Three-component biginelli cyclocondensation reaction using C-glycosylated substrates. Preparation of a collection of dihydropyrimidinone glycoconjugates and the synthesis of C-glycosylated monastrol analogues

Article abstract of DOI:10.1021/jo0202076

The aldehyde-ketoester-urea cyclocondensation reaction has been revisited using C-glycosylated reagents with the aim of exploring a potential entry to a library of dihydropyrimidinone glycoconjugates. A collection of 13 mono- and bis-C-glycosylated dihydropyrimidinones has been prepared by a parallel synthesis approach using the three-component promoter CuCl/AcOH/BF₃· Et₂O. The sugar residues have been installed at either N1, C4, or C6 in the monoglycosylated derivatives and at both the C4 and C6 in the bisglycosylated products. The mono- and bisglycosylated products at C4 and C6 were obtained as mixtures of diastereoisomers with good to excellent selectivities due to the asymmetric induction by the sugar residue in the formation of the C4 stereocenter of the dihydropyrimidinone ring. Individual stereoisomers were isolated as pure compounds and their structures assigned with the aid of X-ray crystallography and chiroptical properties. As a demonstration of this new concept in the Biginelli reaction, the synthesis of two C4 epimer monastrol analogues bearing the ribofuranosyl moiety at C6 has been described.

Full text of DOI:10.1021/jo0202076

Th r ee-Com p on en t Bigin elli Cyclocon d en sa tion Rea ction Usin g
C-Glycosyla ted Su bstr a tes. P r ep a r a tion of a Collection of
Dih yd r op yr im id in on e Glycocon ju ga tes a n d th e Syn th esis of
C-Glycosyla ted Mon a str ol An a logu es†
Alessandro Dondoni,*,‡ Alessandro Massi,‡ Simona Sabbatini,‡ and Valerio Bertolasi§
Laboratorio di Chimica Organica, Dipartimento di Chimica, Universita` di Ferrara, Via L. Borsari 46,
44100 Ferrara, Italy, and Centro di Strutturistica Diffrattometrica, Dipartimento di Chimica, Universita`
di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy
adn@dns.unife.it
Received March 25, 2002
The aldehyde-ketoester-urea cyclocondensation reaction has been revisited using C-glycosylated
reagents with the aim of exploring a potential entry to a library of dihydropyrimidinone
glycoconjugates. A collection of 13 mono- and bis-C-glycosylated dihydropyrimidinones has been
prepared by a parallel synthesis approach using the three-component promoter CuCl/AcOH/BF3‚
Et2O. The sugar residues have been installed at either N1, C4, or C6 in the monoglycosylated
derivatives and at both the C4 and C6 in the bisglycosylated products. The mono- and bisglycosylated
products at C4 and C6 were obtained as mixtures of diastereoisomers with good to excellent
selectivities due to the asymmetric induction by the sugar residue in the formation of the C4
stereocenter of the dihydropyrimidinone ring. Individual stereoisomers were isolated as pure
compounds and their structures assigned with the aid of X-ray crystallography and chiroptical
properties. As a demonstration of this new concept in the Biginelli reaction, the synthesis of two
C4 epimer monastrol analogues bearing the ribofuranosyl moiety at C6 has been described.
In tr od u ction
In the main stream of the current interest in one-pot
multicomponent reactions1 that permit a rapid access to
combinatorial libraries of organic molecules for efficient
lead structure identification and optimization in drug
discovery,2 the acid-catalyzed condensation of aldehyde,
â-ketoester, and urea (or thiourea) (Figure 1), known as
the Biginelli reaction from the name of its inventor,3 is
receiving increased attention.4 More than 100 years ago,
Biginelli intuitively anticipated the synthetic potential
F IGURE 1. Biginelli cyclocondensation reaction leading to
the dihydropyrimidine (DHPM) framework.
of multicomponent reactions by combining in a single
flask the reactants of two different reactions having one
component in common.5 The result of the three-compo-
nent reaction was a new product that was correctly
characterized as a substituted 3,4-dihydropyrimidin-
2(1H)-one (DHPM). The synthetic potential of the Bigi-
nelli reaction has been recognized and exploited in
relatively recent years by the synthesis of numerous
DHPMs as well as their sulfur analogues using both
solution- and solid-phase reaction techniques.6 Improved
procedures using different types of catalysts7 and condi-
* To whom correspondence should be addressed. Fax: +39 0532
291167.
† Dedicated to Professor Albert Padwa on the occasion of his 65th
birthday.
‡ Laboratorio di Chimica Organica.
§ Centro di Strutturistica Diffrattometrica. Address correspondence
concerning crystallography to this author. Fax: +39 0532 240709.
E-mail: m38@unife.it.
(1) Passerini three-component and Ugi four-component condensa-
tions are the most popular among many other reactions for their wide
scope and synthetic utility. For reviews, see: (a) Bienayme´, H.; Hulme,
C.; Oddon, G.; Schmitt, P. Chem. Eur. J . 2000, 6, 3321. (b) Do¨mling,
A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(2) (a) Dolle, R. E.; Nelson, K. H. J . Comb. Chem. 1999, 1, 235. (b)
Nuss, J . M.; Renhowe, P. A. Curr. Opin. Drug Discuss. Dev. 1999, 2,
631. (c) Oliver, S. F.; Abell, C. Curr. Opin. Chem. Biol. 1999, 3, 299.
(d) Obrecht, D.; Villalgordo, J . M. In Solid-Supported Combinatorial
and Parallel Synthesis of Small-Molecular-Weight Compounds Librar-
ies; Baldwin, J . E., Williams, R. M., Eds.; Pergamon Press: New York,
1998. (e) Thompson, L. A.; Ellman, J . A. Chem. Rev. 1996, 96, 555. (f)
Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29,
144.
(5) Quite fairly, Biginelli stated (ref 3) that his research was inspired
by the earlier work of R. Behrend on the urea-ketoester coupling and
U. Schiff on the urea-aldehyde coupling.
(6) (a) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879. (b) Kappe, C. O.
Bioorg. Med. Chem. Lett. 2000, 10, 49. (c) Kappe, C. O.; Falsone, S. F.;
Fabian, W. M. F.; Belaj, F. Heterocycles 1999, 51, 77. (d) McDonald,
A. I.; Overman, L. E. J . Org. Chem. 1999, 64, 1520. (e) Kappe, C. O. J .
Org. Chem. 1997, 62, 7201. (f) Studer, A.; J eger, P.; Wipf, P.; Curran,
D. P. J . Org. Chem. 1997, 62, 2917. (g) Wipf, P.; Cunningham, A.
Tetrahedron Lett. 1995, 36, 7819.
(3) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
(4) For a review, see: Kappe, C. O. Tetrahedron 1993, 49, 6937.
10.1021/jo0202076 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/05/2002
J . Org. Chem. 2002, 67, 6979-6994
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Dondoni et al.
investigated class of dihydropyrimidinones, namely their
C-glycosyl derivatives.15 We are aware of only a few
reports dealing with the use of rather simple sugar
aldehydes (2,3-O-isopropylidene-D-glyceraldehyde, 2,4-O-
ethylidene-D-threose and D-erythrose, 2,5-anhydro-alde-
hydo-D-xylose) in the Biginelli reaction.16 Aside from the
simple expectation that the presence of hydroxy-free
sugar residues in the Biginelli products should increase
the water solubility and bioavailability, other interesting
biological properties may arise from glycosylation con-
sidering the extensive and essential role of carbohydrate
molecules in the complex machinery of various glycocon-
jugate biological activity.17 Glycosylation of heterocycles
that are rich in biological activity is a field of increasing
interest as shown, for example, by the synthesis of
various guanidinoglycosides displaying improved biologi-
cal properties (anti-influenza and anti-HIV activities)
with respect to the nonglycosylated guanidino deriva-
tives.18 In fact, an attractive aspect of C-glycosylated
Biginelli products is their resemblance to C-nucleosides,
i.e., carbon-linked glycoside analogues of N-linked natu-
ral products. In addition, the synthesis of these C-
glycoconjugates19 is a current topic of research in me-
dicinal chemistry due to the well-established potent
activity of various nucleosides as anticancer and antiviral
agents.20
F IGURE 2. Dihydropyridine and dihydropyrimidine deriva-
tives of pharmaceutical relevance.
tions8 have been reported with the aim of overcoming the
main drawbacks of the Biginelli reaction, which are
represented by the modest yields and/or some difficulties
in product isolation when a large excess of one reagent
is employed.
Despite the fact that the biological activity of 4-aryl-
substituted DHPMs is strictly dependent on the absolute
configuration at the C4 stereocenter,6a,13 the Biginelli
reaction has been mostly carried out in an achiral
version. The separation of enantiomers has been reported
using chemical and enzymatic methods or preparative
chromatographic techniques with chiral supports.6a,21
Hence, an additional reason for which we have been
spurred to use glycosylated reagents in the Biginelli
reaction stems from the desire to achieve some internal
asymmetric induction and thus obtain diastereomerically
pure DHPMs derivatives.
The considerable interest for DHPM-type products
stems from their structural similarity to dihydropyridines
(Hantzsch products, DHPs),9 a class of compounds show-
ing remarkable pharmacological properties as calcium
channel antagonists, and finding extensive use as thera-
peutics in the clinical treatment of cardiovascular dis-
eases such as hypertension, cardiac arrhytmias, or
angina pectoris.10 Nifedipine 111 (Figure 2) is a well-
known DHP derivative that is marketed as a drug for
these types of diseases. DHPMs exhibit similar biological
profiles to DHPs12 as shown, for instance, by the 4-aryl
derivatives 2 and 3. Other biological activities of DHPMs
have been also disclosed, including that of R1a adrenergic
receptor antagonists as drug candidates for the treatment
of benign prostatic hyperplasia.13 Noteworthy is the
recently identified lead compound 4 (monastrol) of a new
class of anticancer agents acting as cell division (mitosis)
blockers.14 Hence, it was of some interest to us to explore
a route leading to a collection of hitherto scarcely
Resu lts a n d Discu ssion
Syn th esis of Glycosyla ted Rea gen ts. The aim of
this work was to prepare a collection of monoglycosylated
and multiple glycosylated DHPM derivatives at N1, C4,
and C6 via parallel synthesis employing the Biginelli
reaction of suitably C-glycosylated reactants. A further
(7) (a) Kumar, K. A.; Kasthuraiah, M.; Reddy, C. S.; Reddy, C. D.
Tetrahedron Lett. 2001, 42, 7873. (b) Lu, J .; Bai, Y.; Wang, Z.; Yang,
B.; Ma, H. Tetrahedron Lett. 2000, 41, 9075. (c) Ranu, B. C.; Hajra,
A.; J ana, U. J . Org. Chem. 2000, 65, 6270. (d) Ma, Y.; Qian, C.; Wang,
L.; Yang, M. J . Org. Chem. 2000, 65, 3864. (e) Bigi, F.; Carloni, S.;
Frullanti, B.; Maggi, R.; Sartori, G. Tetrahedron Lett. 1999, 40, 3465.
(f) Hu, E. H.; Sidler, D. R.; Dolling, U. H. J . Org. Chem. 1998, 63,
3454. (g) Kappe, C. O.; Falsone, S. F. Synlett 1998, 718.
(8) (a) Peng, J .; Deng, Y. Tetrahedron Lett. 2001, 42, 5917. (b)
Stadler, A.; Kappe, C. O. J . Chem. Soc., Perkin Trans. 2 2000, 1363.
(9) Eisner, U.; Kuthan, J . Chem. Rev. 1972, 72, 1.
(10) For an updated list of leading references on this topic, see: J auk,
B.; Belaj, F.; Kappe, C. O. J . Chem. Soc., Perkin Trans. 1 1999, 307.
(11) Bossert, F.; Vater, W. US Pat. 3485847, 1969.
(12) (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.
(13) For a survey on this topic with leading references, see: Kappe,
C. O. Eur. J . Med. Chem. 2000, 35, 1043.
(14) Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J .; King, R. W.;
Schreiber, S. L.; Mitchison, T. J . Science 1999, 286, 971.
(15) For a preliminary report on this subject, see: Dondoni, A.; Massi,
A.; Sabbatini, S. Tetrahedron Lett. 2001, 42, 4495.
(16) (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.
(17) (a) Essentials of Glycobiology; Varki, A., Cummings, R., Esko,
J ., Freeze, H., Hart, G., Marth, J ., Eds.; Cold Spring Harbor Laboratory
Press: New York, 1999. (b) Varki, A. Glycobiology 1993, 3, 97.
(18) For a recent report on the synthesis of new guanidine-sugars
and leading references to earlier work on these glycoconjugates, see:
Lin, P.; Lee, C. L.; Sim, M. M. J . Org. Chem. 2001, 66, 8243.
(19) Postema, M. H. D. C-Glycoside Synthesis; CRC Press: Boca
Raton, 1995; p 303.
(20) (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-Kattan, 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.
(21) Schnell, B.; Krenn, W.; Faber, K.; Kappe, C. O. J . Chem. Soc.,
Perkin Trans. 1 2000, 4382.
6980 J . Org. Chem., Vol. 67, No. 20, 2002

Biginelli Cyclocondensation Reaction Using C-Glycosylated Substrates
SCHEME 1
SCHEME 2
and galactosyl derivatives 8a and 8b. The reaction
sequence involved the reduction (NaBH4) of the sugar
aldehydes 5a and 5b into the corresponding alcohols and
transformation of these compounds into the glycosylm-
ethyl azides 7a and 7b by the use of diphenylphosphoryl
azide (DPPA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
and sodium azide. The catalytic hydrogenation of these
azides afforded the corresponding amines which upon
condensation with nitrourea were transformed into the
ureido sugars 8a and 8b following a literature proce-
dure.26 The reduction of the azido to the amino group
required some caution such as a short reaction time (20
min) in order to avoid the removal of the O-benzyl groups
from the sugar moiety. It is noteworthy that all steps in
this reaction sequence were high yield reactions, and
therefore compounds 8a and 8b were isolated in very
good overall yields (76-84%).
The above route to glycosylmethyl ureas proved to be
not viable in the case of the mannopyranosyl derivative
8c due to a failure to obtain the corresponding sugar
azide 7c. In fact, treatment of the alcohol derived from
the reduction of the aldehyde 5c with DPPA, DBU, and
NaN3 did not proceed beyond the formation of a glyco-
sylmethyl phosphate. The ureido sugar 8c as well as the
ribofuranosyl and galactopyranosyl derivatives 8a and
8b were conveniently prepared starting from the sugar
nitriles 9a -c via reduction to amines and condensation
with nitrourea (Scheme 2). While this method appears
to be quite efficient, its main drawback consists of access
to the starting glycosyl cyanides 9a -c since these
â-linked anomers are obtained as minor isomers by
C-glycosidation reaction of glycosyl acetates with TM-
SCN.27
element of diversity was also foreseen by the use of
different sugar residues in each substrate. A glycosidic
carbon-carbon linkage in the reaction partners was a
structural prerequisite to ensure substantial stability
toward chemical and enzymatic degradation of the re-
sulting glycosylated DHPM products.
Various anomeric sugar aldehydes (formyl C-glyco-
sides) that we needed in this program were accessible in
practical quantities starting from sugar lactones through
our thiazole-based formylation method.22 Hence, the
â-linked O-benzyl-protected formyl ribofuranoside23 5a ,
galactopyranoside22b 5b , and mannopyranoside22b 5c
derivatives (Scheme 1) were prepared from the corre-
sponding perbenzylated lactones as described. Moreover,
these sugar aldehydes proved to be convenient precursors
of the corresponding C-glycosyl â-ketoesters 6a -c in
satisfactory yield (60-75%) via BF3‚Et2O-promoted cou-
pling with ethyl diazoacetate (Scheme 1) according to a
literature procedure.24 The same aldehydes also turned
out to be useful intermediates for the preparation of
glycosylmethyl ureas25 as shown in the case of the ribosyl
Bigin elli Rea ction s. Given the plethora of catalysts
and conditions that have been proposed for the execution
of the Biginelli reaction,6-8 the model cyclocondensation
of the O-tetrabenzylated formyl C-galactopyranoside 5b,
ethyl acetoacetate, and urea was studied under different
reaction conditions (Table 1). Crucial to this program was
finding a suitable acid additive that would be tolerated
by the rather sensitive sugar moieties. Entries 1-4 of
Table 1 indicated unsatisfactory conditions whereas
entries 5-8 showed promising results. A convenient
additive (Table 1, entry 9) consisted of a three-component
system as a promoter constituted by CuCl/AcOH /BF3‚
(22) (a) Dondoni, A. Pure Appl. Chem. 2000, 72, 1577. (b) Dondoni,
A.; Scherrmann, M.-C. J . Org. Chem. 1994, 59, 6404.
(23) It has to be noted that the â-D-configured formyl C-ribofura-
noside 5a was erroneously reported (ref 22b) to be the R-isomer. For a
revision, see: Dondoni, A.; Formaglio, P.; Marra, A.; Massi, A.
Tetrahedron 2001, 57, 7719.
(25) The attachment of the sugar moiety to the urea through a
methylene bridge was designed in order to ensure higher stability with
respect to the N-glycosyl derivative.
(26) Winkley, M. W. Carbohydr. Res. 1973, 31, 245.
(27) (a) Togo, H.; Ishigami, S. Fujii, M.; Ikuma, T.; Yokoyama, M.
J . Chem. Soc., Perkin Trans. 1 1994, 2931. (b) Igarashi, Y.; Shiozawa,
T.; Ichikawa, Y. Bioorg. Med. Chem. Lett. 1997, 7, 613 and references
therein.
(24) Dhavale, D. D.; Bhujbal, N. N.; J oshi, P.; Desai, S. G. Carbo-
hydr. Res. 1994, 263, 303.
J . Org. Chem, Vol. 67, No. 20, 2002 6981

Dondoni et al.
TABLE 1. Stu d y of th e Mod el Bigin elli Rea ction a
diastereoisomers. These stereochemical outcomes are
consistent with the main reaction pathway that has been
recently identified in the Biginelli reaction.6a The pro-
posed mechanism consists of an initial step of condensa-
tion between the aldehyde and urea to form an N-
acyliminium ion intermediate that is trapped by the
ketoester to give an open-chain ureide (R-amidoalkylation
sequence), which in turn cyclizes to the final product.
Since the C4 stereocenter of the DHPM ring is estab-
lished in the N-acyliminium ketoester carbon-carbon
bond-forming reaction, it is reasonable that chiral resi-
dues in the aldehyde and ketoester exert some internal
asymmetric induction while chiral moieties in the urea
are inefficient.
Cyclocondensations were also carried out using two
glycosylated reaction partners, i.e., the aldehydes and
ketoesters (Table 2). Mixtures of bisglycosylated DHPM
derivatives 15a -c were obtained in modest chemical
yields very likely because of the bulkiness of the two
reactants. On the other hand, the level of asymmetric
induction was much higher than in the above monogly-
cosylated products, which indicates that the two sugar
components match quite well in the creation of the C4
stereocenter with a preferred configuration. As antici-
pated by the modest yields of isolated products 15a -c,
the cyclocondensation employing three glycosylated reac-
tion partners became problematic due to the considerable
steric interactions. Attempts to preparing the DHPM
trisglycoconjugate 16a by cyclocondensation of the ribosyl
derivatives 5a , 6a , and 8a has failed so far as this
compound was only detected by mass spectroscopy in the
crude reaction mixture.
run additive (equiv) solvent T (°C) time (h) % yieldb of 11b
1
2
3
4
5
6
7
8
aq HCl (cat.)
EtOH
reflux
reflux
15
48
48
14
14
14
14
14
5
5
montmorillonitec THF
montmorillonitec toluene 100
InCl3 (cat.)
InCl3(1)
Yb(OTf)3 (cat.)
Yb(OTf)3 (1)
CuCl (cat.)
AcOH (cat)
BF3 Et2O (1.3)
CuCl (1)
10
12
27
32
60
35
THF
THF
THF
THF
THF
reflux
reflux
reflux
reflux
65
9
THF
THF
65
65
14
24
48
65
AcOH (0.2)
BF3 Et2O (1.3)
10 CuCl (1)
AcOH (0.2)
BF3 Et2O (1.3)
a
All reactions were run with 0.5 mmol of 5b, 1 equiv of ethyl
acetoacetate, and 1.5 equiv of urea in 2 mL of solvent in the
b
presence of 4 Å molecular sieves. Isolated yields of mixtures of
diastereoisomers (ca. 5:1 by NMR). c Montmorillonite KSF.
Et2O in noncatalytic amount.28 Optimized conditions were
established in THF as a solvent using a reaction tem-
perature and time of 65 °C and 24 h, respectively (Table
1, entry 10). It has to be noted that in all cases the
product 11b consisted of a mixture of diastereoisomers
with a marked predominance of one over the other (ca.
5:1).
Due to the satisfactory results of the CuCl/AcOH/BF3‚
Et2O-promoted cyclocondensation of the sugar aldehyde
5b, the reactions of some of the possible combinations of
glycosylated reagents 5, 6, 8, ethyl acetoacetate, aryl
aldehydes, and urea were carried out in a parallel
manner in order to obtain a collection of mono- and
polyglycosylated DHPMs (Table 2). The use of a single
glycosylated partner afforded the DHPM glycoconjugate
triads 11a -c, 12a -c, and 14a -c in which the hetero-
cyclic ring featured a single sugar residue at C4, C6, and
N1, respectively. Compound 13a represented a type of
DHPM derivative that partly resembled compound 3 of
Figure 2 since the phenyl ring at C4 was ortho substi-
tuted by a trifluoromethyl group. All products 11-14 of
these Biginelli reactions were obtained as mixtures of
diastereoisomers due to the formation of the stereocenter
at C4 of the DHPM ring. The overall yields ranged from
the excellent value (92%) of 12a to the modest value
(40%) of 14c. Stereoselectivities varied in a significant
range as well since the C4 and C6 glycosylated com-
pounds (R)-11b and (S)-12b were obtained with good
stereoisomeric excess whereas all the N1-glycosylated
derivatives 14a -c were obtained as ca. 1:1 mixtures of
In Table 2 are reported the structures of the major
diastereoisomers obtained in the various cyclocondensa-
tion reactions that have been examined. In fact, the
isomers of each reaction mixture were adequately sepa-
rated by chromatography and each individual compound
was characterized through its NMR and mass spectral
data. The absolute configuration at C4 was assigned by
a circular dichroism study using the O-debenzylated
derivatives (see below). The removal of the O-benzyl
groups from the sugar residues was carried out in almost
quantitative manner by hydrogenation over Pd(OH)2. In
addition to the structural assignment, the sugar O-
debenzylated derivatives 11a ′-15c′ shown in Table 2 and
their epimers at C4 are products of considerable impor-
tance since they are suitable substrates for biological and
pharmacological studies. In closing this section, it is
worth pointing out that all of the glycosylated Biginelli
products prepared can be viewed as members of new
classes of mono- and bis-C-nucleosides. The method
(28) The use of catalytic CuCl as described in ref 7f afforded the
Biginelli product in much lower yield (ca. 30%). It is likely that the
presence of powdered 4-Å molecular sieves, acting as acid sponge,
interfered with the action of the heterogeneous promoter.
6982 J . Org. Chem., Vol. 67, No. 20, 2002

Biginelli Cyclocondensation Reaction Using C-Glycosylated Substrates
TABLE 2. 3,4-Dih yd r op yr im id in -2(1H)-on e Glycocon ju ga tes 11-15 P r ep a r ed a
a
All Biginelli reactions were run in THF at 65 °C using the mixture CuCl/AcOH/BF3‚Et2O as additive (for details see the Experimental
Section). Only the major diastereoisomer is shown. c Overall yield of the mixture of diastereoisomers.
b
J . Org. Chem, Vol. 67, No. 20, 2002 6983

Dondoni et al.
described herein is, therefore, a new approach to C-
nucleosides via a one-pot multicomponent cycloconden-
sation reaction.
Str u ctu r e Assign m en ts. Structure and absolute con-
figuration assignments of compounds 11-15 were per-
formed using mono- and bidimensional 1H and 13C NMR
spectroscopic analysis in conjunction with chiroptical
data, i.e., Cotton effects (CE), as determined by circular
dichroism (CD). The X-ray structure determination of one
crystalline compound was also carried out. The â-linkage
at the anomeric carbon (C1′) of the sugar moieties was
confirmed for all compounds by estimating the J 1′,2′ values
or by the aid of NOE measurements, as appropriate. In
fact, galactopyranosyl derivatives showed J 1′,2′ values
around 9.0 Hz while the ribofuranosyl and mannopyra-
nosyl derivatives displayed probing NOE values between
H1′ and H4′ or H1′ and H5′, respectively. These results
indicate that the stereochemical integrity at the anomeric
carbon of the glycosylated reagents 5, 6, and 8 was
retained in the course of the three-component cyclocon-
densation reactions. The assignment of the absolute
configuration at the C4 stereocenter was initially based
on the comparison of CD spectra with those of DHPMs
with known absolute configuration.29 The observed CD
spectra (Figure 3) of the 4-phenyl-6-(â-D-ribofuranosyl)
derivative (S)-12a ′ (Table 2) and its C4 (R)-epimer
appeared to be very similar to those reported for other
(S)- and (R)-configured 4-aryl-DHPMs,29a-c being of the
mirror-image type and exhibiting two bands of opposite
sign at 300 and 230 nm. Although the risk of deducing
the absolute stereochemistry by direct comparison of CD
spectra has been stressed by several authors,30 this
experimental approach has proved to be reliable so far
for the determination of the C4 configuration of various
biologically active DHMPs.29b,c Therefore, the CD spec-
trum showing a positive long wavelength and a negative
short wavelength ∆ꢀ was attributed to the stereoisomer
(S)-12a ′ in complete agreement with previously reported
assignments.29a Very similar CD spectra of the mirror-
image type showing the same minus-plus couplet were
also observed for each pair of diastereoisomers of 4-aryl
C6-glycosylated DHMPs 12b′, 12c′, and 13a ′ and N1-
glycosylated DHPMs 14a ′-c′. Accordingly, the 4S-con-
figuration was assigned to those diastereoisomers show-
ing in their CD spectra positive sign of the first (ca. 300
nm) and negative sign of the second band (ca. 230 nm)
on the basis of the previously described experimental
method.29a
F IGURE 3. Experimental CD spectra of (S)-12a ′ and (R)-12a ′.
F IGURE 4. Experimental CD spectra of (S)-11a ′ and (R)-11a ′.
similar CD data of various 4-alkyl DHPMs.29d Since
similar shapes were also observed in the CD spectra of
the C4 glycosylated compounds 11b′ and 11c′ and the
C4 and C6 bis-glycosylated derivatives 15a ′-c′, the
absolute R configuration at C4 was assigned following
the same reasoning. These structure assignments were
confirmed by the X-ray crystallographic analysis of the
C4 glycosylated derivative32 (R)-17b whose deprotected
derivative (R)-17b′ showed the same shape in the CD
spectrum (two bands with negative sign at ca. 290 and
240 nm) observed for all the above C4 glycosylated
compounds which were assigned the R-configuration.
Syn th esis of C-Glycosylated Mon astr ol An alogu es.
Out of a 16320-member collection of small-molecules,
monastrol 4 (Figure 2) has been identified as a compound
that specifically affects mitosis without targeting tobu-
lin.14 It has been established that monastrol activity
consists of the specific and reversible inhibition of the
motility of the mitotic kinesin Eg5, a motor protein
known to be required for spindle bipolarity. Due to this
biological activity combined with cell permeability, mo-
nastrol can be considered as a lead compound for the
development of new anticancer drugs. The synthesis of
The CD spectra of (4R)- and (4S)-6-methyl-4-(â-D-
ribofuranosyl) derivatives 11a ′ (Table 2) appeared as
mirror images as well but exhibited two bands of like sign
at ca. 290 and 240 nm (Figure 4). The CD spectrum
showing two negative Cotton effects was tentatively
assigned to the (4R) diastereoisomer31 in agreement with
(29) (a) Krenn, W.; Verdino, P.; Uray, G.; Faber, K.; Kappe, C. O.
Chirality 1999, 11, 659. (b) Schnell, B.; Strauss, U. T.; Verdino, P.;
Faber, K. ; Kappe, C. O.Tetrahedron: Asymmetry 2000, 11, 1449. (c)
Kappe, C. O.; Shishkin, O. V.; Uray, G.; Verdino, P. Tetrahedron 2000,
56, 1859. (d) Uray, G.; Verdino, P.; Belaj, F.; Kappe, C. O.; Fabian, W.
M. F. J . Org. Chem. 2001, 66, 6685.
(30) (a) Hansen, A. E.; Bouman, T. D. Adv. Chem. Phys. 1980, 44,
545. (b) Ripa, L.; Hallberg, A.; Sandstro¨m, J . J . Am. Chem. Soc. 1997,
119, 5701.
(32) Compound (R)-17b was prepared by selective debenzylation of
the corresponding O-benzyl ester which was in turn obtained by the
standard cyclocondensation reaction using benzyl acetoacetate, urea,
and the aldehyde 5b (see the Experimental Section).
(31) It has to be noted that the assignment of the opposite config-
uration with respect to the ref 29d is due to the different substituent
priorities.
6984 J . Org. Chem., Vol. 67, No. 20, 2002

Biginelli Cyclocondensation Reaction Using C-Glycosylated Substrates
glycosylated monastrol analogues would, therefore, ap-
pear to be of great interest.
Wishing to prepare a C6-glycosylated modified monas-
trol via cyclocondensation of the ribofuranosyl-containing
F IGURE 5. Experimental CD spectra of 19a and 19b.
SCHEME 3
ketoester 6a with 3-hydroxybenzaldehyde and thiourea
(Scheme 3), we found that the three-component CuCl/
AcOH/BF3‚Et2O promoter was not compatible with the
latter sulfur-containing reagent since the reaction did not
produce appreciable amounts of product. Instead, the use
of 0.5 equiv of Yb(OTf)3 proved to be quite beneficial since
with this Lewis acid the reaction afforded the C6-
glycosylated dihydropyrimidinethione 18 in fair yield
(66%) as a mixture of diastereoisomers in a 2:1 ratio.
Attempts to remove the O-benzyl groups from the
sugar moiety of 18 via Pd-catalyzed hydrogenolysis
proved to be unsuccessful due to the inactivation of the
catalyst by the thione group. Under these conditions,
most of the starting compound 18 was recovered unal-
tered or decomposed to give desulfurated material.
Hence, the two diastereoisomers 18a and 18b were
separated by chromatography and each individual prod-
uct was subjected to debenzylation using BCl3 in meth-
ylene dichloride solution at low temperature followed by
quenching with a 1:1 mixture of ethanol-methylene
dichloride. The yield of this debenzylation procedure was
quite fair (75%). The resulting hydroxy-free derivatives
19a and 19b were suitable compounds for the absolute
configuration assignment at the C4 stereocenter by the
CD method as described above for the 4-aryl-6-glyco-
syldihydropyrimidinones 12a ′-c′ and 13a ′ (see Table 2).
As the mirror-image type CD spectra of the major and
minor stereoisomer 19a and 19b shown in Figure 5 were
similar to that of Figure 3 and to those of monastrol
enantiomers,29c it can be deduced that also in this case
the major stereoisomer was that with the (4S) configu-
ration.
SCHEME 4
droxy groups33 (Scheme 4). It was hoped that the easily
removable ester groups from the sugar residue would
provide a high yield protocol. Instead, the Yb(OTf)3-
promoted cyclocondensation of 20 with 3-acetoxybenzal-
dehyde34 and thiourea afforded a mixture of the C6-
substituted furyl dihydropyrimidinethiones 21 and its
O-acetyl derivative 22 in a 2:1 ratio in 69% overall yield
(Scheme 4). The removal of the benzoyl and acetyl
protective groups by basic treatment afforded racemic
furyl dihydropyrimidinethione 23 as a single product (RD
(33) Morelli, C. F.; Manferdini, M.; Veronese, A. C. Tetrahedron
1999, 55, 10803.
(34) The phenolic hydroxy group was protected in order to avoid
possible transesterification reactions by the O-benzoyl groups.
An alternative synthetic route leading to the glycocon-
jugates 19a and 19b was explored using the known
C-glycosylated ketoester 20 having O-benzoylated hy-
J . Org. Chem, Vol. 67, No. 20, 2002 6985

Dondoni et al.
Cl2 (3 × 30 mL). The organic layer was dried (Na2SO4) and
concentrated. The residue was eluted from a short column of
silica gel with 6:1 cyclohexane-AcOEt to give 6a (622 mg, 60%)
) 0). These results can be explained by assuming that
compound 20 is highly unstable under the Biginelli
reaction conditions and undergoes a fast elimination of
two molecules of benzoic acid to give a furyl ketoester,
which in turn takes part in an achiral cyclocondensation
process.
as a white amorphous solid. [R]2D0 ) +81.0 (c 0.6, CHCl3). H
1
NMR (DMSO-d6, 120 °C): δ ) 7.40-7.20 (m, 15 H, 3 Ph), 4.66,
4.62 (2 d, 2 H, J ) 11.0 Hz, PhCH2), 4.62, 4.54 (2 d, 2 H, J )
12.0 Hz, PhCH2), 4.56, 4.52 (2 d, 2 H, J ) 11.5 Hz, PhCH2),
4.48 (d, 1 H, J 1′,2′ ) 5.0 Hz, H-1′), 4.25 (dd, 1 H, J 2′,3′ ) 4.8 Hz,
H-2′), 4.20 (ddd, 1 H, J 3′,4′ ) 5.2 Hz, J 4′,5′a ) 4.0 Hz, J 4′,5′b ) 4.8
Hz, H-4′), 4.10 (q, 2 H, J ) 7.0 Hz, CH2CH3), 3.95 (dd, 1 H,
H-3′), 3.67 (dd, 1 H, J 5′a,5′b ) 11.0 Hz, H-5′a), 3.66, 3.61 (2 d, 2
H, J ) 14.5 Hz, 2 H-2), 3.59 (dd, 1 H, H-5′b), 1.20 (t, 3 H,
CH3). Anal. Calcd for C31H34O7 (518.60): C, 71.80; H, 6.61.
Found: C, 71.82; H, 6.65.
In conclusion, it has been shown that the three-
component Biginelli reaction can be applied for the
synthesis of different mono- and bis-C-glycosylated
DHPMs. Given the availability of various glycosylated
aldehydes, ketoesters, and ureas, this methodology should
permit 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. It is noteworthy that
the Biginelli reactions with glycosylated ketoesters and
aldehydes occur with satisfactory asymmetric induction
leading to chiral products with a given configuration at
the C4 stereocenter of the DHPM ring. This is a remark-
able result in view of the strict dependence of the
biological properties of this pharmacophore on the con-
figuration at C4. Within the framework of this concept,
it appears that it is possible to prepare chiral glycosylated
monastrol analogues for an extensive exploration to
discover new anticancer drugs.
Eth yl 3-Oxo-3-(2′,3′,4′,6′-tetr a -O-ben zyl-â-D-ga la ctop y-
r a n osyl)p r op a n oa te (6b). Aldehyde 5b (1.10 g, 2.00 mmol)
was treated as described for the preparation of 6a . Column
chromatography on silica gel of the residue with 6:1 cyclohex-
ane-AcOEt afforded 6b (958 mg, 75%) as a syrup. [R]D20
)
1
+22.0 (c 0.9, CHCl3). H NMR (DMSO-d6, 120 °C): δ ) 7.50-
7.20 (m, 20 H, 5 Ph), 4.86, 4.58 (2 d, 2 H, J ) 11.5 Hz, PhCH2),
4.80, 4.59 (2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.75, 4.69 (2 d, 2 H,
J ) 11.2 Hz, PhCH2), 4.53, 4.49 (2 d, 2 H, J ) 11.6 Hz, PhCH2),
4.13-4.04 (m, 3 H), 3.99-3.92 (m, 2 H), 3.87-3.76 (m, 2 H),
3.65 (dd, 1 H, J 5′,6′a ) 6.0 Hz, J 6′a,6′b ) 10.2 Hz, H-6′a), 3.60 (s,
2 H, 2 H-2), 3.59 (dd, 1 H, J 5′,6′b ) 6.8 Hz, H-6′b), 1.17 (t, 3 H,
J ) 7.0 Hz,CH3). Anal. Calcd for C39H42O8 (638.75): C, 73.33;
H, 6.63. Found: C, 73.28; H, 6.60.
Eth yl 3-Oxo-3-(2′,3′,4′,6′-tetr a -O-ben zyl-â-D-m a n n op y-
r a n osyl)p r op a n oa te (6c). Aldehyde 5c (1.10 g, 2.00 mmol)
was treated as described for the preparation of 6a . Column
chromatography on silica gel of the residue with 6:1 cyclohex-
Exp er im en ta l Section
All moisture-sensitive reactions were performed under a
nitrogen atmosphere using oven-dried glassware. Solvents
were dried over standard drying agent and freshly distilled
prior to use. Commercially available powdered 4 Å molecular
sieves (5 µm average particle size) were used without further
activation. Reactions were monitored by TLC on silica gel 60
ane-AcOEt afforded 6c (920 mg, 72%) as a syrup. [R]D20
)
1
+11.2 (c 1.5, CHCl3). H NMR (DMSO-d6, 120 °C): δ ) 7.50-
7.20 (m, 20 H, 5 Ph), 4.83 and 4.70 (2 d, 2 H, J ) 11.5 Hz,
PhCH2), 4.80 and 4.61 (2 d, 2 H, J ) 11.0 Hz, PhCH2), 4.80
and 4.50 (2 d, 2 H, J ) 11.2 Hz, PhCH2), 4.62 and 4.54 (2 d, 2
H, J ) 12.0 Hz, PhCH2), 4.42 (dd, 1 H, J 1′,2′ ) 0.8 Hz, J 2′,3′
)
F
254 with detection by charring with sulfuric acid. Flash column
chromatography35 was performed on silica gel 60 (230-400
mesh). Melting points were determined with capillary
apparatus. Optical rotations were measured at 20 ( 2 °C in
1.0 Hz, H-2′), 4.17 (d, 1 H, H-1′), 4.09 (dq, 2 H, J ) 2.0, J )
7.0 Hz, CH2CH3), 3.88 (dd, 1 H, J 3′,4′ ) 8.8 Hz, J 4′,5′ ) 9.0 Hz,
H-4′), 3.85-3.73 (m, 3 H, H-3′, H-6′a, H-6′b), 3.72 and 3.48 (2
d, 2 H, J ) 15.5 Hz, 2 H-2), 3.55 (ddd, 1 H, J 5′,6′a ) 3.0 Hz,
J 5′,6′b ) 4.0 Hz, H-5′), 1.18 (t, 3 H, J ) 7.0 Hz,CH3). Anal. Calcd
for C39H42O8 (638.75): C, 73.33; H, 6.63. Found: C, 73.31; H,
6.61.
(2′,3′,5′-Tr i-O-b en zyl-â-D-r ib ofu r a n osyl)m et h yl Azid e
(7a ). To a cooled (0 °C), stirred solution of aldehyde 5a (864
mg, 2.00 mmol) in CH3OH (10 mL) was added NaBH4 (113
mg, 3.00 mmol). The mixture was stirred at 0 °C for an
additional 10 min, diluted with acetone (2 mL), warmed to
room temperature, and concentrated. The residue was sus-
pended in CH2Cl2 (80 mL), washed with H2O (2 × 10 mL),
dried (Na2SO4), and concentrated to give (2′,3′,5′-tri-O-benzyl-
â-D-ribofuranosyl)methyl alcohol (851 mg, ∼98%) at least 95%
pure by NMR analysis and suitable for the next step (for
analytical data see ref 23).
To a stirred solution of the above crude alcohol (851 mg,
∼1.96 mmol), diphenylphosphoryl azide (1.27 mL, 5.88 mmol),
and anhydrous DMF (8 mL) was added 1,8-diazabicyclo[5.4.0]-
undec-7-ene (292 µL, 1.96 mmol). The solution was warmed
to 100 °C and stirred for 2 h. Then NaN3 (382 mg, 5.88 mmol)
was added in one portion and the mixture stirred at 100 °C
for an additional 2 h. The mixture was cooled to room
temperature, diluted with H2O (10 mL), and extracted with
Et2O (3 × 40 mL). The organic layer was dried (Na2SO4) and
concentrated. The residue was eluted from a column of silica
gel with 7:1 cyclohexane-AcOEt to give 7a (883 mg, 98%) as
a yellow oil. [R]D20 ) -65.0 (c 1.2, CHCl3) (lit.36 [R]2D5 ) -62.8).
1H NMR: δ ) 7.45-7.20 (m, 15 H, 3 Ph), 4.61 and 4.48 (2 d, 2
a
the stated solvent; [R]D values are given in 10-1 deg cm2 g-1
1H (300 MHz) and 13C (75 MHz) NMR spectra were recorded
for CDCl3 solutions at room temperature unless otherwise
specified. Assignments were aided by homo- and heteronuclear
two-dimensional experiments. For bisglycosylated DHPMs
15a -c and 15a ′-c′ r, g, and m refer to ribo, galacto, and
manno moieties, respectively; r4 and r6 refer to ribo moieties
linked to the 4 and 6 positions of the heterocycle, respectively.
MALDI-TOF mass spectra were acquired using R-cyano-4-
hydroxycinnamic acid as the matrix. CD measurements were
carried out using a 0.1 cm path length cell with a volume of
350 µL at 20 °C with methanol as solvent. Spectra were
recorded between 360 and 200 nm with 1 nm resolution at a
scan speed of 10 nm/min and resulted from averaging two
scans. The final spectra were baseline-corrected by subtracting
the corresponding methanol spectrum obtained under identical
conditions. Aldehydes 5a -c,22b,23 nitriles 9a -c,27 and â-ke-
toester 2033 were synthesized as described.
.
Eth yl 3-Oxo-3-(2′,3′,5′-tr i-O-ben zyl-â-D-r ibofu r a n osyl)-
p r op a n oa te (6a ). A mixture of aldehyde 5a (864 mg, 2.00
mmol), ethyl diazoacetate (0.32 mL, 3.00 mmol), activated 4-Å
powdered molecular sieves (600 mg), and anhydrous CH2Cl2
(15 mL) was stirred at room temperature for 15 min and then
cooled to 0 °C. To the mixture was added drop by drop a
solution of BF3‚Et2O (127 µL, 1.00 mmol) in anhydrous CH2-
Cl2 (2 mL), controlling the N2 evolution at a low steady rate.
The mixture was stirred at 0 °C for an additional 30 min,
diluted with 10% NaHCO3 (10 mL), warmed to room temper-
ature, filtered through a pad of Celite, and extracted with CH2-
(36) Ogawa, T.; Kikuchi, T.; Matsui, M.; Ohrui, H.; Kuzuhara, H.;
Emoto, S. Agric. Biol. Chem. 1971, 35, 1825.
(35) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
6986 J . Org. Chem., Vol. 67, No. 20, 2002

Biginelli Cyclocondensation Reaction Using C-Glycosylated Substrates
H, J ) 11.0 Hz, PhCH2), 4.59 (s, 2 H, PhCH2), 4.58 and 4.52
(2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.30-4.23 (m, 1 H, H-4′), 4.20
H, J 1a,1b ) 14.5 Hz, J 1b,1′ ) 3.0 Hz, H-1b). Anal. Calcd for
28H32N2O5 (476.56): C, 70.57; H, 6.77; N, 5.88. Found: C,
70.50; H, 6.71; N, 5.87.
C
(ddd, 1 H, J 1a, ) 4.0, J 1b,1′ ) 5.0 Hz, J 1′,2′ ) 6.0 Hz, H-1′),
1′
3.94 (dd, 1 H, J 2′,3′ ) 5.0 Hz, J 3′,4′ ) 3.5 Hz, H-3′), 3.87 (dd, 1
H, H-2′), 3.58-3.49 (m, 3 H, H-1a, H-5′a, H-5′b), 3.22 (dd, 1
H, J 1a,1b ) 13.0 Hz, H-1b). Anal. Calcd for C27H29N3O4
(459.54): C, 70.57; H, 6.36; N, 9.14. Found: C, 70.50; H, 6.31;
N, 9.09.
(2′,3′,4′,6′-Tetr a -O-ben zyl-â-D-ga la ctop yr a n osyl)m eth -
yl Azid e (7b). Aldehyde 5b (1.10 g, 2.00 mmol) was treated
as described for the preparation of 7a . In the first step, crude
(2′,3′,4′,6′-tetra-O-benzyl-â-D-galactopyranosyl)methyl alcohol
(1.10 g, ∼99%) was obtained at least 95% pure by NMR
analysis and suitable for the next step (for analytical data see
ref 37).
Rou te B. To a stirred mixture of LiAlH4 (304 mg, 8.00
mmol) and anhydrous THF (10 mL) was added a solution of
sugar nitrile 9a (858 mg, 2.00 mmol) in anhydrous THF (2
mL). The mixture was stirred under reflux for 30 min, cooled
to room temperature, and diluted with 28% NH4OH (1 mL).
The mixture was stirred at room temperature for an additional
30 min, filtered through a pad of Celite, and concentrated to
give crude (2′,3′,5′-tri-O-benzyl-â-D-ribofuranosyl)methylamine
(857 mg, ∼99%) at least 95% pure by NMR analysis and
suitable for the next step.
To a stirred solution of the above crude amine (857, ∼1.98
mmol) in absolute EtOH was added nitrourea (252 mg, 2.40
mmol) in one portion. The mixture was stirred under reflux
for 1.5 h, cooled to room temperature, and concentrated. The
residue was eluted from a column of silica gel with 20:1 AcOEt/
MeOH to give 8a (755 mg, 80%).
(2′,3′,4′,6′-Tetr a -O-ben zyl-â-D-ga la ctop yr a n osyl)m eth y-
lu r ea (8b). Rou te A. Azide 7b (870 mg, 1.50 mmol) was
treated as described for the preparation of 8a . In the first step,
crude (2′,3′,4′,6′-tetra-O-benzyl-â-D-galactopyranosyl)methy-
lamine (821 mg, ∼99%) was obtained at least 95% pure by
NMR analysis and suitable for the next step. 1H NMR: δ )
7.50-7.20 (m, 20 H, 4 Ph), 4.95 and 4.63 (2 d, 2 H, J ) 11.0
Hz, PhCH2), 4.94 and 4.65 (2 d, 2 H, J ) 11.2 Hz, PhCH2),
4.78 and 4.70 (2 d, 2 H, J ) 11.5 Hz, PhCH2), 4.48 and 4.43 (2
d, 2 H, J ) 11.8 Hz, PhCH2), 4.00 (dd, 1 H, J 3′,4′ ) 2.7 Hz, J 4′,5′
) ∼0.5 Hz, H-4′), 3.75 (dd, 1 H, J 1′,2′ ) 8.9 Hz, J 2′,3′ ) 9.0 Hz,
H-2′), 3.64 (dd, 1 H, H-3′), 3.63-3.48 (m, 3 H, H-5′, H-6′a,
H-6′b), 3.26 (bddd, 1 H, H-1′), 3.04 (bdd, 1 H, H-1a), 2.77 (bdd,
1 H, H-1b).
Treatment of the above crude amine (821 mg, ∼1.49 mmol)
as described for the preparation of 8a afforded 8b (762 mg,
86%) as a white amorphous solid. [R]2D0 ) 8.0 (c 0.4, CHCl3).
1H NMR: δ ) 7.50-7.20 (m, 20 H, 4 Ph), 4.97 and 4.59 (2 d, 2
H, J ) 11.2 Hz, PhCH2), 4.93 and 4.68 (2 d, 2 H, J ) 11.0 Hz,
PhCH2), 4.87 (bs, 1 H, NH), 4.80 and 4.72 (2 d, 2 H, J ) 12.0
Hz, PhCH2), 4.47 (s, 2 H, PhCH2), 4.34 (bs, 2 H, NH2), 3.98
(dd, 1 H, J 3′,4′ ) 2.7 Hz, J 4′,5′ ) ∼ 0.5 Hz, H-4′), 3.80 (dd, 1 H,
J 1′,2′ ) 8.9 Hz, J 2′,3′ ) 9.0 Hz, H-2′), 3.63 (dd, 1 H, H-3′), 3.59-
3.40 (m, 5 H, 2 H-1, H-5′, 2 H-6′), 3.41-3.30 (m, 1 H, H-1′).
Anal. Calcd for C36H40N2O6 (596.71): C, 72.46; H, 6.76; N, 4.69.
Found: C, 72.53; H, 6.80; N, 4.73.
Rou te B. Treatment of sugar nitrile 9b (1.10 g, 2.00 mmol)
as described for the preparation of 8a afforded 8b (1.02 g, 86%).
(2′,3′,4′,6′-Tetr a -O-ben zyl-â-D-m a n n op yr a n osyl)m eth y-
lu r ea (8c). Sugar nitrile 9c (1.10 g, 2.00 mmol) was treated
as described for the preparation of 8a (route B). In the first
step, crude (2′,3′,4′,6′-tetra-O-benzyl-â-D-mannopyranosyl)m-
ethylamine (1.09 g, ∼99%) was obtained at least 95% pure by
NMR analysis and suitable for the next step. 1H NMR: δ )
7.50-7.10 (m, 20 H, 4 Ph), 5.20 and 4.72 (2 d, 2 H, J ) 11.8
Hz, PhCH2), 4.91 and 4.57 (2 d, 2 H, J ) 11.0 Hz, PhCH2),
4.82 and 4.76 (2 d, 2 H, J ) 11.5 Hz, PhCH2), 4.65 and 4.57 (2
d, 2 H, J ) 12.0 Hz, PhCH2), 3.94 (dd, 1 H, J 3′,4′ ) 8.9 Hz, J 4′,5′
) 9.0 Hz, H-4′), 3.87 (dd, 1 H, J 1′,2′ ) ∼0.5 Hz, J 2′,3′ ) 2.8 Hz,
H-2′), 3.78 (dd, 1 H, J 5′,6′a ) 2.0 Hz, J 6′a,6′b ) 10.5 Hz, H-6′a),
3.72 (dd, 1 H, J 5′,6′b ) 5.0 Hz, H-6′b), 3.65 (dd, 1 H, H-3′), 3.49
(ddd, 1 H, H-5′), 3.25 (ddd, 1 H, J 1a,1′ ) 7.0 Hz, J 1b,1′ ) 5.5 Hz,
H-1′), 3.01 (dd, 1 H, J 1a,1b ) 13.0 Hz, H-1a), 2.64 (dd, 1 H,
H-1b).
To a stirred solution of the above crude alcohol (1.10 g, ∼1.98
mmol), diphenylphosphoryl azide (1.28 mL, 5.94 mmol), and
anhydrous DMF (8 mL) was added 1,8-diazabicyclo[5.4.0]-
undec-7-ene (295 µL, 1.98 mmol). The solution was warmed
to 100 °C and stirred for 2 h. Then NaN3 (386 mg, 5.94 mmol)
was added in one portion and the mixture stirred at 100 °C
for an additional 12 h. The mixture was cooled to room
temperature, diluted with H2O (10 mL), and extracted with
Et2O (3 × 40 mL). The organic layer was dried (Na2SO4) and
concentrated. The residue was eluted from a column of silica
gel with 12:1 cyclohexane-AcOEt to give 7b (1.10 g, 96%) as
a yellow oil. [R]2D0 ) -23.1 (c 3.1, CHCl3). H NMR: δ ) 7.50-
1
7.20 (m, 20 H, 4 Ph), 4.99 and 4.67 (2 d, 2 H, J ) 11.2 Hz,
PhCH2), 4.98 and 4.64 (2 d, 2 H, J ) 11.0 Hz, PhCH2), 4.80
and 4.70 (2 d, 2 H, J ) 12.0 Hz, PhCH2), 4.53 and 4.45 (2 d, 2
H, J ) 11.5 Hz, PhCH2), 4.20 (dd, 1 H, J 3′,4′ ) 2.7 Hz, J 4′,5′
)
∼0.5 Hz, H-4′), 3.90 (dd, 1 H, J 1′,2′ ) 8.9 Hz, J 2′,3′ ) 9.0 Hz,
H-2′), 3.66 (dd, 1 H, H-3′), 3.65-3.58 (m, 3 H, H-5′, H-6′a,
H-6′b), 3.53-3.45 (m, 2 H, H-1a, H-1′), 3.39 (dd, 1 H, J 1a,1b
)
13.0 Hz, J 1b,1′ ) 6.5 Hz, H-1b). Anal. Calcd for C35H37N3O5
(579.69): C, 72.52; H, 6.43; N, 7.25. Found: C, 72.60; H, 6.48;
N, 7.32.
(2′,3′,5′-Tr i-O-ben zyl-â-D-r ibofu r an osyl)m eth ylu r ea (8a).
Rou te A. A vigorously stirred mixture of 7a (689 mg, 1.50
mmol), 20% palladium hydroxide on carbon (345 mg), and
AcOEt (8 mL) was degassed under vacuum and saturated with
hydrogen (by a H2-filled balloon) three times. The suspension
was stirred at room temperature for 20 min under a slightly
positive pressure of hydrogen (balloon), filtered through a plug
of cotton, and concentrated to give (2′,3′,5′-tri-O-benzyl-â-D-
ribofuranosyl)methylamine (643 mg, ∼99%) at least 95% pure
1
by NMR analysis and suitable for the next step. H NMR δ )
7.45-7.20 (m, 15 H, 3 Ph), 4.65 and 4.52 (2 d, 2 H, J ) 12.0
Hz, PhCH2), 4.63 and 4.58 (2 d, 2 H, J ) 11.8 Hz, PhCH2),
4.58 and 4.52 (2 d, 2 H, J ) 11.5 Hz, PhCH2), 4.24 (ddd, 1 H,
J 3′,4′ ) 5.5 Hz, J 4′,5′a ) 3.5 Hz, J 4′,5′b ) 4.0 Hz, H-4′), 4.07 (ddd,
1 H, J 1a,1′ ) 3.0 Hz, J 1b,1′ ) 5.5 Hz, J 1′,2′ ) 6.5 Hz, H-1′), 3.96
(dd, 1 H, J 2′,3′ ) 5.0 Hz, H-3′), 3.80 (dd, 1 H, H-2′), 3.58 (dd, 1
H, J 5′a,5′b ) 10.5 Hz, H-5′a), 3.53 (dd, 1 H, H-5′b), 2.97 (dd, 1
H, J 1a,1b ) 13.5 Hz, H-1a), 2.71 (dd, 1 H, H-1b).
To a stirred solution of the above crude amine (643 mg,
∼1.48 mmol) in absolute EtOH was added nitrourea (187 mg,
1.78 mmol) in one portion. The mixture was stirred under
reflux for 1.5 h, cooled to room temperature, and concentrated.
The residue was eluted from a column of silica gel with 20:1
AcOEt-MeOH to give 8a (566 mg, 80%) as a white solid: mp
89-90 °C (cyclohexane-AcOEt). [R]2D0 ) 18.0 (c 1.0, EtOH)
(lit.26 [R]2D6 ) 18.7 (c 1.0, EtOH)). H NMR: δ ) 7.50-7.20 (m,
1
15 H, 3 Ph), 5.05 (bs, 1 H, NH), 4.66 and 4.35 (2 d, 2 H, J )
11.0 Hz, PhCH2), 4.62 and 4.57 (2 d, 2 H, J ) 11.5 Hz, PhCH2),
4.49 and 4.45 (2 d, 2 H, J ) 12.0 Hz, PhCH2), 4.24-4.10 (m,
2 H, H-1′, H-4′), 3.99 (dd, 1 H, J ) 5.0, J ) 6.0 Hz, H-2′ or
H-3′), 3.90 (dd, 1 H, J ) 3.5, 5.0 Hz, H-2′ or H-3′), 3.80 (dd, 1
H, J 4′,5′a ) 3.0 Hz, J 5′a,5′b ) 10.8 Hz, H-5′a), 3.59 (dd, 1 H, J 4′,5′b
) 2.5 Hz, H-5′b), 3.57-3.36 (m, 3 H, H-1a, NH2), 3.19 (dd, 1
Treatment of the above crude amine (1.09 g, ∼1.98 mmol)
as described for the preparation of 8a afforded 8c (1.00 g, 85%)
as a white foam. [R]D20 ) 4.7 (c 1.2, CHCl3). 1H NMR: δ )
7.50-7.10 (m, 20 H, 4 Ph), 4.99 and 4.55 (2 d, 2 H, J ) 11.0
Hz, PhCH2), 4.95 (bs, 1 H, NH), 4.91 and 4.65 (2 d, 2 H, J )
11.5 Hz, PhCH2), 4.80 and 4.74 (2 d, 2 H, J ) 11.2 Hz, PhCH2),
4.55 and 4.48 (2 d, 2 H, J ) 12.0 Hz, PhCH2), 4.32 (bs, 2 H,
NH2), 3.93 (dd, 1 H, J 3′,4′ ) 8.9 Hz, J 4′,5′ ) 9.0 Hz, H-4′), 3.82
(dd, 1 H, J 1′,2′ ) ∼0.5 Hz, J 2′,3′ ) 2.8 Hz, H-2′), 3.70 (dd, 1 H,
(37) Dondoni, A.; Marra, A.; Massi, A. Tetrahedron 1998, 54, 2827.
J . Org. Chem, Vol. 67, No. 20, 2002 6987

Dondoni et al.
J 5′,6′a ) 3.0 Hz, J 6′a,6′b ) 10.5 Hz, H-6′a), 3.65 (dd, 1 H, J 5′,6′b
)
H, J ) 7.0 Hz, CH2CH3). Anal. Calcd for C42H46N2O8 (706.82):
C, 71.37; H, 6.56; N, 3.96. Found: C, 71.41; H, 6.51; N, 4.00.
(4R)- an d (4S)-4-(2′,3′,4′,6′-Tetr a-O-ben zyl-â-D-m an n opy-
r a n osyl)-6-m eth yl-2-oxo-1,2,3,4-tetr a h yd r op yr im id in e-5-
ca r boxylic Acid Eth yl Ester s (11c). Column chromatogra-
phy with 2:1 cyclohexane-AcOEt afforded first (R)-11c (302
mg, 43%) as a white foam. [R]2D0 ) -58.5 (c 1.2, CHCl3). 1H
NMR: δ ) 8.00 (bs, 1 H, NH), 7.50-7.10 (m, 20 H, 4 Ph), 5.74
(bs, 1 H, NH), 5.19 and 4.51 (2 d, 2 H, J ) 11.8 Hz, PhCH2),
4.88 and 4.72 (2 d, 2 H, J ) 11.2 Hz, PhCH2), 4.82 (s, 2 H,
PhCH2), 4.75 and 4.68 (2 d, 2 H, J ) 11.2 Hz, PhCH2), 4.29
(bdd, 1 H, H-4), 4.14 (q, 2 H, J ) 7.0 Hz, CH2CH3), 4.02 (dd,
3.5 Hz, H-6′b), 3.59 (dd, 1 H, H-3′), 3.40 (ddd, 1 H, H-5′), 3.34-
3.24 (m, 2 H, 2 H-1). Anal. Calcd for C36H40N2O6 (596.71): C,
72.46; H, 6.76; N, 4.69. Found: C, 72.51; H, 6.79; N, 4.71.
Gen er a l P r oced u r e for th e Syn th esis of C4-, C6-, a n d
Bisglycosyla ted DHP Ms 11a -c, 12a -c, 13a , a n d 15a -c.
A mixture of aldehyde (1.00 mmol), â-ketoester (1.00 mmol),
urea (1.50 mmol), BF3‚OEt2 (165 µL, 1.30 mmol), CuCl (99 mg,
1.00 mmol), glacial acetic acid (11 µL, 0.20 mmol), powdered
4-Å molecular sieves (300 mg), and anhydrous THF (5 mL)
was stirred at 65 °C for 24 h. The mixture was cooled to room
temperature, quenched with Et3N, filtered through a pad of
Celite, and concentrated. The residue was suspended in EtOAc
(100 mL) and washed with H2O (2 × 10 mL). The organic
phase was dried (Na2SO4), concentrated, and eluted from a
column of silica gel with the suitable elution system to give
the corresponding dihydropyrimidinones.
1 H, J 3′,4′ ) 9.5 Hz, J 4′,5′ ) 9.0 Hz, H-4′), 3.98 (dd, 1 H, J 1′,2′
)
∼0.5 Hz, J 2′,3′ ) 2.2 Hz, H-2′), 3.82 (dd, 1 H, J 5′,6′a ) 4.5 Hz,
J 6′a,6′b ) 11.8 Hz, H-6′a), 3.72 (dd, 1 H, J 5′,6′b ) 1.0 Hz, H-6′b),
3.63 (dd, 1 H, H-3′), 3.46 (ddd, 1 H, H-5′), 3.32 (bdd, 1 H, H-1′),
2.15 (s, 3 H, CH3), 1.20 (t, 3 H, CH2CH3). Anal. Calcd for
(4R)- a n d (4S)-4-(2′,3′,5′-Tr i-O-ben zyl-â-D-r ibofu r a n o-
syl)-6-m eth yl-2-oxo-1,2,3,4-tetr a h yd r op yr im id in e-5-ca r -
boxylic Acid Eth yl Ester s (11a ). Column chromatography
with 1.5:1 cyclohexane-AcOEt afforded first (S)-11a (93 mg,
C
42H46N2O8 (706.82): C, 71.37; H, 6.56; N, 3.96. Found: C,
71.35; H, 6.55; N, 3.90.
Eluted second was (S)-11c (101 mg, 14%) as a white foam.
[R]2D0 ) 60.5 (c 1.4, CHCl3). H NMR: δ ) 7.50-7.10 (m, 20 H,
1
16%) as a white foam. [R]2D0 ) 41.1 (c 1.2, CHCl3). H NMR: δ
1
4 Ph), 6.85 (bs, 1 H, NH), 5.11 and 4.78 (2 d, 2 H, J ) 11.8 Hz,
PhCH2), 4.87 and 4.60 (2 d, 2 H, J ) 11.5 Hz, PhCH2), 4.87
and 4.57 (2 d, 2 H, J ) 12.0 Hz, PhCH2), 4.66 and 4.48 (2 d, 2
H, J ) 12.1 Hz, PhCH2), 4.63 (d, 1 H, J 1′,4 ) 8.0 Hz, H-4), 4.41
(bs, 1 H, NH), 4.22-4.08 (m, 2 H, CH2CH3), 4.04 (dd, 1 H, J 3′,4′
) 9.5 Hz, J 4′,5′ ) 9.2 Hz, H-4′), 3.98 (dd, 1 H, J 1′,2′ ) ∼0.5 Hz,
) 7.50 (bs, 1 H, NH), 7.48-7.15 (m, 15 H, 3 Ph), 6.18 (bs, 1 H,
NH), 4.63 and 4.53 (2 d, 2 H, J ) 12.0 Hz, PhCH2), 4.61 (d, 1
H, J 1′,4 ) 2.1 Hz, H-4), 4.42 and 4.26 (2 d, 2 H, J ) 11.5 Hz,
PhCH2), 4.41 and 4.37 (2 d, 2 H, J ) 10.5 Hz, PhCH2), 4.33
(dd, 1 H, J 1′,2′ ) 2.2 Hz, H-1′), 4.21 (q, 2 H, J ) 7.0 Hz, CH2-
CH3), 4.13 (ddd, 1 H, J ′3′,4′ ) 7.8 Hz, J 4′,5′a ) 3.0 Hz, J 4′,5′b
)
J 2′,3′ ) 2.2 Hz, H-2′), 3.75 (dd, 1 H, J 5′,6′a ) 4.5 Hz, J 6′a,6′b
)
2.8 Hz, H-4′), 4.01 (dd, 1 H, J 2′,3′ ) 5.5 Hz, H-3′), 3.82 (dd, 1 H,
H-2′), 3.76 (dd, 1 H, J 5′a,5′b ) 10.8 Hz, H-5′a), 3.52 (dd, 1 H,
H-5′b), 2.22 (s, 3 H, CH3), 1.30 (t, 3 H, CH2CH3). Anal. Calcd
for C34H38N2O7 (586.67): C, 69.61; H, 6.53; N, 4.77. Found:
C, 69.55; H, 6.53; N, 4.70.
10.8 Hz, H-6′a), 3.67 (dd, 1 H, J 5′,6′b ) 1.5 Hz, H-6′b), 3.59 (dd,
1 H, H-3′), 3.36 (ddd, 1 H, H-5′), 3.27 (dd, 1 H, H-1′), 2.22 (s,
3 H, CH3), 1.24 (t, 3 H, J ) 7.0 Hz, CH2CH3). Anal. Calcd for
C
42H46N2O8 (706.82): C, 71.37; H, 6.56; N, 3.96. Found: C,
71.48; H, 6.63; N, 3.99.
Eluted second was (R)-11a (278 mg, 47%) as a white solid.
Mp: 149-150 °C (cyclohexane). [R]2D0 ) -65 (c 0.3, CHCl3). 1H
NMR: δ ) 7.50-7.10 (m, 15 H, 3 Ph), 7.00 (bs, 1 H, NH), 5.38
(bs, 1 H, NH), 4.57 and 4.47 (2 d, 2 H, J ) 12.0 Hz, PhCH2),
4.50 (s, 2 H, PhCH2), 4.49 and 4.44 (2 d, 2 H, J ) 11.2 Hz,
PhCH2), 4.26 (dd, 1 H, J 1′,4 ) 3.2 Hz, J 4,NH ) 6.1 Hz, H-4),
4.21 (ddd, 1 H, J 3′,4′ ) 4.5 Hz, J 4′,5′a ) 4.0 Hz, J 4′,5′b ) 3.9 Hz,
(4R)- a n d (4S)-6-(2′,3′,5′-Tr i-O-ben zyl-â-D-r ibofu r a n o-
syl)-2-oxo-4-p h en yl-1,2,3,4-tetr a h yd r op yr im id in e-5-ca r -
boxylic Acid Eth yl Ester s (12a ). Column chromatography
with 4:1 cyclohexane-AcOEt afforded first (R)-12a (149 mg,
23%) as a white foam. [R]2D0 ) 25.1 (c 0.9, CHCl3). 1H NMR
(C6D6): δ ) 10.08 (bs, 1 H, NH), 7.60-6.90 (m, 20 H, 4 Ph),
6.12 (s, 1 H, H-1′), 5.44 (bs, 1 H, NH), 5.14 (d, 1 H, J 4,NH ) 3.0
Hz, H-4), 5.08 and 4.96 (2 d, 2 H, J ) 12.0 Hz, PhCH2), 4.89
and 4.41 (2 d, 2 H, J ) 12.2 Hz, PhCH2), 4.40 (ddd, 1 H, J 3′,4′
) 9.0 Hz, J 4′,5′a ) 2.0 Hz, J 4′,5′b ) ∼0.5 Hz, H-4′), 4.20 (dd, 1 H,
J 2′,3′ ) 4.0 Hz, H-3′), 4.13 (d, 1 H, H-2′), 4.10 and 3.85 (2 d, 2
H, J ) 11.8 Hz, PhCH2), 3.88-3.76 (m, 2 H, CH2CH3), 3.61
(dd, 1 H, J 5′a,5′b ) 10.8 Hz, H-5′a), 3.33 (dd, 1 H, H-5′b), 1.20
(t, 3 H, J ) 7.0 Hz, CH2CH3). Anal. Calcd for C39H40N2O7
(648.74): C, 72.20; H, 6.21; N, 4.32. Found: C, 72.30; H, 6.25;
N, 4.41.
H-4′), 4.08 (q, 2 H, J ) 7.0 Hz, CH2CH3), 4.06 (dd, 1 H, J 1′,2′
)
5.8 Hz, H-1′), 4.01 (dd, 1 H, J 2′,3′ ) 5.0 Hz, H-3′), 3.88 (dd, 1 H,
H-2′), 3.55 (dd, 1 H, J 5′a,5′b ) 10.5 Hz, H-5′a), 3.46 (dd, 1 H,
H-5′b), 2.24 (s, 3 H, CH3), 1.21 (t, 3 H, CH2CH3). Anal. Calcd
for C34H38N2O7 (586.67): C, 69.61; H, 6.53; N, 4.77. Found:
C, 69.58; H, 6.51; N, 4.76.
(4R)- a n d (4S)-4-(2′,3′,4′,6′-Tetr a -O-ben zyl-â-D-ga la cto-
p yr a n osyl)-6-m eth yl-2-oxo-1,2,3,4-tetr a h yd r op yr im id in e-
5-ca r boxylic Acid Eth yl Ester s (11b). Column chromatog-
raphy with 2:1 cyclohexane-AcOEt afforded first (R)-11b (383
Eluted second was (S)-12a (448 mg, 69%) as a white foam.
mg, 54%) as a white foam. [R]2D0 ) -101.3 (c 1.2, CHCl3). H
[R]2D0 ) 139.2 (c 1.6, CHCl3). H NMR: δ ) 9.22 (bs, 1 H, NH),
1
1
NMR: δ ) 7.50-7.15 (m, 20 H, 4 Ph), 6.70 (bs, 1 H, NH), 4.98
and 4.62 (2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.94 and 4.72 (2 d, 2
H, J ) 11.2 Hz, PhCH2), 4.77 and 4.67 (2 d, 2 H, J ) 11.0 Hz,
PhCH2), 4.51 (bs, 1 H, NH), 4.50 (d, 1 H, J 1′,4 ) ∼0.5 Hz, H-4),
4.42 and 4.35 (2 d, 2 H, J ) 12.0 Hz, PhCH2), 4.22-4.12 (m,
2 H, CH2CH3), 3.96 (dd, 1 H, J 3′,4′ ) 3.0 Hz, J 4′,5′ ) ∼0.5 Hz,
H-4′), 3.91 (dd, 1 H, J 1′,2′ ) 9.2 Hz, J 2′,3′ ) 9.5 Hz, H-2′), 3.64
(dd, 1 H, H-3′), 3.56-3.45 (m, 3 H, H-5′, 2 H-6′), 3.23 (dd, 1 H,
H-1′), 2.18 (s, 3 H, CH3), 1.30 (t, 3 H, J ) 7.0 Hz, CH2CH3).
Anal. Calcd for C42H46N2O8 (706.82): C, 71.37; H, 6.56; N, 3.96.
Found: C, 71.45; H, 6.58; N, 4.03.
7.50-7.10 (m, 20 H, 4 Ph), 5.86 (d, 1 H, J 1,′2′ ) ∼ 0.5 Hz, H-1′),
5.46 (d, 1 H, J 4,NH ) 2.2 Hz, H-4), 5.35 (bd, 1 H, NH), 4.91 and
4.73 (2 d, 2 H, J ) 11.5 Hz, PhCH2), 4.82 and 4.64 (2 d, 2 H,
J ) 12.0 Hz, PhCH2), 4.45 and 4.31 (2 d, 2 H, J ) 11.8 Hz,
PhCH2), 4.29 (ddd, 1 H, J 3′,4′ ) 8.5 Hz, J 4′,5′a ) 2.1 Hz, J 4′,5′b
)
∼0.5 Hz, H-4′), 4.20-4.02 (m, 3 H, H-3′, CH2CH3), 3.95 (dd, 1
H, J 2′,3′ ) 5.0 Hz, H-2′), 3.86 (dd, 1 H, J 5′a,5′b ) 10.8 Hz, H-5′a),
3.60 (dd, 1 H, H-5′b), 1.17 (t, 3 H, J ) 7.0 Hz, CH2CH3). Anal.
Calcd for C39H40N2O7 (648.74): C, 72.20; H, 6.21; N, 4.32.
Found: C, 72.25; H, 6.32; N, 4.40.
(4R)- a n d (4S)-6-(2′,3′,4′,6′-Tetr a -O-ben zyl-â-D-ga la cto-
p yr a n osyl)-2-oxo-4-p h en yl-1,2,3,4-tetr a h yd r op yr im id in e-
5-ca r boxylic Acid Eth yl Ester s (12b). Column chromatog-
raphy with 10:1 diisopropyl ether-AcOEt (containing 5% of
CH2Cl2) afforded first (R)-12b (96 mg, 13%) as a white foam:
Eluted second was (S)-11b (77 mg, 11%) as a white foam.
[R]2D0 ) 29.6 (c 0.9, CHCl3). H NMR (C6D6): δ ) 8.11 (bs, 1 H,
1
NH), 7.50-6.95 (m, 20 H, 4 Ph), 5.62 (bs, 1 H, NH), 5.00 and
4.54 (2 d, 2 H, J ) 11.5 Hz, PhCH2), 4.99 and 4.54 (2 d, 2 H,
J ) 11.8 Hz, PhCH2), 4.90 (bs, 1 H, H-4), 4.27 and 4.21 (2 d,
2 H, J ) 12.0 Hz, PhCH2), 4.27 and 4.16 (2 d, 2 H, J ) 11.2
Hz, PhCH2), 4.22 (dd, 1 H, J 1′,2′ ) 9.0 Hz, J 2′,3′ ) 9.2 Hz, H-2′),
4.05-3.88 (m, 3 H, H-1′, CH2CH3), 3.84 (dd, 1 H, J 3′,4′ ) 2.8
Hz, J 4′,5′ ) ∼0.5 Hz, H-4′), 3.66-3.58 and 3.52-3.45 (2m, 3 H,
H-5′, 2 H-6′), 3.42 (dd, 1 H, H-3′), 1.82 (s, 3 H, CH3), 0.95 (t, 3
[R]2D0 ) -3 (c 0.3, CHCl3). H NMR: δ ) 7.40-7.20 (m, 25 H, 5
1
Ph), 7.19 (bs, 1H, NH), 5.54 (d, 1 H, J 1′,2′ ) 9.2 Hz, H-1′), 5.37
(d, 1 H, J 4,NH ) 2.0 Hz, H-4), 5.08 (bd, 1 H, NH), 4.95 and 4.62
(2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.85 and 4.61 (2 d, 2 H, J )
11.2 Hz, PhCH2), 4.75 (s, 2 H, PhCH2), 4.48 and 4.44 (2 d, 2
H, J ) 11.5 Hz, PhCH2), 4.00 (dd, 1 H, J 3′,4′ ) 2.8 Hz, J 4′,5′
)
6988 J . Org. Chem., Vol. 67, No. 20, 2002

Biginelli Cyclocondensation Reaction Using C-Glycosylated Substrates
∼0.5 Hz, H-4′), 3.98 and 3.78 (2dq, 2 H, J ) 7.0, 11.0 Hz, CH2-
CH3), 3.93 (dd, 1 H, J 2′,3′ ) 9.2 Hz, H-2′), 3.71 (ddd, 1 H, J 5′,6′a
) 5.5 Hz, J 5′,6′b ) 7.0 Hz, H-5′), 3.68 (dd, 1 H, H-3′), 3.59 (dd,
1 H, J 6′a,6′b ) 9.5 Hz, H-6′a), 3.53 (dd, 1 H, H-6′b), 1.00 (t, 3 H,
J ) 7.0 Hz, CH2CH3). Anal. Calcd for C47H48N2O8 (768.89): C,
73.42; H, 6.29; N, 3.64. Found: C, 73.41; H, 6.28; N, 3.63.
Eluted second was (S)-12b (481 mg, 63%) as a white foam.
[R]2D0 ) 72.5 (c 0.9, CHCl3). 1H NMR: δ ) 7.40-7.25, 7.18-
7.00, and 6.80-6.60 (3 m, 25 H, 5 Ph), 7.20 (bs, 1 H, NH),
5.68 (d, 1 H, J 1′,2′ ) 9.0 Hz, H-1′), 5.47 (d, 1 H, J 4,NH ) 2.5 Hz,
H-4), 5.42 (bd, 1 H, NH), 4.94 and 4.61 (2 d, 2 H, J ) 11.5 Hz,
PhCH2), 4.72 and 4.67 (2 d, 2 H, J ) 12.0 Hz, PhCH2), 4.67
and 4.15 (2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.50 and 4.43 (2 d, 2
H, J ) 11.2 Hz, PhCH2), 4.08-3.92 (m, 2 H, CH2CH3), 3.98
(dd, 1 H, J 3′,4′ ) 2.8 Hz, J 4′,5′ ) ∼0.5 Hz, H-4′), 3.86 (dd, 1 H,
J 2′,3′ ) 9.2 Hz, H-2′), 3.70 (ddd, 1 H, J 5′,6′a ) 5.8 Hz, J 5′,6′b ) 6.9
Hz, H-5′), 3.69 (dd, 1 H, H-3′), 3.59 (dd, 1 H, J 6′a,6′b ) 10.0 Hz,
H-6′a), 3.53 (dd, 1 H, H-6′b), 1.15 (t, 3 H, J ) 7.0 Hz, CH2CH3).
Anal. Calcd for C47H48N2O8 (768.89): C, 73.42; H, 6.29; N, 3.64.
Found: C, 73.40; H, 6.25; N, 3.61.
4.21 (dd, 1 H, J 2′,3′ ) 4.0 Hz, H-3′), 4.13 (d, 1 H, H-2′), 4.01 (q,
2 H, J ) 7.0 Hz, CH2CH3), 3.87 (dd, 1 H, J 5′a,5′b ) 10.8 Hz,
H-5′a), 3.63 (dd, 1 H, H-5′b), 1.00 (t, 3 H, CH2CH3). Anal. Calcd
for C40H39F3N2O7 (716.74): C, 67.03; H, 5.48; F, 7.95; N, 3.91.
Found: C, 67.00; H, 5.41; F, 7.91; N, 3.88.
(4R)- a n d (4S)-4,6-Bis(2′,3′,5′-tr i-O-ben zyl-â-D-r ibofu r a -
n osyl)-2-oxo-1,2,3,4-t et r a h yd r op yr im id in e-5-ca r boxylic
Acid Eth yl Ester s (15a ). Column chromatography with 3:1
cyclohexane-AcOEt afforded first (S)-15a (41 mg, 4%) as a
white foam. [R]2D0 ) 75 (c 0.4, CHCl3). H NMR selected data:
1
δ ) 9.41 (bs, 1 H, NH), 7.50-7.10 (m, 30 H, 6 Ph), 6.01 (bs, 1
H, NH), 5.78 (s, 1 H, H-1r6), 4.09-4.00 (m, 2 H, H-2r6, H-3r4),
2.92 (dd, 1 H, J 4,5a ) 2.5 Hz, J 5a,5b ) 10.8 Hz, H-5ar6), 3.89
(dd, 1 H, J 1,2 ) 2.0 Hz, J 2,3 ) 5.5 Hz, H-2r4), 3.76 (dd, 1 H,
J 4,5a ) 3.0 Hz, J 5a,5b ) 10.8 Hz, H-5ar4), 3.60 (dd, 1 H, J 4,5b
)
∼0.5 Hz, H-5br6), 3.53 (dd, 1 H, J 4,5b ) 3.2 Hz, H-5br4), 1.29
(t, 3 H, J ) 7.0 Hz, CH2CH3). MALDI-TOF MS: 976.1 (M+
+
H), 999.4 (M+ + Na), 1014.7 (M+ + K). Anal. Calcd for
C59H62N2O11 (975.13): C, 72.67; H, 6.41; N, 2.87. Found: C,
72.61; H, 6.35; N, 2.84.
Eluted second was (R)-15a (369 mg, 38%) as a white foam.
[R]2D0 ) 6.4 (c 1.0, CHCl3). 1H NMR selected data: δ ) 9.20 (bs,
1 H, NH), 7.50-7.10 (m, 30 H, 6 Ph), 5.76 (s, 1 H, H-1r6), 5.08
(bs, 1 H, NH), 3.93 (d, 1 H, J 2,3 ) 4.0 Hz, H-2r6), 3.89 (dd, 1
(4R)- an d (4S)-6-(2′,3′,4′,6′-Tetr a-O-ben zyl-â-D-m an n opy-
r a n osyl)-2-oxo-4-p h en yl-1,2,3,4-tetr a h yd r op yr im id in e-5-
ca r boxylic Acid Eth yl Ester s (12c). Column chromatogra-
phy with 3:1 cyclohexane-AcOEt afforded first (S)-12c (405
mg, 53%) as a white foam. [R]2D0 ) 29.7 (c 2.1, CHCl3). 1H
NMR: δ ) 7.60 (bd, 1 H, J ) ∼0.5 Hz, NH), 7.45-7.15 (m, 25
H, 5 Ph), 5.42 (bdd, 1 H, J ) ∼0.5 Hz, J 4,NH ) 2.0 Hz, NH),
5.15 (s, 1 H, H-1′), 5.10 (d, 1 H, H-4), 4.92 and 4.57 (2 d, 2 H,
J ) 11.2 Hz, PhCH2), 4.82 and 4.64 (2 d, 2 H, J ) 11.5 Hz,
PhCH2), 4.81 and 4.75 (2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.63
H, J 1,2 ) 5.5 Hz, J 2,3 ) 6.5 Hz, H-2r4), 3.77 (dd, 1 H, J 4,5a
)
2.5 Hz, J 5a,5b ) 10.8 Hz, H-5ar6), 3.53 (dd, 1 H, J 4,5b ) ∼0.5
Hz, H-5br6), 3.48 (dd, 1 H, J 4,5a ) 4.5 Hz, J 5a,5b ) 10.2 Hz,
H-5ar4), 3.44 (dd, 1 H, J 4,5b ) 5.0 Hz, H-5br4), 1.26 (t, 3 H, J
) 7.0 Hz, CH2CH3). MALDI-TOF MS: 998.2 (M+ + Na), 1014.4
(M+ + K). Anal. Calcd for C59H62N2O11 (975.13): C, 72.67; H,
6.41; N, 2.87. Found: C, 72.60; H, 6.38; N, 2.80.
and 4.59 (2 d, 2 H, J ) 12.0 Hz, PhCH2), 4.35 (d, 1 H, J 2′,3′
)
2.5 Hz, H-2′), 4.05-3.95 (m, 2 H, CH2CH3), 3.92 (dd, 1 H, J 3′,4′
) 9.0 Hz, J 4′,5′ ) 9.2 Hz, H-4′), 3.79 (dd, 1 H, H-3′), 3.78 (dd,
1 H, J 5′,6′a ) 1.8 Hz, J 6′a,6′b ) 11.0 Hz, H-6′a), 3.71 (dd, 1 H,
J 5′,6′b ) 5.5 Hz, H-6′b), 3.59 (ddd, 1 H, H-5′), 1.12 (t, 3 H, J )
7.0 Hz, CH2CH3). Anal. Calcd for C47H48N2O8 (768.89): C,
73.42; H, 6.29; N, 3.64. Found: C, 73.38; H, 6.34; N, 3.68.
(4R)- a n d (4S)-4-(2′,3′,4′,6′-Tetr a -O-ben zyl-â-D-ga la cto-
p yr a n osyl)-6-(2′′,3′′,5′′-tr i-O-ben zyl-â-D-r ibofu r a n osyl)-2-
oxo-1,2,3,4-tetr a h yd r op yr im id in e-5-ca r boxylic Acid Eth -
yl Ester s (15b). Column chromatography with 10:1 toluene-
AcOEt afforded first (S)-15b (35 mg, 3%) as a white foam.
[R]2D0 ) -10 (c 0.3, CHCl3). 1H NMR selected data: δ ) 9.18
Eluted second was (R)-12c (135 mg, 17%). [R]2D0 ) 66.6 (c
(bs, 1 H, NH), 7.50-7.10 (m, 35 H, 7 Ph), 5.72 (d, 1 H, J 1,2
)
1
∼0.5 Hz, H-1r), 5.49 (bs, 1 H, NH), 4.65 (dd, 1 H, J 4,NH ) 2.5
Hz, J 4,1g ) 1.5 Hz, H-4), 4.48 and 4.42 (2 d, 2 H, J ) 11.5 Hz,
PhCH2), 4.37 and 4.24 (2 d, 2 H, J ) 11.2 Hz, PhCH2), 4.05
(dd, 1 H, J 1,2 ) 9.0 Hz, J 2,3 ) 9.2 Hz, H-2g), 3.99 (dd, 1 H, J 3,4
) 2.8 Hz, J 4,5 ) ∼0.5 Hz, H-4g), 3.91 (dd, 1 H, J 2,3 ) 4.2 Hz,
H-2r), 3.78 (dd, 1 H, J 4,5a ) 2.8 Hz, J 5a,5b ) 10.8 Hz, H-5ar),
3.67 (dd, 1 H, H-3g), 1.18 (t, 3 H, J ) 7.0 Hz, CH2CH3). MALDI-
TOF MS: 1118.0 (M+ + Na), 1134.2 (M+ + K). Anal. Calcd for
1.0, CHCl3). H NMR: δ ) 7.62 (bd, 1 H, J ) ∼0.5 Hz, NH),
7.40-7.00 (m, 25 H, 5 Ph), 5.51 (d, 1 H, J 4,NH ) 2.5 Hz, H-4),
5.38 (bdd, 1 H, J ) ∼0.5 Hz, J 4,NH ) 2.5 Hz, NH), 5.22 (d, 1 H,
J 1′,2′ ) ∼0.5 Hz, H-1′), 4.87 and 4.53 (2 d, 2 H, J ) 11.2 Hz,
PhCH2), 4.81 and 4.38 (2 d, 2 H, J ) 11.5 Hz, PhCH2), 4.71
and 4.65 (2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.61 (s, 2 H, PhCH2),
4.29 (dd, 1 H, J 2′,3′ ) 2.5 Hz, H-2′), 4.14 (q, 2 H, J ) 7.0 Hz,
CH2CH3), 3.89 (dd, 1 H, J 3′,4′ ) 9.2 Hz, J 4′,5′ ) 9.5 Hz, H-4′),
C
67H70N2O12 (1095.28): C, 73.47; H, 6.44; N, 2.56. Found: C,
3.80 (dd, 1 H, H-3′), 3.78 (dd, 1 H, J 5′,6′a ) 1.0 Hz, J 6′a,6′b
)
73.41; H, 6.39; N, 2.58.
10.8 Hz, H-6′a), 3.69 (dd, 1 H, J 5′,6′b ) 5.5 Hz, H-6′b), 3.63 (ddd,
1 H, H-5′), 1.12 (t, 3 H, CH2CH3). Anal. Calcd for C47H48N2O8
(768.89): C, 73.42; H, 6.29; N, 3.64. Found: C, 73.45; H, 6.31;
N, 3.60.
Eluted second was (R)-15b (349 mg, 32%) as a white foam.
[R]2D0 ) -61.6 (c 1.1, CHCl3). H NMR selected data: δ ) 8.95
1
(bs, 1 H, NH), 7.50-7.10 (m, 35 H, 7 Ph), 5.92 (s, 1 H, H-1r),
4.61 (dd, 1 H, J 4,NH ) 2.5 Hz, J 4,1g ) ∼0.5 Hz, H-4), 4.05 (dd,
(4R)- a n d (4S)-6-(2′,3′,5′-Tr i-O-ben zyl-â-D-r ibofu r a n o-
syl)-4-[2-(tr iflu or om eth yl)p h en yl]-2-oxo-1,2,3,4-tetr a h y-
d r op yr im id in e-5-ca r b oxylic Acid E t h yl E st er s (13a ).
Column chromatography with 25:2:1 CH2Cl2-cyclohexane-
AcOEt afforded first (R)-13a (196 mg, 27%) slightly contami-
1 H, J 3,4 ) 2.8 Hz, J 4,5 ) ∼0.5 Hz, H-4g), 4.03 (dd, 1 H, J 2,3
4.0 Hz, J 3,4 ) 8.2 Hz, H-3r), 3.99 (dd, 1 H, J 1,2 ) 9.0 Hz, J 2,3
)
)
9.2 Hz, H-2g), 3.95 (d, 1 H, H-2r), 3.81 (dd, 1 H, J 4,5a ) 2.5 Hz,
J 5a,5b ) 10.8 Hz, H-5ar), 3.68 (dd, 1 H, H-3g), 3.61-3.52 (m, 2
H, H-5br, H-6ag), 3.49 (dd, 1 H, J 5,6b ) 4.5 Hz, J 6a,6b ) 9.5 Hz,
H-6bg), 3.28-3.21 (m, 2 H, H-1g, H-5g), 1.29 (t, 3 H, J ) 7.0
Hz, CH2CH3). MALDI-TOF MS: 1096.3 (M+ + H), 1118.0 (M+
+ Na), 1134.2 (M+ + K), 1156.9 (M+ + Na + K). Anal. Calcd
for C67H70N2O12 (1095.28): C, 73.47; H, 6.44; N, 2.56. Found:
C, 73.40; H, 6.38; N, 2.50.
1
nated by uncharacterized byproducts. H NMR: δ ) 9.60 (bs,
1 H, NH), 7.80-7.10 (m, 19 H, Ph), 6.04 (s, 1 H, H-1′), 5.85
(bs, 1 H, H-4), 5.20 (bs, 1 H, NH), 4.99 and 4.90 (2 d, 2 H, J )
11.8 Hz, PhCH2), 4.84 and 4.62 (2 d, 2 H, J ) 12.0 Hz, PhCH2),
4.38 and 4.23 (2 d, 2 H, J ) 11.5 Hz, PhCH2), 4.33 (ddd, 1 H,
J 3′,4′ ) 9.0 Hz, J 4′,5′a ) 2.0 Hz, J 4′,5′b ) ∼0.5 Hz, H-4′), 4.17-
4.08 (m, 2 H, H-2′, H-3′), 4.07-3.92 (m, 2 H, CH2CH3), 3.91
(dd, 1 H, J 5′a,5′b ) 10.8 Hz, H-5′a), 3.61 (dd, 1 H, H-5′b), 0.98
(t, 3 H, J ) 7.0 Hz, CH2CH3).
(4R)- an d (4S)-4-(2′,3′,4′,6′-Tetr a-O-ben zyl-â-D-m an n opy-
r a n osyl)-6-(2′′,3′′,5′′-tr i-O-ben zyl-â-D-r ibofu r a n osyl)-2-oxo-
1,2,3,4-t et r a h yd r op yr im id in e-5-ca r boxylic Acid E t h yl
Ester s (15c). Column chromatography with 3:1 cyclohexane-
AcOEt afforded first (R)-15c (348 mg, 32%) as a white foam.
Eluted second was (S)-13a (392 mg, 55%) as a white foam.
[R]2D0 ) 92.3 (c 0.9, CHCl3). H NMR: δ ) 9.39 (bs, 1 H, NH),
1
[R]2D0 ) -6.5 (c 1.0, CHCl3). H NMR selected data: δ ) 8.90
1
7.80-7.20 (m, 19 H, Ph), 5.99 (s, 1 H, H-1′), 5.92 (d, 1 H, J 4,NH
) 2.0 Hz, H-4), 5.15 (bd, 1 H, NH), 5.03 and 4.88 (2 d, 2 H, J
) 11.5 Hz, PhCH2), 4.83 and 4.64 (2 d, 2 H, J ) 12.0 Hz,
PhCH2), 4.48 and 4.37 (2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.34
(ddd, 1 H, J 3′,4′ ) 9.0 Hz, J 4′,5′a ) 2.5 Hz, J 4′,5′b ) ∼0.5 Hz, H-4′),
(bs, 1 H, NH), 7.50-7.10 (m, 35 H, 7 Ph), 5.84 (d, 1 H, J 1,2
)
1.8 Hz, H-1r), 5.68 (bs, 1 H, NH), 5.19 and 4.72 (2 d, 2 H, J )
11.8 Hz, PhCH2), 4.33 (bdd, 1 H, H-4), 4.23 (ddd, 1 H, J 3,4
8.0 Hz, J 4,5a ) 2.5 Hz, J 4,5b ) 1.0 Hz, H-4r), 4.13 (dd, 1 H, J 2,3
)
J . Org. Chem, Vol. 67, No. 20, 2002 6989

Dondoni et al.
) 2.5 Hz, H-3r), 4.03 (dd, 1 H, J 3,4 ) 9.0 Hz, J 4,5 ) 9.2 Hz,
H-4m), 3.95 (dd, 1 H, H-2r), 3.94 (dd, 1 H, J 1,2 ) ∼0.5 Hz, J 2,3
) 2.2 Hz, H-2m), 3.86 (dd, 1 H, J 5,6a ) 5.0 Hz, J 6a,6b ) 12.0
Hz, H-6am), 3.73 (dd, 1 H, J 5a,5b ) 10.8 Hz, H-5ar), 3.61 (dd,
1 H, H-3m), 3.59 (dd, 1 H, J 5,6b ) 1.0 Hz, H-6bm), 3.53 (dd, 1
H, H-5br), 3.41 (ddd, 1 H, H-5m), 3.24 (bdd, 1 H, H-1m), 1.17
(4R)- a n d (4S)-1-[(2′,3′,4′,6′-Tet r a -O-b en zyl-â-D-m a n -
n op yr a n osyl)m eth yl]-6-m eth yl-2-oxo-4-p h en yl-1,2,3,4-tet-
r a h yd r op yr im id in e-5-ca r boxylic Acid Eth yl Ester s (14c).
Column chromatography with 3:1 cyclohexane-AcOEt af-
forded 14c (318 mg, 40%) as a ∼1:1 mixture of (4R)- and (4S)-
stereoisomers. 1H NMR selected data for ∼1:1 mixture of
stereoisomers: δ ) 7.50-7.10 (m, 25 H, Ph), 5.40 (bs, 0.5 H,
NH), 5.39 (d, 0.5 H, J ) 3.0 Hz, H-4), 5.34 (bd, 0.5 H, J ) 3.0
Hz, NH), 5.32 (d, 0.5 H, J ) 3.0 Hz, H-4), 5.09 (d, 1 H, J )
12.0 Hz, PhCH2), 4.92 (d, 0.5 H, J ) 11.2 Hz, PhCH2), 4.90 (d,
0.5 H, J ) 11.2 Hz, PhCH2), 2.60 (s, 1.5 H, CH3), 2.58 (s, 1.5
H, CH3), 1.17 (t, 1.5 H, J ) 7.0 Hz, CH2CH3), 1.15 (t, 1.5 H, J
) 7.0 Hz, CH2CH3). MALDI-TOF MS: 797.5 (M+ + H), 830.2
(M+ + Na), 836.7 (M+ + K). Anal. Calcd for C49H52N2O8
(796.95): C, 73.85; H, 6.58; N, 3.52. Found: C, 73.80; H, 6.51
N, 3.43.
(t, 3 H, J ) 7.0 Hz, CH2CH3); MALDI-TOF MS: 1118.2 (M+
+
Na), 1134.1 (M+ + K). Anal. Calcd for C67H70N2O12 (1095.28):
C, 73.47; H, 6.44; N, 2.56. Found: C, 73.55; H, 6.50; N, 2.60.
Eluted second was (S)-15c (49 mg, 4%) slightly contami-
nated by the major isomer. 1H NMR selected data: δ ) 9.28
(bs, 1 H, NH), 5.91 (d, 1 H, J 1,2 ) 1.0 Hz, H-1r), 5.76 (bs, 1 H,
NH), 1.22 (t, 3 H, J ) 7.0 Hz, CH2CH3). MALDI-TOF MS:
1118.1 (M+ + Na), 1134.0 (M+ + K). Anal. Calcd for C67H70N2O12
(1095.28): C, 73.47; H, 6.44; N, 2.56. Found: C, 73.50; H, 6.51;
N, 2.66.
(4R)- a n d (4S)-4,6-Tr is-(2′,3′,5′-t r i-O-b en zyl-â-D-r ib o-
fu r a n osyl)-2-oxo-1,2,3,4-tetr a h yd r op yr im id in e-5-ca r box-
ylic Acid Eth yl Ester s (16a ). MALDI-TOF MS analysis of
Gen er a l P r oced u r e for th e Syn th esis of N1- a n d
Tr isglycosyla ted DHP Ms 14a -c a n d 16a . A mixture of
aldehyde (3.00 mmol), â-ketoester (3.00 mmol), glycosylmethyl
urea (1.00 mmol), BF3‚OEt2 (0.49 mL, 3.90 mmol), CuCl (297
mg, 3.00 mmol), glacial acetic acid (34 µL, 0.60 mmol),
powdered 4-Å molecular sieves (500 mg), and anhydrous THF
(8 mL) was stirred at 65 °C for 24 h. The mixture was cooled
to room temperature, quenched with Et3N, filtered through a
pad of Celite, and concentrated. The residue was suspended
in EtOAc (100 mL) and washed with H2O (2 × 10 mL). The
organic phase was dried (Na2SO4), concentrated, and eluted
from a column of silica gel with the suitable elution system to
give the corresponding dihydropyrimidinones.
(4R)- a n d (4S)-1-[(2′,3′,5′-Tr i-O-ben zyl-â-D-r ibofu r a n o-
syl)m eth yl]-6-m eth yl-2-oxo-4-p h en yl-1,2,3,4-tetr a h yd r o-
p yr im id in e-5-ca r boxylic Acid Eth yl Ester s (14a ). Column
chromatography with 2:1 cyclohexane-AcOEt afforded 14a
(325 mg, 48%) as a ∼1:1 mixture of (4R)- and (4S)-stereoiso-
mers. 1H NMR selected data for ∼1:1 mixture of stereoisomers:
δ ) 5.81 (d, 0.5 H, J ) 2.5 Hz, NH), 5.77 (d, 0.5 H, J ) 2.2 Hz,
NH), 5.38 (d, 0.5 H, J ) 2.5 Hz, H-4), 5.35 (d, 0.5 H, J ) 2.2
Hz, H-4), 2.58 (s, 3 H, CH3), 1.18 (t, 1.5 H, J ) 7.0 Hz,
CH2CH3), 1.15 (t, 1.5 H, J ) 7.0 Hz, CH2CH3). MALDI-TOF
MS: 677.5 (M+ + H), 699.9 (M+ + Na), 716.1 (M+ + K). Anal.
Calcd for C41H44N2O7 (676.80): C, 72.76; H, 6.55; N, 4.14.
Found: C, 72.75; H, 6.50; N, 4.08.
crude 16a : 1392.1 (M+ + H), 1414.2 (M+ + Na), 1430.1 (M+
+
K).
Gen er a l P r oced u r e for th e Syn th esis of C4-, C6-, N1-,
a n d Bisglycosyla ted DHP Ms 11a ′-c′ to 15a ′-c′. A vigor-
ously stirred mixture of benzylated DHPM (0.30 mmol), 20%
palladium hydroxide on carbon (50 w/w of substrate), AcOEt
(4 mL), and EtOH (4 mL) was degassed under vacuum and
saturated with hydrogen (by a H2-filled balloon) three times.
After the mixture was stirred under a slightly positive pressure
of hydrogen (balloon) at room temperature for 3-5 h, pal-
ladium hydroxide on carbon was filtered off through a plug of
cotton and washed thoroughly with MeOH (2 mL), H2O (0.5
mL), and DMF (2 mL). The combined filtrates were concen-
trated to give the corresponding deprotected DHPM in almost
quantitative yield.
(4R)-6-Met h yl-2-oxo-4-(â-D-r ib ofu r a n osyl)-1,2,3,4-t et -
r a h yd r op yr im id in e-5-ca r boxylic Acid Eth yl Ester ((R)-
11a ′). Mp: 264-266 °C (MeOH). [R]2D0 ) -148 (c 0.2, H2O). 1H
NMR (DMSO-d6 + D2O, 70 °C): δ ) 4.16-4.02 (m, 2 H, CH2-
CH3), 4.10 (d, 1 H, J 1′,4) 5.0 Hz, H-4), 3.86 (dd, 1 H, J 1′,2′ ) 4.8
Hz, J 2′,3′ ) 5.0 Hz, H-2′), 3.76 (dd, 1 H, J 3′,4′ ) 5.1 Hz, H-3′),
3.64 (ddd, 1 H, J 4′,5′a ) 4.2 Hz, J 4′,5′b ) 4.8 Hz, H-4′), 3.59 (dd,
1 H, H-1′), 3.45 (dd, 1 H, J 5′a,5′b ) 11.2 Hz, H-5′a), 3.33 (dd, 1
H, H-5′b), 2.18 (s, 3 H, CH3), 1.20 (t, 3 H, J ) 7.0 Hz, CH2CH3).
13C NMR (DMSO-d6): δ ) 165.5, 153.4, 149.9, 96.3, 85.2, 83.1,
71.1, 70.6, 61.5, 59.1, 51.6, 17.9, 14.2. MALDI-TOF MS: 340.0
(M+ + Na), 356.0 (M+ + K). Anal. Calcd for C13H20N2O7
(316.31): C, 49.36; H, 6.37; N, 8.86. Found: C, 49.38; H, 6.30;
N, 8.80.
(4S)-6-Met h yl-2-oxo-4-(â-D-r ib ofu r a n osyl)-1,2,3,4-t et -
r a h yd r op yr im id in e-5-ca r boxylic Acid Eth yl Ester ((S)-
11a ′). Amorphous solid. [R]2D0 ) 121 (c 0.6, DMF). 1H NMR
(DMSO-d6): δ ) 9.05 (bs, 1 H, NH), 7.10 (bs, 1 H, NH), 4.21
(bdd, 1 H, J 1′,4 ) 3.0 Hz, J 4,NH ) 3.2 Hz, H-4), 4.08 (q, 2 H, J
) 7.0 Hz, CH2CH3), 3.79 (dd, 1 H, J 1′,2′ ) 2.8 Hz, J 2′,3′ ) 5.5
Hz, H-2′), 3.72 (dd, 1 H, H-1′), 3.71 (dd, 1 H, J 3′,4′ ) 3.0 Hz,
H-3′), 3.59 (dd, 1 H, J 4′,5′a ) 2.8 Hz, J 5′a,5′b ) 11.5 Hz, H-5′a),
3.55 (ddd, 1 H, J 4′,5′b ) 3.5 Hz, H-4′), 3.43 (dd, 1 H, H-5′b),
2.18 (s, 3 H, CH3), 1.20 (t, 3 H, CH2CH3). 13C NMR (DMSO-
d6): δ ) 165.4, 152.2, 149.7, 95.2, 87.1, 82.1, 70.5, 60.6, 59.2,
52.7, 18.0, 14.2. MALDI-TOF MS: 317.9 (M+ + H), 324.0 (M+
+ Li), 339.6 (M+ + Na). Anal. Calcd for C13H20N2O7 (316.31):
C, 49.36; H, 6.37; N, 8.86. Found: C, 49.30; H, 6.36; N, 8.83.
(4R)-4-(â-D-Ga la ct op yr a n osyl)-6-m et h yl-2-oxo-1,2,3,4-
tetr ah ydr opyr im idin e-5-car boxylic Acid Eth yl Ester ((R)-
11b′). Amorphous solid. [R]2D0 ) -117.3 (c 0.9, MeOH). 1H
NMR (CD3OD): δ ) 4.66 (d, 1 H, J 1′,4) 2.8 Hz, H-4), 4.19 (q,
2 H, J ) 7.0 Hz, CH2CH3), 3.85 (dd, 1 H, J 3′,4′ ) 2.7 Hz, J 4′,5′
) ∼0.5 Hz, H-4′), 3.71 (dd, 1 H, J 1′,2′ ) 9.5 Hz, J 2′,3′ ) 9.3 Hz,
H-2′), 3.68 (dd, 1 H, J 5′,6′a ) 6.0 Hz, J 6′a,6′b ) 10.8 Hz, H-6′a),
3.63 (dd, 1 H, J 5′,6′b ) 6.2 Hz, H-6′b), 3.45 (dd, 1 H, H-3′), 3.42
(ddd, 1 H, H-5′), 3.14 (dd, 1 H, H-1′), 2.28 (s, 3 H, CH3), 1.28
(t, 3 H, CH2CH3). 13C NMR (CD3OD): δ ) 167.8, 156.9, 150.8,
(4R)- a n d (4S)-1-[(2′,3′,4′,6′-Tetr a -O-ben zyl-â-D-ga la c-
top yr a n osyl)m eth yl]-6-m eth yl-2-oxo-4-p h en yl-1,2,3,4-tet-
r a h yd r op yr im id in e-5-ca r boxylic Acid Eth yl Ester s (14b).
Column chromatography with 3:1 cyclohexane-AcOEt af-
forded first (S)-14b (166 mg, 21%) as a white foam. [R]D20
)
-46.9 (c 0.8, CHCl3). 1H NMR: δ ) 7.50-7.10 (m, 25 H, 5 Ph),
5.40 (d, 1 H, J 4,NH ) 3.2 Hz, H-4), 5.32 (bd, 1 H, NH), 4.96 and
4.72 (2 d, 2 H, J ) 11.5 Hz, PhCH2), 4.96 and 4.60 (2 d, 2 H,
J ) 11.8 Hz, PhCH2), 4.74 and 4.67 (2 d, 2 H, J ) 11.2 Hz,
PhCH2), 4.38 (s, 2 H, PhCH2), 4.15-4.02 (m, 2 H, CH2CH3),
4.00 (dd, 1 H, J 3′,4′ ) 2.8 Hz, J 4′,5′ ) ∼0.5 Hz, H-4′), 3.70 (dd,
1 H, J 1′,2′ ) 9.0 Hz, J 2′,3′ ) 9.2 Hz, H-2′), 3.61 (dd, 1 H, H-3′),
3.57-3.34 (m, 6 H, H-1′, H-5′, 2 H-6′, CH2N), 2.55 (s, 3 H, CH3),
1.18 (t, 3 H, J ) 7.0 Hz, CH2CH3). MALDI-TOF MS: 797.1
(M+ + H), 820.0 (M+ + Na), 836.1 (M+ + K). Anal. Calcd for
C
49H52N2O8 (796.95): C, 73.85; H, 6.58; N, 3.52. Found: C,
73.90; H, 6.62; N, 3.58.
Eluted second was (R)-14b (161 mg, 20%) as a white foam.
[R]2D0 ) -8 (c 0.4, CHCl3). H NMR: δ ) 7.50-7.10 (m, 25 H, 5
1
Ph), 5.33 (s, 1 H, H-4), 5.32 (bs, 1 H, NH), 5.01 and 4.68 (2 d,
2 H, J ) 11.2 Hz, PhCH2), 4.95 and 4.62 (2 d, 2 H, J ) 11.5
Hz, PhCH2), 4.76 and 4.66 (2 d, 2 H, J ) 11.8 Hz, PhCH2),
4.41 (s, 2 H, PhCH2), 4.08 (q, 2 H, J ) 7.0 Hz, CH2CH3), 4.04
(dd, 1 H, J 3′,4′ ) 2.8 Hz, J 4′,5′ ) ∼0.5 Hz, H-4′), 3.76 (dd, 1 H,
J 1′,2′ ) 9.0 Hz, J 2′,3′ ) 9.2 Hz, H-2′), 3.63 (dd, 1 H, H-3′), 3.62-
3.40 (m, 6 H, H-1′, H-5′, 2 H-6′, CH2N), 2.48 (s, 3 H, CH3),
1.17 (t, 3 H, J ) 7.0 Hz, CH2CH3). MALDI-TOF MS: 797.1
(M+ + H), 829.8 (M+ + Na), 836.0 (M+ + K). Anal. Calcd for
C
49H52N2O8 (796.95): C, 73.85; H, 6.58; N, 3.52. Found: C,
73.91; H, 6.64 N, 3.51.
6990 J . Org. Chem., Vol. 67, No. 20, 2002

Biginelli Cyclocondensation Reaction Using C-Glycosylated Substrates
98.9, 83.4, 80.1, 76.6, 70.7, 68.1, 62.5, 61.0, 52.2, 18.3, 14.6.
MALDI-TOF MS: 347.0 (M+ + H), 353.5 (M+ + Li), 369.5 (M+
+ Na), 385.8 (M+ + K). Anal. Calcd for C14H22N2O8 (346.33):
C, 48.55; H, 6.40; N. 8.09. Found: C, 48.60; H, 6.45; N, 8.12.
75.8, 71.1, 71.0, 62.6, 60.2, 56.4, 14.0. MALDI-TOF MS: 409.6
(M+ + H), 415.6 (M+ + Li), 431.7 (M+ + Na), 448.3 (M+ + K).
Anal. Calcd for C19H24N2O8 (408.40): C, 55.88; H, 5.92; N, 6.86.
Found: C, 55.81; H, 5.97; N, 6.80.
(4S)-6-(â-D-Ma n n op yr a n osyl)-2-oxo-4-p h en yl-1,2,3,4-
tetr ah ydr opyr im idin e-5-car boxylic Acid Eth yl Ester ((S)-
(4R)-4-(â-D-Ma n n op yr a n osyl)-6-m et h yl-2-oxo-1,2,3,4-
tetr ah ydr opyr im idin e-5-car boxylic acid Eth yl Ester ((R)-
11c′). Amorphous solid. [R]2D0 ) -175.4 (c 0.5, MeOH). 1H
NMR (CD3OD): δ ) 4.44 (d, 1 H, J 1′,4 ) 7.0 Hz, H-4), 4.30-
12c′). Amorphous solid. [R]2D0 ) 27.9 (c 1.1, MeOH). H NMR
1
(pyridine-d5): δ ) 9.15 (bs, 2 H, 2 NH), 7.70-7.50 and 7.30-
7.10 (2m, 5 H, Ph), 5.91 (s, 1 H, H-1′), 5.57 (d, 1 H, J 4,NH ) 2.8
Hz, H-4), 5.03 (d, 1 H, J 2′,3′ ) 2.5 Hz, H-2′), 4.86 (dd, 1 H, J 3′,4′
) 9.2 Hz, J 4′,5′ ) 9.5 Hz, H-4′), 4.52 (dd, 1 H, J 5′,6′a ) 1.5 Hz,
J 6′a,6′b ) 11.0 Hz, H-6′a), 4.43 (dd, 1 H, J 5′,6′b ) 5.0 Hz, H-6′b),
4.39 (dd, 1 H, H-3′), 4.06-3.98 (m, 3 H, CH2CH3, H-5′), 0.98
(t, 3 H, J ) 7.0 Hz, CH2CH3). 13C NMR (pyridine-d5): δ )
165.5, 153.3, 150.1, 145.5, 128.9, 128.8, 127.8, 127.2, 127.1,
99.5, 83.0, 76.2, 76.0, 72.4, 68.0, 62.4, 60.1, 55.7, 14.1. MALDI-
TOF MS: 409.5 (M+ + H), 431.5 (M+ + Na), 448.2 (M+ + K).
Anal. Calcd for C19H24N2O8 (408.40): C, 55.88; H, 5.92; N, 6.86.
Found: C, 55.93; H, 5.99; N, 6.98.
4.16 (m, 2 H, CH2CH3), 3.89 (dd, 1 H, J 5′,6′a ) 2.5 Hz, J 6′a,6′b
)
11.8 Hz, H-6′a), 3.69 (dd, 1 H, J 1′,2′ ) ∼0.5 Hz, J 2′,3′ ) 3.5 Hz,
H-2′), 3.67 (dd, 1 H, J 5′,6′b ) 6.2 Hz, H-6′b), 3.55 (dd, 1 H, J 3′,4′
) 9.5 Hz, J 4′.5′ ) 9.2 Hz, H-4′), 3.41 (dd, 1 H, H-3′), 3.36 (dd,
1 H, H-1′), 3.21 (ddd, 1 H, H-5′), 2.30 (s, 3 H, CH3), 1.33 (t, 3
H, J ) 7.0 Hz, CH2CH3). 13C NMR (CD3OD): δ ) 169.0, 156.6,
151.5, 98.6, 82.0, 80.7, 76.0, 71.2, 69.1, 63.6, 61.8, 53.3, 18.7,
14.6. MALDI-TOF MS: 347.5 (M+ + H), 353.6 (M+ + Li), 369.6
(M+ + Na), 385.8 (M+ + K). Anal. Calcd for C14H22N2O8
(346.33): C, 48.55; H, 6.40; N. 8.09. Found: C, 48.51; H, 6.32;
N, 8.00.
(4S)-4-[2-(Tr iflu or om et h yl)p h en yl]-2-oxo-6-(â-D-r ib o-
fu r an osyl)-1,2,3,4-tetr ah ydr opyr im idin e-5-car boxylic Acid
Eth yl Ester ((S)-13a ′). Amorphous solid. [R]2D0 ) 48.5 (c 1.2,
(4S)-4-(â-D-Ma n n op yr a n osyl)-6-m et h yl-2-oxo-1,2,3,4-
tetr ah ydr opyr im idin e-5-car boxylic Acid Eth yl Ester ((S)-
11c′). The compound was recovered slightly contaminated by
1
1
MeOH). H NMR (CD3OD): δ ) 7.80-7.40 (m, 4 H, Ph), 5.86
uncharacterized byproducts. H NMR (CD3OD): δ ) 4.66 (d,
(s, 1 H, H-4), 5.66 (d, 1 H, J 1′,2′ ) 2.0 Hz, H-1′), 4.32 (dd, 1 H,
J 2′,3′ ) 4.5 Hz, J 3′,4′ ) 8.0 Hz, H-3′), 4.25 (dd, 1 H, H-2′), 4.06
(ddd, 1 H, J 4′,5′a ) 2.0 Hz, J 4′,5′b ) ∼0.5 Hz, H-4′), 4.02 (dd, 1
H, J 5′a,5′b ) 10.8 Hz, H-5′a), 4.00 (q, 2 H, J ) 7.0 Hz, CH2CH3),
3.83 (dd, 1 H, H-5′b), 0.98 (t, 3 H, CH2CH3). 13C NMR (CD3-
OD): δ ) 166.1, 153.5, 152.7, 143.5, 134.8, 129.6, 129.5, 127.6,
127.2, 127.1, 99.8, 83.9, 81.6, 79.5, 71.2, 61.3, 60.6, 52.6, 14.2.
MALDI-TOF MS: 447.6 (M+ + H), 469.9 (M+ + Na), 485.9
(M+ + K). Anal. Calcd for C19H21F3N2O7 (446.37): C, 51.12;
H, 4.74; F, 12.77; N, 6.28. Found: C, 51.15; H, 4.78; F, 12.70;
N, 6.30.
1 H, J 1′,4 ) 7.8 Hz, H-4), 4.28-4.12 (m, 2 H, CH2CH3), 3.92
(dd, 1 H, J 1′,2′ ) ∼0.5 Hz, J 2′,3′ ) 3.5 Hz, H-2′), 3.78 (dd, 1 H,
J 5′,6′a ) 2.5 Hz, J 6′a,6′b) 11.2 Hz, H-6′a), 3.70 (dd, 1 H, J 5′,6′b
)
4.5 Hz, H-6′b), 3.64 (dd, 1 H, J 3′,4′ ) 9.5 Hz, J 4′,5′ ) 9.2 Hz,
H-4′), 3.42 (dd, 1 H, H-3′), 3.41 (dd, 1 H, H-1′), 3.15 (ddd, 1 H,
H-5′), 2.24 (s, 3 H, CH3), 1.31 (t, 3 H, J ) 7.0 Hz, CH2CH3);
13C NMR (CD3OD): δ ) 168.6, 156.0, 148.3, 100.6, 82.0, 80.1,
76.5, 69.7, 68.7, 63.0, 61.3, 52.2, 18.0, 14.6; MALDI-TOF MS:
347.2 (M+ + H), 353.5 (M+ + Li), 369.5 (M+ + Na), 385.7 (M+
+ K).
(4S)-2-Oxo-4-p h en yl-6-(â-D-r ib ofu r a n osyl)-1,2,3,4-t et -
r a h yd r op yr im id in e-5-ca r boxylic Acid Eth yl Ester ((S)-
(4R)-4-[2-(Tr iflu or om et h yl)p h en yl]-2-oxo-6-(â-D-r ib o-
fu r an osyl)-1,2,3,4-tetr ah ydr opyr im idin e-5-car boxylic Acid
Eth yl Ester ((R)-13a ′). The compound was recovered slightly
12a ′). Amorphous solid. [R]2D0 ) 58.5 (c 1.5, MeOH). H NMR
1
(pyridine-d5): δ ) 10.58 (bs, 1 H, NH), 9.00 (bd, 1 H, J 4,NH
)
1
contaminated by uncharacterized byproducts. H NMR (CD3-
1.0 Hz, NH), 7.80-7.00 (m, 5 H, Ph), 6.35 (s, 1 H, H-1′), 5.72
(d, 1 H, H-4), 5.08 (dd, 1 H, J 2′,3′ ) 4.5 Hz, J 3′,4′ ) 8.2 Hz, H-3′),
4.79 (d, 1 H, H-2′), 4.70 (ddd, 1 H, J 4′,5′a ) 2.0 Hz, J 4′,5′b ) ∼0.5
Hz, H-4′), 4.46 (dd, 1 H, J 5′a,5′b ) 11.0 Hz, H-5′a), 4.35 (dd, 1
H, H-5′b), 4.10-3.40 (m, 2 H, CH2CH3), 1.04 (t, 3 H, J ) 7.0
Hz, CH2CH3). 13C NMR (CD3OD): δ ) 166.6, 154.6, 151.0,
145.4, 129.7, 129.6, 128.9, 128.8, 127.6, 101.1, 83.6, 81.3, 79.6,
71.0, 61.4, 60.5, 56.4, 14.5. MALDI-TOF MS: 379.8 (M+ + H),
386.1 (M+ + Li), 402.1 (M+ + Na), 418.2 (M+ + K). Anal. Calcd
for C18H22N2O7 (378.38): C, 57.14; H, 5.86; N, 7.40. Found:
C, 57.12; H, 5.80; N, 7.32.
OD): δ ) 7.80-7.20 (m, 4 H, Ph), 5.79 (s, 1 H, H-4), 5.74 (d, 1
H, J 1′,2′ ) 2.0 Hz, H-1′), 4.23 (dd, 1 H, J 2′,3′ ) 4.5 Hz, J 3′,4′
)
7.5 Hz, H-3′), 4.16 (dd, 1 H, H-2′), 4.04 (ddd, 1 H, J 4′,5′a ) 2.0
Hz, J 4′;5′b ) ∼0.5 Hz, H-4′), 4.01 (dd, 1 H, J 5′a,5′b ) 10.8 Hz,
H-5′a), 3.99 (q, 2 H, J ) 7.0 Hz, CH2CH3), 3.83 (dd, 1 H, H-5′b),
0.99 (t, 3 H, CH2CH3). 13C NMR (CD3OD): δ ) 166.1, 153.8,
152.7, 143.3, 134.4, 129.6, 129.4, 127.7, 127.1, 127.0, 100.1,
84.1, 81.6, 79.3, 71.3, 61.3, 60.7, 52.4, 14.2. MALDI-TOF MS:
447.5 (M+ + H), 469.7 (M+ + Na).
(4R)- a n d (4S)-6-Met h yl-2-oxo-4-p h en yl-1-[(â-D-r ib o-
fu r a n osyl)m et h yl]-1,2,3,4-t et r a h yd r op yr im id in e-5-ca r -
boxylic Acid Eth yl Ester s (14a ′). 1H NMR (pyridine-d5)
selected data for ∼1:1 mixture of (4R)- and (4S)-stereoisomers:
δ ) 9.22 (d, 0.5 H, J ) 2.5 Hz, NH), 9.15 (d, 0.5 H, J ) 2.2 Hz,
NH), 5.70 (d, 0.5 H, J ) 2.5 Hz, H-4), 5.68 (d, 0.5 H, J ) 2.2
Hz, H-4), 2.83 (s, 1.5 H, CH3), 2.74 (s, 1.5 H, CH3), 1.02 (t, 1.5
H, J ) 7.0 Hz, CH2CH3), 0.99 (t, 1.5 H, J ) 7.0 Hz, CH2CH3).
13C NMR (pyridine-d5) selected data for ∼1:1 mixture of (4R)-
and (4S)-stereoisomers: δ ) 165.9, 154.6, 153.8, 147.8, 147.4,
105.6, 104.8, 14.1, 14.0. MALDI-TOF MS: 413.8 (M+ + Li),
429.8 (M+ + Na), 445.6 (M+ + K). Anal. Calcd for C20H26N2O7
(406.43): C, 59.10; H, 6.45; N, 6.89. Found: C, 59.19; H, 6.48;
N, 6.73.
(4R)-2-Oxo-4-p h en yl-6-(â-D-r ib ofu r a n osyl)-1,2,3,4-t et -
r a h yd r op yr im id in e-5-ca r boxylic Acid Eth yl Ester ((R)-
12a ′). The compound was recovered slightly contaminated by
uncharacterized byproducts. 1H NMR (pyridine-d5): δ ) 10.75
(bs, 1 H, NH), 9.08 (bd, 1 H, J 4,NH ) 3.0 Hz, NH), 7.80-7.00
(m, 5 H, Ph), 6.37 (d, 1 H, J 1′,2′ ) 1.0 Hz, H-1′), 5.68 (d, 1 H,
H-4), 5.05 (dd, 1 H, J 2′,3′ ) 4.5 Hz, J 3′,4′ ) 8.0 Hz, H-3′), 4.76
(dd, 1 H, H-2′), 4.66 (ddd, 1 H, J 4′,5′a ) 2.0 Hz, J 4′,5′b ) ∼0.5
Hz, H-4′), 4.47 (dd, 1 H, J 5′a,5′b ) 11.0 Hz, H-5′a), 4.38 (dd, 1
H, H-5′b), 4.05 (q, 2 H, J ) 7.0 Hz, CH2CH3), 1.08 (t, 3 H,
CH2CH3). MALDI-TOF MS: 379.7 (M+ + H), 402.2 (M+ + Na).
(4S)-6-(â-D-Ga la ct op yr a n osyl)-2-oxo-4-p h en yl-1,2,3,4-
tetr ah ydr opyr im idin e-5-car boxylic Acid Eth yl Ester ((S)-
(4S)-1-[(â-D-Ga la ctop yr a n osyl)m eth yl]-6-m eth yl-2-oxo-
4-p h en yl-1,2,3,4-tetr a h yd r op yr im id in e-5-ca r boxylic Acid
Eth yl Ester ((S)-14b′). Syrup. [R]2D0 ) -62.6 (c 0.8, MeOH).
12b′). Amorphous solid. [R]2D0 ) 62.5 (c 0.4, MeOH). H NMR
1
(pyridine-d5): δ ) 9.77 (bs, 1 H, NH), 9.24 (bd, 1 H, J 4,NH
)
1H NMR (DMSO-d6) selected data: δ ) 7.90 (d, 1 H, J 4,NH
)
3.0 Hz, NH), 7.87-7.81 and 7.25-7.10 (2m, 5 H, Ph), 6.29 (d,
1 H, J 1′,2′ ) 9.5 Hz, H-1′), 5.78 (d, 1 H, H-4), 4.88 (dd, 1 H, J 2′,3′
) 9.1 Hz, H-2′), 4.57 (dd, 1 H, J 3′,4′ ) 2.8 Hz, J 4′,5′ ) ∼0.5 Hz,
H-4′), 4.46 (dd, 1 H, J 5′,6′a ) 6.5 Hz, J 6′a,6′b ) 11.8 Hz, H-6′a),
4.37 (dd, 1 H, J 5′,6′b ) 5.0 Hz, H-6′b), 4.24 (ddd, 1 H, H-5′),
4.22 (dd, 1 H, H-3′), 4.02-3.82 (m, 2 H, CH2CH3), 0.94 (t, 3 H,
J ) 7.0 Hz, CH2CH3). 13C NMR (pyridine-d5): δ ) 166.2, 153.8,
150.3, 145.3, 129.0, 127.8, 127.7, 123.9, 123.8, 103.0, 82.0, 77.3,
3.0 Hz, NH), 7.40-7.10 (m, 5 H, Ph), 5.07 (d, 1 H, H-4), 4.05-
3.90 (m, 2 H, CH2CH3), 1.08 (t, 3 H, J ) 7.0 Hz, CH2CH3). 13C
NMR (DMSO-d6): δ ) 165.5, 152.3, 151.7, 144.0, 128.4, 128.3,
127.2, 126.4, 126.3, 102.6, 79.7, 78.2, 74.4, 69.1, 67.8, 59.6, 59.3,
52.8, 42.9, 16.3, 14.0. MALDI-TOF MS: 437.7 (M+ + H), 459.9
(M+ + Na). Anal. Calcd for C21H28N2O8 (436.46): C, 57.79; H,
6.47; N, 6.42. Found: C, 57.70; H, 6.48; N, 6.51.
J . Org. Chem, Vol. 67, No. 20, 2002 6991

Dondoni et al.
(4R)- an d (4S)-1-[(â-D-Man n opyr an osyl)m eth yl]-6-m eth -
yl-2-oxo-4-ph en yl-1,2,3,4-tetr ah ydr opyr im idin e-5-car box-
ylic Acid Eth yl Ester s (14c′). Syrup. 1H NMR (DMSO-d6)
selected data for ∼1:1 mixture of (4R)- and (4S)-stereoisomers:
δ ) 8.00 (d, 0.5 H, J ) 3.5 Hz, NH), 7.95 (d, 0.5 H, J ) 3.5 Hz,
NH), 7.40-7.10 (m, 5 H, Ph), 5.18 (d, 0.5 H, J ) 3.5 Hz, H-4),
5.09 (d, 0.5 H, J ) 3.5 Hz, H-4), 2.57 (s, 1.5 H, CH3), 2.56 (s,
1.5 H, CH3), 1.14 (t, 1.5 H, J ) 7.0 Hz, CH2CH3), 1.09 (t, 1.5
H, J ) 7.0 Hz, CH2CH3). 13C NMR (DMSO-d6) selected data
for ∼1:1 mixture of (4R)- and (4S)-stereoisomers: δ ) 167.8,
167.7, 156.0, 155.7, 151.9, 150.7, 145.0, 144.9, 106.4, 105.6,
16.9, 16.7, 14.5, 14.2. MALDI-TOF MS: 437.5 (M+ + H), 459.8
(M+ + Na). Anal. Calcd for C21H28N2O8 (436.46): C, 57.79; H,
6.47; N, 6.42. Found: C, 57.83; H, 6.41; N, 6.40.
mmol), benzyl acetoacetetate (346 µL, 2.00 mmol), urea (180
mg, 3.00 mmol), Yb(OTf)3 (1.24 g, 2.00 mmol), and anhydrous
THF (10 mL) was stirred under reflux for 20 h. The mixture
was cooled to room temperature, diluted with EtOAc (100 mL),
and washed with H2O (2 × 10 mL). The organic phase was
dried (Na2SO4), concentrated, and eluted from a column of
silica gel with 2:1 cyclohexane-AcOEt to give first (4R)-4-
(2′,3′,4′,6′-tetra-O-benzyl-â-D-galactopyranosyl)-6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylic acid benzyl ester
1
(833 mg, 54%) as a white foam. H NMR: δ ) 7.50-7.20 (m,
25 H, 5 Ph), 6.18 (bd, 1 H, J ) ∼0.5 Hz, NH), 5.20 (s, 2 H,
PhCH2), 4.95 and 4.62 (2 d, 2 H, J ) 12.0 Hz, PhCH2), 4.94
and 4.67 (2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.78 and 4.73 (2 d, 2
H, J ) 11.2 Hz, PhCH2), 4.49 (bdd, 1 H, J 4,NH ) 4.5 Hz, J 1′,4
)
1.0 Hz, H-4), 4.41 and 4.35 (2 d, 2 H, J ) 11.5 Hz, PhCH2),
4.05 (bdd, 1 H, J ) ∼0.5 Hz, J 4,NH ) 4.5 Hz, NH), 3.95 (dd, 1
(4R)-2-Oxo-4,6-bis-(â-D-r ibofu r a n osyl)-1,2,3,4-tetr a h y-
d r op yr im id in e-5-ca r boxylic Acid Eth yl Ester ((R)-15a ′).
Amorphous solid. [R]2D0 ) -72.5 (c 1.3, MeOH). 1H NMR
(pyridine-d5): δ ) 10.42 (bs, 1 H, NH), 8.83 (s, 1 H, NH), 6.32
(s, 1 H, H-1r6), 5.07 (dd, 1 H, J 2,3 ) 4.2 Hz, J 3,4 ) 8.5 Hz,
H, J 3′,4′ ) 2.8 Hz, J 4′,5′ ) ∼0.5 Hz, H-4′), 3.88 (dd, 1 H, J 1′,2′
)
9.5 Hz, J 2′,3′ ) 9.2 Hz, H-2′), 3.61 (dd, 1 H, H-3′), 3.54-3.41
(m, 3 H, H-5′, 2 H-6′), 3.22 (dd, 1 H, H-1′), 2.17 (s, 3 H, CH3).
MALDI-TOF MS: 791.7 (M+ + Na), 807.5 (M+ + K). Anal.
Calcd for C47H48N2O8 (768.89): C, 73.42; H, 6.29; N, 3.64.
Found: C, 73.40; H, 6.22; N, 3.58.
H-3r6), 5.05 (d, 1 H, J 4,1r4 ) 4.0 Hz, H-4), 4.87 (dd, 1 H, J 1,2
6.5 Hz, J 2,3 ) 4.8 Hz, H-2r4), 4.86 (d, 1 H, H-2r6), 4.67 (dd, 1
H, J 3,4 ) 6.0 Hz, H-3r4), 4.64 (ddd, 1 H, J 4,5a ) 2.0 Hz, J 4,5b
)
)
Eluted second was (4S)-4-(2′,3′,4′,6′-tetra-O-benzyl-â-D-ga-
lactopyranosyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylic acid benzyl ester (167 mg, 11%) as a white foam.
1H NMR: δ ) 7.50-7.10 (m, 25 H, 5 Ph), 6.39 (bs, 1 H, NH),
5.55 (bs, 1 H, NH), 5.21 and 5.07 (2 d, 2 H, J ) 12.0 Hz,
PhCH2), 5.09 and 4.54 (2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.95
and 4.55 (2 d, 2 H, J ) 11.5 Hz, PhCH2), 4.72 (bs, 1 H, H-4),
4.71 and 4.59 (2 d, 2 H, J ) 12.1 Hz, PhCH2), 4.46 and 4.41 (2
d, 2 H, J ) 11.2 Hz, PhCH2), 4.09 (dd, 1 H, J 1′,2′ ) 9.0 Hz, J 2′,3′
) 9.1 Hz, H-2′), 3.97 (dd, 1 H, J 3′,4′ ) 2.8 Hz, J 4′,5′ ) ∼0.5 Hz,
H-4′), 3.65 (dd, 1 H, H-3′), 3.62 (dd, 1 H, H-1′), 3.55-4.80 (m,
3 H, H-5′, 2 H-6′), 1.92 (s, 3 H, CH3). MALDI-TOF MS: 792.0
(M+ + Na), 808.1 (M+ + K). Anal. Calcd for C47H48N2O8
(768.89): C, 73.42; H, 6.29; N, 3.64. Found: C, 73.50; H, 6.31;
N, 3.65.
∼0.5 Hz, H-4r6), 4.52 (dd, 1 H, J 1,2 ) 6.5 Hz, H-1r4), 4.44 (ddd,
1 H, J 4,5a ) 4.5 Hz, J 4,5b ) 4.8 Hz, H-4r4), 4.40 (dd, 1 H, J 5a,5b
) 12.0 Hz, H-5ar6), 4.30 (dd, 1 H, H-5br6), 4.11 (q, 2 H, J )
7.0 Hz, CH2CH3), 4.06 (dd, 1 H, J 5a,5b ) 12.0 Hz, H-5ar4), 4.00
(dd, 1 H, H-5br4), 1.12 (t, 3 H, CH3). 13C NMR (D2O): δ )
166.5, 155.4, 150.9, 96.9, 85.0, 83.2, 81.5, 80.0, 77.8, 72.0, 71.5,
69.3, 62.4, 61.8, 59.1, 52.4, 13.6. MALDI-TOF MS: 441.8 (M+
+ Li), 458.6 (M+ + Na). Anal. Calcd for C17H26N2O11 (434.40):
C, 47.00; H, 6.03; N, 6.45. Found: C, 47.10; H, 6.05; N, 6.40.
(4R)-4-(â-D-Ga la ctop yr a n osyl)-2-oxo-6-(â-D-r ibofu r a n o-
syl)-1,2,3,4-tetr a h yd r op yr im id in e-5-ca r boxylic Acid Eth -
yl Ester ((R)-15b′). Amorphous solid. [R]2D0 ) -43.8 (c 0.7,
1
MeOH). H NMR (pyridine-d5): δ ) 10.42 (s, 1 H, NH), 8.78
(bd, 1 H, J 4,NH ) 2.0 Hz, NH), 6.53 (d, 1 H, J 1,2 ) 0.8 Hz, H-1r),
5.51 (dd, 1 H, J 4,1g) 2.8 Hz, H-4), 5.16 (dd, 1 H, J 2,3 ) 4.0 Hz,
A vigorously stirred mixture of 20% palladium hydroxide
on carbon (150 mg), Ambersep 900 OH (300 mg),38 AcOEt (2
mL), and CH2Cl2 (2 mL) was degassed under vacuum and
saturated with hydrogen (by a H2-filled balloon) three times.
To this mixture was added a solution of (4R)-4-(2′,3′,4′,6′-tetra-
O-benzyl-â-D-galactopyranosyl)-6-methyl-2-oxo-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylic acid benzyl ester (100 mg, 0.13
mmol) in CH2Cl2 (2 mL) previously degassed and saturated
with hydrogen as described before. After the mixture was
stirred under a slightly positive pressure of hydrogen (balloon)
at room temperature for 1.5 h, palladium hydroxide on carbon
and Ambersep 900 OH were filtered off through a pad of Celite
and the mixture was then suspended in CH2Cl2 (4 mL). This
mixture was diluted with AcOH (0.5 mL) and shaken for 30
min. Then palladium hydroxide on carbon and Ambersep 900
OH were filtered off through a pad of Celite and washed
thoroughly with CH2Cl2 and MeOH. The combined filtrates
were concentrated to give (R)-17b (70 mg, 78%) as a white
J 3,4 ) 8.0 Hz, H-3r), 5.08 (dd, 1 H, H-2r), 4.87 (dd, 1 H, J 1,2
)
9.5 Hz, J 2,3 ) 9.2 Hz, H-2g), 4.72 (ddd, 1 H, J 4,5a ) 2.0 Hz,
J 4,5b ) ∼0.5 Hz, H-4r), 4.57 (dd, 1 H, J 3,4 ) 3.5 Hz, J 4,5 ) ∼0.5
Hz, H-4g), 4.47 (dd, 1 H, J 5a,5b ) 11.5 Hz, H-5ar), 4.37 (dd, 1
H, H-5br), 4.33 (dd, 1 H, J 5,6a ) 6.2 Hz, J 6a,6b ) 11.5 Hz, H-6ag),
4.27 (dd, 1 H, J 5,6b ) 6.0 Hz, H-6bg), 4.22 (q, 2 H, J ) 7.0 Hz,
CH2CH3), 4.12 (dd, 1 H, H-3g), 3.88 (ddd, 1 H, H-5g), 3.85 (dd,
1 H, H-1g), 1.19 (t, 3 H, CH3). 13C NMR (pyridine-d5): δ )
166.0, 154.9, 153.9, 96.3, 83.7, 83.5, 81.6, 80.5, 79.6, 77.1, 71.1,
70.3, 68.1, 62.2, 60.1, 59.8, 52.6, 14.5. MALDI-TOF MS: 471.8
(M+ + Li), 487.7 (M+ + Na), 503.9 (M+ + K). Anal. Calcd for
C
18H28N2O12 (464.42): C. 46.55; H, 6.08; N, 6.03. Found: C,
46.60; H, 6.10, N, 6.09.
(4R)-4-(â-D-Ma n n op yr a n osyl)-2-oxo-6-(â-D-r ibofu r a n o-
syl)-1,2,3,4-tetr a h yd r op yr im id in e-5-ca r boxylic Acid Eth -
yl Ester ((R)-15c′). Amorphous solid. [R]2D0 ) -62.4 (c 0.6,
1
MeOH). H NMR (pyridine-d5): δ ) 10.42 (bs, 1 H, NH), 7.90
(bs, 1 H, NH), 6.24 (d, 1 H, J 1,2 ) 1.0 Hz, H-1r), 5.09 (dd, 1 H,
J 4,NH ) 2.5 Hz, J 4,1m ) 4.5 Hz, H-4), 5.05 (dd, 1 H, J 2,3 ) 4.0
Hz, J 3,4 ) 8.2 Hz, H-3r), 4.80 (dd, 1 H, H-2r), 4.64 (ddd, 1 H,
J 4,5a ) 2.0 Hz, J 4,5b ) ∼0.5 Hz, H-4r), 4.47 (dd, 1 H, J 3,4 ) 9.0
Hz, J 4,5 ) 9.2 Hz, H-4m), 4.39 (d, 1 H, J 2,3 ) 3.5 Hz, H-2m),
4.38 (dd, 1 H, J 5a,5b ) 10.8 Hz, H-5ar), 4.29 (dd, 1 H, H-5br),
4.29 (dd, 1 H, J 5,6a ) 2.5 Hz, J 6a,6b ) 11.0 Hz, H-6am), 4.24-
4.10 (m, 2 H, CH2CH3), 4.13 (dd, 1 H, J 5,6b ) 5.0 Hz, H-6bm),
3.96 (dd, 1 H, H-3m), 3.87 (d, 1 H, H-1m), 3.64 (ddd, 1 H,
H-5m), 1.18 (t, 3 H, J ) 7.0 Hz, CH2CH3). 13C NMR (pyridine-
d5): δ ) 166.5, 155.5, 153.9, 96.7, 83.7, 81.9, 81.5, 81.0, 80.0,
76.3, 72.5, 71.0, 68.9, 63.5, 60.5, 60.0, 54.5, 14.4. MALDI-TOF
MS: 487.8 (M+ + Na), 503.8 (M+ + K). Anal. Calcd for
1
solid at least 95% pure by NMR analysis. H NMR (CDCl3 +
CD3OD): δ ) 7.50-7.10 (m, 20 H, 4 Ph), 6.82 (bs, 1 H, NH),
4.96 and 4.62 (2 d, 2 H, J ) 11.8 Hz, PhCH2), 4.94 and 4.77 (2
d, 2 H, J ) 11.5 Hz, PhCH2), 4.75 and 4.65 (2 d, 2 H, J ) 11.2
Hz, PhCH2), 4.46 (bs, 1 H, H-4), 4.40 and 4.34 (2 d, 2 H, J )
11.0 Hz, PhCH2), 3.94 (dd, 1 H, J 1′,2′ ) 9.0 Hz, J 2′,3′ ) 9.1 Hz,
H-2′), 3.93 (dd, 1 H, J 3′,4′ ) 2.8 Hz, J 4′,5′ ) ∼0.5 Hz, H-4′), 3.65
(dd, 1 H, H-3′), 3.62 (bs, 1 H, NH), 3.54-3.42 (m, 3 H, H-5′, 2
H-6′), 3.32 (dd, 1 H, J 1′,4 ) ∼0.5 Hz, H-1′), 2.19 (s, 3 H, CH3).
MALDI-TOF MS: 701.9 (M+ + Na), 717.8 (M+ + K).
Crystallization from ethanol afforded small crystals of (R)-
17b suitable for elemental and X-ray diffraction analysis. Anal.
Calcd for C40H42N2O8 (678.77): C, 70.78; H, 6.24; N, 4.13.
Found: C, 70.77; H, 6.23; N, 4.12.
C
18H28N2O12 (464.42): C. 46.55; H, 6.08; N, 6.03. Found: C,
46.51; H, 6.00, N, 6.01.
(4R)-4-(2′,3′,4′,6′-Tetr a -O-ben zyl-â-D-ga la ctop yr a n osyl)-
6-m eth yl-2-oxo-1,2,3,4-tetr a h yd r op yr im id in e-5-ca r boxy-
lic Acid ((R)-17b). A mixture of aldehyde 5b (1.10 g, 2.00
(38) Ambersep 900 OH was purchased from Fluka. This resin was
washed with methanol and dried in vacuo before use.
6992 J . Org. Chem., Vol. 67, No. 20, 2002

Biginelli Cyclocondensation Reaction Using C-Glycosylated Substrates
(4R)-4-(â-D-Ga la ct op yr a n osyl)-6-m et h yl-2-oxo-1,2,3,4-
tetr a h yd r op yr im id in e-5-ca r boxylic Acid ((R)-17b′). A
vigorously stirred mixture of (4R)-4-(2′,3′,4′,6′-tetra-O-benzyl-
â-D-galactopyranosyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyri-
midine-5-carboxylic acid benzyl ester (300 mg, 0.39 mmol), 20%
palladium hydroxide on carbon (200 mg), CH2Cl2 (4 mL),
AcOEt (2 mL), and MeOH (4 mL) was degassed under vacuum
and saturated with hydrogen (by a H2-filled balloon) three
times. After the mixture was stirred under a slightly positive
pressure of hydrogen (balloon) at room temperature for 8 h,
palladium hydroxide on carbon was filtered off through a plug
of cotton and the mixture washed thoroughly with MeOH (2
mL), H2O (0.5 mL), and DMF (2 mL). The combined filtrates
were concentrated to give (R)-17b′ (118 mg, 95%) as a white
amorphous solid. 1H NMR (CD3OD + D2O): δ ) 4.65 (bs, 1 H,
H-4), 3.87 (dd, 1 H, J 3′,4′ ) 3.0 Hz, J 4′,5′ ) ∼0.5 Hz, H-4′), 3.72
(dd, 1 H, J 1′,2′ ) 9.0 Hz, J 2′,3′ ) 9.1 Hz, H-2′), 3.68 (dd, 1 H,
solvent evaporated. The compound (absorbed on silica gel) was
subjected to column chromatography with 10:1:0.1 CH2Cl2-
MeOH-28% NH4OH to give, following solvent evaporation,
19a (90 mg, 75%) as a white solid. [R]2D0 ) 56.8 (c 1.6, MeOH).
1H NMR (pyridine-d5): δ ) 11.60 (bs, 1 H, OH), 11.24 (bs, 1
H, NH), 8.01 (bs, 1 H, NH), 7.46 (dd, 1 H, J ) 1.0, 1.2 Hz,
H-2Ph), 7.18 (ddd, 1 H, J ) 1.0, 1.5, 7.5 Hz, H-4Ph), 7.13 (dd,
1 H, J ) 7.5, 7.8 Hz, H-5Ph), 7.01 (ddd, 1 H, J ) 1.2, 1.5, 7.8
Hz, H-6Ph), 6.31 (d, 1 H, J 1′,2′ ) ∼0.5 Hz, H-1′), 5.75 (d, 1 H,
J 4,NH ) ∼0.5 Hz, H-4), 4.98 (dd, 1 H, J 2′,3′ ) 4.5 Hz, J 3′,4′ ) 8.0
Hz, H-3′), 4.74 (dd, 1 H, H-2′), 4.69 (ddd, 1 H, J 4′,5′a ) 2.2 Hz,
J 4′,5′b ) ∼0.5 Hz, H-4′), 4.46 (dd, 1 H, J 5′a,5′b ) 10.8 Hz, H-5′a),
4.32 (dd, 1 H, H-5′b), 4.14-3.98 (m, 2 H, CH
2CH3), 1.09 (t, 3
H, J ) 7.0 Hz, CH2CH3). 13C NMR (pyridine-d5): δ ) 176.1,
165.5, 159.4, 148.2, 146.7, 130.4, 117.8, 115.9, 114.7, 100.9,
83.6, 81.2, 79.6, 71.3, 60.4, 59.9, 56.1, 14.1. MALDI-TOF MS:
434.1 (M+
+ Na). Anal. Calcd for C18H22N2O7S (410.44): C,
J 5′,6′a ) 4.5 Hz, J 6′a,6′b ) 11.5 Hz, H-6′a), 3.63 (dd, 1 H, J 5′,6′b
)
52.67; H, 5.40; N, 6.83; S, 7.81. Found: C, 52.60; H, 5.41; N,
6.80; S, 7.85.
6.2 Hz, H-6′b), 3.47 (dd, 1 H, H-3′), 3.44 (ddd, 1 H, H-5′), 3.19
(dd, 1 H, J 1′,4 ) 2.5 Hz, H-1′), 2.28 (s, 3 H, CH3). MALDI-TOF
MS: 341.5 (M+ + Na), 357.4 (M+ + K). Anal. Calcd for
(4R )-4-(3-H yd r oxyp h e n yl)-6-(â-D -r ib ofu r a n osyl)-2-
th ioxo-1,2,3,4-tetr a h yd r op yr im id in e-5-ca r boxylic Acid
Eth yl Ester (19b). Dihydropyrimidinethione 18b (200 mg,
0.29 mmol) was treated as described for the preparation of 19a
to give 19b (90 mg, 75%) as a white solid. [R]2D0 ) -80.8 (c 0.9,
C
12H18N2O8 (318.28): C, 45.28; H, 5.70; N, 8.80. Found: C,
45.21; H, 5.68; N, 8.75.
(4S)-6-(2′,3′,5′-Tr i-O-ben zyl-â-D-r ibofu r a n osyl)-4-(3-h y-
d r oxyp h en yl)-2-t h ioxo-1,2,3,4-t et r a h yd r op yr im id in e-5-
ca r boxylic Acid Eth yl Ester (18a ) a n d (4R)-6-(2′,3′,5′-Tr i-
O-ben zyl-â-D-r ibofu r an osyl)-4-(3-h ydr oxyph en yl)-2-th ioxo-
1,2,3,4-t et r a h yd r op yr im id in e-5-ca r boxylic Acid E t h yl
Ester (18b). A mixture of 3-hydroxybenzaldehyde (122 mg,
1.00 mmol), â-ketoester 6a (518 mg, 1.00 mmol), thiourea (228
mg, 3.00 mmol), Yb(OTf)3 (310 mg, 0.50 mmol), and anhydrous
THF (5 mL) was stirred under reflux for 20 h. The mixture
was cooled to room temperature, diluted with EtOAc (100 mL),
and washed with H2O (2 × 10 mL). The organic phase was
dried (Na2SO4), concentrated, and eluted from a column of
silica gel with 4:1 cyclohexane-AcOEt to give first 18b (150
mg, 22%) as a white foam. [R]2D0 ) -24.1 (c 1.0, CHCl3). 1H
NMR: δ ) 10.38 (bs, 1 H, NH), 7.60-7.10 and 6.90-6.70 (2m,
19 H, Ph), 7.08 (bs, 1 H, OH), 5.90 (d, 1 H, J 1′,2′ ) ∼0.5 Hz,
H-1′), 5.43 (bs, 1 H, NH), 5.32 (d, 1 H, J 4,NH ) 2.8 Hz, H-4),
5.18 and 4.70 (2 d, 2 H, J ) 12.0 Hz, PhCH2), 4.90 and 4.83 (2
d, 2 H, J ) 11.5 Hz, PhCH2), 4.40 and 4.28 (2 d, 2 H, J ) 11.2
Hz, PhCH2), 4.28 (ddd, 1 H, J 3′,4′ ) 8.8 Hz, J 4′,5′a ) 2.5 Hz,
J 4′,5′b ) ∼0.5 Hz, H-4′), 4.21-4.08 (m, 3 H, CH2CH3, H-3′), 4.05
(dd, 1 H, J 2′,3′ ) 5.0 Hz, H-2′), 3.86 (dd, 1 H, J 5′a,5′b ) 10.8 Hz,
H-5′a), 3.58 (dd, 1 H, H-5′b), 1.17 (t, 3 H, J ) 7.0 Hz, CH2CH3).
Anal. Calcd for C39H40N2O7S (680.81): C, 68.80; H, 5.92; N,
4.11; S, 4.71. Found: C, 68.81; H, 5.93; N, 4.15, S, 4.76.
Eluted second was 18a (299 mg, 44%) as a white foam.
[R]2D0 ) 59.9 (c 1.4, CHCl3). 1H NMR: δ ) 10.32 (bs, 1
H, NH), 7.55-7.15 and 6.90-6.70 (2m, 20 H, Ph, OH), 5.83
(d, 1 H, J 1′,2′ ) ∼0.5 Hz, H-1′), 5.66 (bs, 1 H, NH), 5.39 (d, 1 H,
J 4,NH ) 2.8 Hz, H-4), 5.06 and 4.74 (2 d, 2 H, J ) 12.0 Hz,
PhCH2), 4.86 and 4.69 (2 d, 2 H, J ) 11.5 Hz, PhCH2), 4.40
and 4.29 (2 d, 2 H, J ) 11.2 Hz, PhCH2), 4.28 (ddd, 1 H, J 3′,4′
) 8.5 Hz, J 4′,5′a ) 2.5 Hz, J 4′,5′b ) ∼0.5 Hz, H-4′), 4.21-4.04
(m, 2 H, CH2CH3), 4.08 (dd, 1 H, J 2′,3′ ) 4.5 Hz, H-3′), 3.95
(dd, 1 H, H-2′), 3.87 (dd, 1 H, J 5′a,5′b ) 10.8 Hz, H-5′a), 3.57
(dd, 1 H, H-5′b), 1.18 (t, 3 H, J ) 7.0 Hz, CH2CH3). Anal. Calcd
for C39H40N2O7S (680.81): C, 68.80; H, 5.92; N, 4.11; S, 4.71.
Found: C, 68.85; H, 5.95; N, 4.10, S, 4.78.
1
MeOH). H NMR (pyridine-d5 + D2O): δ ) 7.54 (dd, 1 H, J )
1.0, 1.2 Hz, H-2Ph), 7.21 (ddd, 1 H, J ) 1.0, 3.0, 7.8 Hz, H-4Ph),
7.19 (dd, 1 H, J ) 7.5, 7.8 Hz, H-5Ph), 7.08 (ddd, 1 H, J ) 1.2,
3.0, 7.5 Hz, H-6Ph), 6.32 (d, 1 H, J 1′,2′ ) 2.0 Hz, H-1′), 5.73 (s
1 H, H-4), 5.02 (dd, 1 H, J 2′,3′ ) 4.5 Hz, J 3′,4′ ) 8.0 Hz, H-3′),
4.73 (dd, 1 H, H-2′), 4.68 (ddd, 1 H, J 4′,5′a ) 2.0 Hz, J 4′,5′b
)
∼0.5 Hz, H-4′), 4.42 (dd, 1 H, J 5′a,5′b ) 10.8 Hz, H-5′a), 4.37
(dd, 1 H, H-5′b), 4.14-4.00 (m, 2 H, CH2CH3), 1.10 (t, 3 H, J
) 7.0 Hz, CH2CH3). 13C NMR (pyridine-d5): δ ) 176.4, 165.9,
159.3, 148.1, 146.4, 130.5, 118.2, 116.0, 114.8, 101.9, 84.1, 81.6,
78.9, 71.8, 60.7, 60.2, 56.0, 14.4. MALDI-TOF MS: 411.7 (M+
+ H), 433.7 (M+ + Na), 449.9 (M+ + K). Anal. Calcd for
C
18H22N2O7S (410.44): C, 52.67; H, 5.40; N, 6.83; S, 7.81.
Found: C, 52.61; H, 5.45; N, 6.83; S, 7.84.
6-(5-Ben zoyloxym eth ylfu r an -2-yl)-4-(3-h ydr oxyph en yl)-
2-th ioxo-1,2,3,4-tetr a h yd r op yr im id in e-5-ca r boxylic Acid
Eth yl Ester (21) a n d 4-(3-Acetoxyp h en yl)-6-(5-ben zoy-
loxym eth ylfu r a n -2-yl)-2-th ioxo-1,2,3,4-tetr a h yd r op yr im i-
d in e-5-ca r boxylic Acid Eth yl Ester (22). A mixture of
3-acetoxybenzaldehyde (164 mg, 1.00 mmol), â-ketoester 2033
(560 mg, 1.00 mmol), thiourea (228 mg, 3.00 mmol), Yb(OTf)3
(620 mg, 1.00 mmol), and anhydrous THF (5 mL) was stirred
under reflux for 20 h. The mixture was cooled to room
temperature, diluted with EtOAc (100 mL), and washed with
H2O (2 × 10 mL). The organic phase was dried (Na2SO4),
concentrated, and eluted from a column of silica gel with 3:1
cyclohexane-AcOEt to give first 22 (120 mg, 23%) as a yellow
syrup. [R]2D0 ) 0.0 (c 1.0, CHCl3). H NMR: δ ) 8.28 (bs, 1 H,
1
NH), 8.12-8.07 and 7.63-7.02 (2m, 9 H, Ph), 7.38 and 6.66 (2
d, 2 H, J ) 3.5 Hz, H-3Fur, H-4Fur), 5.59 (d, 1 H, J 4,NH ) 3.0
Hz, H-4), 5.44 (bs, 1 H, NH), 5.37 (s, 2 H, CH2OBz), 4.17 (q, 2
H, J ) 7.0 Hz, CH2CH3), 2.31 (s, 3 H, CH3), 1.16 (t, 3 H,
CH2CH3). Anal. Calcd for C27H24N2O7S (520.55): C, 62.30; H,
4.65; N, 5.38; S, 6.16. Found: C, 62.35; H, 4.66; N, 5.40; S,
6.21.
Eluted second was 21 (220 mg, 46%) as yellow syrup.
[R]2D0 ) 0.0 (c ) 1.4, CHCl3). 1H NMR: δ ) 8.30 (bs, 1
H, NH), 8.11-8.05 and 7.63-7.34 (2m, 5 H, Ph), 7.54 (bs, 1
H, OH), 7.32 and 6.65 (2 d, 2 H, J ) 3.5 Hz, H-3Fur, H-4Fur),
7.22-7.14 and 6.92-6.74 (2m, 4 H, Ph), 5.95 (bs, 1 H, NH),
5.53 (d, 1 H, J 4,NH ) 3.0 Hz, H-4), 5.35 (s, 2 H, CH2OBz), 4.17
(q, 2 H, J ) 7.0 Hz, CH2CH3), 1.15 (t, 3 H, CH2CH3). Anal.
Calcd for C25H22N2O6S (478.52): C, 62.75; H, 4.63; N, 5.85; S,
6.70. Found: C, 62.70, H, 4.61; N, 5.80.
6-(5-Hyd r oxym eth ylfu r a n -2-yl)-4-(3-h yd r oxyp h en yl)-2-
th ioxo-1,2,3,4-tetr a h yd r op yr im id in e-5-ca r boxylic Acid
Eth yl Ester (23). To a stirred solution of 21 (200 mg, 0.42
mmol) in MeOH (2 mL) was added NaOMe (0.5 M solution in
(4S)-4-(3-Hydr oxyph en yl)-6-(â-D-r ibofu r an osyl)-2-th ioxo-
1,2,3,4-t et r a h yd r op yr im id in e-5-ca r b oxylic Acid E t h yl
Ester (19a ). To a cooled (-70 °C), stirred solution of 18a (200
mg, 0.29 mmol) in anhydrous CH2Cl2 was added boron trichlo-
ride (1.0 M solution in CH2Cl2, 2.64 mL, 2.64 mmol) dropwise,
and stirring was continued at -70 °C for 10 min. The solution
was then warmed to 0 °C and stirred for an additional 1.5 h.
The excess of boron trichloride was quenched at -70 °C with
EtOH/CH2Cl2 (1:1, 5 mL). The solution was warmed to room
temperature and adjusted to pH 5 with 3 N aqueous sodium
hydroxide. A minimal amount of silica gel was added and the
J . Org. Chem, Vol. 67, No. 20, 2002 6993

Dondoni et al.
MeOH, 2 mL), and stirring was continued at room temperature
for 1 h. The solution was then neutralized with AcOH. A
minimal amount of silica gel was added and the solvent
evaporated. The compound (absorbed on silica gel) was sub-
jected to column chromatography with 1:1 cyclohexane-AcOEt
to give, following solvent evaporation, 23 (149 mg, 95%) as a
structure was solved by direct methods (SIR92) and refined
on F2 (SHELXL-97) for 464 parameters. Refinement converged
at a final wR2 value of 0.0976, R1 ) 0.0516 (for 5511
reflections with I > 2σ(I)), S ) 1.074. All non-H atoms were
refined anisotropically; the N-H and O-H hydrogen atoms
were refined isotropically; all other hydrogen atoms were
included on calculated positions, riding on their carrier atoms.
A final difference Fourier showed no residual density outside
yellow syrup. [R]2D0 ) 0.0 (c ) 1.2, MeOH). H NMR (CD3OD):
1
δ ) 7.22-7.14, 6.90-6.84, and 6.77-6.70 (3m, 4 H, Ph), 7.03
and 6.48 (2 d, 2 H, J ) 3.5 Hz, H-3Fur, H-4Fur), 5.38 (s, 1 H,
H-4), 4.58 (s, 2 H, CH2OH), 4.08 (q, 2 H, J ) 7.0 Hz, CH2-
-0.20 and 0.21 Å-3
.
CH3), 1.12 (t, 3 H, CH2CH3). MALDI-TOF MS: 375.8 (M+
+
Ack n ow led gm en t . We gratefully acknowledge
MURST and University of Ferrara for financial support.
We thank Professor G. Vertuani for the assistance in
CD spectra recording and the Department of Pharma-
ceutical Chemistry for the access to the relevant instru-
mentation.
H), 397.6 (M+ + Na), 413.8 (M+ + K). Anal. Calcd for
18H18N2O5S (374.41): C, 57.74; H, 4.85; N, 7.48; S, 8.56.
C
Found: C, 57.83; H, 4.89; N, 7.50; S, 8.65.
Treatment of dihydropyrimidinethione 22 (200 mg, 0.38
mmol) under the above conditions afforded 23 in comparable
yield.
Cr ysta l d a ta for com p ou n d (R)-17b: C40H42N2O8, Mr )
678.76, colorless crystal (0.07 × 0.26 × 0.28 mm), orthorhom-
bic, space group P212121 (no. 19) with a ) 8.7960(2) Å, b )
14.8824(3) Å, c ) 28.4846(7) Å, V ) 3728.8(2) Å3, Z ) 4, Dc )
1.209 g cm-3, 19 593 reflections measured, 8067 indipendent,
Rint ) 0.052 (2.54 < θ < 27.5°, T ) 150 K, Mo KR radiation, λ
) 0.710 73 Å) on a Nonius Kappa CCD diffractometer. The
Su p p or tin g In for m a tion Ava ila ble: CIF of compound
(R)-17b and an ORTEP plot of (R)-17b drawn at 40% prob-
ability level. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0202076
6994 J . Org. Chem., Vol. 67, No. 20, 2002