π-Stacking effect on levoglucosenone derived internal chiral auxiliaries. A case of complete enantioselectivity inversion on the Diels-Alder reaction

Article abstract of DOI:10.1021/ol801140g

(Figure Presented) Detailed quantum chemical calculations, experimental evidence, and NMR data rationalize the participation of π-stacking interaction in the highly asymmetric Diels-Alder reaction using levoglucosenone derived internal chiral auxiliaries,

Full text of DOI:10.1021/ol801140g

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3389-3392
π-Stacking Effect on Levoglucosenone
Derived Internal Chiral Auxiliaries. A
Case of Complete Enantioselectivity
Inversion on the Diels-Alder Reaction
†
‡
†
,‡
´
Ariel M. Sarotti, Israel Ferna´ndez, Rolando A. Spanevello, Miguel A. Sierra,*
and Alejandra G. Sua´rez*,†
Instituto de Qu´ımica Rosario, Facultad de Ciencias Bioqu´ımicas y Farmace´uticas,
UniVersidad Nacional de Rosario - CONICET, Suipacha 531,
S2002LRK Rosario, Argentina, and Departamento de Qu´ımica Orga´nica, Facultad de
Qu´ımica, UniVersidad Complutense, 28040-Madrid, Spain
asuarez@fbioyf.unr.edu.ar
Received May 18, 2008
ABSTRACT
Detailed quantum chemical calculations, experimental evidence, and NMR data rationalize the participation of π-stacking interaction in the
highly asymmetric Diels-Alder reaction using levoglucosenone derived internal chiral auxiliaries, including the appealing effect of inversion
of the enantioselectivity by coordination of the substrate with Et2AlCl.
Noncovalent interactions between aromatic rings or other
unsaturated systems are claimed to be responsible for
different phenomena in organic and biological chemistry.1
Thus, it is well documented that π-π overlap may account
for highly selective transformations in the field of asymmetric
synthesis. Nevertheless, the indisputable evidence for the
participation of such an interaction in controlling the ste-
reoselectivity of organic processes has been presented only
in a few cases.23 In the context of our ongoing interest in
the development of new tools for asymmetric synthesis
derived from biomass, we have recently reported the
† Universidad Nacional de Rosario
‡ Universidad Complutense
(2) (a) Jones, G. B.; Chapman, B. J. Synthesis 1995, 475. (b) Ma, L.;
Jiao, P.; Zhang, Q.; Du, D. M.; Xu, J. Tetrahedron: Asymmetry 2007, 18,
878.
(1) Selected revisions on the differents fields: (a) Kim, K. S.; Tarakesh-
war, P.; Lee, J. Y. Chem. ReV. 2000, 100, 4145. (b) Jones, G. B. Tetrahedron
2001, 57, 7999. (c) Mu¨ller-Dethlefs, K.; Hobza, P. Chem. ReV. 2000, 100,
143. (d) Hobza, P.; Sy¨poner, J. Chem. ReV. 1999, 99, 3247. (e) Alkorta, I.;
Rozas, I.; Elguero, J. Chem. Soc. ReV. 1998, 163. (f) Ebat, T.; Fujii, A.;
Mikami, N. Int. ReV. Phys. Chem. 1998, 17, 331. (g) Saigusa, H.; Lim,
E. C. Acc. Chem. Res. 1996, 29, 171. (h) Lester, M. I. AdV. Chem. Phys.
1996, 96, 51. (i) Sun, S.; Bernstein, E. R. J. Phys. Chem. 1996, 100, 13348.
(j) Bernstein, E. R. Annu. ReV. Phys. Chem. 1995, 46, 197. (k) Hobza, P.;
Selzle, H. L.; Schlag, E. W. Chem. ReV. 1994, 94, 1767. (l) Felker, P. M.;
Maxton, P. M.; Schaeffer, M. W. Chem. ReV. 1994, 94, 1787. (m) Neusser,
H. J.; Krause, H. Chem. ReV. 1994, 94, 1829. (n) Mu¨ller-Dethlefs, K.;
Dopfer, O.; Wright, T. G. Chem. ReV. 1994, 94, 1845. (o) Klemperer, W.
Science 1992, 257, 887. (p) Brutschy, B. Chem. ReV. 1992, 92, 1567.
(3) Noncovalent π-π stacking interactions have been proposed to
influence the selectivity of Diels-Alder cycloadditions. See. (a) Miller,
G. P.; Briggs, J. Tetrahedron Lett. 2004, 45, 477. (b) Briggs, J.; Miller,
G. P. C. R. Chemie 2006, 9, 916. (c) McNeil, A. J.; Muller, P.; Whitten,
J. E.; Swager, T. M. J. Am. Chem. Soc. 2006, 128, 12426.
(4) Levoglucosenone is the major product of the pyrolysis of cellulose-
containing material: Sarotti, A. M.; Spanevello, R. A.; Su´arez, A. G. Green
Chem. 2007, 9, 1137.
(5) (a) Sarotti, A. M.; Spanevello, R. A.; Duhayon, C.; Tuchagues, J-P.;
Sua´rez, A. G. Tetrahedron 2007, 63, 241. (b) Sarotti, A. M.; Spanevello,
R. A.; Sua´rez, A. G. Org. Lett. 2006, 8, 1487. (c) Sarotti, A. M.; Spanevello,
R. A.; Sua´rez, A. G. Tetrahedron Lett. 2005, 46, 6987.
10.1021/ol801140g CCC: $40.75
Published on Web 07/17/2008
2008 American Chemical Society

synthesis of different chiral auxiliaries starting from levo-
glucosenone (1)4 and their use in Diels-Alder reactions.5
The facial selectivity of these reactions is very sensitive to
the pendant side chain group of the acrylates like 6.5b Should
this pendant substituent be the origin of the selectivity
of these reactions, compound 6 will offer a paramount
opportunity to determine the role of the π-stacking in the
asymmetric induction, by using the Diels-Alder reaction of
acrylate 6 and cyclopentadiene. The computational and
spectroscopic evidence for this effect are reported herein.
The synthetic approach toward the preparation of com-
pound 6 started with the cycloaddition reaction between 1
and 9-phenoxymethylanthracene (2) yielding only the ortho
adduct 3 under thermally driven conditions (Scheme 1). The
group.6 Additionally, a variable-temperature NMR study was
carried out between 300 and 230 K.6 Upon cooling, the
chemical shifts of the enoate hydrogens moved upfield by
0.24 (H-2′), 0.11 (H-3′trans), and 0.9 ppm (H-3′cis). Some
authors have claimed that this effect could be interpreted in
terms of a conformational equilibrium that is shifted toward
the s-trans conformer at lower temperatures.7 However, the
spectrum at 230 K did not exhibit the two groups of signals
expected for both possible conformers of 6. This observation
suggests that the barrier between the s-cis and s-trans
conformations of the R,ꢀ-unsaturated system 6 is <5 kcal/
mol and both conformations are in fast exchange on the NMR
time scale in the range of temperatures used.
Quantum chemical calculations were used to have a better
understanding about this dynamic process. Since most
popular DFT methods often fail to describe noncovalent
interactions,8 we carried out a detailed conformational study
of 6 at the RI-MP2/def2-SVP level of theory.9 The two more
stable conformations are depicted in Figure 1 being 6-s-cis
Scheme 1. Synthesis of Acrylate 6
Figure 1. RI-MP2/def2-SVP-fully optimized structures of 6. C-C
bond lengths are given in Å.
0.5 kcal/mol lower in energy than 6-s-trans. In both
optimized geometries, the acrylate and the phenoxy ring
approximately lie parallel to each other, and the distances
between them are ca. 3.2-3.3 Å.10 The H···H distances for
both isomers were consistent with the NOE experiments
performed (see Supporting Information). Similar geometries
and energy differences were computed at the M05-2X/def2-
SVP level (∆E ) 0.5 kcal/mol), which was recently
recommended by Truhlar11 to describe noncovalent interac-
tions. The calculated barrier for the s-cis/s-trans intercon-
version is low (7.1 kcal/mol at M05-2X/def2-SVP level),
which accounts for the failure to detect separate NMR signals
for the two conformers at any attainable temperature.
However, this barrier is higher than that computed for the
reduction (NaBH4, CH2Cl2-MeOH, 0 °C) of ketone 3 led
to the formation of two diastereomeric alcohols 4 and 5 (40:
60), which were easily separated by flash chromatography.
Acrylate 6 was obtained by the reaction of acryloyl chloride
with alcohol 5 in the presence of Et3N at 0 °C. All attempts
to synthesize the corresponding acrylic ester from 4 failed,
probably due to the steric hindrance surrounding the alcohol
position. Therefore, alcohol 4 was recycled by oxidation with
PCC regenerating the ketone 3 in excellent yield and
increasing the overall yield of acrylate 6.
The possibility of interaction between the acrylate moiety
and the pendant phenyl ring was examined by NMR.6 The
vinylic protons of compound 6 (6.1-5.4 ppm in CDCl3) were
shielded between 0.40 and 0.60 ppm compared to those of
analogous acrylates having pendant nonaromatic substituents
(6.5-5.9 ppm).5 This shielding effect on the hydrogen atoms
of the double bond caused by the aromatic ring due to the
anisotropy phenomena pointed to a π-stacking interaction
between the aromatic group and the acrylate double bond.1,2
The close proximity between the phenoxy group and the
enoate moiety was further confirmed by NOE experiments.
Irradiation of olefinic protons (H-2′, H-3′cis, and H-3′trans)
resulted in enhancement of ortho-hydrogens of the phenoxy
(7) (a) Mezrhab, B.; Dumas, F.; d′Angelo, J.; Richie, C. J. Org. Chem.
1994, 59, 500. (b) Dumas, F.; Mezrhab, B.; d′Angelo, J. J. Org. Chem.
1996, 61, 2293. (c) Dussault, P. H.; Woller, K. R.; Hillier, M. C. Tetrahedron
2004, 50, 8929.
(8) Grimme, S. J. Comput. Chem. 2004, 25, 1463.
(9) MP2 calculations were performed using the software package
TURBOMOLE: (a) Ahlrichs, R.; Baer, M.; Ha¨ser, M.; Horn, H.; Ko¨lmel,
C. Phys. Lett. Chem. 1989, 162, 165; within the resolution-of-identity (RI)
approximation. (b) Weigend, F.; Ha¨ser, M.; Patzelt, H.; Alhrichs, R. Chem.
Phys. Lett. 1998, 294, 143; using the def2-SVP basis set. (c) Weigend, F.;
Ahlrichs, R. Phys. Chem. Chem. Phys. 2005, 7, 3297.
(10) Similar C-C distances have been found in other π-stacked systems.
See: Yamada, S. Org. Biomol. Chem. 2007, 5, 2903.
(6) See NMR studies in Supporting Information.
(11) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157.
3390
Org. Lett., Vol. 10, No. 16, 2008

analogous system where the CH2dCH group in 6 is replaced
by a saturated ethyl group (1.9 kcal/mol at the M05-2X/
def2-SVP level), which is fully consistent with the π-stacking
proposed above.12 NBO analysis on 6-s-cis (at the M05-2X/
6-311+G*//RI-MP2/def2-SVP level) supports the proposed
π-interaction showing a two-electron stabilizing donation
from the π(CdC, phenoxy ring) orbital to the π*(CdC,
acrylate) orbital (associated second-order energy of -1.27
kcal/mol) as well as the donation from the π(CdC, acrylate)
to the π* CdC phenoxy ring orbital (associated second-order
energy of -1.10 kcal/mol).
Acrylate 6 and cyclopentadiene were reacted in the diverse
reaction conditions compiled in Table 1. All cycloadditions
Figure 2. Calculated reaction profile (B3LYP/def2-SVP+∆ZPVE)
Table 1. Thermal and Lewis Acid Promoted Cycloaddition
Reactions of 6 and Cyclopentadiene
for the reaction between 6 and cyclopentadiene. Solid lines and
dotted lines correspond to the pathways leading to the S- and
R-cycloadducts, respectively.
transformation 6-s-cisfS-adduct (1.2 kcal/mol lower than
the barrier for the transformation 6-s-transfR-adduct), in
very good agreement with the experimental findings.
The reaction between 6 and cyclopentadiene was carried
out next in the presence of Lewis acids. These reactions
produced the reversal of the stereoselectivity provided that
more than 1 equiv of aluminum Lewis acids was used in
the cycloaddition reaction (see Table 1, entries 4-9 and
Supporting Information).
To explain this result (with the concomitant increase in
the endo/exo diastereoselectivity), an extensive NMR study
was undertaken (see Supporting Information). Spectra of 6
in CDCl3 solution show a significant deshielding of H-5
(from 4.72 ppm in the absence of additive to 4.95 ppm in
the presence of 1.5 mol of Et2AlCl) and H-6 (from 3.77 ppm
in the absence of additive to 3.93 ppm in the presence of
1.5 mol of Et2AlCl). An analogous downfield shift is
observed for all the vinylic hydrogens. These findings can
only be explained by the formation of a chelated species
involving the acryloyl oxygen and the oxygen of the 1,6-
anhydro bridge. Two effects derived from this chelation must
be expected: (a) the inversion of the faces of each conformer
accessible to the diene, (b) a considerable increase in the
barrier of the isomerization of the s-cis/s-trans conformers
by the effect of the Al coordination.
Lewis acid
(equiv)
yield
endo
entry
solv. t (°C) t (h) (%)a endo/exob R/Sb
1
2
3
4
5
6
7
8
9
-
-
-
PhMe
PhMe
CH2Cl2
110
25 48
25 48
1.5 88
69:31
73:27
78:22
93:7
95:5
97:3
92:8
95:5
96:4
21:79
16:84
13:87
92:8
94:6
95:5
96:4
97:3
97:3
92
91
92
93
EtAlCl2 (2) CH2Cl2
EtAlCl2 (2) CH2Cl2 -40
EtAlCl2 (2) CH2Cl2 -80
Et2AlCl (2) CH2Cl2
Et2AlCl (2) CH2Cl2 -40
Et2AlCl (2) CH2Cl2 -80
0
1
1
1.5 85
0
1
1
1
84
81
82
a Yield corresponds to isolated products. b Determined by HPLC.
were endo diastereoselective, as predicted by the Alder endo
rule.13 The existence of two conformers in the acrylate 6
reflects the moderate selectivity in its Diels-Alder reaction
with cyclopentadiene, which increases as the temperature of
the reaction decreases. The reaction profile calculated for
both conformers of compound 6 is depicted in Figure 2. The
π-stacking with the pendant phenoxy group blocks one of
the faces of the double bond in both conformers.14 This
interaction vanishes along the reaction coordinate because
the acrylate double bond participates in the cycloaddition.
Therefore, calculations at the B3LYP level can be safely
used.15 The system follows a typical Curtin-Hammett
profile. The lowest activation barrier is found for the
To rationalize these results, the potential energy surface
of the model complex [6-Al]+ was computed. RI-MP2/def2-
SVP calculations showed that the most stable isomers of this
species are again the complexes [6-Al-s-cis]+ and [6-Al-s-
trans]+, with the latter being 1.3 kcal/mol higher in energy
(Figure 3). Both isomers present the NMR-predicted coor-
dination mode between 6 and the Lewis acid.16 Moreover,
the high value of the computed isomerization barrier at the
(12) The computed dissociation energy of the π-π complex between
anisole and methyl acrylate at the RI-MP2/def2-SVP level is 9.8 kcal/mol.
This value may be used to roughly estimate intramolecular π-stacking in
compound 6.
(13) The sense of asymmetric induction was ascertained by hydrolysis
of the adduct 7b. The absolute configuration of the 5-norbornene-2-
carboxylic acid isolated corresponded to the 2-R-enantiomer: Chang, H.;
Zhou, L.; McCargar, R. D.; Mahmud, T.; Hirst, I. Org. Process Res. DeV.
1999, 3, 289.
(15) M05-2X and B3LYP calculations were carried out using the
Gaussian03 (rev. E.01) suite of programs, Frisch M. J. et al. (Full reference
is given in the Supporting Information).
(16) [6-Al-s-cis]+ is ca. 20 kcal/mol more stable than the corresponding
monocoordinated complex.
(14) See fully optimized geometries in the Supporting Information.
Org. Lett., Vol. 10, No. 16, 2008
3391

Figure 3.
RI-MP2/def2-SVP-fully optimized structures of [6-Al]+.
C-C bond lengths are given in Å.
M05-2X/def2-SVP level (8.8 kcal/mol) is also in good
agreement with the conformational preference toward s-cis
for [6-Al]+, making this chelated species the preferred.
Therefore, [6-Al-s-cis]+ is now the reactive species which
leads to the almost exclusive formation of the R-isomer,
especially at low temperatures that secured the single
conformation state of the substrate [6-Al]+.
Figure 4. Calculated reaction profile (B3LYP/def2-SVP+∆ZPVE)
for the reaction between [6-Al]+ and cyclopentadiene. Solid lines
and dotted lines correspond to the pathways leading to the S- and
R-cycloadducts, respectively.
The calculated Diels-Alder reaction profile of [6-Al]+ and
cyclopentadiene shows that the pathway which leads to the
endo-R-adduct from [6-Al-s-cis]+ is kinetically favored, even
over the s-cis/s-trans isomerization (Figure 4). Again, the
stereochemical outcome of the reaction can be explained in
terms of the attack of the diene from the less sterically
hindered (si) enoate π-face in its s-cis conformation, which
is the inverted face compared to that of the metal-free 6-s-
cis analogue. As expected, the computed reaction barriers
are clearly lower compared to those for the uncatalyzed
processes. These results are in very good agreement with
the lower temperatures and reaction times required for these
cycloadditions (Table 1).
In summary, we have presented an appealing effect of
inversion of the enantioselectivity of the Diels-Alder
reaction by coordination of the substrate with Et2AlCl and
explained this effect by a combination of NMR and
computational methodologies. To the best of our knowledge,
this is the first report on detailed quantum chemical calcula-
tions, experimental evidence, and NMR data that provides a
key basis to rationalize the participation of a π-stacking
interaction, which sterically blocks one of the faces of the
double bond involved in the cycloaddition, in a highly
asymmetric chemical transformation.
Acknowledgment. This research was supported by grants
from CONICET and ANPCyT, Argentina, the International
Foundation for Science, Sweden, and the OPCW, The
Netherlands, to A.G.S. and R.A.S. A.M.S. thanks CONICET
and Fundacio´n Josefina Prats for the award of a fellowship.
Support from the MEC (Spain) under grants CTQ2007-
67730-C02-01/BQU, CSD2007-0006 (Programa Consolider-
Ingenio 2010), and CAM-UCM(CCG07-UCM/PPQ-2596) to
M.A.S. is acknowledged. A joint project founded by AECI-
MAE (Spain) A/010083/07 is acknowledged. I.F. is a Ramo´n
y Cajal fellow.
Supporting Information Available: Computational cal-
culation data and experimental procedures for the synthesis
1
of all compounds, characterization data, and copies of H
and 13C NMR spectra of new products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL801140G
3392
Org. Lett., Vol. 10, No. 16, 2008