Experimental and theoretical study of a Diels-Alder reaction between a sugar-derived nitroalkene and cyclopentadiene

Article abstract of DOI:10.1016/j.carres.2010.12.006

The Diels-Alder reaction of a pyranose-derived nitroalkene 1 with cyclopentadiene is described, and the unexpected facial selectivity of the cycloaddition is analyzed by a computational study.

Full text of DOI:10.1016/j.carres.2010.12.006

Carbohydrate Research 346 (2011) 460–464
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Experimental and theoretical study of a Diels–Alder reaction between
a sugar-derived nitroalkene and cyclopentadiene
⇑
María I. Mangione, Ariel M. Sarotti, Alejandra G. Suárez, Rolando A. Spanevello
Instituto de Química de Rosario, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario–CONICET, Suipacha 531, S2002LRK Rosario, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 October 2010
Received in revised form 3 December 2010
Accepted 7 December 2010
Available online 13 December 2010
The Diels–Alder reaction of a pyranose-derived nitroalkene 1 with cyclopentadiene is described, and the
unexpected facial selectivity of the cycloaddition is analyzed by a computational study.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Nitroalkene
Diels–Alder
Sugar-derived dienophile
Computational study
1. Introduction
2. Results and discussion
The Diels–Alder (DA) reaction is one of the most studied and
widely used processes in organic synthesis. This transformation
enables the formation of carbon–carbon bonds and carbon–hetero-
atom bonds in a regio- and stereocontrolled approach, yielding six-
membered rings and a maximum of four stereogenic centers in one
step.1 The use of simple nitroalkenes as dienophiles in DA transfor-
mations has emerged as an attractive strategy in organic synthesis.
The nitro group provides dienophile activating properties, high re-
gio and stereoselectivity, and access to a wide range of functional
groups, such as amides, hydroxylamines, amines, nitrones, oximes,
nitriles, nitrile oxides, nitronates, and carbonyls.2 In addition, it is
well known that nitroalkenes can function either as dienophiles
or heterodienes in Diels–Alder reactions. The competition between
these cycloaddition types is an interesting subject, both from a the-
oretical3 and a practical4 point of view.
The synthesis of 1 was accomplished in four steps and 77% overall
yield from methyl
-glucopyranoside.6 Treatment of nitroalkene 1
a-D
with freshly distilled cyclopentadiene in toluene at 70–80 °C affor-
ded products 3 and 4 in a 1.5:1 ratio and 64% overall isolated yield
after column chromatography (Scheme 1). The reaction tempera-
ture was optimized in order to compare the reaction outcome with
other previously reported results5d and to minimize dimerization
problems of the cyclopentadiene. It was also observed by TLC that
above 100 °C undefined degradation byproducts were produced.
The structural assignments for both products were based on
spectroscopic evidence obtained from homo and heteronuclear
2D NMR studies, as well as from NOE experiments. The signal cor-
relations allowed us to assign all the protons and carbon atoms for
each isomer.
Compound 3 (a-exo) showed the following relevant NMR data:
As part of our program on the enantiospecific synthesis of
biologically important natural products using widely available
carbohydrates,5 we have synthesized methyl 4,6-O-benzylidene-
the norbornene signals appeared at 1.38 and 1.60 ppm for the
methylene protons (the first of them is in the endo-position),
3.03 and 3.86 ppm for the bridgehead protons, 6.18 and
6.44 ppm for the vinylic protons as two double doublets. The car-
bon signals of the norbornene system appeared at 48.0 ppm for
the methylene, 45.5 and 51.4 ppm for the bridgehead carbons,
and 130.9 and 141.9 ppm for the vinylic positions.
The stereochemical outcome was established through nuclear
Overhauser effect (NOE) experiments (Fig. 1): A 2.53% signal
enhancement between H-15endo/H-11 denoted the exo approach;
a 1.37% signal enhancement between H-8/H-13 and 1.80% between
2,3-dideoxy-3-C-nitro-a-D-erythro-hex-2-enopyranoside (1) as a
suitable precursor for carbocyclic systems bearing a quaternary
center.6 Nitroalkene 1 offers an excellent opportunity to determine
the role of the nitro group in the reactivity and stereoselectivity in
DA reactions using carbohydrate-derived dienophiles. The unex-
pected experimental results obtained, along with a computational
study, are reported herein.
H-8/H-14 showed the attack of the cyclopentadiene from the
face of the dienophile in the exo mode.
a-
⇑
Corresponding author. Tel./fax: +54 341 437 0477.
E-mail address: spanevello@iquir-conicet.gov.ar (R.A. Spanevello).
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.12.006

M. I. Mangione et al. / Carbohydrate Research 346 (2011) 460–464
461
Scheme 1.
dienophiles 1 or 5 can take place through four reaction channels,
depending on the approach and orientation of 2 toward the dieno-
phile, namely TS-Na, TS-Nb, TS-Xa, and TS-Xb (the transition
structures were named as follows: the first and second numbers
indicate the dienophile and diene, respectively; the N and X were
used for endo and exo orientation, and
a and b accounts for the fa-
cial approach of diene toward dienophile).
Examination of the reaction surfaces allowed us to locate the
transition structures corresponding for each mode of addition, as
shown in Figure 2. In all cases, the C2–C10 Wiberg bond indices
(WBI) are higher than the respective C3–C40 bond orders, and bond
lengths between C2–C10 are shorter than the C3–C40 distances.
Thus, in the transition structures we found that the C2–C10 bonds
are almost fully developed, while the second C3–C40 bonds are only
emerging. The computed synchronicities are, therefore, quite low
(Sy ranging from 0.74 to 0.84).
Figure 1.
Compound 4 (
a
-endo) showed the following NMR signals: the
norbornene signals appeared at 1.64 and 2.01 ppm for the methy-
lene protons, 3.20 and 3.87 ppm for the bridgehead protons, and
6.10 and 6.39 ppm for the vinylic protons. In the 13C NMR spec-
trum, the norbornene signals appeared at 48.1 ppm for the methy-
lene carbon, at 44.2 and 47.5 ppm for the bridgehead positions, and
at 138.0 and 140.5 ppm for the vinylic carbons.
IRC calculations yielded TS-Na, TS-Xa, and TS-Xb as the only
Also in this case, the stereochemical result was determined by
NOE effect: A 9.40% signal enhancement between H-15endo/H-8
established the approximation of cyclopentadiene from the a-face
of the dienophile in an endo mode, and a 0.84% signal enhancement
between H-13/H-11 corroborated the endo approach of the diene.
Based on these data, we could unequivocally identify the major
saddle points connecting reactants and products. Therefore, these
TSs correspond to a normal electron demand Diels–Alder path
leading to the corresponding [4+2] cycloadduct in a concerted
fashion. However, our calculations show that TS-1+2-Nb and TS-
5+2-Nb lead to nitronate (Int1) and vinyl-dihydropyran (Int2)
intermediates, respectively (Scheme 3).
and minor compounds 3 and 4 as the exo-
respectively.
a and endo-a adducts,
Both Int1 and Int2 correspond to a [2+4] cycloadduct, resulting
from a [2+4] heterocycloaddition. Further exploration of the poten-
tial energy surface (PES) allows one to find TS-1+2-Nb-2 and TS-
5+2-Nb-2 that implies the conversion of formal [2+4] cycloadducts
Int1 and Int2 into the formal [4+2] cycloadducts P-1+2-Nb and P-
5+2-Nb, respectively. This conversion is associated with a Claisen
rearrangement, which is a [3,3] sigmatropic shift. There are several
examples in the literature of cross-[4+2] cycloaddition reactions,
that is, a tandem hetero Diels–Alder cycloaddition/[3,3] sigmatrop-
ic shift.3 It is also important to point out that all efforts to locate
[4+2]-Nb transition structures merged in their [2+4] counterpart.
This could be attributed to the unfavorable steric interaction be-
tween H-50a and H-4 that would arise in the (hypothetically)
[4+2] TSs.
It is well documented that the
p-facial selectivity observed in
cycloaddition reactions of dienophiles structurally related to 1 is
mainly governed by steric effects.7,8 Typically, the anomeric alkoxy
group serves as an element of stereocontrol, thus leading the diene
to attack from the opposite face.7,8 Since the bicyclic dienophile 1 is
conformationally rigid, the steric hindrance produced by the
anomeric methoxy group should preclude any addition from the
a
-face of the molecule, as we observed when using similar
dienophiles.5d For instance, the reaction between aldehyde 5 with
cyclopentadiene afforded exo-b cycloadduct 6 as the only detect-
able product (Scheme 2). Similar b cycloadducts were obtained
with other sugar-derived dienophiles bearing different exocyclic
electron-withdrawing groups.7b
Calculated Gibbs free-energy activation barriers suggest that a-
However, in the DA reaction between 1 and 2, a-face selectivity
face addition should be strongly favored for the 1+2 reaction, while
the b mode of addition should be preferred for the reaction be-
tween 5 and 2. The computed endo/exo ratios are 30:70 (toluene)
and 10:90 (toluene) for the 1+2 and 5+2 systems, respectively. It
is also important to point out that the energy activation barriers
computed for both systems under study are similar in magnitude;
therefore, both 2 and 5 should display similar reactivity toward
cyclopentadiene. Although these results are in excellent agreement
with the experimental findings discussed above, we aimed to
indentify the governing factors that influence the unusual selectiv-
ity in the reaction between 1 and 2.
was observed, which constitutes a surprising and unexpected result.
We found precedents in the literature regarding the peculiar fa-
cial selectivity of this nitroalkene and also analogous vinyl sulfones
that could not explain the intriguing facial selectivity when these
compounds were used as Michael acceptors.9
These facts prompted us to undertake a theoretical investiga-
tion by performing several DFT calculations at the B3LYP/6-31Gꢀ
level of theory10 in order to understand the origins of the unex-
pected stereoselectivities observed in the cycloaddition reaction.
The Diels–Alder reactions between cyclopentadiene (2) and
The proximity between oxygen atoms Oa and Ob (Fig. 2) leads
to repulsive electrostatic interactions, which in turn might have a
crucial effect in the relative stabilization of competitive transition
O
OMe
H
O
OMe
+
xylene
80 ºC
O
O
Ph
O
Ph
O
51%
OHC
CHO
A complete computational study of the Diels–Alder reaction between 5 and 2 had
been already described using the semiempirical AM1 method.7a However, we have
recalculated the 5+2 system at the B3LYP/6-31Gꢀ level of theory in order to obtain
comparable results.
5
2
6
Scheme 2.

462
M. I. Mangione et al. / Carbohydrate Research 346 (2011) 460–464
Figure 2. Optimized geometries for the TSs of the cycloaddition reaction of cyclopentadiene with 1 and 5 with selected distances in Å and Wiberg bond indices (in
parentheses). Free energies relative to reactants in the gas phase and in solution (in parentheses) are shown in kcal molꢁ1
.
structures. The calculated Coulombic forces using the Mulliken
partial charges were in good agreement with the relative energies
between diastereomeric transition structures.à For instance, the
therefore, the energy barriers for both modes of addition are nearly
the same.
To examine whether additional electronic factors contribute to-
ward the relative stabilization between competing transition
structures, a natural bonding analysis was performed. Interest-
most stable transition structure (TS-1+2-Xa was found to exhibit
the lowest Coulombic interaction of all TSs. It is important to point
out that in the reaction between 5 and 2 the aldehyde moiety adopts
a cisoid conformation in the most stable TS located for each mode of
addition. As a consequence, the large distance between Oa and Ob
prevails over any significant Coulombic repulsion; therefore, the ob-
served b selectivity should be attributed to steric effects. However, in
ingly, the lowest energy transition structure TS-1+2-X
a exhibits
improved delocalization over that of the corresponding TS-1+2-
Xb in accordance with the predicted selectivity. In the case of TS-
5+2-Xa and TS-5+2-Xb, the analogous NBO analysis reveals similar
electronic delocalization for both TSs.
the transoid arrangement the
a
approach exhibits
a
lower
In summary, we have presented an appealing effect of inversion
Coulombic interaction as compared to that of the b approach;
of p-facial selectivity in a Diels–Alder reaction between a sugar-
derived nitroalkene and cyclopentadiene compared with other
previously studied dienophilic systems. DFT calculations have
shown that differential electrostatic interactions and electronic
à
In an effort to establish the magnitude of these interactions, we carried out
further calculations that are described in detail in the Supplementary data.

M. I. Mangione et al. / Carbohydrate Research 346 (2011) 460–464
463
Scheme 3.
delocalization operating in the diastereomeric transition structures
may be invoked, at least in part, as the origins of this unexpected
result. Finally, calculations based on Gibbs free energies of the
competing TSs correctly reproduced the experimentally observed
997, 1047, 1219, 1344, 1458, 1530 (NO2), 1541, 2363, 2859,
2994; 1H NMR (CDCl3, 200 MHz): d 1.38 (d, 1H, Jgem = 9.4 Hz, H-
15b), 1.60 (d, 1H, Jgem = 9.4 Hz, H-15a), 3.03 (br s, 1H, H-12), 3.33
(s, 3H, OCH3), 3.56 (dd, 1H, Jgem = J8,7ax = 9.6 Hz, H-7ax), 3.62 (m,
1H, H-8), 3.71 (dd, 1H, J10,11 = 8.2 Hz, J11,12 = 3.7 Hz, H-11), 3.86
(d, 1H, J1,14 = 3.2 Hz, H-1), 4.05 (d, 1H, J3,8 = 9.6 Hz, H-3), 4.21
(dd, 1H, Jgem = 9.6 Hz, J7eq,8 = 4.2 Hz, H-7eq), 5.12 (d, 1H,
J10,11 = 8.2 Hz, H-10), 5.52 (s, 1H, H-5), 6.18 (dd, 1H,
J13,14 = 5.3 Hz, J1,14 = 3.2 Hz, H-14), 6.44 (dd, 1H, J13,14 = 5.3 Hz,
J12,13 = 3.0 Hz, H-13), 7.35–7.53 (m, 5H, aromatics); 13C NMR
(CDCl3, 50 MHz): d 45.5 (C-12), 48.0 (C-15), 50.4 (C-11), 51.4
(C-1), 55.1 (OCH3), 60.6 (C-8), 69.9 (C-7), 82.5 (C-3), 97.7
(C-10), 99.4 (C-2), 102.0 (C-5), 126.1 (2C aromatics, C-ortho),
128.2 (2C aromatics, C-meta), 129.0 (1C aromatic, C-para), 130.9
(C-13), 137.1 (1C aromatic, C-ipso), 141.9 (C-14); HRFABMS:
endo/exo and p-facial selectivities.
3. Experimental
3.1. General
Melting points were taken on a Leitz Wetzlar Microscope Heat-
ing Stage, Model 350 apparatus and are uncorrected. Optical rota-
tions were recorded with a Jasco DIP 1000 polarimeter. 1D and 2D
NMR spectra were recorded on a Bruker AC-200 spectrometer with
TMS as the internal standard and CDCl3 as the solvent. Reactions
were monitored by TLC on 0.25 mm E. Merck Silica Gel 60 F254
plates using UV light (254 nm) and anisaldehyde–H2SO4–HOAc as
the developing agent. Flash column chromatography using E.
Merck Silica Gel 60H was performed by gradient elution of mixture
of n-hexane with increasing volumes of EtOAc. Reactions were run
under an argon atmosphere with dry, freshly anhyd distilled sol-
vents. Yields refer to chromatographically and spectroscopically
homogeneous materials.
calcd for
360.14490.
C
19H21NO6 [M+H+] m/z 360.14458; found m/z
3.2.2. (1S,2R,3S,5R,8R,10S,11R,12R) 10-Methoxy-2-nitro-5-phenyl-
4,6,9-trioxatetracyclo[10.2.1.02,11.03,8]pentadec-13-ene (4)
Compound 4 (18.3 mg, 21%) white crystalline solid; mp 132.0–
133.0 °C; ½a 2D0
ꢂ
ꢁ51.0 (c 0.39, CHCl3); IR (KBr,
m
max cmꢁ1): 745, 812,
1088, 1348, 1450, 1533, 1541 (NO2), 2365, 2855, 2969; 1H NMR
(CDCl3, 200 MHz): d 1.64 (ddd, 1H, Jgem = 9.9 Hz, J15b,12 = 1.7 Hz,
J15b,1 = 1.5 Hz, H-15b), 2.01 (br d, 1H, Jgem = 9.9 Hz, H-15a), 3.11
3.2. Preparation of cycloadducts 3 and 4
(dd, 1H, J10,11 = 7.9 Hz, J11,12 = 2.8 Hz, H-11), 3.20 (br s, 1H, H-
12), 3.41 (s, 3H, OCH3), 3.71 (dd, 1H, Jgem = J7ax,8 = 9.8 Hz, H-7ax),
3.83 (ddd, 1H, J8,7ax = J8,3 = 9.8 Hz, J8,7eq = 4.0 Hz, H-8), 3.87 (br s,
1H, H-1), 4.07 (d, 1H, J3,8 = 9.8 Hz, H-3), 4.36 (dd, 1H, Jgem = 9.8 Hz,
J7eq,8 = 4.0 Hz, H-7eq), 5.15 (d, 1H, J10,11 = 7.9 Hz, H-10), 5.59 (s,
1H, H-5), 6.10 (dd, 1H, J13,14 = 5.6 Hz, J1,14 = 2.7 Hz, H-14), 6.39
(dd, 1H, J13,14 = 5.6 Hz, J12,13 = 3.3 Hz, H-13), 7.35–7.56 (m, 5H,
aromatics); 13C NMR (CDCl3, 50 MHz): d 44.2 (C-12), 46.3 (C-
11), 47.5 (C-1), 48.1 (C-15), 55.5 (OCH3), 60.8 (C-8), 70.1 (C-7),
81.9 (C-3), 98.0 (C-10), 99.4 (C-2), 102.1 (C-5), 126.0 (2C aromat-
ics, C-ortho), 128.2 (2C aromatics, C-meta), 129.0 (1C aromatic, C-
para), 136.9 (1C aromatic, C-ipso), 138.0 (C-13), 140.5 (C-14);
HRFABMS: calcd for C19H21NO6 [M+H+] m/z 360.14458; found
m/z 360.14630.
Nitroalkene 1 (70.3 mg, 0.24 mmol) was dried azeotropically
with anhyd benzene and dissolved in anhyd toluene (2.4 mL) un-
der an argon atmosphere at room temperature. To this solution
freshly cracked cyclopentadiene (0.2 mL, 2.4 mmol) was added,
and the mixture was heated at 70–80 °C for 3 days. The organic sol-
vent was concentrated under reduced pressure, and the residue
was purified by flash column chromatography. Both products were
crystallized from EtOAc–hexanes.
3.2.1. (1R,2R,3S,5R,8R,10S,11R,12S) 10-Methoxy-2-nitro-5-phenyl-
4,6,9-trioxatetracyclo[10.2.1.02,11.03,8]pentadec-13-ene (3)
Compound 3 (36.6 mg, 43%); white crystalline solid; mp 160.0–
160.5 °C; ½a 2D2
ꢂ
99.6 (c 1.55, CHCl3); IR (KBr, mmax cmꢁ1): 760, 912,

464
M. I. Mangione et al. / Carbohydrate Research 346 (2011) 460–464
Reactions; Oxford University Press: New York, 1999; (c) Nicolau, K. C.; Snyder,
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1668–1698.
All density functional theory (DFT) calculations were carried out
with the B3LYP10 functional and the 6-31Gꢀ basis set,11 using
GAUSSIAN 03.12 Geometries for all structures were fully optimized,
and frequency calculations were used to confirm the nature of the
stationary points. All transition structures were confirmed to have
only one imaginary frequency corresponding to the formation of
the expected bonds. Intrinsic reaction coordinate (IRC) calculations
were performed to determine the connections between stationary
points. To analyze the formation and breaking of bonds, Wiberg
bond indices (WBIs) were calculated by using the natural bond
orbital (NBO) program13 as implemented in GAUSSIAN 03. Reported
thermochemical properties include zero-point energies (ZPEs)
without scaling and were calculated at 1 atm and 298.15 K. Free
energies in solution were computed on the structures optimized
in the gas phase with the polarizable continuum model (PCM) as
implemented in GAUSSIAN 03 with toluene as the solvent.14
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Acknowledgments
This research was supported by the Agencia Nacional de Promo-
ción Científica y Tecnológica, the Consejo Nacional de Investigaci-
ones Científicas y Técnicas, and Universidad Nacional de Rosario
from Argentina through the grants to A.G.S. and R.A.S.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.carres.2010.12.006.
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