Two- and three-component Hantzsch reaction using C-glycosylated reagents. Approach to the asymmetric synthesis of 1,4-diyhydropyridines

Article abstract of DOI:10.1055/s-2002-19321

Two- and three-component Hantzsch-type cyclocondensation reactions were carried out under thermal conditions using C-glycosylated reagents, namely sugar aldehydes, ketoesters, and enamines. Two different series of 1,4-dihydropyridines bearing C-glycosyl m

Full text of DOI:10.1055/s-2002-19321

LETTER
89
Two- and Three-Component Hantzsch Reaction Using C-Glycosylated
Reagents. Approach to the Asymmetric Synthesis of 1,4-Diyhydropyridines
Two- and
T
hree-C
l
ompon
e
e
nt
H
antzsc
s
h
R
eactio
s
nUsing
C
a
-Glycosyla
n
ted Reagentsdro Dondoni,* Alessandro Massi, Erik Minghini
Dipartimento di Chimica, Laboratorio di Chimica Organica, Università di Ferrara, Via L. Borsari 46, I-44100 Ferrara, Italy
Fax +39(0532)291167; E-mail: adn@dns.unife.it
Received 31 August 2001
and three-component Hantzsch-type 1,4-dihydropyridine
(DHP) synthesis9 using C-glycosylated reagents (Figure
1). Cycloadducts bearing sugar residues at C6
(R2 = sugar) are obtained as mixtures of diastereomers
Abstract: Two- and three-component Hantzsch-type cycloconden-
sation reactions were carried out under thermal conditions using C-
glycosylated reagents, namely sugar aldehydes, ketoesters, and
enamines. Two different series of 1,4-dihydropyridines bearing C-
glycosyl moieties at C4 and C6 were obtained in good to excellent and therefore the method can be used to prepare 4-aryl
overall yields (61–90%). The asymmetric induction due to carbohy-
drate residues was also investigated.
substituted DHP’s with a given configuration at C4. Also
DHP’s are well known pharmaceutically active com-
Key words: multicomponent reaction, Hantzsch condensation, C-
glycosides, heterocycles, 1,4-dihydropyridines
pounds exhibiting similar effects to DHMP’s mainly as
calcium channel ligands.10,11 Nefedipine12 and congeners
were introduced into the market several years ago as drugs
for cardiovascular and antihypertensive therapy. However
The improvement of the activity and selectivity of com- the pharmacological activity of chiral 4-aryl DHP’s de-
pounds possessing ’privileged’core structures, which have pends on the configuration of the stereocenter at C4 of the
historically been rich in biological activity is an important heterocyclic ring, which determines whether the com-
task in drug discovery, which requires access to a large pound acts as a calcium antagonist or as a calcium ago-
number of products for laboratory experimentation.1 Par- nist.11a Hence, a stereoselective route to this class of
allel combinatorial synthesis proved in the last decade to compounds is extremely important. Unfortunately most of
be a formidable approach capable of fulfilling efficiently the enantioselective synthetic methods known so far are of
the pressing need for this multitude of products.2
low efficiency and not generally applicable.13 To date we
are not aware of earlier asymmetric synthesis of 4-aryl
DHP’s using carbohydrate residues as inducers of chirali-
ty.14
Molecular diversity can be reached in different ways, in-
cluding the change of substituents or residues linked to a
given scaffold, the interchange of the position of heteroa-
toms, and less frequently by variation of the configuration In this initial study we selected per-O-benzylated carbo-
of stereocenters.3 Carbohydrate residues are present in nu- hydrate building blocks with the -D-ribo and -D-galacto
merous pharmaceutically active compounds4 and, being
hydrophilic and chiral moieties, not only may serve to im-
prove the pharmacokinetic and dynamic properties but
Sugar
also can induce new and unexpected properties at the level
H
O
of molecular recognition between drugs and their recep-
tors. Quite surprisingly carbohydrate-based reagents have
not been extensively employed in synthetic approaches
leading to libraries of low-molecular-weight molecules.5
Hence we started a program directed toward revisiting
classical and recent multicomponent reactions which have
escaped the involvement of carbohydrate residues in the
preparation of pharmaceutically active compounds.
CO2Et
Me
EtO2C
R2
O
H2N
R1
=
R2 = Me
Sugar
R1
EtO2C
R2
CO2Et
In light of this we have recently examined the three-com-
ponent Biginelli cyclocondensation reaction of an alde-
N
H
Me
hyde,
a
ketoester, and urea6 leading to 3,4-
7
dihydropyrimidin-2-(1H)-ones (DHMP’s), a class of
compounds which are mainly known to be active as calci-
um channel blockers and antihypertensive agents.8 Herein
we report the results of a related study dealing with two-
Sugar
R
1 = Ar R2
=
R1
O
EtO2C
Sugar
CO2Et
Me
NH2
Synlett 2002, No. 1, 28 12 2001. Article Identifier:
1437-2096,E;2002,0,01,0089,0092,ftx,en;D20101ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
Figure 1

90
A. Dondoni et al.
LETTER
configuration. The anomeric sugar aldehydes 1a and 1b
(formyl C-glycosides) were readily available from sugar
lactones through our thiazole-based formylation meth-
od.15 The procedure described in our recent paper,6 afford-
ed the compounds C-ribofuranosyl and C-
galactopyranosyl -ketoesters 2a and 2b which in turn
were transformed into the hitherto unreported sugar
enamines16 3a and 3b in excellent yield (95%) (Scheme
1). Compounds 1, 2, and 3 constitute the full set of C-gly-
cosyl reagents required for the Hantzsch condensation.
Sugar
H
O
1a,1b
CO2Et
Me
EtO2C
Me
O
H2N
4
5
71% (for a)
90% (for b)
4-Å MS
EtOH, reflux,48h
Sugar
EtO2C
Sugar
EtO2C
Sugar
Sugar
EtO2C
Me
CO2Et
Me
60-75%
95%
O
NH2
H
O
N
H
2a,b (R = Bn)
3a,b (R = Bn)
1a,1b (R = Bn)
6a,6b (R = Bn)
7a,7b (R = H)
H2, Pd(OH)2
(95%)
OR
RO
RO
RO
RO
OR
O
OR
Scheme 2
Sugar
=
O
H
H
(ratio, 1:1:1) in refluxing EtOH for 48 hours. This reaction
afforded the target DHP derivative16 9a as a mixture of di-
astereoisomers (ratio, 60:40) in very low yield (10%). In
the alternative route, the cyclocondensation of the sugar
a
b
Scheme 1
As a model reaction, the cyclocondensation of the ribo- ketoester 2a with benzaldehyde and ethyl aminocrotonate
furanoside aldehyde 1a, ethyl acetoacetate 4, and ethyl 5 afforded an even lower yield of 9a (5%). Unsatisfactory
aminocrotonate 5 (ratio, 1:1:1) in refluxing EtOH (molec- results were also obtained using acidic promoters
ular sieves) gave after 48 hours the 4-C-ribosyl DHP [Yb(OTf)3 and HOAc] and higher temperatures (DMF,
derivative16 6a in 71% yield (Scheme 2). The -linkage at 150 °C) in both three-component based routes to 9a.
the anomeric carbon of the sugar fragment was confirmed
by NOE experiments, thus indicating that the stereochem-
ical integrity at C2 of the aldehyde 1a was retained during
the three-component cycloaddition. Subsequently, the re-
moval of the benzyl groups from the sugar moiety of 6a
was carried out by hydrogenation [H2, Pd(OH)2] affording
the C-ribosyl DHP derivative16 7a in almost quantitative
yield. The same reaction sequence was repeated starting
from the galactopyranoside aldehyde 1b to give the 4-C-
galactosyl DHP derivative16 7b in 88% overall yield. A
different set of conditions were also tested to shorten re-
action times and improve the conversion of the valuable
sugar aldehydes 1a,b into the corresponding DHP deriva-
tives 6a,b. Thus, the use of one equivalent of Yb(OTf)3 in
refluxing THF (molecular sieves) for 12 hours afforded
the galacto derivative 6b in higher yield (95%), while un-
der the same conditions the ribo derivative 6a was ob-
tained in much lower yield (28%). In the latter case we
observed that the Yb(OTf)3 induced 1,2-elimination of
BnOH from the ribosyl residue of the sugar aldehyde 1a.
However, the resulting unsaturated aldehyde participated
in the cyclocondensation process as well to give the cor-
responding 1,2-dihydro-DHP derivative of 6a.
Ph
H
O
EtO2C
8
CO2Et
Me
H
O
BnO
NH2
O
BnO
4
OBn
3a
4-Å MS
EtOH, reflux,48h
10%
20% de
Ph
EtO2C
CO2Et
Me
*
H
O
N
H
BnO
BnO
OBn
9a
4-Å MS
5%
EtOH, reflux,48h
0% de
Ph
H
O
EtO2C
8
CO2Et
Me
H
O
In order to approach the class of 6-C-glycosyl 4-aryl
DHP’s, two convergent routes based on three-component
Hantzsch-type reactions were investigated (Scheme 3).
Initially we considered the cyclocondensation of the sugar
enamine 3a with benzaldehyde and ethyl acetoacetate 4
O
BnO
H2N
5
BnO
OBn
2a
Scheme 3
Synlett 2002, No. 1, 89–92 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Two- and Three-Component Hantzsch Reaction Using C-Glycosylated Reagents
91
Therefore, the two-component variant of the Hantzsch re- aryl DHP’s exploiting carbohydrate moieties as inducers
action, which involves the cyclocondensation of amino- of chirality at C4 of the heterocyclic ring has been
crotonates with enones (Knoevenagel condensation achieved. Due to the importance of chiral 4-aryl DHP’s as
products) was considered. Having in hand the C-glycosyl pharmaceutically active compounds, an extensive explo-
reagents 3a and 3b, we preferred aminocrotonate-type de- ration of biological properties of their C6-glycosylated
rivatives to enones as components bearing the carbohy- analogs of type 10 designed to preserve unaltered the
drate moiety. The synthesis of the 6-C-ribosyl 4-phenyl structure of the active site of the DHP ring will become of
DHP derivative 9a was first examined (Scheme 4). Thus, great interest.
the C-ribosyl enamine 3a was reacted with excess enone17
11 (5 equiv) in DMF (molecular sieves) at 150 °C for 48
Acknowledgement
hours. Reaction workup involved addition of aminometh-
ylated polystyrene18 (AM-resin) to selectively remove the
We gratefully thank the University of Ferrara for financial support.
excess enone 11. This operation facilitated the chromato-
graphic separation of 9a which was obtained as a mixture
References
of diastereoisomers (ratio, 60:40) in 71% yield.19 The
(1) Wermuth, C. G. The Practice of Medicinal Chemistry;
Academic Press: San Diego, 1996.
(2) For reviews see: (a) Hermkens, P. H. H.; Ottenheijm, H. C.
same synthesis-purification procedure was repeated start-
ing from the C-galactosyl enamine 3b to give the DHP
derivative16 9b (mixture of diastereoisomers in 65:35 ra-
J.; Rees, D. C. Tetrahedron 1997, 53, 5643. (b) Thompson,
L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555. (c) Fruchtel,
J. S.; Jung, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 17.
tio) in 61% yield. Subsequent catalytic hydrogenation of
9a,b afforded the corresponding debenzylated products16
10a,b in almost quantitative yield.19 Unfortunately, at-
(3) Gierasch, T. M.; Chytil, M.; Didiuk, M. T.; Park, J. Y.;
Urban, J. J.; Nola, S. P.; Verdine, G. L. Org. Lett. 2000, 2,
3999.
(4) Witczak, Z. J. Curr. Med. Chem. 1995, 1, 392.
(5) Lockhoff, O. Angew. Chem. Int. Ed. 1998, 37, 3436.
(6) Dondoni, A.; Massi, A.; Sabbatini, S. Tetrahedron Lett.
2001, 42, 4495.
(7) (a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360. For a
recent review see: (b)Kappe, C. O. Acc. Chem. Res. 2000,
33, 879.
(8) (a) Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.;
Moreland, S.; Hedberg, A.; O’Reilly, B. C. J. Med. Chem.
1991, 34, 806; and references therein. (b) Atwal, K. S.;
Rovnyak, G. C.; Kimball, S. D.; Floyd, D. M.; Moreland, S.;
Swanson, B. N.; Gougoutas, J. Z.; Schwartz, J.; Smillie, K.
M.; Malley, M. F. J. Med. Chem. 1990, 33, 2629.
(9) Hantzsch, A. Ann. Chem. 1882, 215, 1.
tempts to assign the absolute configuration at the newly
created C4 stereocenter of the DHP ring by X-ray crystal
analysis of 10a,b or their derivatives have been unsuc-
cessful so far due to the lack of suitably crystalline prod-
ucts. Nevertheless, the possibility of increasing the level
of diastereoselectivity in the synthesis of 4-phenyl DHP
derivatives 9a,b was actively pursued. Thus, the cyclo-
condensation of 3a with 11 (1:5 ratio) in refluxing toluene
for 12 hours using HOAc (2 equiv) as a promoter afforded
9a in slightly lower yield (65%) but higher diastereomeric
ratio (75:25). On the other hand, under the same condi-
tions the C-galactosyl enamine 3b gave the corresponding
DHP derivatives 9b in much lower yield (20% vs. 61%)
and same diastereomeric ratio (67:33).20
(10) For reviews see: (a) Sausins, A.; Duburs, G. Khim.
Geterotsikl. Soedin. 1993, 579. (b) Sausins, A.; Duburs, G.
Heterocycles 1988, 27, 291. (c) Stout, D. M.; Meyers, A. I.
Chem. Rev. 1982, 82, 223. (d) Kutney, J. P. Heterocycles
1977, 7, 593. (e) Eisner, U.; Kuthan, J. Chem. Rev. 1972, 72,
1.
Ph
EtO2C
Sugar
CO2Et
Me
NH2
3a,3b
O
11
(11) (a) Goldmann, S.; Stoltefuss, J. Angew. Chem., Int. Ed. Engl.
1991, 30, 1559. (b) Triggle, D. J.; Langs, D. A.; Janis, R. A.
Med. Res. Rev. 1989, 9, 123. (c) Bossert, F.; Meyer, H.;
Wehinger, E. Angew. Chem., Int. Ed. Engl. 1981, 20, 762.
(12) Bossert F., Vater W.; US Pat. 3 485 847, 1969.
(13) For a recent discussion on this issue and an approach to the
enantioselective synthesis of DHP’s see: Straub, A.; Goehrt,
A. Angew. Chem., Int. Ed. Engl. 1996, 35, 2662.
(14) Sugar aldehydes have been used in the Hantzsch reaction for
the synthesis of chiral 4-alkyl DHP’s. However, these DHP
derivatives showed different biological properties of the
corresponding 4-aryl congeners. See: Martin, N.; Martinez-
Grau, A.; Seoane, C.; Marco, J. L.; Albert, A.; Cano, F. H.
Tetrahedron: Asymmetry 1995, 6, 877.
1. 4-Å MS
DMF, 150 °C,48h
71% (for a)
61% (for b)
2.
NH2
Ph
*
EtO2C
Sugar
CO2Et
N
H
Me
9a,9b (R = Bn)
10a,10b (R = H)
H2, Pd(OH)2
(95%)
(15) (a) Dondoni, A. Pure Appl. Chem. 2000, 72, 1577.
(b) Dondoni, A.; Scherrmann, M.-C. J. Org. Chem. 1994, 59,
6404.
Scheme 4
In conclusion, we have demonstrated that three- and two-
component Hantzsch reactions can be applied to the syn-
thesis of C4- and C6-glycosylated DHP’s by using suit-
able sugar reagents. The first asymmetric synthesis of 4-
(16) Enamine 3a was obtained as single geometric isomer while
3b appeared to be ~1:1 mixture of E and Z isomers. Specific
rotation values are reported. Ribo series: 3a: [ ]20D +19
(c 1.1, CHCl3). 6a: [ ]20 +39 (c 0.9, CHCl3). 7a: [ ]20 +4
D
D
Synlett 2002, No. 1, 89–92 ISSN 0936-5214 © Thieme Stuttgart · New York

92
A. Dondoni et al.
LETTER
(c 1.0, MeOH). 9a(major): [ ]20 +103 (c 1.5, CHCl3).
cyclohexane-EtOAc, 9:1 to give first major-9a (154 mmol,
43%). Eluted second was minor-9a (102 mg, 28%). A
vigorously stirred mixture of major-9a (154 mg, 0.21
mmol), 20% Pd(OH)2 on activated carbon (80 mg), AcOEt
(2 mL) and EtOH (2 mL) was degassed under vacuum and
saturated with H2 (by a H2-filled balloon) three times. The
suspension was stirred at room temperature for 2 h under a
slightly pressure of H2(balloon), then filtered through a pad
of Celite and concentrated to afford major-10a (91 mg,
D
9a (minor): [ ]20 +136 (c 0.8, CHCl3). 10a (major): [ ]20
D
D
= +11 (c 1.7, MeOH). 10a(minor): [ ]20 = +84 (c 1.0,
D
MeOH). Galacto series: 6b: [ ]20 +72 (c 1.4, CHCl3). 7b:
D
[ ]20 –26 (c 0.8, MeOH). 9b(major): [ ]20 +33 (c 1.1,
D
D
CHCl3).
(17) Enone 11 was prepared by standard Knoevenagel
condensation of benzaldehyde and ethyl acetoacetate:
Knoevenagel, E. Ber. 1896, 29, 172.
(18) Aminomethylated polystyrene (AM-resin) was purchased
from Novabiochem.
95%) as a white amorphous solid. 1H NMR (CD3OD):
9.15 (s, 1 H, NH), 7.35–7.05 (m, 5 H, Ph), 5.51 (d, 1 H,
=
(19) General experimental procedure for the two-component
Hantzsch reaction leading to 6-C-glycosyl 4-phenyl DHP’s:
A mixture of enamine 3a (258 mg, 0.5 mmol), enone 11 (545
mg, 2.5 mmol), activated 4-Å molecular sieves (200 mg),
and anhyd DMF (2 mL) was stirred at 150 °C for 48 h, then
cooled to r.t., filtered through a pad of Celite, and
concentrated. The residue was diluted with CH2Cl2 (5 mL)
and treated with aminomethylated polystyrene18 (1.0 g, 2.5
mmol of ~2.5 mmol/g resin). The suspension was stirred for
an additional 2 h then the resin was filtered off and washed
thoroughly with CH2Cl2. The combined filtrates were
concentrated and eluted from a column of silica gel with
J1’,2’ = 0.5 Hz, H-1'), 4.95 (s, 1 H, H-4), 4.20–3.90 (m, 8 H, 2
OCH2CH3, H-2', H-3', H-4', H-5'a), 3.84 (d, 1 H,
J5’a,5’b = 12.0 Hz, H-5'b), 2.30 (s, 3 H, CH3), 1.24 (t, 3 H,
J = 7.0 Hz, OCH2CH3), 1.23 (t, 3 H, J = 7.0 Hz, OCH2CH3).
13C NMR (CD3OD) selected data: = 168.4, 167. 6, 148.5,
148.0, 145.6, 103.6, 101.5, 82.0, 78.4, 65.4, 59.9, 59.1, 39.7,
17.2, 13.4. MALDI-TOF MS: 448.2 (M++H), 470.5
(M++Na). Anal. Calcd for C23H29NO8: C, 61.73; H, 6.53; N,
3.13. Found: C, 61.78; H, 6.55; N, 3.18.
(20) The 1,2-elimination of BnOH occurred in the galactosyl
moiety of 9b to give the corresponding 1,2-dihydro-
derivative as a main product in 60% yield.
Synlett 2002, No. 1, 89–92 ISSN 0936-5214 © Thieme Stuttgart · New York