The origin of stereoselectivity in cycloaddition reactions promoted by stereoisomers of 8-phenylmenthyl glyoxylate oxime

Article abstract of DOI:10.1016/j.tet.2013.03.033

A structural study of three synthesized stereoisomeric oximes, (-)-8-phenylmenthyl glyoxylate oxime (8-PMGO), (+)-8-phenylneomenthyl glyoxylate oxime (8-PnMGO), and (-)-8-phenylisoneomenthyl glyoxylate oxime (8-PinMGO), was performed by means of variable temperature ¹H NMR spectroscopy, X-ray crystallography, and ab initio calculations. It was found that in 8-PMGO a conformation where the phenyl and oxime moieties are stacked is significantly favored, whereas in the other stereoisomers this preference was not so evident. The conformational differences found between the isomers were used to rationalize the outcome of the reaction (simultaneous 1,3-cycloaddition and aza-Diels-Alder reaction) between the referred oximes and cyclopentadiene, in which the stereoselectivity was evaluated and found to be nicely reproduced by a simple conformational analysis. The global results indicate that the stereoselectivity of the studied oximes, a bit higher for 8-PMGO, originates from their particular conformational distribution, in which the phenyloxime aromatic interaction plays a decisive role.

Full text of DOI:10.1016/j.tet.2013.03.033

Tetrahedron xxx (2013) 1e10
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The origin of stereoselectivity in cycloaddition reactions promoted
by stereoisomers of 8-phenylmenthyl glyoxylate oxime
,
a
b
c
Carlos A.D. Sousa a , Carlos F.R.A.C. Lima , Mariana Andrade , Xerardo García-Mera ,
*
a,
*
ꢀ
Jose E. Rodriguez-Borges
a
~
Centro de Investigac¸ ao em Química, Department of Chemistry and Biochemistry, Faculty of Science, University of Porto, Rua do Campo Alegre,
4169-007 Porto, Portugal
b Centro de Materiais da Universidade do Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal
c Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, E-15782 Santiago de Compostela, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A structural study of three synthesized stereoisomeric oximes, (ꢀ)-8-phenylmenthyl glyoxylate oxime
(8-PMGO), (þ)-8-phenylneomenthyl glyoxylate oxime (8-PnMGO), and (ꢀ)-8-phenylisoneomenthyl
glyoxylate oxime (8-PinMGO), was performed by means of variable temperature 1H NMR spectroscopy,
X-ray crystallography, and ab initio calculations. It was found that in 8-PMGO a conformation where the
phenyl and oxime moieties are stacked is significantly favored, whereas in the other stereoisomers this
preference was not so evident. The conformational differences found between the isomers were used to
rationalize the outcome of the reaction (simultaneous 1,3-cycloaddition and aza-DielseAlder reaction)
between the referred oximes and cyclopentadiene, in which the stereoselectivity was evaluated and
found to be nicely reproduced by a simple conformational analysis. The global results indicate that the
stereoselectivity of the studied oximes, a bit higher for 8-PMGO, originates from their particular con-
formational distribution, in which the phenyl∙oxime aromatic interaction plays a decisive role.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 12 December 2012
Received in revised form 6 March 2013
Accepted 8 March 2013
Available online xxx
Keywords:
8-Phenylmenthyl glyoxylate oximes
Stereoselectivity
Chiral auxiliary
Aza-DielseAlder
1,3-Cycloaddition
Aromatic interactions
1. Introduction
diastereomeric excess. Some computational calculations6 and ex-
perimental data7 seem to sustain this interpretation. In fact, the
Since the introduction of 8-phenylmenthol as a chiral auxiliary
by Corey,1 there are not many examples of the usage of its stereo-
isomers.2 Just recently the other 8-phenylmenthol stereoisomers
have been used and proved to have potential as chiral auxiliaries in
asymmetric synthesis, particularly in aza-DielseAlder reactions.3
From the time when 8-phenylmenthol started to be used, it
exhibited excellent results as chiral auxiliary, leading to high di-
astereomeric and enantiomeric excesses in asymmetric synthe-
sis,1,2,4 this essential feature being considered to be related to its
structure.1d,5 In solution, even when it is complexed to Lewis acids,
the phenyl group of an acrylate ester of 8-phenylmenthol (as an
example) is believed to be positioned so as to allow an attractive
structures of the compounds obtained from reactions between ac-
rylate esters and dienes (as cyclopentadiene, CPD), in which
8-phenylmenthol is used as chiral auxiliary, as well as the observed
diastereoselectivities, are in agreement with the described analysis.
Nonetheless, in the cases of aza-DielseAlder reactions, in which the
dienophile is usually an imine, such interpretation is expected to be
more complex. Comparatively to acrylates, imines may adopt di-
verse conformations (e.g., s-cis/s-trans and E/Z conformations),
allowing more possible structures to exist in solution. Moreover,
such conformations may be strongly dependent on the reaction
conditions as solvent, temperature, presence of a catalyst and on
the catalyst itself. Considering this, and also the increase on the
application of the other 8-phenylmenthol stereoisomers in asym-
metric synthesis, we intended to compare and rationalize the
resulting stereoselectivity in cycloaddition reactions when those
different stereoisomers are employed as chiral auxiliaries. To do
this, (ꢀ)-8-phenylmenthyl, (þ)-8-phenylneomenthyl, and (ꢀ)-8-
phenylisoneomenthyl glyoxylate oximes (8-PMGO, 8-PnMGO, and
8-PinMGO, respectively) (Fig. 1) were structurally analyzed in so-
lution, condensed and gas phases; in addition, 8-PMGO and
8-PnMGO were reacted with CPD in order to evaluate their
interaction between the
p double bond of the acryloyl group and
the aromatic ring, which is well positioned under the acrylic ester
p
1d
ꢁ
system at a favorable stacked
As a result of this interaction, the phenyl ring blocks one of the
diastereotopic faces of the acrylic ester system, thus forcing the
pep spacing of approximately 3.5 A.
p
approach of the reactants from the other side, giving rise to a large
* Corresponding authors. Fax: þ351 220 402 659; e-mail addresses: carlos.sousa@
fc.up.pt (C.A.D. Sousa), jrborges@fc.up.pt (J.E. Rodriguez-Borges).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.033
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C.A.D. Sousa et al. / Tetrahedron xxx (2013) 1e10
phenyl ring and the glyoxylate oxime moiety in both 8-PnMGO and
8-PinMGO.
The effect of the temperature on the 1H NMR spectra was also
studied. Signals for characteristic protons of the 8-phenylmenthyl
moiety for each of the three oximes [50-CH3, 2ꢁ 80-CH3 (repre-
sented as a, b, and c, respectively), and PheHpara] were monitored,
showing negligible changes in the chemical shifts with tempera-
ture. Concerning the Himine signals of 8-PnMGO and 8-PinMGO, one
can verify that the dependence of their chemical shift with tem-
perature is very small (see Supplementary data). The plot of Dd
against T for 8-PMGO is presented in Fig. 2. In this case a significant
downfield shift of the imine proton is observed as the temperature
increases, which can be due to thermal displacement from the
Fig. 1. Structural formulas of the oximes considered in this work, and respective
abbreviations.
enantioselectivities by analyzing the obtained cycloadducts
(the isoxazolidines being the major products).8
conformation in which the intramolecular p/p stacking exists.
2. Results and discussion
2.1. Synthesis
(ꢀ)-8-phenylmenthol (1a), (þ)-8-phenylneomenthol (1b), and
(ꢀ)-8-phenylisoneomenthol (1c) were synthesized according to
the literature.3a The correspondent acrylates (2aec) were prepared
by treatment with acryloyl chloride in the presence of triethyl-
amine. The oxidative cleavage of the acrylate’s double bond
by OsO4/NaIO4 provided the respective glyoxylates (3aec).2,3d
8-PMGO, 8-PnMGO, and 8-PinMGO (4aec, respectively) were
synthesized according to a previously reported method,8 from their
respective glyoxylates by treatment with hydroxylamine hydro-
chloride in the presence of triethylamine and a catalytic amount of
DMAP (Scheme 1).
Fig. 2. Temperature dependence of the proton chemical shifts, Dd, in 8-PMGO. Legend:
- OH; ꢁ CH3 a; CH3 b; > CH3 c; þ PheHpara; C Himine
D
.
NOEs NMR were also performed for the three oximes. Some NOE
effect between Himine and the aryl protons in 8-PMGO was ob-
served. On the contrary, for 8-PnMGO and 8-PinMGO, a small NOE
signal was observed between Himine and 80-CH3 protons while no
(or a negligible) NOE signal was detected between Himine and the
aryl protons (see Supplementary data for more details).
In summary, the NMR results are consistent with the fact that in
8-PMGO the phenyl ring and the glyoxylate oxime
p system es-
tablish an intramolecular interaction; however there are no
p/p
evidences for this same interaction in 8-PnMGO and 8-PinMGO.
In view of these results we carried out an ab initio computa-
tional study in order to better understand the conformational
behavior of the studied oximes. The torsional potentials about
the dihedral angle, f1, depicted in Fig. 3 for 8-PMGO, 8-PnMGO,
and 1-(2-cyclohexylpropan-2-yl)benzene were obtained at the
SCS-MP2/cc-pVDZ level of theory.11 Since there are conformers
able to establish intramolecular aromatic interactions, which in-
volve a large fraction of dispersion forces, the use of a method
that accounts for correlation energy is mandatory. SCS-MP2/cc-
pVDZ has been employed before to yield fairly accurate results
on relatively large aromatic systems with intramolecular aromatic
Scheme 1. Procedure adopted for the synthesis of the studied oximes.
2.2. Conformational study
For each oxime, 1H NMR spectra were recorded at several tem-
peratures in CDCl3 and the chemical shifts (d) of the more signifi-
cant protons were plotted against T. All the values were scaled by
considering
d at the lower temperature as zero.
The 1H NMR spectra (see Supplementary data) show that the
Himine signal in 8-PMGO (6.79 ppm) has a high upfield shift relative
to both 8-PnMGO and 8-PinMGO (
spectively). This fact suggests the existence of a significant degree
d
¼7.45 and 7.50 ppm, re-
of
p/p stacking between the phenyl ring and the glyoxylate oxime
p
system in 8-PMGO, the upfield shift arising from the shielding
effect produced by the magnetic anisotropy of the phenyl ring.9 On
the other hand, the chemical shifts of the Himine for the other iso-
mers are similar to those of other aliphatic E aldoximes,10 which
Fig. 3. Schematic representation of the dihedral angle, f1, considered for the evalua-
tion of the internal rotation profiles in (2-cyclohexylpropan-2-yl)benzene (R¼H),
8-PMGO, and 8-PnMGO/8-PinMGO (R¼OeC(O)eC(H)]NeOH).
suggests that no significant
p/p stacking occurs between the
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C.A.D. Sousa et al. / Tetrahedron xxx (2013) 1e10
3
interactions.12 In the calculations, the C(R)eCeCePh dihedral
angle was frozen at regular intervals and the rest of the molecule
was allowed to relax. The methyl group in the position C5 of the
cyclohexane ring was not considered in the calculations, since its
influence in the equilibrium geometries and torsional potentials
is expected to be negligible, thus improving the speed of the
calculations. Without the methyl group, 8-PinMGO is the enan-
tiomer of 8-PnMGO, being molecules energetically not distin-
guishable. Hence, the calculations for 8-PnMGO also apply to the
8-PinMGO case. The results for the total electronic energies ob-
tained from the optimized structures of the selected compounds,
as well as the detailed results for the torsional potential energy
profiles, are presented in Supplementary data.
The influence of the s-cis/s-trans conformation of the imine
moiety in the torsional potentials of the titled compounds was
estimated by computing the relative energies of the respective
conformers for methyl glyoxylate oxime (R0¼CH3 in Fig. 7) at the
B3LYP/6-311þþG(d,p) and SCS-MP2/cc-pVDZ levels. Both methods
show that the conformers are nearly isoenergetic with a barrier of
interconversion of about 20 kJ molꢀ1 (further details presented as
Supplementary data), which indicates roughly equimolar equilib-
rium and rapid interconversion between the conformers at ambi-
ent temperature. However, from a practical point of view, the
extrapolation of the structures of the three oximes in gas phase (or
even in solution) for a reaction course must be careful. For example,
in a cycloaddition reaction, the presence of an acid catalyst is nor-
mally required, which may influence the structure of the oxime. In
fact, the addition of an acid catalyst as Hþ, and thus nitrogen pro-
tonation, will probably favor the s-cis conformer of the imine
moiety, since stronger H-bonds in esters commonly involve the
carbonyl oxygen instead of the alkoxy group.13 This assumption was
checked by calculating the relative energies of the nitrogen-
protonated s-cis/s-trans methyl glyoxylate oxime conformers,
showing that the s-cis isomer is favored by approximately
10 kJ molꢀ1 (details in Supplementary data).
Fig. 5. Rotation about the C(cyclohexane)eO bond leads to other minima in 8-PnMGO
(top) and 8-PMGO (bottom). The C2 conformer of 8-PnMGO is substantially less stable
than C1. In 8-PMGO the energetic distinction between C1 and C2 is not so obvious, and
thus the two conformations will be considered henceforth. Gas phase SCS-MP2/cc-pVDZ
result is presented. Some H atoms are omitted for clarity.
8-PinMGO. However, it must be noted that solvation may slightly
affect the torsional profiles, since in solution internal rotations are
generally more restricted than in the gas phase and CDCl3 has the
ability to establish CH/
p
interactions with aromatic rings.14 The
potential energy profiles for the C(R)eCeCePh torsion in the con-
sidered compounds are presented in Figs. 6e8.
Even though a complete structural study should include a full
characterization of the torsional profiles in the s-trans isomers as
well, it is assumed that the s-trans profiles will not deviate from the
s-cis ones in any considerable extent. In this way, the s-cis con-
formers were considered for full characterization of the torsional
profiles. The fact that the s-cis conformation is the one adopted in
the crystal phase of 8-PnMGO also supports our choice (see Fig. 10).
The vibrational degree of freedom corresponding to the C(cyclo-
hexyl)eO bond rotation (Fig. 5) must also be considered for a full
characterization of these systems, since it leads to additional
minima in the potential energy surfaces (PES) of 8-PMGO and 8-
PnMGO. A quick inspection of Fig. 5 shows that in 8-PnMGO the
C2 conformer is substantially less stable than C1; C1 is also the
conformation adopted in the crystal phase, further supporting this
observation. In this way, conformer C2 was not included in the
computational study. However, for 8-PMGO the energetic differ-
entiation is not so obvious and thus the C(R)eCeCePh torsional
potential was also sketched for the C2 conformation.
Fig. 6. Potential energy profile for the internal rotation about the C(R)eCeCePh
dihedral angle for 1-(2-cyclohexylpropan-2-yl)benzene, R¼H, at the SCS-MP2/cc-pVDZ
level of theory.
The gas phase computational results are, in principle, a good
approximation to solution, considering the CDCl3 solvent used in
the VT 1H NMR experiments, which should not be capable of in-
ducing significant structural changes in 8-PMGO, 8-PnMGO, and
Fig. 7. Potential energy profile for the internal rotation about the C(R)eCeCePh
dihedral angle for 8-PnMGO and 8-PinMGO at the SCS-MP2/cc-pVDZ level of theory,
considering the s-cis conformer of the imine moiety.
Fig. 4. The s-cis/s-trans isomerism in the imine moiety of the considered oximes.
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C.A.D. Sousa et al. / Tetrahedron xxx (2013) 1e10
populations of the A2 and A3 conformers, increasing the deshield-
ing effect of the A3 conformer, the A2 one having a practically null
stereochemical effect on the imine proton chemical shift. The
combination of these effects is consistent with the pronounced
deshielding of this proton as T increases, observed experimentally
by VT 1H NMR. This situation is similar for the C1 conformer.
In contrast, the near symmetric potential associated with
8-PnMGO and 8-PinMGO (Fig. 7) is in accord with the negligible
change in chemical shift with temperature for these compounds,
since the increase in T will not change significantly the conformers’
relative population. As can be seen in Fig. 9 (bottom), conformer B1
places the imine proton in a deshielding region of the phenyl ring,
while conformer B3 places it in a shielding region of the aromatic
ring current. In conformer B2 the phenyl and methyl groups are
sufficiently far away and no significant shielding/deshielding ef-
fects are expected. This implies that the observed
d (ppm) has
a shielding contribution from the B3 conformer, and a deshielding
contribution from the B1 conformer. Given the symmetry of the
derived torsional potential, conformers B1 and B3 are nearly iso-
energetic and, relative to one another, evenly populated at all T,
contributing with similar weights for the overall shielding effect
relative to the phenyl group. These two opposite effects shall nearly
cancel each other resulting in an observed chemical shift very
similar to that of a simple aldoxime, in nice agreement with the
experimental results.
It is also worth noting the nice agreement observed between the
theoretical and experimental NOE-NMR results. For 8-PMGO, the
only significant NOE effects are those consistent with the A1 and/or
A3 geometries, in agreement with the higher A1 population found in
the computational calculations. No NOE effect characteristic of the A2
geometry was observed. For 8-PnMGO and 8-PinMGO, considerable
NOE signals were observed for short contacts that are expected to
occur in all the B1, B2, and B3 conformations (see Supplementary data
for more details), in agreement with the more symmetrical torsional
potential calculated for these compounds (Fig. 7).
Fig. 8. Potential energy profile for the internal rotation about the C(R)eCeCePh
dihedral angle for the C1 (C, dotted line) and C2 (:, full line) conformers of 8-PMGO
at the SCS-MP2/cc-pVDZ level of theory, considering the s-cis conformer of the imine
moiety.
While for 8-PnMGO and 8-PinMGO (Fig. 7) this potential is near
symmetric, resembling the (2-cyclohexylpropan-2-yl)benzene case
(Fig. 6), for both the C1 and C2 conformers of 8-PMGO (Fig. 8) there
is an important asymmetry in the torsional potential that clearly
favors the A1 conformer over A2 and A3. As shown in Fig. 9 (top) for
the C2 conformer, the relative position of the phenyl group in A1 is
such that the imine proton experiences a significant shielding effect
due to the close proximity of the benzene ring current, contributing
to the upfield shift observed in NMR. By inspection of Fig. 9 one can
see that in A2 the imine proton is far away from any significant
steric effect, indicating that in this conformation the chemical shift
of this proton must be very similar to the imine group alone. In
contrast, in A3, the imine proton is in a deshielding region relative
to the benzene ring current. In this way, as T increases, the mole-
cules will have a lower average population of the A1 conformer,
diluting the shielding effect felt in this conformation, but higher
In Fig. 10 is presented the X-ray crystal structure of 8-PnMGO
(4b).15 As can be seen, the molecular structure corresponds ap-
proximately to the optimized B2 minimum geometry obtained in
the gas phase computational calculations.
Fig. 10. A view of (þ)-8-phenylneomenthyl glyoxylate oxime (4b)15 showing the
atom-labeling scheme. Displacement ellipsoids are drawn at the 50% probability level.
The carbonyl C]O and imine C]N moieties are in the s-cis type
conformation, whereas the hydroxyl group has E configuration.
In addition to the OeH/O relatively strong intermolecular in-
teractions, the molecules of 8-PnMGO are linked by intermolecular
Fig. 9. Optimized geometries at the SCS-MP2/cc-pVDZ level for the minima of the C2
conformer in 8-PMGO (top) and for the minima of 8-PnMGO (bottom). Some hydro-
gens are omitted for clarity. The pictures emphasize the relative orientation between
the imine and phenyl groups.
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C.A.D. Sousa et al. / Tetrahedron xxx (2013) 1e10
5
p
ime
/
p
interactions between the phenyl ring and the glyoxylate ox-
In this work, the cycloaddition reactions between 8-PMGO/8-
PnMGO and CPD were performed according to our method,8 as
represented in Scheme 2, using BF3 or Hþ (trifluoroacetic acid, TFA)
as catalysts at ꢀ20 ꢃC. Table 1 summarizes the results in terms of
total yield, selectivity for the 1,3- over the 1,4-cycloaddition
(aza-DielseAlder) and the ratio of the two diastereoisomers of 11
(a or b) obtained from the cycloaddition reaction. The cycloaddition
reaction with 8-PinMGO (4c) was not performed because
8-phenylisoneomenthol (1c) is a minor product in the synthesis of
8-phenylmenthol isomers, and the application and evaluation of 1c
as chiral auxiliary was already described for aza-DielseAlder re-
actions in terms of its enantioselectivity.3g
p system, leading to the formation of [001] chains, as depicted
in Fig. 11. The existence of the intermolecular
8-PnMGO is a strong proof that these two
p/p
interaction in
p
systems can indeed
interact favorably, thus supporting the existence of its intra-
molecular counterpart in 8-PMGO and 8-PnMGO/8-PinMGO.
8-PinMGO is structurally very similar to 8-PnMGO, the only differ-
ence being the equatorial position of the corresponding C3B methyl
group. In 8-PinMGO, the mentioned methyl group will lie partially
over the glyoxylate oxime
mation of the intermolecular
of a neighboring molecule. These observations can be related with
the lower tendency to crystallize observed for 8-PinMGO.
p
system and possibly preclude the for-
interaction with the phenyl ring
p/p
Table 1
Total yield (
h), regioselectivity, and 1,3-cycloaddition diastereoselectivity obtained
for the reactions between 4a,4b and CPD
Entry
Oxime
Cat.
htotal/%
Selectivity (%)
1,3 vs 1,4
Selectivity (%)
a
11/110
cycloadditiona
1
2
3
8-PMGO
d
db
40
32
d
60
80
d
TFA
BF3
91/09
80/20
4
5
8-PnMGO
TFA
BF3
38
36
60
75
78/22
73/27
a
Values determined from 1H NMR analyses of the mixture of the obtained
adducts.
b
Traces of 11a were detected by 1H NMR analysis.
As in the previously reported cycloaddition between 5 and CPD,8
the total yield of the reaction was moderate, the starting material
being partially recovered. In the same way, the 1,3-cycloaddition
was preferred over the 1,4-cycloaddition, in particular when BF3
was used as catalyst. Only the asymmetric induction of the
1,3-cycloaddition reaction was evaluated, as the aza-DielseAlder
adducts 9 and 10 (a or b) were clearly the minor products over 11
(see Supplementary data). Hence, for each performed reaction, the
diastereoisomeric ratios 11a/110a or 11b/110b were quantified by 1H
NMR analysis of the reaction mixture.
Fig. 11. Part of the crystal structure of 8-PnMGO. Dashed line shows the
p/p
interaction between the phenyl ring and the glyoxylate oxime
p system (the distance
ꢁ
between centroids is 3.791 A), creating a chain along the [001] direction. H atoms are
omitted for clarity.
2.3. Cycloaddition reactions
Considering the structures of 8-PMGO and 8-PnMGO in CH2Cl2
solution in the presence of a catalyst as TFA (Hþ), one can ratio-
nalize the outcome of the cycloaddition reaction according to
Scheme 3. The presence of a catalyst as BF3 leads to comparable
results, the 11/110 selectivity being slightly lower. This result agrees
well with the previously reported mechanism, which states that
BF3 coordinates to the oxygen atom of the hydroxyl group pro-
moting a prototropic displacement of the hydroxyl hydrogen to the
nitrogen atom, forming a BF3enitrone complex.8b So, in practical
terms, the use of either Hþ or BF3 results in the N-protonation of the
oxime, thus stabilizing the s-cis conformation by about 10 kJ molꢀ1
due to the formation of an intramolecular hydrogen bond with the
carbonyl oxygen.8b In the case of 8-PMGO, CPD will effectively
approach by the sterically unobstructed Re face of the nitrogen
trigonal atom, affording (ꢀ)-8-phenylmenthyl (1S,4S,5S)-(2-oxa-3-
azabicyclo[3.3.0]oct-7-ene)-4-carboxylate (11a) as major product.
Similarly, CPD efficiently approaches by the sterically unhindered Si
face of 8-PnMGO, giving (þ)-8-phenylneomenthyl (1R,4R,5R)-(2-
oxa-3-azabicyclo[3.3.0]oct-7-ene)-4-carboxylate (11b) as the
major diastereoisomer. Despite only the products of the
1,3-cycloaddition were considered and properly quantified and
characterized, the stereochemistry of the minor adducts that result
from 1,4-cycloaddition may be analogously rationalized. The ste-
reochemistry of the identified aza-DielseAlder adducts, as well as
the comparative quantification when each catalyst was employed,
are presented in Supplementary data.
The cycloaddition reactions are among the most important tools
for synthesis in organic chemistry, being crucial for the preparation
of natural products and biologically active substances. N-Func-
tionalized isoxazolidines have been prepared from 1,3-dipolar cy-
cloadditions between nitrones and alkenes,16e18 and their
derivatives may possess antifungal,19 antibacterial,20 and antiviral
activities.21 The preparation of non-functionalized isoxazolidines
was previously reported.8,22 A detailed mechanistic study on the
cycloaddition reaction between CPD and methyl glyoxylate oxime
(5) under acid catalysis, affording a mixture of the aza-DielseAlder
reaction products [exo and endo isomers of (ꢂ)-2-hydroxy-2-
azabicyclo[2.2.1]hept-5-ene-3-carboxylate, 6 and 7, respectively]
and the 1,3-cycloaddition adduct [methyl (1RS,4RS,5RS)-(2-oxa-3-
azabicyclo[3.3.0]oct-7-ene)-4-carboxylate, 8], was also reported
(Scheme 2) by our research group.8b
Scheme 2. Cycloaddition reaction between methyl glyoxylate oxime (5) and CPD,
under acid catalysis. 8-PMd(ꢀ)-8-phenylmenthyl; 8-PnMd(þ)-8-phenylneomenthyl.
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C.A.D. Sousa et al. / Tetrahedron xxx (2013) 1e10
these approximations, the statistical population of each conformer,
pi, was calculated using the Boltzmann equation:
X
pi ¼ expðꢀEi=RTÞ=
fexpðꢀEi=RTÞg
(1)
where the temperature, T, used was equal to the experimental
conditions (T¼253 K), R is the ideal gas constant, and Ei is the rel-
ative energy of each conformer, i, calculated by superimposing
D
E(s-cis/s-trans) for R0¼CH3 to all minima presented in Figs. 7 and
8. The calculated statistical distributions for 8-PMGO and 8-PnMGO
using TFA as catalyst are presented in Tables 2 and 3, respectively.
The results using no catalyst and using BF3 as catalyst are presented
in the Supplementary data.
Table 2
Calculated statistical distribution of all relevant conformers of 8-PMGO, at T¼253 K,
considering TFA as the catalyst
Conformer
C1
Erel/kJ molꢀ1
pi/%
11/110 Selectivity
efficiency
A1 cis
A1 trans
A2 cis
A2 trans
A3 cis
A3 trans
7.5
17.8
14.1
24.4
17.1
27.4
2.5
0.0
0.1
0.0
0.0
0.0
0/100
100/0
50/50
50/50
33/67
67/33
Scheme 3. Representation of the CPD approach to the oximes 4a (8-PMGO) and 4b
(8-PnMGO) to afford the respective 1,3-cycloadducts. From the usage of BF3 as catalyst
would result a similar figure, the BF3 substituting the hydroxyl’s group hydrogen.
C2
A1 cis
A1 trans
A2 cis
A2 trans
A3 cis
A3 trans
0.0
10.3
6.5
16.8
6.5
88.6
0.7
4.0
0.0
4.0
0.0
100/0
0/100
50/50
50/50
67/33
33/67
16.8
It was verified that some of the obtained diastereoisomers
possess identical Rf in various eluents, which makes their separa-
tion a rather difficult task. Therefore, some of the compounds were
characterized as a mixture of two pairs of diastereoisomers. By this
reason, along with the fact of being minor adducts, their precise
quantification was not possible.
In what concerns the possible E/Z isomerization relative to the
oxime moiety, it seems realistic to assume that E conformation is
preferred, in particular in solution and crystal phases; in fact, this
preference is quite standard for glyoxylate derived oximes.8,23
Nevertheless, the hypothetical E/Z isomerization occurring with
cycloaddition reactions would be irrelevant, since the nitrogen
atom in the final adduct exists as a tertiary amine capable of un-
dergoing inversion of the lone pair of electrons to achieve the most
stable conformation.
Table 3
Calculated statistical distribution of all relevant conformers of 8-PnMGO, at
T¼253 K, considering TFA as the catalyst
Conformer
Erel/kJ molꢀ1
pi/%
11/110 Selectivity
efficiency
C1
B
B
B
B
B
B
1 cis
1 trans
2 cis
2 trans
3 cis
3 trans
0.0
10.3
2.5
12.8
0.5
47.4
0.4
14.4
0.1
37.4
0.3
67/33
33/67
50/50
50/50
100/0
0/100
10.8
Based on the computational study presented in Section 2.2, the
11/110 stereoselectivity (Table 1) can in principle be reproduced on
quantitative terms. For that, the relative populations of all relevant
stable conformations of 8-PMGO and 8-PnMGO/8-PinMGO need to
be known. However, since the reaction takes place after pro-
tonation of the oxime’s nitrogen (either directly by TFA or indirectly
by BF3) the resulting protonated species must be considered. Since
a full conformational study is still a hard task to perform adequately
on these relative large molecular systems, the following approxi-
mations were employed: (1) the conformational distributions as-
sociated to the potential energy profiles for internal rotation about
the C(R)eCeCePh dihedral for the C1 conformer of 8-PnMGO
(Fig. 7), and the C1 and C2 conformers of 8-PMGO (Fig. 8) were
assumed to be unchanged after protonation; (2) the s-cis/s-trans
equilibrium presented in Fig. 4 for the protonated species were
evaluated based on the calculations performed for R0¼CH3 (with
and without BF3 coordinated to the hydroxyl’s oxygen). These as-
sumptions are valid if after protonation the reaction takes place
relatively fast, allowing only s-cis/s-trans interconversion to occur
and preventing the slower interconversions connected by the
C(R)eCeCePh dihedral angle. Moreover, one must assume that the
s-cis/s-trans equilibria are independent of R0 (Fig. 4). Considering
As can be inferred from the molecular geometries presented in
Fig. 9, each conformer is more or less effective in inducing stereo-
selectivity. For instance, in A1 the Si face of the oxime is almost
completely blocked by the phenyl ring, virtually excluding the
possibility of a CPD attack from that side. In A2 neither face is
blocked, hence no stereoselectivity is expected from this con-
former. A Re/Si selectivity for the CPD approach (and consequently
the formation of 11/110) of 100/0 and 50/50 was assumed to each
case, respectively. However, for conformers A3 and B1 there is an
intermediate selectivity, one face being only partially blocked by
the phenyl ring. For these cases, the CPD approach for the attack
from the unobstructed face was assumed to be twice as probable as
from the more obstructed one, which gives a selectivity of 67/33.
Although this is only a rough approximation, we believe that it is
a reasonable value: in the A3 and B1 conformers (Fig. 9) nearly a half
of one face of the glyoxylate oxime
p system is blocked by the
phenyl ring. The sum-product of pi and 11/110 selectivity efficiency
then yields the expected total stereoselectivity of 8-PMGO and
8-PnMGO. Table 4 presents the calculated selectivity for 11 asso-
ciated to these compounds when TFA and BF3 were used as cata-
lysts. The calculated 11 selectivity that would be expected if no
catalyst was used is also presented for comparison.
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C.A.D. Sousa et al. / Tetrahedron xxx (2013) 1e10
7
Table 4
were measured on a conventional thermostated polarimeter using
a sodium lamp. Elementary analyses were obtained on a micro-
analyser apparatus.
Experimental and calculated 11 selectivity associated to 8-PMGO and 8-PnMGO
using no catalyst, and TFA and BF3 as catalysts
Oxime
Catalyst
11 Selectivity
4.2. NMR spectroscopy
Experimental
Calculated
8-PMGO
d
d
91
80
37
93
76
NMR analyses were performed in a Bruker Avance III 400,
equipped with a 5 mm broad band observe (bbo) probe, using
TMS as internal standard for 1H and 13C, and NH3 for 15N nucleus
TFA
BF3
8-PnMGO
d
d
78
73
42
77
66
(
15N chemical shifts were recorded as HMBC). Low temperatures
TFA
BF3
were achieved by cooling the sample in the probe by means of
flowing vapor of liquid nitrogen. Temperature calibrations were
performed with a 4% MeOH in MeOD-d4 solution. The overall
uncertainty associated with the temperature measurements is
estimated as ꢂ1 K. NMR analysis of 2b was performed in a Bruker
AMX 300.
Table 3 shows that this simple conformational analysis does
a good job on quantitatively predicting the stereoselectivity in
cycloaddition reactions using 8-PMGO and 8-PnMGO/8-PinMGO
as chiral auxiliaries. The calculated 11/110 selectivities must be
treated with care since some important approximations, which
may not exactly hold, were considered in our methodology.
However, this study points out that stereoselectivity in these
systems is crucially linked to conformational distribution, which in
turn is dictated by intramolecular interactions. The use of catalysts,
such as TFA or BF3 can have an important influence on confor-
mational distribution. For instance, without protonation of the
oxime’s nitrogen, the s-cis conformer would not be favored to any
significant extent, and thus a lower stereoselectivity would be
expected. The lower 11 selectivity using BF3 can be explained by
4.3. Computational details
All theoretical calculations were performed using the Gaussian
03 software package.24 The full and partial geometry optimizations
for 1-(2-cyclohexylpropan-2-yl)benzene, 8-PMGO, and 8-PnMGO
were performed using the MollerePlesset perturbation theory
with a second order perturbation (MP2) and the correlation con-
sistent basis set cc-pVDZ.
4.4. X-ray crystallography
the fact that
D
E(s-cis/s-trans) is of 10.3 kJ molꢀ1 for TFA and of
only 3.0 kJ molꢀ1 for BF3. For 8-PinMGO, a selectivity efficiency
similar to 8-PnMGO is expected, but with the opposite stereo
configuration.
Crystals of 8-PnMGO were obtained by slow evaporation of
a dichloromethane/methanol solution. Data collection, cell re-
finement, and data reduction were made with the software package
of a Bruker AXS APEX II-CCD area detector diffractometer. Absorp-
tion correction was performed with SADABS.25 The structure was
solved using the software SIR9726 and refined with SHELXL97.27
Molecular graphics were produced by ORTEP,28 MERCURY,29 and
PLATON.30 The complete set of structural parameters in CIF format is
available as an Electronic Supplementary Publication from the
Cambridge Crystallographic Data Centre (CCDC 787450).15 In-
formation about crystal data, data acquisition conditions, and re-
finement parameters are presented in Supplementary data. All
H atoms were found in a differential Fourier map and placed geo-
metrically idealized and constrained to ride on their parent atoms
3. Conclusions
The establishment of the structures of the titled compounds in
solution is of great assistance for the prediction and interpretation
of the outcome of asymmetrical synthesis in which the stereoiso-
mers of 8-phenylmenthol are employed as chiral auxiliaries. From
this study we conclude that 8-PMGO and 8-PinMGO block the Si
face (regarding the trigonal nitrogen atom) of the glyoxylic moiety
and 8-PnMGO hinders the Re face; additionally, Si face is expected
to be more efficiently blocked if (ꢀ)-8-phenylmenthol is preferred
over (ꢀ)-8-phenylisoneomenthol.
ꢁ
[CeH¼0.95e1.00 A and Uiso(H)¼1.2 and 1.5 Ueq(C)].
The prediction of the cycloadduct’s stereochemistry in asym-
metrical aza-DielseAlder reactions, based on the combination of
these findings with the knowledge of the reaction mechanism, is in
complete agreement with experimental results involving glyoxylate
imines derived from stereoisomers of 8-phenylmenthol.3f,g In this
particular work we were able to qualitatively and quantitatively
predict the stereochemistry of both 1,3- and 1,4-cycloaddition of
CPD with glyoxylate oximes derived from stereoisomers of
8-phenylmenthol with excellent accuracy.
4.5. Mass spectrometry
ESI-MS analyses were performed on a liquid 35 chromatography
Finnigan Surveyor equipment, coupled to a mass detector Finnigan
LQC DECA XP MX with an API and an ESI interface. HRMS were
performed by ESI-TOF analyses on a Bruker Microtof equipment
coupled to an HPLC Agilent 1100.
4.6. Synthesis
4. Experimental
4.1. General
4.6.1. General procedure for the synthesis of 2aec. To a solution of
pure 1a (0.76 g, 3.2 mmol) in dry dichloromethane (10 ml) under
argon atmosphere, a catalytic amount of DMAP (ca. 5%) and trie-
thylamine (0.92 ml, 6.6 mmol) were added. The solution was placed
into an ice bath and a solution of acryloyl chloride (0.54 ml,
6.6 mmol) in dry dichloromethane (4 ml) was slowly added. The
mixture was left to react during 3 h in an ice bath. After addition of
water (20 ml), the phases were separated and the aqueous layer
was extracted with dichloromethane (3ꢁ20 ml). The organic layers
were dried over anhydrous Na2SO4, filtered and the solvent re-
moved at reduced pressure. After flash chromatography (SiO2),
All reactions were carried out under anhydrous conditions.
Solvents were dried according to standard procedures and distilled
prior to use. All reagents were commercially available and used
without further purification, unless otherwise stated. Flash column
ꢁ
chromatography was performed on silica gel (60A,,230,240 mesh)
and analytical thin-layer chromatography (TLC) on pre-coated silica
gel 60 F254 plates using iodine vapor and/or UV light (254 nm) for
visualization. Melting points were determined on an electrother-
mal melting point apparatus and are uncorrected. Optical rotations
a yellow oil 2a was obtained (
h¼89%). Similar procedure was
Please cite this article in press as: Sousa, C. A.D.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.033

8
C.A.D. Sousa et al. / Tetrahedron xxx (2013) 1e10
adopted for the synthesis of 2b (
corresponding alcohols.
h
¼87%) and 2c (
h
¼85%) from the
4.6.3.2. 8-PMGO (4a). 1H NMR (400 MHz, CDCl3):
OH), 7.11e7.29 (m, 4HPh), 7.10e7.15 (m, 1H, Hpara), 6.79 (s, 1H,
d
¼9.91 (br s,
H
imine), 4.98 (dt, J¼10.7, 4.5 Hz, 1H, H18-PM), 2.04e2.13 (m, 1H),
4.6.1.1. (1R,2S,5R)-5-Methyl-2-(2-phenylprop-2-yl)cyclohexyl ac-
rylate (2a). 1H NMR (400 MHz, CDCl3):
1.86e1.94 (m, 1H), 1.76e1.83 (m, 1H), 1.63e1.71 (m, 1H), 1.41e1.55
d
¼7.21e7.29 (m, 4HPh), 7.0e
(m, 1H), 1.23 and 1.31 (2s, 6H, 80-(CH3)2), 0.90e1.20 (m, 4H), 0.88 (d,
7.13 (m, 1H, Hpara), 5.96e6.05 (m, 1H, CH]CHaHb), 5.54e5.62 (m,
2H, CH]CHaHb and CH]CH2), 4.86 (dt, J¼10.7, 4.4 Hz, 1H, H18-PM),
1.30 and 1.22 (2s, 6H, 80-(CH3)2), 0.86 (d, J¼6.5 Hz, 3H, 50-CH3),
2.00e2.09 (m, 1H), 1.88e1.95 (m, 1H), 1.60e1.71 (m, 2H), 1.42e1.54
J¼6.5 Hz, 50-CH3); 13C NMR (100 MHz, CDCl3):
¼161.2 (COO), 151.1
d
(Cipso), 141.7 (C]N), 128.0 (CPh), 125.3 (CPh), 125.1 (Cpara), 75.5
(C18-PM), 50.4, 41.4, 39.5, 34.3, 31.2, 28.5, 26.3, 24.0, 21.7; 15N NMR
(40 MHz, CDCl3):
d
¼396; ESI-TOF: calculated for [C18H26NO3þNa]þ
(m, 1H), 0.90e1.16 (m, 3H). 13C NMR (100 MHz, CDCl3):
d
¼165.4
(MþNaþ) 326.17, found 326.1724; [
a]
ꢀ1.5 (c 1, CHCl3);
22
D
(COO), 151.5 (Cipso), 129.9 (C3), 128.9 (C2), 128.0 (CPh), 125.4 (CPh),
125.0 (CPh), 74.5 (CH), 50.5 (CH), 41.6 (CH2), 39.7 (C80), 34.6 (CH2),
31.3 (CH), 27.5 (80-CH3), 26.6 (CH2), 25.3 (80-CH3), 21.8 (50-CH3);
4.6.3.3. 8-PnMGO (4b). 1H NMR (400 MHz, CDCl3):
OH), 7.45 (s, 1H, Himine), 7.25e7.30 (m, 4HPh), 7.15e7.20 (m, 1H,
d¼9.30 (br s,
ESI-MS: calculated for [C19H26O2þH]þ (MþHþ) 287.19, found
Hpara), 5.07 (s, H18-PnM), 1.89e1.93 (m, 1H), 1.72e1.79 (m, 1H),
25
287.52; [
a
]
ꢀ9.5 (c 1, CHCl3).
1.55e1.70 (m, 5H), 1.33 and 1.34 (2s, 6H, 80-(CH3)2), 1.00e1.08 (m,
1H), 0.89e0.92 (m, 1H), 0.81 (d, J¼6.6 Hz, 3H, 50-CH3); 13C NMR
D
4.6.1.2. (1S,2S,5R)-5-Methyl-2-(2-phenylprop-2-yl)cyclohexyl ac-
rylate (2b). 1H NMR (300 MHz, CDCl3):
(dd, J¼17.3, 1.5 Hz, 1H, CH]CHaHb), 6.08 (dd, J¼17.3, 10.4 Hz, 1H,
CH]CH2), 5.80 (dd, J¼10.4, 1.5 Hz, 1H, CH]CHaHb), 5.04 (s, 1H,
H18-PnM), 1.53e1.97 (m, 6H, CH2), 1.35 (s, 6H, 80-(CH3)2), 0.84 (d,
(100 MHz, CDCl3):
d¼162.5 (COO), 149.9 (Cipso), 142.8 (C]N), 129.0
d¼7.16e7.30 (m, 5HPh), 6.35
(CPh), 126.9 (CPh), 126.7 (Cpara), 74.2 (C18-PnM), 52.1, 40.9, 40.6 (CH2),
36.1 (CH2), 28.0, 27.6, 26.9, 23.2 (CH2), 22.0; 15N NMR (40 MHz,
CDCl3):
d
¼396; ESI-MS: calculated for [C18H26NO3þH]þ (MþHþ)
304.26, calculated for [C18H26NO3þNa]þ (MþNaþ) 326.17, found
J¼6.3 Hz, 3H, 50-CH3). 13C NMR (75 MHz, CDCl3):
d
¼165.6 (COO),
304,28 and 326.25; [
a
]
24 þ47.0 (c 1, CHCl3); mp¼119e121 ꢃC.
D
149.8 (Cipso), 130.5 (C3), 129.8 (C2), 128.4 (CPh), 126.4 (CPh), 126.0
(CPh), 71.9 (CH), 51.7 (CH), 40.3 (C8), 35.8 (CH2), 30.2 (CH2), 27.3
4.6.3.4. 8-PinMGO (4c). 1H NMR (400 MHz, CDCl3):
s, OH), 7.50 (s, 1H, Himine), 7.30e7.33 (m, 4HPh), 7.18e7.25 (m, 1H,
d¼10.10 (br
(80-CH3), 27.1 (80-CH3), 26.5 (CH), 22.9 (CH2), 22.5 (50-CH3); ESI-MS:
25
calculated for [C19H26O2þH]þ (MþHþ) 287.19, found 287.56; [
þ53.1 (c 1, CHCl3).
a
]
Hpara), 5.05 (s, H18-PinM), 1.80e2.00 (m, 4H), 1.45e1.70 (m, 5H), 1.38
D
and 1.39 (2s, 6H, 80-(CH3)2), 1.02 (d, J¼7.4 Hz, 3H, 50-CH3); 13C NMR
(100 MHz, CDCl3):
d
¼162.3 (COO), 149.8 (Cipso), 143.1 (C]N), 129.0
4.6.1.3. (1R,2R,5R)-5-Methyl-2-(2-phenylprop-2-yl)cyclohexyl
acrylate (2c). 1H NMR (400 MHz, CDCl3):
(CPh), 126.9 (CPh), 125.6 (Cpara), 74.7 (C18-PinM), 52.3; 41.1, 37.1 (CH2),
d¼7.18e7.44 (m, 5HPh),
33.0 (CH2), 28.2, 27.0, 26.5, 21.2, 18.24 (CH2); 15N NMR (40 MHz,
6.35 (dd, J¼17.4, 1.4 Hz, 1H, CH]CHaHb), 6.09 (dd, J¼17.4, 10.4 Hz,
1H, CH]CH2), 5.83 (dd, J¼10.4, 1.4 Hz, 1H, CH]CHaHb), 5.00 (s, 1H,
H18-PinM), 1.45e1.98 (m, 6H, CH2), 1.35 and 1.36 (2s, 6H, 80-(CH3)2),
CDCl3):
326.17, found 326.1724; [
d
¼398; ESI-TOF: calculated for [C18H26NO3þNa]þ (MþNaþ)
a]
24 ꢀ50.2 (c 1, CHCl3).
D
1.01 (d, J¼7.4 Hz, 3H, 50-CH3). 13C NMR (100 MHz, CDCl3):
d
¼166.1
4.6.4. General procedure for the acid-mediated cycloaddition re-
action of oximes (4a and 4b) with CPD. To a stirred solution of oxime
4 (0.50 g, 1.7 mmol) in dry CH2Cl2 (15 ml) under argon atmosphere,
at temperature ꢀ20 ꢃC, the catalyst (1 equiv, according to Table 3)
and CPD (0.14 ml, 1.7 mmol) were added. After the mixture was left
to react during 2.5 h, additional CPD (0.14 ml, 1.7 mmol) was added
and the reaction was left to react during further 2.5 h. The reaction
mixture was neutralized with aqueous saturated solution of NaHCO3
(7 ml) and was allowed to heat to the room temperature under
stirring overnight. The two phases were separated and the aqueous
phase was extracted with CH2Cl2 (3ꢁ15 ml). The organic extracts
were rinsed with brine, dried, and evaporated. The obtained residue
was washed and triturated under methanol (15 ml); after filtration
(COO), 150.2 (Cipso), 131.0 (C3), 130.4 (C2), 128.9 (CPh), 126.9 (CPh),
126.4 (CPh), 72.8 (CH), 52.4 (CH), 41.1 (C8), 37.1 (CH2), 33.1 (CH2),
27.6 (80-CH3), 26.7 (CH), 27.4 (80-CH3), 21.3 (50-CH3), 18.3 (CH2);
ESI-MS: calculated for [C19H26O2þH]þ (MþHþ) 287.19, found
287.53.
4.6.2. General procedure for the synthesis of 3aec.2,3d To a stirring
solution of 2aec (0.50 g, 1.75 mmol) in 3/1 dioxane/water (20 ml),
a 0.01 M solution of OsO4 in dioxane/water 3/1 (1.1 ml) was added.
After 5 min, NaIO4 (0.75 g, 3.50 mmol) was added in small portions
and the mixture was left to react overnight. After addition of water
(30 ml), the mixture was extracted with ethyl acetate (3ꢁ30 ml). The
organic layers were dried over anhydrous Na2SO4, filtered and the
solvent removed at reduced pressure to afford the corresponding
glyoxylates 3aec (yields: 3a-99%; 3b-91%; 3c-90%). No purification
was needed, the product being used directly in the next reaction.
€
through a Buckner funnel with Celite plus silica under reduced
pressure, all the precipitate was removed to give a clear solution that
was evaporated again. The oily mixture was submitted to chro-
matographic columns (SiO2, Hex/AcOEt, 1/1), the fractions corre-
sponding to two distinct compositions being separated and being
subject of a new chromatographic column each (first mixture, SiO2,
Hex/AcOEt, 1/2; second mixture, SiO2, Hex/AcOEt, 1/3). The process
was repeated when necessary until they succeed to obtain good
NMR spectra. None of the compounds was fully isolated, the yields
being determined by NMR and present in Table 3.
4.6.3. Procedure for the synthesis of oximes
4.6.3.1. 8-PMGO (4a). To 2.30 g (33.1 mmol) of NH2OH$HCl in
anhydrous dichloromethane (30 ml), a catalytic amount of DMAP
(ca. 5%), anhydrous triethylamine (4.65 ml, 33.4 mmol) and
8-phenylmenthyl glyoxylate 3a (0.95 g, 32.0 mmol) were added.
The mixture was left to react overnight under argon atmosphere at
room temperature. After addition of water (20 ml) and subsequent
phase separation, the aqueous layer was extracted with dichloro-
methane (3ꢁ20 ml). The organic extracts were dried over anhy-
drous Na2SO4 and the solvent evaporated under low pressure.
When necessary, purification was performed by flash chromatog-
raphy (SiO2, Hex/AcOEt). Similar procedures were adopted for the
synthesis of 8-PnMGO and 8-PinMGO. Virtually unitary yields were
obtained.
4.6.4.1. Compound 9a. 1H NMR (400 MHz, CDCl3):
d
¼7.25e7.36
(m, 5HPh), 7.10e7.19 (m, 1HPh), 6.43e6.48 (m, 1H, H5), 6.24
(dd, J¼5.6, 2.0 Hz, 1H, H6), 4.94 (m, H18PM), 4.21 (s, 1H, H1), 2.68
(s, 1H, H4), 2.30 (d, J¼2.1 Hz, 1H, H3), 1.35e2.15 (m,
5H8-PMþH7synþH7anti), 1.59 (d, J¼9.2 Hz, 1H8-PM), 1.21 and 1.33
(2s, 6H, 8-(CH3)2-8PM), 0.90e1.20 (m, H28-PM), 0.88 (d, J¼6.5 Hz,
H3, 5-CH3-8PM); 13C NMR (100 MHz, CDCl3):
(8-Cipso), 137.9 (C5), 133.1 (C6), 128.0 (2ꢁ CPh), 125.4 (2ꢁ CPh),
d
¼171.6 (COO), 151.7
Please cite this article in press as: Sousa, C. A.D.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.033

C.A.D. Sousa et al. / Tetrahedron xxx (2013) 1e10
9
125.0 (Cpara), 75.0 (C18PM), 70.5 (C3), 69.0 (C1), 50.4 (C28PM), 47.2
(C4), 45.0 (C7), 41.6 (CH2), 39.6 (C88-PM), 34.6 (CH2), 31.2 (C58PM),
26.5 (CH2), 24.7 and 28.1 (2ꢁ 8-CH3-8PM), 21.8 (5-CH3-8PM); 15N
(2s, 6H, 8-(CH3)2-8PnM), 0.77e0.99 (m, 2H8-PnM), 0.82 (d, J¼6.6 Hz,
3H, 5-CH3-8PnM).
NMR (40 MHz, CDCl3):
d
¼148.
4.6.4.7. Compound 11b. 1H NMR (400 MHz, CDCl3):
d¼7.26e7.35
(m, 5HPh), 7.17e7.24 (m, 1HPh), 6.05e6.10 (m, 1H, H8), 5.55 (ddd,
J¼5.6, 4.4, 2.1 Hz,1H, H7), 5.41e5.45 (m,1H, H1), 5.32e5.50 (br s,1H,
NH), 5.05e5.08 (s,1H, H18-PnM), 3.88 (d, J¼7.9 Hz,1H, H4), 3.33e3.41
(m,1H, H5), 2.38e2.47 (m,1H, H6syn), 2.12 (dquint, J¼18.1, 2.3 Hz,1H,
H6anti),1.88 (ddd, J¼14.4, 6.0, 3.6Hz,1H8-PnM),1.72e1.82 (m,1H8-PnM),
1.46e1.70 (m, 4H8-PnM), 1.33 and 1.34 (2s, 6H, 8-(CH3)2-8PnM),
0.96e1.10 (m, 2H8-PnM), 0.85 (d, J¼6.5 Hz, 3H, 5-CH3-8PnM); 13C NMR
4.6.4.2. Compound 11a. 1H NMR (400 MHz, CDCl3):
d
¼7.27e7.37
(m, 5HPh), 7.14e7.21 (m, 1HPh), 6.00e6.05 (m, 1H, H8), 5.58 (ddd,
J¼5.6, 4.3, 2.1 Hz,1H, H7), 5.29 (d, J¼6.8 Hz,1H, H1), 5.05e5.45 (br s,
1H, NH), 4.89 (dt, J¼10.8, 4.4 Hz, 1H, H18PM), 3.09 (d, J¼8.1 Hz, 1H,
H4), 2.95e3.30 (m, 1H, H5), 2.31e2.40 (m, 1H, H6syn), 2.05e2.13 (m,
1H8-PM), 2.01 (dquint, J¼18.2, 2.3 Hz, 1H, H6anti), 1.86e1.94 (m, 1H8-
PM), 1.81 (dq, J¼13.4, 3.4 Hz, 1H8-PM), 1.67e1.74 (m, 1H8-PM),
1.43e1.55 (m, 2H8-PM), 1.32 and 1.23 (2s, 6H, 8-(CH3)2-8PM),
1.13e1.19 (m, 1H8-PM), 0.97e1.03 (m, 1H8-PM), 0.91 (d, J¼6.5 Hz, 3H,
(100 MHz, CDCl3):
d¼168.5 (COO), 148.9 (8-Cipso), 137.6 (C8), 128.1
(2ꢁ CPh) and 126.0 (2ꢁ CPh), 126.0 (C7), 125.8 (Cpara), 92.0 (C1), 72.4
(C18-PnM), 67.4 (C4), 51.0 (C28-PnM), 45.8 (C5), 39.9 (CH2), 39.9
(C88-PnM), 35.2 (CH2), 34.2 (C6), 27.0 (2ꢁ 8-CH3-8PnM), 26.0, 22.3
5-CH3-8PM); 13C NMR (100 MHz, CDCl3):
d
¼169.7 (COO), 152.4
(8-Cipso), 138.4 (C8), 128.9 (2ꢁ CPh) and 129.0 (2ꢁ CPh), 126.2 (C7),
126.1 (Cpara), 92.7 (C1), 76.2 (C18PM), 66.7 (C4), 51.2 (C28PM), 46.3
(C5), 42.3 (CH2), 40.4 (C88PM), 35.4 (C6), 35.4 (CH2), 32.2, 29.6, 27.3
(CH2), 21.9 (5-CH3-8PnM); 15N NMR (40 MHz, CDCl3):
d
¼141; ESI-TOF:
calculated for [C23H31NO3þH]þ (MþHþ) 370.23, found 370.2377.
(CH2), 24.9, 22.7; 15N NMR (40 MHz, CDCl3):
d
¼142; ESI-TOF: cal-
4.6.4.8. Compound 11b0. 1H NMR (400 MHz, CDCl3):
22
culated for [C23H31NO3þH]þ (MþHþ) 370.23, found 370.2377, [
ꢀ19.2 (c 0.32, CHCl3).
a
]
d
¼7.26e7.35 (m, 5HPh), 7.17e7.24 (m, 1HPh), 6.10e6.14 (m, 1H, H8),
D
5.67 (ddd, J¼5.6, 4.4, 2.1 Hz, 1H, H7), 5.44e5.48 (m, 1H, H1),
5.32e5.50 (br s, 1H, NH), 5.03e5.06 (s, 1H, H18-PnM), 3.98 (d,
J¼7.8 Hz, 1H, H4), 3.41e3.49 (m, 1H, H5), 2.49e2.58 (m, 1H, H6syn),
2.26 (dquint, J¼18.1, 2.3 Hz, 1H, H6anti), 2.00 (ddd, J¼14.4, 6.0,
3.6 Hz, 1H8-PnM), 1.72e1.82 (m, 1H8-PnM), 1.46e1.70 (m, 4H8-PnM),
1.33 and 1.34 (2s, 6H, 8-(CH3)2-8PnM), 0.96e1.10 (m, 2H8-PnM), 0.84
4.6.4.3. Compound 11a0. 1H NMR (400 MHz, CDCl3):
¼7.27e7.37 (m, 5HPh), 7.14e7.21 (m, 1HPh), 6.08e6.12 (m, 1H, H8),
d
5.63 (ddd, J¼5.6, 4.3, 2.1 Hz, 1H, H7), 5.37 (d, J¼6.6 Hz, 1H, H1),
5.05e5.45 (br s,1H, NH), 4.86 (dt, J¼10.8, 4.3 Hz,1H, H18PM), 3.69 (d,
J¼7.7 Hz, 1H, H4), 3.16e3.23 (m, 1H, H5), 2.40e2.49 (m, 1H, H6syn),
2.24e2.31 (m, 1H, H6anti), 0.93e2.14 (m, 8H8-PM), 1.37 and 1.26 (2s,
6H, 8-(CH3)2-8PM), 0.88 (d, J¼6.5 Hz, 3H, 5-CH3-8PM); 13C NMR
(d, J¼6.5 Hz, 3H, 5-CH3-8PnM); 13C NMR (100 MHz, CDCl3):
¼170.0
d
(COO), 149.5 (8-Cipso), 137.7 (C8), 128.0 (2ꢁ CPh) and 125.8 (2ꢁ CPh),
125.8 (C7), 125.8 (Cpara), 92.0 (C1), 73.5 (C18-PnM), 66.7 (C4), 50.9
(C28-PnM), 45.8 (C5), 39.9 (C88-PnM), 39.8 (CH2), 35.3 (CH2), 34.6 (C6),
26.9 (2ꢁ 8-CH3-8PnM), 25.7, 22.3 (CH2), 21.9; 15N NMR (40 MHz,
(100 MHz, CDCl3):
d
¼169.6 (COO), 152.0 (8-Cipso), 138.6 (C8), 129.3
(2ꢁ CPh) and 128.8 (2ꢁ CPh), 126.7 (C7), 126.3 (Cpara), 77.9 (C1), 73.2
(C18PM), 69.3 (C4), 50.8 (C28PM), 46.6 (C5), 42.5 (CH2), 41.0 (C88PM),
39.1 (CH2), 35.3 (CH2), 32.3, 29.1, 28.0 (CH2), 25.5, 22.6; 15N NMR
CDCl3):
d
¼141.
(40 MHz, CDCl3):
d¼142.
Acknowledgements
ˇ
4.6.4.4. Compound 9b. 1H NMR (400 MHz, CDCl3):
d
¼7.29e7.34
~
Thanks are due to Fundac¸ ao para a Ciencia e Tecnologia (FCT) for
financial support through the re-equipment program REDE/1517/
RMN/2005 and CONC-REEQ/275/QUI. C.A.D.S. acknowledges FCT
for the award of the Research Grants SFRH/BD/31526/2006 and
SFRH/BPD/80100/2011 and C.F.R.A.C.L. for the grant SFRH/BD/
29394/2006.
(m, 5HPh), 7.16e7.23 (m, 1HPh), 6.64e6.67 (m, 1H, H5), 6.31 (dd,
J¼5.6, 2.0 Hz, 1H, 6-H), 4.95e5.10 (1H, H18-PnM), 4.31 (s, 1H, H1),
3.19 (s, 1H, H4), 2.77 (d, J¼2.1 Hz, 1H, H3), 1.52e1.96 (m,
5H8-PnMþH7synþH7anti), 1.45e1.50 (m, 1H8-PnM), 1.33 and 1.38 (2s,
6H, 8-(CH3)2-8PnM), 0.87e1.52 (m, 2H8-PnM), 0.83e0.86 (3H,
5-CH3-8PnM); 13C NMR (100 MHz, CDCl3):
d
¼171.7 (COO), 149.4
(8-Cipso), 138.1 (C5), 133.2 (C6), 127.8e128.1 (2ꢁ CPh), 125.5e126.0
(3ꢁ CPh), 72.1 (C18-PnM), 70.5 (C3), 68.7 (C1), 51.2 (C28PnM), 46.9
(C4), 45.2 (C7), 39.6e40.0 (C88-PnMþCH2), 35.3 (CH2), 26.0e27.1
(C58-PnMþ2ꢁ 8-CH3-8PnM), 22.4 (CH2), 22.0 (5-CH3-8PnM); 15N NMR
Supplementary data
1H NMR and 13C NMR spectra of all compounds plus NOE NMR
data for 8-PMGO, 8-PnMGO and 8-PinMGO, as well as crystallo-
graphic data for 8-PnMGO and detailed computational results can
be found. Supplementary data related to this article can be found
online at http://dx.doi.org/10.1016/j.tet.2013.03.033. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
(40 MHz, CDCl3):
d¼150.
4.6.4.5. Compound 9b0. 1H NMR (400 MHz, CDCl3):
d¼7.29e7.34
(m, 5HPh), 7.16e7.23 (m, 1HPh), 6.61e6.64 (m, 1H, H5), 6.31 (dd,
J¼5.6, 2.0 Hz, 1H, H6), 4.99 (sl, 1H, H18-PnM), 4.31 (s, 1H, H1), 3.05
(s, 1H, H4), 2.78 (d, J¼2.1 Hz, 1H, H3), 1.52e1.96 (m,
5H8-PnMþH7synþH7anti), 1.45e1.50 (m, 1H8-PnM), 1.36 and 1.38 (2s,
6H, 8-(CH3)2-8PnM), 0.87e1.52 (m, 2H8-PnM), 0.84 (d, J¼6.5 Hz, 3H,
References and notes
5-CH3-8PnM); 13C NMR (100 MHz, CDCl3):
d
¼171.5 (COO), 149.3
1. (a) Corey, E. J.; Becker, K. B.; Varma, R. K. J. Am. Chem. Soc.1972, 94, 8616e8618; (b)
Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908e6909; (c) Quinkert, G.;
Schmalz, H.; Dzierzynski, E. M.; Durner, G.; Bats, J. W. Angew. Chem., Int. Ed. Engl.
1986, 25, 992e993; (d) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650e1667.
2. Whitesell, J. K.; Liu, C. L.; Buchanan, C. M.; Chen, H.-H.; Minton, M. A. J. Org.
Chem. 1986, 51, 551e553.
(8-Cipso), 138.0 (C5), 133.1 (C6), 128.0 (2ꢁ CPh), 126.0 (2ꢁ CPh), 125.0
(Cpara), 72.6 (C18-PnM), 70.8 (C3), 69.0 (C1), 51.3 (C28-PnM), 47.2 (C4),
45.3 (C7), 39.8 (C88-PnM), 39.7 (CH2), 35.3 (CH2), 26.0e27.1
(C58-PnMþ2ꢁ 8-CH3-8PnM), 22.4 (CH2), 22.1 (5-CH3-8PnM); 15N NMR
€
3. (a) Halterman, R. L.; Vollhard, K. P. C. Organometallics 1988, 7, 883e892; (b)
Blanco, J. M.; Caamano, O.; Fernandez, F.; García-Mera, X.; Lopez, C.; Rodríguez,
(40 MHz, CDCl3):
d¼150.
~
ꢀ
ꢀ
G.; Rodríguez-Borges, J. E.; Rodríguez-Hergueta. Tetrahedron Lett. 1998, 39,
5663e5666; (c) Fernandez, F.; García-Mera, X.; Lopez, C.; Rodríguez, G.;
Rodríguez-Borges, J. E. Tetrahedron: Asymmetry 2000, 11, 4805e4815; (d)
4.6.4.6. Compound 10b. 1H NMR (400 MHz, CDCl3):
¼7.27e7.35 (m, 5HPh), 7.17e7.24 (m, 1HPh), 6.30 (dd, J¼5.5, 3.3 Hz,
ꢀ
ꢀ
d
~
ꢀ
Caamano, O.; Fernandez, F.; García-Mera, X.; Rodríguez-Borges, J. E. Tetrahedron
1H, H5), 6.21 (dd, J¼5.5, 2.5 Hz,1H, H6), 5.08 (br s, 1H, H18-PnM), 4.16
(s, 1H, H1), 3.67 (d, J¼3.3 Hz, 1H, H3), 3.28 (s, 1H, H4), 2.25 (d,
J¼8.7 Hz, 1H, H7syn), 1.52e1.88 (m, 6H8-PnMþH7anti), 1.33 and 1.34
ꢀ
Lett. 2000, 41, 4123e4125; (e) Fernandez, F.; García-Mera, X.; Rodríguez-Borges,
J. E.; Blanco, J. M. Tetrahedron Lett. 2001, 42, 5239e5240; (f) Fernandez, F.;
ꢀ
García-Mera, X.; Vale, M. L. C.; Rodríguez-Borges, J. E. Synlett 2005, 319e321;
Please cite this article in press as: Sousa, C. A.D.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.033

10
C.A.D. Sousa et al. / Tetrahedron xxx (2013) 1e10
~
ꢀ
(g) Vale, M. L. C.; Rodríguez-Borges, J. E.; Caamano, O.; Fernandez, F.; García-
Mera, X. Tetrahedron 2006, 62, 9475e9482; (h) Xerardo García-Mera, X.;
Rodríguez-Borges, J. E.; Vale, M. L.; Alves, M. J. Tetrahedron 2011, 67, 7162e7172.
2005, 29, 147e152; (c) Hay, M. B.; Wolfe, J. P. Angew. Chem., Int. Ed. 2007, 46,
6492e6494.
18. Romeo, G.; Iannazzo, D.; Piperno, A.; Romeo, R.; Corsaro, A.; Rescifina, A.;
4. (a) Binger, P.; Brinkmann, A.; Richter, W. J. Tetrahedron Lett. 1983, 24, 3599e3602;
(b) Whitesell, J. K.; Bhattacharya, A. K.; Buchanan, C. M.; Chen, H.-H.; Deyo, D.;
James, D.; Liu, C. L.; Minton, M. A. Tetrahedron 1986, 42, 2993e3001; (c) Fraile, J.
M.; García, J. I.; Gracia, D.; Mayoral, J. A.; Pires, E. J. Org. Chem. 1996, 61,
9479e9482; (d) Takagi, R.; Kimura, J.; Shinohara, W.; Ohba, Y.; Takezono, K.;
Hiraga, Y.; Kojima, S.; Ohkata, K. J. Chem. Soc., Perkin Trans. 1 1998, 689e698; (e)
Lerm, M.; Gais, H.-J.; Cheng, K.; Vermeeren, C. J. Am. Chem. Soc. 2003, 125,
9653e9667.
5. Whitesell, J. K.; Bhattacharya, A. K.; Henke, K. J. Chem. Soc., Chem. Commun.
1982, 988e989.
6. Pascual-Teresa, B.; Gonzalez, J.; Asensio, A.; Houk, K. N. J. Am. Chem. Soc. 1995,
117, 4341e4356.
Chiacchio, U. Mini-Rev. Org. Chem. 2005, 2, 59e77.
19. Palmer, G. C.; Ordy, M. J.; Simmons, R. D.; Strand, J. C.; Radov, L. A.; Mullen, G. B.;
Kinsolving, C. R.; Georgiev, V. S.; Mitchell, J. T.; Allen, S. D. Antimicrob. Agents
Chemother. 1989, 33, 895e905.
20. Iannazzo, D. P. A.; Pistara, V.; Rescina, A.; Romeo, R. Tetrahedron 2002, 58,
581e587.
21. (a) Chiacchio, U.; Rescifina, A.; Iannazzo, D.; Piperno, A.; Romeo, R.; Borrello, L.;
Sciortino, M. T.; Balestrieri, E.; Macchi, B.; Mastino, A.; Romeo, G. J. Med. Chem.
2007, 50, 3747e3750; (b) Balestrieri, E.; Matteucci, C.; Ascolani, A.; Piperno, A.;
Romeo, R.; Romeo, G.; Chiacchio, U.; Mastino, A.; Macchi, B. Antimicrob. Agents
Chemother. 2008, 52, 54e64; (c) Loh, B.; Vozzolo, L.; Mok, B. J.; Lee, C. C.;
Fitzmaurice, R. J.; Caddick, S.; Fassati, A. Chem. Biol. Drug Des. 2010, 75, 461e474.
22. (a) Tamura, O.; Mitsuya, T.; Huang, X.; Tsutsumi, Y.; Hattori, S.; Ishibashi, H.
J. Org. Chem. 2005, 70, 10720e10725; (b) Tamura, O.; Morita, N.; Takano, Y.;
Fukui, K.; Okamoto, I.; Huang, X.; Tsutsumi, Y.; Ishibashi, H. Synlett 2007, 658e660.
23. (a) Ritson, D. J.; Cox, R. J.; Berge, J. Org. Biomol. Chem. 2004, 2, 1921e1933.
(b) Sousa, C. A. D. Ph.D. Dissertation, Faculty of Sciences of University of Porto,
Portugal, 2011.
7. Angelo, J.; Maddaluno, J. J. Am. Chem. Soc. 1986, 108, 8112e8114.
8. (a) Sousa, C. A. D.; Vale, M. L. C.; Rodríguez-Borges, J. E.; García-Mera, X.;
Rodríguez-Otero, J. Tetrahedron Lett. 2008, 49, 5777e5781; (b) Sousa, C. A. D.;
Vale, M. L. C.; García-Mera, X.; Rodríguez-Borges, J. E. Tetrahedron 2012, 68,
1682e1687.
€
9. Gunther, H. NMR Spectroscopy: Basic Principles, Concepts and Applications in
Chemistry, 2nd ed;; John Wiley: Chichester, UK and New York, NY, 1995,
Chapter 4.
10. Kleinspehn, G. G.; Jung, J. A.; Studniarz, S. A. J. Org. Chem. 1967, 32, 460e462.
11. Grimme, S. J. Chem. Phys. 2003, 118, 9095e9102.
24. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox,
D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian 03; Revision C.02; Gaussian: Pittsburgh, PA, 2004.
25. Bruker. APEX2, SAINT and SADABS; Bruker AXS: Madison, Wisconsin, USA, 2006.
26. Altomare, A.; Cascarano, C.; Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.;
Burla, M. C.; Polidori, G.; Camalli, M.; Spagna, R. SIR97; University of Bari: Italy,
1997.
27. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112e122.
28. Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
29. Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.;
Towler, M.; van de Streek, J. J. Appl. Crystallogr. 2006, 39, 453e457.
30. Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7e13.
12. (a) Lima, C. F. R. A. C.; Rocha, M. A. A.; Gomes, L. R.; Low, J. N.; Silva, A. M. S.;
Santos, L. M. N. B. F. Chem.dEur. J. 2012, 18, 8934e8943; (b) Lima, C. F. R. A. C.;
€
Rocha, M. A. A.; Schroder, B.; Gomes, L. R.; Low, J. N.; Santos, L. M. N. B. F. J. Phys.
Chem. B 2012, 116, 3557e3570.
13. (a) Abramovich, M. A.; Ginzburg, I. M.; Ioffe, D. V. Theor. Exp. Chem. 1973, 7,
€
€
€€
187e192; (b) Schwobel, J.; Ebert, R.-U.; Kuhne, R.; Schuurmann, G. J. Chem. Inf.
Model. 2009, 49, 956e962.
14. (a) Reeves, L. W.; Schneider, W. G. Can. J. Chem. 1957, 35, 251e261; (b) Tsuzuki,
S. Struct. Bonding (Berlin, Ger.) 2005, 115, 149e193.
15. The crystallographic data for the structure 4b have been deposited at the
Cambridge Crystallographic Data Center as supplementary publication number
CCDC 787450. Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge, CB2, 1EZ, UK.
16. (a) Grigg, R.; Kemp, J.; Thompson, N. Tetrahedron Lett. 1978, 31, 2827e2830; (b)
Grigg, R.; Jordan, M.; Tangthongkum, A. J. Chem. Soc., Perkin Trans. 1 1984,
47e57; (c) Grigg, R. Chem. Soc. Rev. 1987, 16, 89e121; (d) Armstrong, P.; Grigg,
R.; Surendrakumar, S.; Warnock, W. J. Chem. Soc., Chem. Commun. 1987,
1327e1328.
17. (a) Osborn, H. M. I.; Gemmell, N.; Harwood, L. M. J. Chem. Soc., Perkin Trans. 1
2002, 2419e2438; (b) Mobinikhaledi, A.; Foroughifar, N.; Kalate, Z. Turk. J. Chem.
Please cite this article in press as: Sousa, C. A.D.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.033