, M.; Nakajima, M.;
Haneishi, T. J. Chem. Soc., Perkin Trans. 1 1991, 1637.
20. (a) Bichard, C. J. F.; Mitchell, E. P.; Wormald, M. R.; Watson, K. A.; Johnson, L. N.;
Zographos, S. E.; Koutra, D. D.; Oikonomakos, N. K.; Fleet, G. W. J. Tetrahedron
Lett. 1995, 36, 2145; (b) Osz, E.; Szilagyi, L.; Somsak, L.; Benyei, A. Tetrahedron
1999, 55, 2419.
21. Similar
a-facial selectivity has been reported for other addition reactions for
exo-glycals. See for example: (a) Colinas, P.; Jager, V.; Lieberknecht, A.; Bravo, R.
D. Tetrahedron Lett. 2003, 44, 1071; (b) Enderlin, G.; Taillefumier, C.; Didierjean,
C.; Chapleur, Y. Tetrahedron: Asymmetry 2005, 16, 2459; (c) Taillefumier, C.;
Chapleur, Y. Chem. Rev. 2004, 104, 263.
22. Representative procedure: To a solution of exo-glycal 3 (100 mg; 0.186 mmol) in
acetonitrile (1 mL) was added benzaniline 4a (33.8 mg; 0.186 mmol) followed
by Sc(OTf)3 (18.3 mg; 0.0372 mmol). The reaction was stirred at room
temperature under an atmosphere of nitrogen. After 2 h, MnO2 (32.4 mg;
0.372 mmol) was added and the mixture was stirred overnight. The reaction
was diluted with ethyl acetate (15 mL), filtered through Celite, and
concentrated in vacuo. The crude material was purified over silica gel,
eluting with a gradient of 0–40% ethyl acetate in hexanes, to obtain the
product 6a as a colorless oil (87 mg, 65% yield). 1H–NMR (500 MHz, CDCl3): d
8.27 (d, J = 8.5 Hz, 1H), 8.19 (s, 1H), 8.16 (d, J = 7.0 Hz, 2H), 8.03 (d, J = 6.5 Hz,
1H), 7.74 (t, J = 7.75 Hz, 1H), 7.56–7.49 (m, 3H), 7.42–7.31 (m, 14H), 7.30–7.25
(m, 2H), 7.08 (t, J = 7.5 Hz, 1H), 7.00 (t, J = 7.5 Hz, 2H), 6.89 (d, J = 7.5 Hz, 2H),
5.65 (d, J = 1.5 Hz, 1H), 4.67–4.56 (m, 6H), 4.39 (d, J = 11.5 Hz, 1H), 4.16 (d,
J = 8.5 Hz, 1H), 4.11–4.03 (m, 2H), 3.92 (m, 1H), 3.76 (dd, J = 10.0, 3.75 Hz, 1H),
3.68 (dd, J = 10.0, 5.0 Hz, 1H), 3.05 (br s, 1H); 13C NMR (126 MHz, CDCl3): d
157.0, 148.7, 145.7, 139.5, 138.4, 138.3, 137.5, 137.3, 130.8, 129.7, 129.6, 129.1,
128.8, 128.8, 128.7, 128.7, 128.7, 128.3, 128.2, 128.2, 128.1, 128.0, 128.0, 127.9,
126.6, 125.6, 123.1, 118.7,þ81.7, 78.0, 77.0, 75.1, 74.0, 73.8, 72.1, 71.9, 71.4.
HRMS calcd for C48H46NO5 [M+H+]: 716.3371, found 716.3377.
Acknowledgments
P.H.D. gratefully acknowledges Merck Research Laboratories,
Rahway, NJ for financial support. P.H.D. also thanks the following
scientists from Merck Research Laboratories: Dr. George A. Doss
and Dr. Mihkail Reibarkh for their assistance with NMR experi-
ments, Dr. Charles W. Ross III for HRMS analysis, Eric C. Streckfuss
for chromatography suggestions, and Dr. Vincent J. Colandrea for
useful discussions.
References and notes
23. Benzanilines were purchased commercially or synthesized according to
published literature. For
Bigelow, L. A.; Eatough, H. Org. Synth. 1928, 8, 22.
24. To solution of perbenzylated intermediate 6a (70 mg; 0.098 mmol) in
a representative experimental procedure, see:
1. Varki, A. Glycobiology 1993, 3, 97.
2. Pessin, J. E.; Bell, G. I. Annu. Rev. Physiol. 1992, 54, 911.
3. Witczak, Z. J. Curr. Med. Chem. 1995, 1, 392.
4. For a review, see: Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52,
15031.
5. For a review, see: Campoli-Richards, D. M.; Monk, J. P.; Price, A.; Benfield, P.;
Todd, P. A.; Ward, A. Drug 1988, 35, 373.
a
dichloromethane at ꢁ78 °C was added BCl3 (1 M in hexane; 0.39 mL;
0.39 mmol). The reaction was stirred at ꢁ78 °C under an atmosphere of
nitrogen. After one hour, additional BCl3 (1 M in hexanes; 0.195 mL;
0.195 mmol) was introduced, and the reaction was maintained at ꢁ78 °C for

204
P. H. Dobbelaar, C. H. Marzabadi / Tetrahedron Letters 51 (2010) 201–204
one hour. The reaction was quenched with the addition of methanol (2.0 mL).
fractions yielded the product 7a as a white solid (24 mg, 69% yield): 1H NMR
(500 MHz, CD3OD): d 8.34 (d, J = 8.0 Hz, 1H), 8.21 (s, 1H), 8.17–8.13 (m, 3H),
7.77 (t, J = 7.75 Hz, 1H), 7.61 (t, J = 7.75 Hz, 1H), 7.56 (t, J = 7.5 Hz, 2H), 7.53–
7.48 (m, 1H), 5.73 (d, J = 5.0 Hz, 1H), 4.24 (dd, J = 5.0, 2.0 Hz, 1H), 3.78–3.72 (m,
2H), 3.60–3.55 (m, 1H), 3.52 (dd, J = 8.0, 1.5 Hz, 1H). 13C NMR (126 MHz,
CD3OD): d 157.6, 150.0, 148.1, 139.7, 129.6, 129.5, 129.1, 128.7, 127.7, 126.4,
The crude material was concentrated in vacuo. The residue was co-evaporated
twice with methanol, and then purified with a Waters mass directed reverse
phase prep HPLC system. The following chromatographic conditions were
used: (a) column: Waters Xbridge C-18, 30 ꢂ 75 mm, 5
lm; (b) flow rate:
50 mL/min; (c) mobile phase: A = water + ammonium hydroxide (pH 10),
B = acetonitrile; (d) mobile phase gradient method: time = 0 min, A = 98, B = 2;
time = 11 min, A = 65, B = 35; time = 11.2 min, A = 0, B = 100; time = 14.2 min,
A = 98, B = 2; time = 15 min, A = 98, B = 2. Lyophilization of the resulting
þ
125.3, 123.8, 118.2, 72.9, 72.5, 71.9, 71.7, 63.6; HRMS calcd for C20H22NO5
[M+H+]: 356.1492, found 356.1496.