Dihydropyridine C-glycoconjugates by organocatalytic Hantzsch cyclocondensation. Stereoselective synthesis of α-threofuranose C-nucleoside enantiomers

Article abstract of DOI:10.1039/b900422j

The Hantzsch reaction of C-glycosyl aldehyde/enamino ester/β-ketoester systems under l-proline catalysis to give dihydropyridine C-glycoconjugates is reported. Asymmetric cyclocondensations of differentially substituted enamine and β-dicarbonyl components

Full text of DOI:10.1039/b900422j

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Dihydropyridine C-glycoconjugates by organocatalytic Hantzsch
cyclocondensation. Stereoselective synthesis of a-threofuranose
C-nucleoside enantiomers†
Diogo R. B. Ducatti,b,a Alessandro Massi,*a Miguel D. Noseda,b Maria Eugeˆnia R. Duarteb and
Alessandro Dondoni*a
Received 9th January 2009, Accepted 9th January 2009
First published as an Advance Article on the web 24th March 2009
DOI: 10.1039/b900422j
The Hantzsch reaction of C-glycosyl aldehyde/enamino ester/b-ketoester systems under L-proline
catalysis to give dihydropyridine C-glycoconjugates is reported. Asymmetric cyclocondensations of
differentially substituted enamine and b-dicarbonyl components with formyl a-L-C-threofuranoside
and with the a-D-isomer were also carried out. Each reaction occurred with high yet opposite
stereoselectivity (de >95%) so that the pair of a-threofuranose C-nucleoside enantiomers was prepared.
Introduction
Carbohydrate decoration of compounds possessing a firmly
established pharmacological activity such as heterocycles with
privileged structures1 and bioactive natural products2 is a well-
established paradigm of the modern drug discovery process.3
The introduction of carbohydrate fragments onto drug candidate
scaffolds is typically envisaged to improve the pharmacokinetic
and pharmacodynamic profiles of lead compounds4 without
altering their activity and selectivity. Even more significantly, this
Fig. 1 The medicinally relevant C2-glycosylated Nifedipine analogue 1
transformation may give rise to new classes of molecules with
modified and unexpected pharmacological properties due to the
unique functions exerted by carbohydrates at the molecular level.5
Research in this field has been actively carried out in one of
our laboratories over the last five years.6 Efficient syntheses of
pharmacologically active heterocycle C-glycoconjugates have been
reported, including 1,4-dihydropyridines (DHPs),7 pyridines,8
3,4-dihydropyrimidin-2(1H)-ones (DHPMs),9 and b-lactams.10
Towards this aim a set of one-pot multicomponent reactions
(MCRs) employing C-glycosylated reagents were conveniently
exploited. In particular, the Hantzsch three-component reaction
(3CR), i.e. aldehyde/b-ketoester/enamino ester cyclocondensa-
tion, was utilized to generate a collection of structurally and
stereochemically diversified 1,4-DHP C-glycoconjugates.7 One
of the goals of our synthetic efforts was the preparation of
C-glycosylated analogues of medicinally relevant DHPs such
as the C2-glycosylated Nifedipine analogue 1 (Fig. 1).11 Inter-
est in DHP C-glycosides arose also from the realization that
these compounds were new C-nucleosides displaying the 1,4-
dihydropyridine residue as the base. The C4-ribosyl derivative 2 is
an example of this class of compounds (Fig. 1).12
and the artificial C-nucleoside 2.
We also addressed the issue regarding the asymmetry of the
DHP C4 stereocenter induced by the chiral sugar moiety in one
of the reagents (b-ketoester or enamino ester). It is well known
that C4 DHP epimers often display opposite pharmacological
profiles.11 Although modest degrees of asymmetric induction
(de <50%) were registered under different conditions (thermal7
and microwave dielectric heating,8 and Yb(III)-catalysis7), the
above asymmetric multicomponent reaction (AMCR) approach13
allowed the synthesis of DHP C-glycoconjugates in a pure
stereoisomeric form. In the present paper we report on the
extension and improvement of the previous work. In particular, we
have established a novel (organocatalytic) and mild procedure for
the Hantzsch 3CR of different and rare C-glycosyl aldehydes. In
addition, we have found conditions for its execution in a fully
stereoselective manner (de >95%) to give biologically relevant
C-nucleosides which were not accessible by the previously em-
ployed procedures.7,8
Results and discussion
aDipartimento di Chimica, Laboratorio di Chimica Organica, Universita`
di Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy. E-mail: adn@unife.it,
msslsn@unife.it
The sugar derivatives to be employed in the planned Hantzsch
reactions were the C-glycosyl aldehydes 3–7, ent-3, and ent-4
shown in Fig. 2. These carbohydrate building blocks (CBBs), all
displaying the D- or L-threofuranosyl unit and one also displaying
a sulfate group, were readily available in our laboratories by partial
or complete depolymerization of red seaweed polysaccharides
(Agarose and Kappa-carrageenan).14 The presence of the sulfate
bDepartamento de Bioqu´ımica e Biologia Molecular, Universidade Federal
do Parana´, Centro Polite´cnico, CEP 81–531–990, PO Box 19046, Curitiba,
Brazil
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of compounds 11a–11e and 13, and 1H NMR spectrum of epi-11a.
See DOI: 10.1039/b900422j
1980 | Org. Biomol. Chem., 2009, 7, 1980–1986
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Table 1 Optimization of the reaction conditions for the three-component
Hantzsch cyclocondensation of aldehyde 3
Yield (%)
Entry Catalyst (equiv.) Solvent Time (h) Temp (◦C) 11a a/epi-11a b
Fig. 2 C-Glycosyl aldehydes prepared from red seaweed polysaccharides.
1c
2c
/
/
MeOH
MeOH
MeOH
MeOH
THF
CH2Cl2 48
benzene 48
MeOH
MeOH
MeOH
48
1.5
48
48
48
70
110d
25
25
25
25
25
25
25
25
25
50
25
15/-
5/-
20/5
35/-
5/-
19/10
5/-
35/-
37/-
40/-
45/-
48/5
50/-
55/-
35/5
40/-
44/-
group and threofuranosyl moiety were of great relevance for our
program toward the identification of bioactive DHP glycoconju-
gates. In fact, sulfated carbohydrates have been demonstrated to be
involved in many recognition processes,15 while chiral hydroxylated
tetrahydrofuran fragments have been identified in several bioactive
natural products.16
3c
10a (1.0)
10b (0.1)
10b (0.1)
10b (0.1)
10b (0.1)
10b (0.3)
10b (1.0)
10b (0.1)
10b (0.1)
10b (0.1)
10b (0.1)
10b (0.1)
10b (0.1)
10c (0.1)
10d (0.1)
4c
5c
6c
7c
8c
48
48
48
9c
10e
11e
12e
13f
14f
15f
16f
17f
The perbenzylated 3,6-anhydro-L-galactose aldehyde 3 was
selected as a suitable substrate for an optimization study of the
planned Hantzsch reaction. We felt that a successful approach with
this aldehyde that contained an easily epimerizable a-stereocenter
could be also applied to aldehydes 4–7. Among the many reaction
conditions that have been proposed for the execution of the
Hantzsch cyclocondensation,17 those that proved to be most
efficient in our previous investigations7,8 were selected for the
benchmark reaction of aldehyde 3, methyl acetoacetate 8, and
methyl aminocrotonate 9 (Table 1). Accordingly, this reaction was
performed using equimolar amounts of all components (entry 1)
under standard thermal conditions (MeOH, molecular sieves,
MeOH 168
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
48
48
48
2
48
48
50
110d
25
25
a Isolated yield. b Estimated yield by 1H NMR analysis. c Reactions
performed with equimolar amounts of components in the presence of
4 A MS. d Experiment run in a Biotage Initiator (temperature was
˚
measured externally by an IR sensor). e Reactions performed with equimo-
lar amounts of components without MS. f Reactions performed with
1.5 equiv. of 8 and 9 without MS.
◦
70 C, 48 h) as previously reported.7 Unexpectedly, evaporation
of the solvent afforded a complex reaction mixture, from which
the target symmetrically substituted DHP 11a was isolated in
low yield (15%). An even lower yield◦ (5%) was obtained by
microwave (MW) dielectric heating (110 C) (entry 2),8 very likely
because of substantial decomposition of aldehyde 3. Therefore, the
cyclocondensation was next performed under milder conditions
(MeOH, molecular sieves, rt, 48 h) using Yb(OTf)3 as the
promoter.7 This metal-catalyzed procedure afforded 11a in low
yield (20%) along with its epimer epi-11a (5%, entry 3). At this
stage, the use of L-proline 10b organocatalyst was envisaged to
increase the reaction output and, at the same time, preserve the
configurational integrity of the aldehyde 3 a-stereocenter. This
decision stemmed from an analysis of the original Hantzsch
reaction mechanism (Scheme 1) and previous studies on proline
catalytic activity. These demonstrated that proline is capable of
efficiently promoting Hantzsch-type reactions of simple achiral
substrates,18 and can catalyze aldol reactions of chiral a-hydroxy
aldehydes without producing a-epimerization.19 Hence, we spec-
ulated that preferential b-ketoester 8 activation by proline via
enamine II occurred in the aldol-type Knoevenagel condensation
to give adduct III (Scheme 1). Indeed, performing the model
cyclocondensation in MeOH at room temperature under L-proline
10b catalysis (10 mol%) afforded the target DHP 11a in 35% yield
without any evident epimerization as judged by 1H NMR analysis
(entry 4). This result is in agreement with the hypothesis that
enamine II is formed faster than aldehyde-derived enamine I.
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time by means of MW irradiation were met with scarce success,
with 11a recovered in lower yields along with epi-11a (entry
15). Finally, (S)-5-(pyrrolidin-2-yl)-1H-tetrazole 10c and (S)-1-(2-
pyrroldinylmethyl)pyrrolidine/TFA 10d organocatalysts proved
to be suitable promoters of the model cyclocondensation although
less effective than L-proline 10b (entries 16–17).
With the above information in hand, we extended the ap-
plication of the optimized procedure to the Hantzsch 3CR of
C-glycosyl aldehydes 4–7, ent-3, and ent-4 (Table 2). As a general
trend, we observed that the higher the complexity of the starting
aldehydes, the lower was the yield of the corresponding DHP
C-glycoconjugate 11. It is noteworthy that the availability of sugar
components with opposite stereochemistry enabled access to both
enantiomers of the target DHPs (pairs 11a/ent-11a and 11b/
ent-11b). Notably, derivatives 11b and ent-11b constitute a novel
class of artificial C-nucleosides displaying the rare threofuranoside
moiety anomerically linked to the unusual DHP heterocyclic base.
The main interest in such compounds lies in the generation of
modified sequences of (3¢→2¢)-a-L-threose oligonucleotides (TNA
oligos).20 These unnatural nucleic acid polymers feature a five-
bond backbone in place of the six-bond backbone of DNA
and RNA. Even with the shorter backbone, TNA oligos are
capable of cross-hybridizing with complementary DNA and RNA
sequences. Research on TNA oligos and their analogues is being
actively pursued in biomedicinal chemistry, as demonstrated by
the recent proposal concerning the role of TNA as an evolutionary
progenitor of RNA.21
The scope of the L-proline-catalyzed Hantzsch 3CR was then
extended to the preparation of unsymmetrically substituted
C4-glycosylated DHPs. Crucial for this study was establishing
the role of the carbohydrate residue and proline, i.e. the internal
and external chiral inductors respectively, in the formation of the
DHP C4 stereocenter. After some experimentation,22 we found
that the cyclocondensation of aldehyde 4 with 2,4-pentanedione
12 and methyl aminocrotonate 9 under L-proline 10b catalysis
(10 mol%) in MeOH at room temperature for five days afforded
the target glycosylated DHP 13 in fair yield (50%) and excellent
diastereoselectivity (de >95%; Table 3, entry 1). The same
model reaction was then performed by using D-proline 10e and
pyrrolidine/acetic acid 10f as the catalysts (entries 2–3). In both
cases, the DHP 13 was again isolated as the sole stereoisomer.
Hence, external asymmetric induction by the L-proline catalyst
was reasonably excluded while the presence of the chiral glycoside
moiety appeared to be crucial in the stereodefining step (Michael-
type addition) of the Hantzsch reaction. This was unequivocally
confirmed by the stereoselective formation of enantiomer ent-13
from the L-proline-catalyzed cyclocondensation of aldehyde ent-4
with diketone 12 and enamino ester 9 (entry 4). Unfortunately,
we have been unable so far to obtain suitable crystals of 13 or
ent-13 for X-ray structural determination and therefore the
absolute configuration at the C4 stereocenter of the DHP ring
remains unassigned.
Scheme 1 The proposed reaction pathway.
Then, according to the original Hantzsch cyclocondensation
mechanism, the reaction proceeded via Michael-type addition of
the enamino ester 9 to III to give IV, whose dehydration led to the
final product 11a.
The optimization study proceeded by considering other aspects
of the reaction, such as the use of different solvents, a higher
loading of proline catalyst, and the removal of the molecular sieves.
While the replacement of MeOH as the solvent was detrimental
(entries 5–7), the reaction was almost unaffected by increasing the
amount of catalyst (entries 8–9). On the other hand, the absence
of molecular sieves (entry 10) produced a slightly higher yield
of 11a (40% vs. 35%), which confirmed the importance of the
hydrolysis step for the catalyst turnover. A longer reaction time
(entry 11) as well as a higher temperature (entry 12) improved
the reaction outcome, although some epimerization took place
in the latter run. Thus, the best yield of 11a ◦(55%) was obtained
by performing the reaction in MeOH at 50 C for 48 h without
molecular sieves under L-proline 10b catalysis (10 mol%) and
with an excess (1.5 equiv.) of methyl acetoacetate 8 and methyl
aminocrotonate 9 (entry 14). Attempts to reducing the reaction
Conclusions
In summary, we have presented the first organocatalytic
aldehyde/b-ketoester/enamine three-component variant of the
Hantzsch reaction, which potentially allows for variation in all
positions of the DHP ring. Particularly, we have demonstrated
1982 | Org. Biomol. Chem., 2009, 7, 1980–1986
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Table 2 DHP C-Glycoconjugates prepareda
Table 2 (Contd.)
Entry
1
Aldehyde
Product (Yield)b
Entry
7
Aldehyde
Product (Yield)b
3
7
2
ent-3
a Reactions performed with 0.28 mmol of aldehyde, 8 (1.5 equiv.) and 9
(1.5 equiv.) in 1.5 mL of MeOH. b Isolated yield.
Table 3 Study of the asymmetric inductiona
3
4
4
ent-4
5
5
Entry
Aldehyde
Catalyst
Product
Yield (%)b
de (%)c
1
2
3
4
4
10b
10e
10f
10b
13
50
48
50
47
>95
>95
>95
>95
4
13
4
13
ent-13
ent-4
a Reactions performed with 0.28 mmol of aldehyde, 9 (1.5 equiv.), 12
(1.5 equiv.) in 1.5 mL of MeOH and in the presence of 4 A MS. b Isolated
˚
yield. c Estimated by 1H NMR analysis.
6
6
that the use of L-proline catalyst opened a suitable reaction
window for the Hantzsch reaction of sensitive components such
as sugar aldehydes 3–7. The procedure disclosed has been applied
to the synthesis of symmetrically and unsymmetrically substituted
DHP C-glycoconjugates of biological relevance. It is noteworthy
that the asymmetric variant occurred with high stereoselectivity
(de >95%). This is a remarkable result in view of the strict
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dependence of the biological properties of DHP-based drug
candidates on the configuration at C4 of the heterocyclic
ring.
2 H, H-4, H-6b), 3.97 (dd, 1 H, J2,3 = 5.0 Hz, H-2), 3.88 (dd, 1 H,
J5,6a = 4.8, J6a,6b = 10.5 Hz, H-6a). 13C NMR: d = 202.0, 137.5,
137.0, 128.5, 128.4, 128.3, 128.2 127.8, 127.7, 83.4, 83.0, 82.6, 82.3,
73.2, 71.9, 71.9, 71.1. MALDI-TOF MS: 471.3 (M+ + K). Anal.
Calcd for C27H28O5 (432.19): C, 74.98; H, 6.53. Found: C, 75.00;
H, 6.54.
Experimental section
Reactions were monitored by TLC on silica gel 60 F254 with
detection by charring either with sulfuric acid (conc. H2SO4/EtOH
1:9) or 0.5% orcinol in conc. H2SO4/EtOH 1:20. Flash column
chromatography was performed on silica gel 60 (230–400 mesh).
Optimized procedure for the synthesis of symmetrically substituted
DHPs 11a–e, and ent-11a,b
Optical rotations were measured at 20
2
◦C in the stated
A screw-capped vial containing a magnetic bar was charged with
the sugar aldehyde (0.28 mmol), 8 (45 mL, 0.42 mmol), 9 (48 mg,
0.42 mmol), L-proline 10b (3 mg, 0.028 mmol) and anhydrous
MeOH (1.5 mL). The mixture was vigorously stirred, degassed
in vacuo and saturated with Ar (3 ¥). The mixture was stirred at
1
solvent; [a]D values are given in 10-1 deg cm2 g-1. H (300 MHz)
and 13C (75 MHz) NMR spectra were recorded for CDCl3
solutions at room temperature unless otherwise specified. Peak
1
assignments were aided by H–1H COSY and gradient–HMQC
◦
50 C for 48 h and then concentrated. The resulting residue was
experiments. MALDI-TOF mass spectra were acquired using
a-cyano-4-hydroxycinnamic acid as the matrix. ESI MS analyses
were performed in positive or negative-ion mode with samples
dissolved in a mixture of MeCN/H2O 1:1. Aldehydes 3–7, ent-3,
and ent-4 are known compounds and were prepared as described.14
The procedure for the preparation of aldehyde 3 is herein described
as a representative example.
eluted from a column of silica gel with a suitable elution system to
give the corresponding DHP derivative.
Dimethyl 4-((R)-benzyloxy((2S,3R,4S)-3,4-bis(benzyloxy)
tetrahydrofuran-2-yl)methyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate (11a)
Column chromatography with 2:1 cyclohexane-AcOEt afforded
11a (97 mg, 55%) as a colorless syrup; [a]D = -38.0 (c 0.9, CHCl3).
Rf = 0.16 (2:1 cyclohexane–AcOEt). 1H NMR: d = 7.40–7.20 (m,
15 H), 5.60 (br. s, 1 H), 4.50, 4.47 (2 d, J = 12.0 Hz, 2 H), 4.46 (s,
2 H), 4.45 (d, J = 12.0 Hz, 1 H), 4.43 (d, J = 4.5 Hz, 1 H), 4.36 (d,
J = 12.0 Hz, 1 H), 4.03 (ddd, J = 2.5, J = 3.0, J = 5.0 Hz, 1 H),
4.00 (dd, J = 4.5, J = 2.5 Hz, 1 H), 3.96 (dd, J = 3.0, J = 9.5 Hz,
1 H), 3.83 (dd, J = 5.0, J = 9.5 Hz, 1 H), 3.81 (t, J = 4.5 Hz, 1
H), 3.62, 3.59 (2 s, 6 H), 3.36 (t, J = 4.5 Hz, 1 H), 2.30, 2.20 (2 s, 6
H); 13C NMR: d = 168.3, 146.1, 145.6, 141.1, 139.0, 138.1, 128.3,
128.2, 128.0, 127.7, 127.5, 127.2, 100.3, 99.3, 85.0, 83.3, 81.4, 74.2,
71.9, 71.4, 71.2, 51.0, 36.0, 19.6, 19.4. ESI MS: 628.5 (M + H+);
650.6 (M + Na+). Anal. Calcd for C37H41NO8 (627.28): C, 70.79;
H, 6.58; N, 2.23. Found: C, 70.88; H, 6.50; N, 2.15.
2,4,5-Tri-O-benzyl-3,6-anhydro-aldehydo-L-galactose (3)
A mixture of commercial agar23 (6.0 g), EtSH (9.0 mL), 37% HCl
◦
(3.0 mL), and MeOH (48 mL) was warmed to 60 C and stirred
at this temperature for 17 h. The mixture was then cooled to
room temperature, neutralized with 1M NaOH solution, and kept
under a nitrogen flow to remove unreacted EtSH. The mixture was
then concentrated under vacuum to give a solid residue, which
was suspended in H2O (80 mL) and then extracted with Et2O
(5 ¥ 100 mL). The combined organic phases were dried (Na2SO4)
and concentrated to give a crude extract (3.18 g) containing the
dithioacetal derivative of the hydroxy-free aldehyde 3.
To a cooled (0 ◦C), stirred mixture of the above crude material
and DMF (50 mL) was added NaH portionwise (1.92 g, 48.0 mmol
of a 60% suspension in mineral oil) and, after 30 min, benzyl
bromide (3.7 mL, 31.2 mmol). The mixture was stirred at room
temperature for 40 min, then treated with MeOH (10 mL), stirred
for an additional 10 min, diluted with H2O (80 mL), and extracted
with Et2O (3 ¥ 100 mL). The combined organic phases were dried
(Na2SO4), concentrated, and eluted from a column of silica gel
with 15:1 cyclohexane–AcOEt to give the dithioacetal derivative
of aldehyde 3 (3.8 g, 50% from starting agar)23 as a colorless syrup.
To a cooled (0 ◦C), stirred mixture of the above dithioacetal
derivative (1.22 g, 2.26 mmol), THF (4.5 mL) and Et2O (11 mL), a
solution of H5IO6 (1.03 g, 4.52 mmol) in THF (2.3 mL) was added
dropwise. The resulting mixture was warmed to room temperature,
stirred for 20 min, diluted with 1M phosphate buffer (75 mL), and
extracted with Et2O (200 mL). The organic phase was washed with
10% aqueous Na2SO3 solution (2 ¥ 50 mL), dried (Na2SO4), and
concentrated to give 3 (0.94 g, 95%) as a colorless syrup at least
95% pure as established by 1H NMR analysis. An analytical sample
was obtained by flash chromatography with 5:1 cyclohexane–
AcOEt as the eluent; [a]D = -24.4 (c 1.0, CHCl3); Rf = 0.26 (5:1
cyclohexane–AcOEt). 1H NMR: d = 9.68 (d, 1 H, J1,2 = 1.4 Hz,
H-1), 7.40–7.20 (m, 15 H, Ph), 4.74, 4.56, 4.48, 4.45, 4.43 (5 d, 6 H,
J = 12.0 Hz, PhCH2), 4.17–4.10 (m, 2 H, H-5, H-3), 4.07–4.01 (m,
Dimethyl 4-((S)-benzyloxy((2R,3S,4R)-3,4-bis(benzyloxy)
tetrahydrofuran-2-yl)methyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate (ent-11a)
Column chromatography with 2:1 cyclohexane–AcOEt afforded
ent-11a (91 mg, 52%) as a colorless syrup; [a]D = +38.5 (c 1.0,
CHCl3). Rf = 0.16 (2:1 cyclohexane–AcOEt). 1H and 13C NMR as
11a. ESI MS: 628.6 (M + H+); 650.4 (M + Na+). Anal. Calcd for
C37H41NO8 (627.28): C, 70.79; H, 6.58; N, 2.23. Found: C, 70.65;
H, 6.66; N, 2.30.
Dimethyl 4-(2¢,3¢-di-O-benzyl-a-L-threofuranosyl)-1,4-dihydro-
2,6-dimethylpyridine-3,5-dicarboxylate (11b)
Column chromatography with 3:1 cyclohexane–AcOEt afforded
11b (95 mg, 67%) as a colorless syrup; [a]D= +5.6 (c 1.9, CHCl3).
Rf = 0.33 (3:1 cyclohexane–AcOEt). 1H NMR (CDCl3): d = 7.40–
7.20 (m, 10 H, Ph), 6.00 (br., s, 1 H, NH), 4.49, (d, J = 11.5 Hz,
1 H, PhCH2), 4.45 (s, 1 H, PhCH2), 4.44 (d, J = 11.5 Hz, 1 H,
PhCH2), 4.43 (d, J1¢4 = 7.5 Hz, 1 H, H-4), 4.42 (d, J = 11.5 Hz,
1 H, PhCH2), 4.06 (dd, J1¢,2¢ = 3.5, J2¢,3¢ = 2.0 Hz, 1 H, H-2¢), 4.03
1984 | Org. Biomol. Chem., 2009, 7, 1980–1986
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(ddd, 1 H, H-3¢), 3.86, 3.85 (2 s, 2 H, H-4a¢, H-4b¢), 3.69 (dd, 1 H,
H-1¢), 3.65, 3.60 (2 s, 6 H, OCH3), 2.34, 2.30 (2 s, 6 H, CH3); 13
NMR: d = 168.7, 168.3, 146.9, 145.6, 138.5, 138.4, 128.6, 128.5,
127.9, 127.8, 127.7, 100.6, 99.5, 86.6, 84.4, 84.1, 71.7, 71.2, 52.6,
51.2, 35.9, 19.9, 19.8. ESI MS: 508.7 (M + H+); 530.6 (M + Na+).
Anal. Calcd for C29H33NO7 (507.23): C, 68.62; H, 6.55; N, 2.76.
Found: C, 68.75; H, 6.48; N, 2.71.
J = 6.5, J = 12.0 Hz, 1 H), 3.46–3.39 (m, 3 H), 3.36 (dd, J =
3.5, J = 6.0 Hz, 1 H), 2.18, 2.07 (2 s, 6 H); 13C NMR: d = 168.5,
168.4, 145.8, 145.0, 139.2, 139.1, 138.7, 138.5, 137.7, 128.5, 128.4,
128.3, 128.1, 128.0, 127.9, 127.8, 127.6, 127.4, 127.3, 127.2, 103.9,
100.3, 100.1, 86.0, 84.4, 83.1, 81.9, 80.7, 79.2, 74.7, 74.6, 74.1, 73.5,
73.4, 73.2, 73.0, 72.1, 71.1, 68.7, 51.1, 36.0, 19.5, 19.1. ESI MS:
1060.6 (M + H+) 1082.6 (M + Na+). Anal. Calcd for C64H69NO13
(1059.48): C, 72.50; H, 6.56; N, 1.32. Found: C, 72.63; H, 6.49; N,
1.28.
C
Dimethyl 4-(2¢,3¢-di-O-benzyl-a-D-threofuranosyl)-1,4-
dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (ent-11b)
Dimethyl 4-((S)-benzyloxy((2R,3S,4R)-4-(benzyloxy)-3-
((2S,3R,4R,5S,6R)-3,4-bis(benzyloxy)-6-(benzyloxymethyl)-5-
sulfate-tetrahydro-2H-pyran-2-yloxy)tetrahydrofuran-2-
yl)methyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (11e)
Column chromatography with 3:1 cyclohexane–AcOEt afforded
11b (97 mg, 68%) as a colorless syrup; [a]D= -5.4 (c 0.8, CHCl3).
Rf = 0.33 (3:1 cyclohexane–AcOEt). 1H and 13C NMR as 11b. ESI
MS: 508.9 (M + H+); 530.8 (M + Na+). Anal. Calcd for C29H33NO7
(507.23): C, 68.62; H, 6.55; N, 2.76. Found: C, 68.55; H, 6.62; N,
2.83.
Column chromatography with 15:1 AcOEt–MeOH afforded 11e
(88 mg, 30%) at least 90% pure as established by 1H NMR analysis.
Rf = 0.27 (15:1 AcOEt–MeOH). 1H NMR (acetone-d6): d = 7.90
(s, 1 H), 7.60–7.10 (m, 25 H), 5.08, (d, J = 12.0 Hz, 1 H), 5.00 (dd,
J = 2.0, J = 3.1, Hz, 1 H), 4.80, 4.70, 4.60, 4.59, 4.58 (5 d, J =
12.0 Hz, 5 H), 4.52 (d, J = 7.5, Hz, 1 H), 4.51 (d, J = 6.0, Hz,
1 H), 4.50 (d, J = 12.0 Hz, 1 H), 4.48 (s, 1 H), 4.47, 4.46 (2 d, J =
12.0 Hz, 1 H), 4.40 (dd, J = 4.5, J = 1.7 Hz, 1 H), 4.30 (ddd, J =
1.7, J = 2.5, J = 5.0 Hz, 1 H), 4.00 (dd, J = 4.2, J = 10.0 Hz,
1 H), 3.87 (dd, J = 2.5, J = 9.5 Hz, 1 H), 3.86 (t, J = 4.5 Hz,
1 H), 3.81–3.70 (m, 3 H), 3.63 (dd, J = 3.1, J = 9.5 Hz, 1 H), 3.54
(dd, J = 7.5, J = 9.5 Hz, 1 H), 3.50, 3.48 (2 s, 6 H), 3.42 (dd, J =
4.0, J = 6.0 Hz, 1 H), 2.30, 2.20 (2 s, 6 H); 13C NMR (acetone-
d6): d = 168.1, 146.4, 145.9, 139.3, 139.1, 139.0, 128.3, 128.1,
128.0, 127.9, 127.8 127.7, 127.6, 127.5, 127.1, 127.0, 126.8, 103.2,
99.5, 99.1, 85.0, 84.4, 81.7, 79.8, 78.7, 74.3 74.2, 73.6, 72.6, 71.8,
71.5, 70.9, 70.8, 70.4, 50.1, 50.0, 36.1, 17.9, 17.6. ESI MS: 1049.4
(M - H).
Dimethyl 4-((R)-benzyloxy((2S,3R,4S)-4-(benzyloxy)-3-
((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)
tetrahydro-2H-pyran-2-yloxy)tetrahydrofuran-2-yl)methyl)-
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (11c)
Column chromatography with 2.5:1 cyclohexane–AcOEt afforded
11c (110 mg, 37%) as a colorless syrup; [a]D= -11.7 (c 1.2, CHCl3).
1
Rf = 0.15 (2.5:1 cyclohexane–AcOEt). H NMR: d = 7.40–7.15
(m, 30 H), 6.00 (br. s, 1 H), 4.98, 4.84, 4.79, 4.75, 4.74, 4.66, 4.58,
4.55 (8 d, J = 12.0 Hz, 8 H), 4.49–4.42 (m, 4 H), 4.40 (d, J =
12.0 Hz, 1 H), 4.38 (d, J = 7.5 Hz, 1 H), 4.37 (d, J = 12.0 Hz,
1 H), 4.08 (ddd, J = 2.5, J = 3.5, J = 5.0 Hz, 1 H), 3.91 (dd, J =
2.0, J = 3.5 Hz, 1 H), 3.90 (dd, J = 4.5, J = 4.0 Hz, 1 H), 3.89
(dd, J = 3.5, J = 9.5 Hz, 1 H), 3.81 (dd, J = 5.0, J = 9.5 Hz, 1 H),
3.76 (dd, J = 7.5, J = 9.5 Hz, 1 H), 3.59, 3.56 (2 s, 6 H), 3.58–3.52
(m, 3 H), 3.49 (dd, J = 3.5, J = 9.5 Hz, 1 H), 3.43 (dd, J = 4.5,
J = 6.0 Hz, 1 H), 2.25, 2.17 (2 s, 6 H);13C NMR: d = 168.6. 168.4,
146.2, 145.0, 139.3, 138.6, 138.5, 138.4, 138.1, 137.5, 128.5, 128.4,
128.2, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.5, 127.4, 127.3,
127.0, 102.0, 100.0, 99.4, 83.8, 83.2, 82.9, 82.2, 81.4, 79.1, 75.1,
74.7, 74.0, 73.7, 73.5, 73.3, 73.0, 71.0, 68.7, 51.0, 50.9, 35.8, 19.2,
19.0. ESI MS: 1060.7 (M + H+) 1082.8 (M + Na+). Anal. Calcd
for C64H69NO13 (1059.48): C, 72.50; H, 6.56; N, 1.32. Found: C,
72.63; H, 6.49; N, 1.27.
Dimethyl 4-((S)-benzyloxy((2S,3R,4S)-3,4-bis(benzyloxy)-
tetrahydrofuran-2-yl)methyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate (epi-11a)
A screw-capped vial containing a magnetic bar was charged with
the sugar aldehyde 3 (121 mg, 0.28 mmol), 8 (30 mL, 0.28 mmol), 9
(35 mg, 0.28 mmol), L-proline 10b (3 mg, 0.028 mmol), molecular
sieves (~100 mg) and anhydrous CH2Cl2 (1.5 mL). The mixture
was vigorously stirred, degassed in vacuo and saturated with Ar
(3 ¥). The mixture was stirred at 25 ◦C for 48 h, filtered through a
pad of Celite, and washed thoroughly with MeOH. The combined
filtrates were concentrated and the resulting residue was eluted
from a column of silica gel with 2:1 cyclohexane–AcOEt to give
first epi-11a (16 mg, 10%) at least 70% pure as established by 1H
NMR analysis. Rf = 0.24 (2:1 cyclohexane-AcOEt). 1H NMR: d =
7.40–7.20 (m, 15 H), 5.59 (br. s, 1 H), 4.61, 4.60 (2 d, J = 12.0 Hz,
2 H), 4.54 (d, J = 5.0 Hz, 1 H), 4.51, 4.48 (2 d, J = 12.0 Hz, 2 H),
4.40 (s, 2 H), 4.25 (dd, J = 1.3, J = 3.0 Hz, 1 H), 4.04 (ddd, J =
1.3, J = 3.0, J = 5.0 Hz, 1 H), 3.94 (dd, J = 3.0, J = 5.5 Hz, 1 H),
3.89 (dd, J = 5.0, J = 10.0, 1 H), 3.87 (dd, J = 3.0, J = 10.0 Hz,
1 H), 3.69, 3.52 (2 s, 6 H), 3.49 (dd, J = 5.0, J = 5.5 Hz, 1 H),
2.29, 2.19 (2 s, 6 H). ESI MS: 628.4 (M + H+); 650.5 (M + Na+).
Eluted second was 11a (33 mg, 19%).
Dimethyl 4-((S)-benzyloxy((2R,3S,4R)-4-(benzyloxy)-3-
((2S,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)
tetrahydro-2H-pyran-2-yloxy)tetrahydrofuran-2-yl)methyl)-
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (11d)
Column chromatography with 2.5:1 cyclohexane–AcOEt afforded
11d (106 mg, 36%) as a colorless syrup; [a]D = +8.8 (c 1.2, CHCl3).
Rf = 0.15 (2.5:1 cyclohexane–AcOEt).1H NMR: d = 7.50–7.10 (m,
30 H), 5.38 (br. s, 1 H), 4.91, 4.83, 4.69, (3 d, J = 11.5 Hz, 3 H),
4.67 (s, 2 H), 4.60, 4.56, 4.52, 4.50, (4 d, J = 11.5 Hz, 4 H), 4.47
(d, J = 6.0 Hz, 1H), 4.41 (d, J = 11.5 Hz, 1 H), 4.32 (s, 2 H), 4.28
(d, J = 7.5 Hz, 1 H), 4.25 (ddd, J = 1.5, J = 2.5, J = 5.0 Hz,
1 H) 4.20 (dd, J = 5.0, J = 1.5 Hz, 1 H), 3.95 (dd, J = 2.5, J =
9.5 Hz, 1 H), 3.86 (dd, J = 2.0, J = 3.0 Hz, 1 H), 3.81 (dd, J =
5.0, J = 9.5 Hz, 1 H), 3.80 (dd, J = 3.5, J = 5.0 Hz, 1 H), 3.73
(dd, J = 7.5, J = 10.0 Hz, 1 H), 3.55, 3.52 (2 s, 6 H), 3.50 (dd,
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Methyl 4-(2¢,3¢-di-O-benzyl-a-L-threofuranosyl)-1,4-dihydro-2,
6-dimethylpyridine-3-acetyl-5-carboxylate (13)
Chem., 1999, 1, 32–45; (c) G. Wess, Drug Discov. Today, 2002, 7, 533–
535.
4 R. W. Gantt, R. D. Goff, G. J. Williams and J. S. Thorson, Angew.
Chem., Int. Ed., 2008, 47, 8889–8892.
A screw-capped vial containing a magnetic bar was charged with
the sugar aldehyde 4 (88 mg, 0.28 mmol), 12 (45 mL, 0.42 mmol), 9
(48 mg, 0.42 mmol), L-proline 10b (3 mg, 0.028 mmol), molecular
sieves (~100 mg) and anhydrous MeOH (1.5 mL). The mixture
was vigorously stirred, degassed in vacuo and saturated with Ar
(3 ¥). The mixture was stirred at 25 ◦C for 5 days, filtered through a
pad of Celite, and washed thoroughly with MeOH. The combined
filtrates were concentrated and the resulting residue was eluted
from a column of silica gel with 15:1 i-Pr2O–MeCN to give 13
(68 mg, 50%) as a colorless syrup. [a]D = +31.3 (c 0.5, CHCl3).
Rf = 0.35 (15:1 i-Pr2O–MeCN).1H NMR: 1H NMR (benzene-d6):
d = 7.33–7.00 (m, 10 H, Ph), 4.73 (d, J1¢4 = 6.0 Hz, 1 H, H-4),
4.54 (br., s, 1 H, NH), 4.45, 4.40, 4.18, 4.12 (4 d, J = 11.7 Hz, 1 H,
PhCH2), 4.06 (dd, J1¢,2¢ = 4.3 Hz, 1 H, H-1¢), 4.00 (dd, J2¢,3¢ = 1.5 Hz,
1 H, H-2¢), 3.88–3.84 (m, 2 H, H-3¢, H-4b¢), 3.70 (dd, J3¢,4a¢ = 5.6,
J4a¢,4b¢ = 10.5 Hz, 1 H, H-4a¢), 3.45 (s, 3 H, OCH3), 2.34 (s, 3 H,
COCH3), 1.92, 1.84 (2 s, 6 H, CH3); 13C NMR (benzene-d6): d =
198.3, 167.6, 145.3, 142.0, 138.5, 138.4, 128.2, 127.9, 127.7, 127.4,
109.2, 99.8, 86.6, 85.1, 83.9, 71.7, 70.8, 70.3, 50.5, 37.3, 28.9, 19.0,
18.8. ESI MS: 492.6 (M + H+); 514.7 (M + Na+). Anal. Calcd for
C29H33NO6 (491.23): C, 70.86; H, 6.77; N, 2.85. Found: C, 70.92;
H, 6.85; N, 2.80.
5 (a) A. Varki, R. Cummings, J. Esko, H. Freeze, G. Hart, and J. Marth,
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11 Nifedipine and several congeners have been introduced on the market
since the 1970s as drugs for the treatment of coronary diseases. The
continuous interest in the pharmacology of 1,4-DHPs arises from the
broad spectrum of their activities (e.g. antihypertensive, neurotropic,
antidiabetic, membrane-protecting, anticancer, antibacterial, and an-
tiviral activities). For a recent review on this topic, see: R. Lavilla,
J. Chem. Soc., Perkin Trans. 1, 2002, 1141–1156.
12 The synthesis of C-nucleosides is a current topic in medicinal chemistry
as demonstrated by the isolation and synthesis of several of these
C-glycoconjugates showing antibiotic, antiviral, and anticancer acti-
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13 D. J. Ramo´n and M. Yus, Angew. Chem., Int. Ed., 2005, 44, 1602–1634.
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2961.
Methyl 4-(2¢,3¢-di-O-benzyl-a-D-threofuranosyl)-1,4-dihydro-2,
6-dimethylpyridine-3-acetyl-5-carboxylate (ent-13)
Treatment of ent-4 (88 mg, 0.28 mmol) as described for the
preparation of 13 gave ent-13 (64 mg, 47%) as a colorless syrup.
1
[a]D = -31.1 (c 0.5, CHCl3). Rf = 0.35 (15:1 i-Pr2O-MeCN). H
and 13C NMR as 13. ESI MS: 492.8 (M + H+); 514.8 (M + Na+).
Anal. Calcd for C29H33NO6 (491.23): C, 70.86; H, 6.77; N, 2.85.
Found: C, 70.78; H, 6.60; N, 2.79.
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17 K. L. Bridgwood, G. Veitch and S. V. Ley, Org. Lett., 2008, 10, 3627–
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18 For the proline-catalyzed synthesis of polyhydroquinoline deriva-
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rya, Tetrahedron, 2007, 63, 1946–1952; (b) N. N. Karade, V. H.
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2007, 4, 16–19. For the 2-[bis(3,5-bis-trifluoromethylphenyl)trimethyl-
silanyloxymethyl]pyrrolidine-catalyzed synthesis of 2,3-substituted 1,4-
DHPs via Hantzsch-type cyclocondensation, see; (c) P. T. Franke, R. L.
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Acknowledgements
M.D.N. and M.E.R.D. are research members of the National
Research Council of Brazil (CNPq). D.R.B.D. is grateful for a
scholarship from CAPES (PDEE-CAPES, Brazil) to spend ten
months at the University of Ferrara. Thanks are given to Mr
P. Formaglio (University of Ferrara, Italy) for NMR measure-
ments. A. D. and A. M. greatly acknowledge the University of
Ferrara for financial support.
19 W. Notz, F. Tanaka and C. F. Barbas III, Acc. Chem. Res., 2004, 37,
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¨
22 The presence in the reaction mixture of molecular sieves proved to be
crucial to avoid the formation of large amounts of the symmetrically
substituted DHP 11b. This compound resulted from partial hydrolysis
of enamine 9 to b-ketoester 8 and their subsequent three-component
condensation with aldehyde 4.
23 One gram of commercial agar that has been used for this project
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1986 | Org. Biomol. Chem., 2009, 7, 1980–1986
This journal is
The Royal Society of Chemistry 2009
©