Towards the synthesis of C-glycosylated dihydropyrimidine libraries via the three-component Biginelli reaction. A novel approach to artificial nucleosides

Article abstract of DOI:10.1016/S0040-4039(01)00769-9

The Lewis acid catalyzed (BF₃·Et₂O, CuCl, AcOH) one-pot three-component cyclocondensation of urea with C-glycosylated aldehydes and β-keto esters (Biginelli reaction) in a combinatorial manner afforded three different series of 3,4-dihydropyrimidin-2(1H)-ones bearing C-glycosyl moieties at C4, C6, and at both C4 and C6.

Full text of DOI:10.1016/S0040-4039(01)00769-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4495–4497
Towards the synthesis of C-glycosylated dihydropyrimidine
libraries via the three-component Biginelli reaction. A novel
approach to artificial nucleosides
Alessandro Dondoni,* Alessandro Massi and Simona Sabbatini
Dipartimento di Chimica, Laboratorio di Chimica Organica, Universita` di Ferrara, Via L. Borsari 46, I-44100 Ferrara, Italy
Received 9 April 2001; accepted 10 May 2001
Abstract—The Lewis acid catalyzed (BF3·Et2O, CuCl, AcOH) one-pot three-component cyclocondensation of urea with C-glyco-
sylated aldehydes and b-keto esters (Biginelli reaction) in a combinatorial manner afforded three different series of 3,4-dihydropy-
rimidin-2(1H)-ones bearing C-glycosyl moieties at C4, C6, and at both C4 and C6. © 2001 Elsevier Science Ltd. All rights
reserved.
The Biginelli reaction is constituted by a one-pot acid-
catalyzed condensation of an aldehyde, a b-ketoester
and an urea leading to 3,4-dihydropyrimidin-2-(1H)-
one (DHPM) (Fig. 1). In the last decade, this three-
component reaction has become the center of increasing
attention1 since it permits a rapid access to combinato-
rial libraries of DHPMs as well as their sulphur ana-
logues using both solution and solid-phase reaction
techniques.2 Improved procedures with different types
of catalysts3 and conditions4 have been reported with
the aim of overcoming the main drawback of the
Biginelli reaction, which is represented by the modest
yields. The considerable interest in DHPM-type prod-
ucts relies on their structural similarity to dihydropy-
bioavailability and water solubility and in the genera-
tion of new families of C-nucleosides, i.e. carbon-linked
glycoside analogues of N-linked natural products.
R3
R3
O
O
acid
catalyst
H
O
R1O
NH
R1O
NH2
O
R2
O
N
H
R2
O
H2N
DHPM
Figure 1. The Biginelli cyclocondensation reaction leading to
a dihydropyrimidine (DHPM) framework.
ridines (DHP),
a
class of compounds showing
remarkable pharmacological properties as calcium
channel antagonists and which are extensively used as
therapeutics in the clinical treatment of cardiovascular
diseases such as hypertension, cardiac arrhythmias, or
angina pectoris.5 Dihydropyrimidinone derivatives
(DHPMs) show similar biological activity.6
It appeared to us of some interest to explore a route for
the creation of a small library of a hitherto scarcely
investigated class of dihydropyrimidinones, such as
their C-glycosyl derivatives.7 Attractive aspects of these
Biginelli compounds lie in an expected increase in
Keywords: Biginelli reaction; dihydropyrimidines; C-glycosides; mul-
ticomponent reaction.
* Corresponding author. Fax: +39-0532291167; e-mail: adn@
dns.unife.it
Scheme 1. Synthesis of C-glycosyl b-keto esters 3 and 4. (a)
,
Ethyl diazoacetate (HC(N2))CO2Et), BF3·Et2O, 4 A MS,
CH2Cl2, 0°C, 10 min.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00769-9

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A. Dondoni et al. / Tetrahedron Letters 42 (2001) 4495–4497
Table 1. C-Glycosylated Biginelli products prepared from
various aldehydes, b-keto esters and ureaa
Various anomeric sugar aldehydes (formyl C-gly-
cosides) which we need in this program are accessible
starting from sugar lactones through our thiazole-based
formylation method.8 The stable b-linked galactopyran-
oside derivative 1 and ribofuranoside derivative 2 were
selected in this initial study.9 The hitherto unreported
C-galactopyranosyl and C-ribofuranosyl b-keto esters 3
and 4 were obtained in satisfactory yield (60–75%) by
BF3·Et2O promoted coupling of the corresponding
aldehydes 1 and 2 with ethyl diazoacetate according to
a literature procedure (Scheme 1).10
yield, ratio of
diastereomersb
aldehyde
β-keto ester
product, 5-10
OR
RO
OR
O
O
H
RO
60%, 5:1
1
CO2Et
EtO2C
NH
*
Me
N
H
O
As a model reaction, the cyclocondensation of the
sugar aldehyde 1, ethyl acetoacetate, and urea (1:1:1.5
ratio) in THF at 65°C (molecular sieves) was efficiently
promoted by CuCl (1.0 equiv.),11 BF3·Et2O (1.3 equiv.)
and AcOH (0.2 equiv.) to give after 24 h the C-galacto-
syl DHPM derivatives 5a as a mixture of diastereomers
5a, R = Bn
5b, R = H
RO
OR
O
O
H
RO
63%, 3:1
2
CO2Et
EtO2C
in a 5:1 ratio and 60% overall yield (Table 1).12
A
NH
*
Me
N
H
O
similar result was obtained with the use of equimolar
ytterbium triflate as a promoter.3b After separation by
chromatography each individual stereoisomer gave con-
sistent 1H, 13C NMR, and MS spectral data. The
b-linkage at the anomeric carbon of the sugar fragment
was confirmed for both compounds by NOE experi-
ments, thus indicating that the stereochemical integrity
at C2 of the aldehyde 1 has been retained during the
three-component cyclocondensation. On the other
hand, the absolute configuration at the newly created
C4 stereocenter of the DHPM ring still remains to be
established. While this assignment is unimportant in the
context of the present study, this goal is actively pur-
sued by attempts to obtain suitable derivatives for
X-ray crystal analysis. Nevertheless the removal of the
O-benzyl groups from the sugar moiety was proven by
hydrogenation (H2, Pd(OH)2) of the mixture of the two
stereoisomers affording the C-galactosyl DHPM
derivatives 5b in almost quantitative yield.13,14 The
above reaction sequence was repeated starting from the
ribofuranoside aldehyde 2 to give the C-ribofuranosyl
derivatives 6a and 6b in comparable yields.12,14 Under
the same reaction conditions and the use of the CuCl,
BF3·Et2O, AcOH mixture as a promoter, the reactions
of the sugar keto esters 3 and 4 with benzaldehyde and
urea were carried out resulting in the corresponding C6
glycosylated DHMPs 7a and 8a as mixtures of
diastereomers in very good overall yields (Table 1).12
Subsequent catalytic hydrogenation of each mixture
afforded the corresponding debenzylated products 7b
and 8b.14 Compounds 5–8 represent a new class of
C-nucleosides featuring a C4- or C6-linked DHPM
ring. Of course the ribofuranosyl derivatives 6 and 8 are
quite attractive as analogues of numerous natural N-
nucleosides of biological relevance.15 Finally, cyclocon-
densation reactions were carried out with two sugar
components, i.e. the aldehydes 1 and 2 and the keto
ester 4, giving rise to the bis-C-glycosylated Biginelli
products 9a and 10a as mixtures of diastereomers,12
which in turn were transformed into the corresponding
debenzylated products 9b and 10b by hydrogenation.14
Compounds 9 and 10 constitute another novelty in this
work since they can be viewed as bis-C-nucleosides.
While it is reasonable that the yields of these coupling
6a, R = Bn
6b, R = H
Ph
EtO2C
NH
*
H
O
75%, 5:1
Ph-CHO
3
RO
RO
N
H
O
OR
OR
7a, R = Bn
7b, R = H
Ph
EtO2C
NH
*
H
O
92%, 3:1
Ph-CHO
4
N
H
O
RO
RO
OR
8a, R = Bn
8b, R = H
OR
RO
OR
O
RO
35%, 10:1
1
4
H
EtO2C
NH
*
H
O
N
H
O
RO
RO
OR
9a, R = Bn
9b, R = H
RO
OR
O
H
RO
42%, 9:1
2
4
EtO2C
NH
*
H
O
N
H
O
RO
RO
OR
10a, R = Bn
10b, R = H
a Reagents and conditions : Aldehyde, β-Keto Ester, Urea, CuCl, BF3.Et2O, AcOH, 4-Å
MS, 65 ˚C,12-24h. b Overall yield of mixture of isolated perbenzylated diastereomers;
ratio of diastereomers determined by 1H-NMR analysis.

A. Dondoni et al. / Tetrahedron Letters 42 (2001) 4495–4497
4497
reactions employing two complex and bulky partners
were rather modest (Table 1), it is quite rewarding that
the levels of diastereoselectivity were much higher than
in the above more simple cases. Evidently the two sugar
components match quite well in the creation of the
DHPM C4 stereocenter with a preferred configuration.
Hence, while the vast majority of examples of Biginelli
reaction involves the use of achiral reagents and enan-
tiomerically pure products have been obtained by
chemical or enzymatic resolution of racemic mixtures,16
the results of the present study indicate a viable route
toward the asymmetric synthesis of the DHPM ring
system, a prerequisite for the development of useful
drugs having this structural motif.17
reaction. See: (a) Ferna`ndez, M. V.; Herrera, F. J. L.;
Cobos, T. L. Heterocycles 1988, 27, 2133; (b) Ferna`ndez,
M. V.; Herrera, F. J. L.; Cobos, T. L. Heterocycles 1986,
24, 679; (c) Sastre, J. A. L.; Molina, J. M. An. Quim.
1978, 74, 353.
8. (a) Dondoni, A. Pure Appl. Chem. 2000, 72, 1577; (b)
Dondoni, A.; Scherrmann, M.-C. J. Org. Chem. 1994, 59,
6404.
9. It has to be noted that the b-D-configured formyl C-ribo-
furanoside 2 was erroneously reported (Ref. 8b) to be the
a-isomer. For a revision, see: Dondoni, A.; Formaglio,
P.; Marra, A.; Massi, A. Tetrahedron, submitted.
10. Dhavale, D. D.; Bhujbal, N. N.; Joshi, P.; Desai, S. G.
Carbohydr. Res. 1994, 263, 303. 3: [h]2D0=+22 (c=0.9,
CHCl3); 4: [h]2D0=+81 (c=0.6, CHCl3).
In conclusion, it appears to be demonstrated that the
three-component Biginelli reaction can be applied to
the synthesis of different mono- and bis-C-glycosylated
DHPMs. Given the availability of various sugar alde-
hydes and keto esters, the access to a combinatorial
library of glycosylated Biginelli products with a wide
range of structural and stereochemical elements of
diversity for an extensive exploration of biological
properties now becomes of interest.
11. The use of catalytic CuCl as described in Ref. 3c afforded
the Biginelli product in much lower yield (ca. 30%). It is
,
likely that the presence of powdered 4 A molecular sieves,
serving as acid sponge, interfered with the action of the
heterogeneous promoter.
12. 5a (major): [h]2D0=−101 (c=1.2, CHCl3). 5a (minor):
[h]2D0=+30 (c=0.9, CHCl3). 6a (major): mp 147–148°C
(from isopropyl ether–EtOAc); [h]2D0=−65 (c=0.3,
CHCl3). 6a (minor): [h]2D0=+41 (c=1.2, CHCl3). 7a
(major): [h]2D0=+73 (c=0.9, CHCl3). 7a (minor): [h]2D0=
−3 (c=0.3, CHCl3). 8a (major): [h]2D0=+139 (c=1.6,
CHCl3). 8a (minor): [h]2D0=+25 (c=0.9, CHCl3). 9a
(major): [h]2D0=−62 (c=1.1, CHCl3). 9a (minor): [h]2D0=
−10 (c=0.3, CHCl3). 10a (major): [h]2D0=+6 (c=1.0,
CHCl3). 10a (minor): [h]2D0=+75 (c=0.4, CHCl3).
13. Only the major stereoisomers of C-glycosyl DHPMs
5b–10b were isolated and characterized.
Acknowledgements
We gratefully thank the University of Ferrara for finan-
cial support.
14. 5b (major): [h]2D0=−117 (c=0.9, MeOH); MALDI-TOF
MS: 347.0 (M++H), 353.5 (M++Li), 369.5 (M++Na),
385.8 (M++K). 6b (major): mp 264–266°C (from H2O);
[h]2D0=−148 (c=0.2, H2O); MALDI-TOF MS: 340.0 (M+
+Na), 356.0 (M++K). 7b (major): [h]2D0=+63 (c=0.4,
MeOH); MALDI-TOF MS: 409.6 (M++H), 415.6 (M++
Li), 431.7 (M++Na), 448.3 (M++K). 8b (major): [h]2D0=
+59 (c=1.5, MeOH); MALDI-TOF MS: 379.8 (M++H),
386.1 (M++Li), 402.1 (M++Na), 418.2 (M++K). 9b
(major): [h]2D0=−44 (c=0.7, MeOH); MALDI-TOF MS:
471.8 (M++Li), 487.7 (M++Na), 503.9 (M++K). 10b
(major): [h]2D0=−73 (c=1.3, MeOH); MALDI-TOF MS:
441.8 (M++Li), 458.6 (M++Na).
15. (a) Hunziker, J.; Leumann, C. In Modern Synthetic
Methods 1995; Ernst, B.; Leumann, C., Eds.; VCH: Basel,
1995; p. 333; (b) Wilson, L. W.; Hager, M. W.; El-Kat-
tan, Y. A.; Liotta, D. C. Synthesis 1995, 1465; (c)
Nucleosides and Nucleotides as Antitumor and Antiviral
Agents; Chu, C. K.; Baker, D. C., Eds.; Plenum Press:
New York, 1993; (d) Huryn, D. M.; Okabe, M. Chem.
Rev. 1992, 92, 1745; (e) Perigaud, C.; Gosselin, G.;
Imbach, J.-L. Nucleosides Nucleotides 1992, 11, 903.
16. Schnell, B.; Strauss, U. T.; Verdino, P.; Faber, K.;
Kappe, C. O. Tetrahedron: Asymmetry 2000, 11, 1449.
17. Rovnyak, G. C.; Kimbal, S. D.; Beyer, B.; Cucinotta, G.;
DiMarco, J. D.; Gougoutas, J.; Hedberg, A.; Malley, M.;
McCarthy, J. P.; Zhang, R.; Moreland, S. J. Med. Chem.
1995, 38, 119.
References
1. For a recent review, see: Kappe, C. O. Acc. Chem. Res.
2000, 33, 879.
2. (a) Kappe, C. O. Bioorg. Med. Chem. Lett. 2000, 10, 49;
(b) Kappe, C. O.; Falsone, S. F.; Fabian, W. M. F.;
Belaj, F. Heterocycles 1999, 51, 77; (c) McDonald, A. I.;
Overman, L. E. J. Org. Chem. 1999, 64, 1520.
3. (a) Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000,
65, 6270; (b) Ma, Y.; Qian, C.; Wang, L.; Yang, M. J.
Org. Chem. 2000, 65, 3864; (c) Hu, E. H.; Sidler, D. R.;
Dolling, U. H. J. Org. Chem. 1998, 63, 3454.
4. Stadler, A.; Kappe, C. O. J. Chem. Soc., Perkin Trans. 2
2000, 1363.
5. For an updated list of leading references on this topic,
see: Jauk, B.; Belaj, F.; Kappe, C. O. J. Chem. Soc.,
Perkin Trans 1 1999, 307.
6. (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 cited 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.
7. We are aware of a few reports dealing with the use of
rather simple sugar aldehydes (2,3-O-isopropylidene-
glyceraldehyde, 2,4-O-ethylidene- -threose and -ery-
D-
D
D
throse, 2,5-anhydro-aldehydo-
D
-xylose) in the Biginelli
.