An alternative mechanism for the 1,4-asymmetric induction in the stereoselective addition of (R)-pantolactone to 2-phenylpropylketene

Article abstract of DOI:10.1590/S0103-50532011000400020

An alternative mechanism for the 1,4-assymmetric induction in the stereoselective addition of (R)-pantolactone to 2-phenylpropylketene was theoretically investigated. A mechanism involving an intermolecular proton transfer assisted by two amine molecules was proposed, which considered the active participation of the dimethylethylamine and its ion as proton transfer agents. In the first step, a neutral dimethylethylamine interacts with the seven-membered ring of the enol intermediate. A specific acid-base interaction is established between the hydroxyl group of the enol and the nitrogen atom of the dimethylethylamine. The neutral dimethylethylamine is basic enough to remove the proton. Another protonated dimethylethylamine is considered to donate its proton to the C=C double bond to give the desired products. The stereochemical outcome was defined by the way that the neutral and protonated dimethylethylamine approached to the enol. The diastereoisomeric ratio found is in good agreement with experiments [for (S, R) and (R, R) it is 99:1]. ?2011 Sociedade Brasileira de Qui?mica.

Full text of DOI:10.1590/S0103-50532011000400020

J. Braz. Chem. Soc., Vol. 22, No. 4, 756-766, 2011.
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Article
A
An Alternative Mechanism for the 1,4-Asymmetric Induction in the Stereoselective
Addition of (R)-Pantolactone to 2-Phenylpropylketene
Alexander M. Silva,a Clarissa O. da Silva,*,a André G. H. Barbosa,b Rosane A. Fontes,a
Sergio Pinheiro,b Marco Edilson F. Limaa and Rosane N. Castroa
aDepartamento de Química, Universidade Federal Rural do Rio Janeiro, Rodovia BR 465, km 47,
23890-000 Seropédica-RJ, Brazil
bInstituto de Química, Universidade Federal Fluminense, 20141-020 Niterói-RJ, Brazil
Um mecanismo alternativo para a indução assimétrica 1,4, na adição estereosseletiva da
(R)-pantolactona ao 2-fenilpropilceteno foi investigado teoricamente. Um mecanismo envolvendo
uma transferência de hidrogênio intermolecular foi proposto, que considera a participação ativa da
dimetiletilamina e seu íon como agentes de transferência de hidrogênio. No primeiro passo, uma
molécula de dimetiletilamina neutra interage com o anel de 7 membros do enol intermediário.
Uma interação ácido-base específica é estabelecida entre o grupo hidroxila do enol e o átomo
de nitrogênio da amina. A amina neutra é básica o suficiente para remover o hidrogênio. Uma
outra molécula de amina protonada doa seu hidrogênio à ligação dupla C=C, para fornecer os
produtos desejados. A estereoquímica foi definida pelo modo como as moléculas de amina neutra
e protonada aproximam-se do enol. O excesso diasteroisomérico encontrado concorda com o dado
experimental [para (S, R) e (R, R) é de 99:1].
An alternative mechanism for the 1,4-assymmetric induction in the stereoselective addition of
(R)-pantolactone to 2-phenylpropylketene was theoretically investigated. A mechanism involving
an intermolecular proton transfer assisted by two amine molecules was proposed, which considered
the active participation of the dimethylethylamine and its ion as proton transfer agents. In the first
step, a neutral dimethylethylamine interacts with the seven-membered ring of the enol intermediate.
A specific acid-base interaction is established between the hydroxyl group of the enol and the
nitrogen atom of the dimethylethylamine. The neutral dimethylethylamine is basic enough to remove
the proton. Another protonated dimethylethylamine is considered to donate its proton to the C=C
double bond to give the desired products. The stereochemical outcome was defined by the way
that the neutral and protonated dimethylethylamine approached to the enol. The diastereoisomeric
ratio found is in good agreement with experiments [for (S, R) and (R, R) it is 99:1].
Keywords: density functional calculations, diastereoselectivity, protonation, alcohols, ketenes
Introduction
were obtained with a diastereoisomeric excess as high as
99% via a reaction of arylmethylketenes generated in situ
with a variety of optically active a-hydroxy esters such
as (R)-pantolactone. Since Larsen et al.5 have published
their results, stereoselective addition of a chiral alcohol to
prochiral ketenes derived from 2-aryl propionic acid has
been widely discussed in the literature.6-9
In this reaction the goal is to transform racemic
a-substituted carboxylic acids into their enantiomerically
enriched esters derivatives. The ketene formation and the
addition of chiral alcohol normally occur in a one-step
procedure being followed by a stereoselective protonation
of the ketene. Since these chiral esters can be hydrolyzed
Diastereoselective addition of a chiral alcohol to a
ketene was reported firstly in 1919.1 Since then, several
groups have tried to improve the diastereoisomeric excess
(% d.e.) of the final product, being successful only those
that use alcohols of limited availability as chiral reagents.2-4
However, in 1989, Larsen et al.5 at Merck developed a
synthetic route where naturally occurring a-hydroxy esters
were used as chiral inductors, yielding very promising
d.e.’s. They had reported that chiral 2-arylpropionic esters
*e-mail: clarissa-dq@ufrrj.br

Vol. 22, No. 4, 2011
Silva et al.
757
without significant racemization, this process is useful for
preparing various types of chiral a-substituted carboxylic
acids with important anti-inflammatory properties (some
examples are ibuprofen, naproxen, ketoprofen, flunoprofen,
etc).10,11
yield giving 2 (methyl 2-phenylpropanoate) as previously
described in the literature.15 Subsequent hydrolysis
furnished rac-3 (2-phenylpropionic acid),16 which was
quantitatively converted into 2-phenylpropionyl chloride
4. The dehydrochlorination of 4 by dimethylethylamine
at room temperature produced the methylphenylketene
5, which upon treatment with (R)-pantolactone led to
the mixtures of the chiral esters 6 (S, R)- and (R, R)-
phenylpropionic acid, a-methyl-,tetrahydro-4,4-dimethyl-
2-oxo-3-furanyl esters in a 99: 1 ratio (98% d. e.).14
Thus, keteneformationandadditionof(R)-pantolactone,
a very efficient commercially available chiral auxiliary,
occurred in one step procedure. The asymmetric
transformation of rac-3 involves the stereoselective addition
of a chiral alcohol to the corresponding prochiral ketene 5
followed by deracemizing protonation of this intermediate.
The tertiary base, used in excess, both catalyzed the
diastereoselective addition of an alcohol to the ketene and
increased the stereoselectivity.
Ketene intermediate (methylphenylketene 5 in
Scheme 1) is generated in situ in the reaction between acyl
chloride (4) and tertiary amines (as dimethylethylamine).
Ketene reacts immediately with the (R)-pantolactone to
give intermediate 7(I), which is in equilibrium with the
enol 7(II) through a hydrogen shift (Scheme 2).
To understand the deracemizing protonation of ketene
in the stereoselective formation of (R, S)-6 by using
(R) pantolactone as chiral inductor, the theoretical route we
have investigated starts from intermediates 7(I) and 7(II)
(which occurs after the alcohol addition to the ketene, as
proposed in reference 6) and takes two different paths. Both
paths involve proton transfer reactions, and the mechanisms
considered for them were: (A) a direct intramolecular
proton transfer not assisted by any amine molecule and
(B) an intermolecular two-step proton transfer catalyzed
by both, an amine molecule which abstracts the proton and
an ammonium salt (an efficient proton donor formed in the
Some studies have shown that the base catalyzed
addition of the chiral alcohol to ketenes derived from
various racemic aryl propionic acids can furnish only one
diastereoisomer.5 Cannizzaro et al.6,9 recently explored
this reaction using quantum mechanical calculations and
provided a quantitative model for its mechanism that
is the most accepted in the literature. They carried out
a very detailed theoretical study of the stereoselective
additions of chiral alcohols, considering different chiral
inductors as (S)-methyl lactate, (S)-3-methyl-2-butanol,
and (S)-pantolactone to ketenes. The proposed mechanism
for the first two chiral inductors states that the alcohol
addition to the ketene catalyzed by trimethylamine is the
rate determinant step, while the keto-enol tautomerization is
the stereoselectivity determinant step. For (S)-pantolactone
instead, the rate and stereoselectivity determinant steps are
the same, the alcohol addition, because the bond rotation
that would furnish a racemic mixture is precluded by a
10.9 kcal/mol energy barrier (see Figure 23 of reference
6). However, in all cases the authors always propose a
transition state with only one amine molecule catalyzing the
intramolecular keto-enol tautomerization, in a conducted
tour mechanism12,13 It should be noted that in the solvation
model used, the calculation of the non-electrostatic
contribution was absent.
In the present work the synthetic route14 for the
preparation of 2-phenyl-propionate pantolactonyl ester is
theoretically revisited. Although it is not the main focus of
thiswork, theparallelexperimentisherementionedtojustify
some choices of the theoretical description. The synthesis
of this compound is outlined in Scheme 1. The alkylation
of ester 1 (methyl phenylacetate) was achieved in good
c
COCl
CO2CH3
b
CO2CH3
CO2H
rac-3
a
1
2
4
O
O
O
O
e
d
O
C
O
+
O
O
O
5
(S, R)-6
(R, R)-6
Scheme 1. (a) THF, NaH (0.1 mol), CH3I (0.15 mol), reflux, 3 h, 83%; (b) KOH/EtOH, r.t., overnight, 90%; (c) SOCl2, reflux, 3 h, 97%; (d) N,N-
dimethylethylamine (1.5 equiv.), 0 °C, 30 min; (e) (R)-pantolactone (1.1 equiv., 0.2 mol L-1 in THF), 0 °C to r.t., 83%, 98% d. e.

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An Alternative Mechanism for the 1,4-Asymmetric Induction in the Stereoselective Addition
J. Braz. Chem. Soc.
O
H
HO
O
O
O
Ar
O
O
Ar
(CH3)2NEt
Cl
O
O
Ar
Ar
C
H
O
O
O
O
Cl
– (CH3)2NEt
H
ketene
racemate
7(I)
7(II)
Scheme 2. Addition of (R)-pantolactone to ketene, generated in situ with simultaneous formation of an ammonium salt.
reaction medium when HCl is generated as a subproduct
of the in situ ketene generation). This proposition is
different from Cannizzaro´s et al.6,9 proposition, in which
the same amine molecule, through the conducted tour
mechanism, assists the tautomerization12,13 (see Scheme 3).
It should be noted that the tertiary amine we have used
was dimethylethylamine, while that in reference 6 was
trimethylamine.
order (MP2) method. These calculations were performed
withthesamebasisset, onthegeometriesfoundforreactants,
intermediates and transition states species involved in both
reaction paths, as single point energy calculations, just to
check the relative energy values found from the density
functional theory description.
.24
The initial structures were obtained from GaussView
All calculations were performed in gas-phase and in THF,
since it is the solvent utilized in the experiments (see
Scheme 1). Although this is an aprotic solvent, with low
relative permittivity and then assumed to work only as
a convenient dispersing media, the differential solvation
effects should not be neglected. Therefore the system was
also studied considering them, which were determined
using the integral equation formalism (IEF)25 version
of the polarized continuum solvation model (PCM).26,27
In this approach the solute is represented as a quantum
mechanical charge distribution inside a cavity of molecular
shape immersed in a macroscopic dielectric with known
relative permittivity e. The electrostatic interaction between
solute and solvent can then be represented in terms of a
set of apparent surface charges located on the cavity. Such
cavity is built from interlocking spheres centered on atoms
or group of atoms. The radii of these spheres are 1.80 Å
for N and O atoms, 2.28 Å for CH or CH2 group of atoms,
2.4 Å for CH3, and 1.44 Å for H atoms of the hydroxyl
groups. Within this approach, both the electrostatic and
non-electrostatic components of the solvation energy were
taken into account.
Methodology and Computational Details
The calculations were performed at the DFT/B3LYP17,18
level with the 6-311G(d,p) basis set, using the Jaguar19 and
Gaussian0320 programs. Geometryoptimizationcalculations
were carried out to obtain the structures of reactants,
products and transition states. After that, their vibrational
frequencies were obtained in order to check whether the
stationary points were correctly located. That is, if there
were just real frequencies for reactants and products, and
only one imaginary frequency for the transition state
associated with the broken bond. The minimum energy
path connecting these structures was obtained through an
intrinsic reaction coordinate (IRC) calculation.21,22 There
has been some concern in the literature about the possible
inability of the B3LYP functional to accurately calculate
reaction barrier heights in some systems containing valence
electron-rich atoms.23 To verify if our results are to any
extent compromised by these facts, we have recalculated
the barrier’s heights with the ab initio Moller-Plesset second
Scheme 3. Assisted (left) intramolecular (as proposed in reference 6) and (right) intermolecular proton transfers.

Vol. 22, No. 4, 2011
Silva et al.
759
In order to proceed, we will present the results for
the calculations for two possible mechanisms. The
first one is very simple and the second one is more
complete. Although the second one is largely favored
in the comparison to available experimental data, the
simplicity of the first one allows us to put in evidence
important non-obvious information about the system.
Thus, the two mechanisms investigated are very different,
and the main distinction between them is related
to the origin of the proton that is transferred. In the
mechanism (A), the proton comes from an intramolecular
donation of the cyclic enol 7(II) formed, as pictured in
Scheme 4.
A second possibility is investigated in mechanism
(B) and concerns on a two-step intermolecular proton
transfer. In the first step, 7(II) has its proton abstracted by
the amine present in the medium, producing the enolate
intermediate 8 (Scheme 5). Another proton is donated to
intermediate 8 from the ammonium salt (formed in situ
when the ketene is produced). The order of such events
should not be inverted, because the amine in the first
step helps to block the access to one side of the double
bond. With this assumption, such proposition explains the
enantiomeric excess experimentally observed.Additionally,
this mechanism precludes the necessity of rotation proposed
by Cannizzaro et al.6,9 as a justification for any enantiomeric
preference.
It is necessary to establish parameters to evaluate
the proposed mechanisms. A sensible choice implies
on the consideration of the theoretical value of the
diastereoisomeric excess. The mechanism that yields a
value of diastereoisomeric excess closer to the experimental
data, should be the most reasonable. The theoretical
evaluation of the diastereoisomeric excess can be performed
through a calculation of the transition states free energies
of the competing reaction pathways. The fundamental
equation of the transition state theory relates the reaction
rate constant k(T) exclusively to the free energy of the
transition state:28
k = (kBT/h) exp(-DG≠rel /RT)
(1)
The symbol DG≠rel indicates the free energy difference
between the transition state and an arbitrarily chosen
reference energy (in this case the enol 7(II) intermediate).
The constants h and kB are Planck and Boltzmann constants,
respectively. Therefore, the ratios between the configuration
of the products (R, R)-6 and (S, R)-6 is given by
[R, R]/[S, R] = exp(-DG≠R /RT) / exp(-DG≠ /RT)
(2)
S
The percentual diastereoisomeric excesses can be
calculated as follows:
Summarizing, the conversion of the enol intermediate
7(II) into pantolactonyl esters (S, R)-6 and (R, R)-6 could
in principle happen through two routes: the intra (A) or
intermolecular (B) protonation of the C=C bond.
(3)
Scheme 4. Mechanism (A): direct intramolecular proton transfer.
H
H
EtN(CH3)2
EtN(CH3)2
O
(CH3)2NEt
O
(CH3)2NEt
O
O
Ar
Ar
Ar
O
O
O
O
O
O
O
O
H
(CH3)2NEt
7(II)
8
Scheme 5. Mechanism (B): an intermolecular proton transfer, catalyzed by an amine molecule, and an ammonium salt in two successive steps.

760
An Alternative Mechanism for the 1,4-Asymmetric Induction in the Stereoselective Addition
J. Braz. Chem. Soc.
Results and Discussion
The structure corresponding to the global minimum was
completely optimized, and the geometrical parameters
remained basically unchanged. The most relevant
geometrical parameters of this structure are shown in
Figure 2.
In both mechanisms investigated, the starting structure
is the enol intermediate 7(II). It can form a seven-member
ring through a hydrogen bond interaction. Due to this, such
structure was investigated in calculations that scanned all
possible values for the dihedral angle φ (φ =C1-C2-O-C3),
which defines the relative orientation of the lactone moiety
in relation to the ketene moiety, through a rotation around
the C3-O bond, as shown in Figure 1.
Figure 2. The enol intermediate 7(II) geometry.
The intramolecular mechanism (A)
In the intramolecular protonation mechanism the
hydroxyl group revolves around the C3-OH bond to bring
the hydrogen atom closer to the bond C3=C4. Then, the
proton transfer to carbon atom C4 occurs. Such motion
clearly implies the breaking of the seven-member ring
structure. The critical energies (electronic energy added to
zero point correction energy) and transition states structures
for the conversion of this intermediate into the (S, R)-6 and
(R, R)-6 are shown in Figure 3.
Figure 1. Potential curve calculated for the angle (φ =C1-C2-O-C3) of
the enol identified in Scheme 2 as 7(II).
From Figure 1 it can be seen that the potential energy
curve for this enol intermediate 7(II) shows as global
minimum a seven-member ring with an hydrogen bond
intramolecular interaction. This strong interaction is
maximized in this conformation, because the oxygen
atom of the hydroxyl group is parallel to the carbonyl.
It is clearly seen that this intramolecular process
demands a very high amount of energy input. We consider
it to be a reasonable result due to all the necessary structural
changes discussed above. The transition state structure for
(S, R)-6 is less stable than that one for (R, R)-6 because
in the first mechanism an additional rotation of the (C6H5)
Figure 3. Reactions barriers for the proton transfer in the intramolecular mechanism (A).

Vol. 22, No. 4, 2011
Silva et al.
761
(CH3)-C4 fragment around the C3-C4 bond is necessary
to furnish the desired stereochemistry.
bond in the ring and forms an acid-base complex, which
structure is shown in Figure 4a. The distance N1…H3 is
1.74 Å.
After inserting the results obtained into equations
2 and 3, we found out that the difference between the
barriers height was only 0.54 kcal/mol. Thus, for this
intramolecular mechanism we obtained a value of 57:43
for the diastereoisomeric (S, R)-6 /(R, R)-6 excess, which
is too far from the experimental data (99:1).5 In other
words, as the height of the barriers is very similar, there is
no diastereoisomeric excess associated with mechanism
(A), practically. It also can be argued that the proton is too
small to be responsible for observed enantioselectivity.
The fact that the calculated barriers are somewhat high and
very similar in magnitude provides favorable conditions
for proton tunneling.29 Even in this case there would be no
significant modification in the calculated diastereoisomeric
excess. It is important to recall that in mechanism (A) it was
considered that the amine molecule played no role in the
intramolecular proton transfer. This is different from what
was proposed by Canizzaro and Houk.6 However, in both
propositions, the transferred proton comes from the chiral
alcohol, which in the present case is the (R)-pantolactone. It
is essential to bear in mind that the reaction studied in this
paper includes a proton transfer step in solution that only
take place in the presence of a proton carrier (the amine
molecule) in a definite concentration. Hence, a meaningful
mechanism must consider the acid-base equilibria with the
proton carrier, knowing that in solution both protonated
and deprotonated forms are present and are probably also
active in the mechanism. To accomplish that, we move to
the description of the intermolecular mechanism (B).
Enolate formation
Dimethylethylamine is basic enough to remove the
proton H3 through an acid-base reaction. Figure 4b shows
the transition state of this reaction. The O3-H3 bond
distance is enlarged from 1.01 Å to 1.22 Å, and N1…H3
distance is shortened from 1.74 Å to 1.28 Å, both in
the transition states after dimethylethylamine molecule
approaches (Table 1). The reaction barrier for this step
is only 0.95 kcal/mol. In practice this result indicates an
absence of barrier. The imaginary vibrational frequency of
this transition state is 824.5i cm-1, and the main components
of these frequency modes are the O3-H3 and N1-H3
stretchings, as expected for a proton-migration reaction.
As can be observed from Table 1, the C3-O3 bond starts
to have a double bond character, changing its length from
1.34Å (a) to 1.28Å (c), while the C3-C4 is slightly enlarged.
Table 1. Geometrical parameters (in Å) for the structures of the reaction
path of Figure 4 (S, R)-6
Structure
Distances
O-C3
(a)
1.38
1.34
1.01
1.74
1.35
-
(b)
1.41
1.31
1.22
1.28
1.36
-
(c)
1.42
1.28
1.47
1.11
1.37
-
(d)
1.43
1.23
-
(e)
1.42
1.23
-
(f)
1.40
1.23
-
C3-O3
O3-H3
N1-H3
C3-C4
N2-H2
C4-H2
-
-
-
1.42
1.10
1.85
1.44
1.18
1.66
1.52
2.59
1.10
The intermolecular mechanism (B)
-
-
-
In this mechanism we have considered an intermolecular
proton transfer assisted by the amine and the ammonium
salt, both acting as catalysts of the reaction. It is known
that for some reactions in condensed phase, like the glucose
mutarotation in aqueous solution,30 the solvent-assisted
pathway is much more favored than the intramolecular
pathway. Taking into account this possibility, and once the
ammonium salt can act as another proton donator besides
the chiral alcohol, the following steps were investigated.
(S, R)-6 formation
After the enolate (structure (c)) formation, the
dimethylethylammonium remains in the O1 carbonyl
oxygen vicinities (not shown in Figure 4), and a second
dimethylethylammonium molecule (generated in situ when
the ketene is formed), attacks the C4 carbon atom by the
opposite side, defining the stereochemistry of the final
product. The structure of the reactive complex between
enolate and this second dimethylethylammonium is shown
in Figure 4d. The optimized structure of the transition state
for the C3=C4 bond protonation is shown in Figure 4e. This
transition state is a (S, R)-6 diastereoisomer. The N2-H2
bond is enlarged from 1.10 Å to 1.18 Å, meanwhile the
distance C4…H2 is shortened from 1.85 Å to 1.66 Å. The
reaction barrier of this step is 0.20 kcal/mol. The imaginary
Diastereoisomer (S, R)-6
Firstly, the interaction of the enol intermediate 7(II)
with dimethylethylamine molecule was studied. When this
tertiary amine gets closer to 7(II) over the seven-member
ring, there is an acid-base interaction between the hydroxyl
group and the nitrogen atom that disrupts the hydrogen

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An Alternative Mechanism for the 1,4-Asymmetric Induction in the Stereoselective Addition
J. Braz. Chem. Soc.
Figure 4. Optimized structures for diastereoisomer (S,R): (a) the interaction complex between the enol intermediate and dimethylethylamine, (b) transition
state and (c) enolate; (d) interaction complex between the enolate and the ammonium ion, (e) transition state and (f) (S,R) final product. Structures (a), (c),
(d) and (f) were obtained from an IRC calculation. Relative energies values are at B3LYP and MP2 levels, respectively.
vibrational frequency of this transition state is 489.1i cm-1,
and the main components of the modes of this frequency
are the N2-H2 and C4-H2 stretchings.
molecule which approaches from the opposite side to
carbonyl group of (R)-pantolactone, which by its turn,
comes from the alkyl halide used to generate the ketene
(and not from the pantolactone).
As can be seen from Table 1, the C3-C4 bond character
changes from a double to a single bond, while its length
enlarges from 1.42Å (a) to 1.52Å (c). C4-H2 bond length
is shortened simultaneously. The optimized structures of
(S, R)-6 and the dimethylethylamine molecule (the reaction
products) are shown in Figure 4f. The distance N2…H2
is enlarged to 2.59 Å. The products are more stable than
the reactive complex by 29.3 kcal/mol, resulting in an
essentially irreversible reaction.
Comparing the height of the barriers for enolate
formation and (S,R) ester formation (Figure 4), it can be
said that the enolate generation is the rate determining step,
being the one used in the calculation of the rate coefficient.
In summary, according to this mechanism, we can
picture the diastereoselective addition of (R)-pantolactone
to isopropylphenylketene as occurring via acid-base
reactions in two intermolecular proton transfer steps. It
is important to mention that the proton transferred to the
planar carbon comes from the dimethylethylammonium
Diaestereoisomer (R, R)-6
In this case, the interaction of the enol intermediate 7(II)
with the dimethylethylamine molecule approaching by the
opposite side was studied. When this tertiary amine gets
closer to 7(II) over the seven-member ring, again there is
an acid-base interaction between the hydroxyl group and
the nitrogen atom that disrupts the hydrogen bond in the
ring, twisting the hydroxyl to the same side of amine, and
forming an acid-base complex, which structure is shown
in Figure 5a. The distance N2…H3 is of 1.72 Å.
Enolate formation
As discussed previously, dimethylethylamine is able
to remove the proton H3 through an acid-base reaction.
Figure 5b shows the transition state for this reaction. The

Vol. 22, No. 4, 2011
Silva et al.
763
O3-H3 bond distance is enlarged from 1.01 Å to 1.32 Å,
and N1…H3 distance is shortened from 1.74 Å to 1.18 Å,
both in the transition states after dimethylethylamine
approach. Comparing such values to those of Table 1 for
the (S, R) enolate formation, it is possible to see that the
N1-O3 distance is the same, being the H3 proton in the
(S, R) transition structure closer to the O3 than in the (R, R)
enolate. Table 2 and Figure 5 show all optimized structures
involved in this reaction pathway for the (R, R) product. The
reaction barrier is 3.97 kcal/mol. The imaginary vibrational
frequency is 254.4i cm-1, corresponding to the O3-H3 and
N1-H3 bond stretchings.
In the elementary reaction responsible for the (S, R)-6
(Figure 4e), it can be seen that the dimethylethylamine
molecule interacts simultaneously with the hydroxyl group
and with the carbonyl group of the pantolactone, getting
more stuck than in the (R, R)-6 formation. In the former
case, the conversion from the reactive complex to the
transition state demands an energy cost almost exclusively
to cleave the O3-H3 bond, followed by the transfer of the
H3 proton to the N1 nitrogen atom.
In the case of the (R, R)-6 formation, however, the
dimethylethylamine molecule interacts only with the
hydroxyl group (Figure 5c), since the carbonyl of the
pantolactone is in an opposite side. In this case the
dimethylethylamine molecule has much more mobility and,
consequently, more energy is necessary for the conversion
of the reactive complex to the transition state. It is so
because beyond the energy cost to activate the O3-H3
bond cleavage, it is necessary to do an extra effort for the
orientation and transportation of the dimethylethylamine
to the hydroxyl group.
The difference of 3.02 kcal/mol between the height
of the barriers of this reaction and that schematically
summarized in Figure 4 can be attributed to the very specific
way the dimethylethylamine molecule interacts with the
enol intermediate.
(R, R)-6 formation
It is assumed again that after the formation of enolate
8 the dimethylethylammonium remains close to it, due to
Figure 5. Optimized structures for diastereoisomer (R,R): (a) the interaction complex between the enol intermediate and dimethylethylamine, (b) transition
state and (c) enolate; (d) interaction complex between the enolate and the ammonium ion, (e) transition state and (f) (R,R) final product. Structures (a), (c),
(d) and (f) were obtained from an IRC calculation. Relative energies values are at B3LYP and MP2 levels, respectively.

764
An Alternative Mechanism for the 1,4-Asymmetric Induction in the Stereoselective Addition
J. Braz. Chem. Soc.
Table 2. Geometrical parameters (in Å) for the structures of the reaction
path of Figure 5 (R, R)-6
in this paper. They are all essentially absorbed by the
ZPE corrections causing no alteration whatsoever in our
proposition.
Structure
Distances
O-C3
(a)
1.39
1.35
1.01
1.72
1.35
-
(b)
1.41
1.30
1.32
1.18
1.36
-
(c)
1.42
1.26
1.93
1.02
1.38
-
(d)
1.43
1.23
-
(e)
1.41
1.22
-
(f)
1.37
1.20
-
The solvation effects
C3-O3
O3-H3
N2-H3
C3-C4
N2-H2
C4-H2
Considering the small values found for the reaction
barriers, the differential solvation effects should necessarily
be taken into account. Beside that, the compounds could
react under different ways in solution, and this possibility
does not give place to any kind of generalizations about
the solvent effects in the reactions studied.
-
-
-
1.41
1.01
1.95
1.44
1.24
1.57
1.52
2.65
1.01
-
-
-
All the structures obtained in the previous calculations
of the intermolecular mechanism have been re-optimized
under the solvation effect. These new results show
that the geometrical parameters of the structures of the
intermolecular mechanism are almost identical to those
listed in Tables 1-4. The most significant changes occur
in the values of the reaction barriers, as can be seen from
data reported in Table 3.
electrostatic interactions. That opens the possibility for
8 to be attacked by a second dimethylethylammonium
molecule (generated in situ), in the opposite side of
that the first proton was transferred to. The structure
of the reactive complex between 8 and this second
dimethylethylammonium ion is shown in Figure 5d. The
optimized structure of the transition state for the C3=C4
bond protonation is shown in Figure 5e. This transition state
is an (R,R) diastereoisomer. The reaction barrier of this step
is 1.43 kcal/mol. The imaginary vibrational frequency of
this transition state is 1007.5i cm-1, corresponding to N2-
H2 and C4-H2 stretchings.
Table 3. Solvent effects on the reaction paths of the intermolecular
mechanism (B) studied. Relative energies are in kcal/mol, and the MP2
values between parentheses follow DFT values
Without ZPE
Gas-phase
In PCM
It should be mentioned that in the (R, R)-6 formation,
following this mechanism, the dimethylethylammonium
that donates the proton to the planar carbon gets closer to the
nucleophilic center located in the vicinities of the carbonyl
of the pantolactone, and this could retard this attack.
After inserting our data into equations 2 and 3, the
obtained difference between the barriers heights for
the enolate formation (the rate determining step in this
bimolecular mechanism) is 3.02 kcal/mol. Hence, for this
bimolecular mechanism we obtain a diastereoisomeric
excess SR/RR value above 99:1, which is in very good
agreement with experimental results.5
Formation step
Enolate
(S,R)
(R,R)
3.97
(S,R)
(R,R)
1.23
0.95
(0.43)
0.20
0.41
(0.46)
0.64
(3.10)
1.43
(1.33)
2.94
Ester
(1.59)
(1.10)
(-1.36)
(0.32)
With ZPE
Enolate
Ester
0.46
(-0.73)
-1.75
(0.35)
2.74
(2.21)
0.35
-0.84
(-0.70)
-0.51
0.28
(0.41)
2.20
(0.12)
(-1.45)
(-0.85)
In Figures 4 and 5 we also compare the B3LYP and
MP2 results for reaction barriers. Both methods agree
on the fact that the barriers for the formation of the (S,R)
isomer are lower than the barriers for the formation of the
(R,R) one. Even so, there are some noticeable differences
between the two descriptions. The main physical advantage
of an MP2 calculation in relation to a DFT/B3LYP one
is that in the former the dispersion effects among the
electrons are included in an approximate way. Thus,
differences in the reaction’s barriers may be associated with
differential dispersion effects ascribed to each calculation
type. However, we believe that these differences are of
no practical consequence for the mechanism proposed
From the B3LYP and MP2 descriptions, the solvent
decreases the reaction barriers of the enolate formation step
in both (S, R) and (R, R) diastereoisomer routes. However, in
the chiral ester formation step, the height of the barriers is
larger in both routes if B3LYP energy values are considered,
but decrease in THF if MP2 results are considered. Then,
the solvation effects seem to be determinant not only to
define the enantiomeric excess, but also to identify the
rate-determining step in the reaction. In the gas-phase
the rate-determining step is the enolate formation, but if
the solvent effects are introduced in the calculations, it is
no longer possible to assure this. The inclusion of ZPE
corrections does not alter the prediction of the observed

Vol. 22, No. 4, 2011
Silva et al.
765
stereoselectivity. However, the resultant negative barriers
preclude us from the calculation of the enantiomeric excess.
The kinetics associated with reactions in multicomponent
solutions is very complex. The full role of the charged
species is not entirely clear. Hence, one should not expect
the present kind of study, and also the other ones present
in the literature, to provide the ultimate dynamic picture of
all processes relevant for the outcome of the reaction. What
should be expected is a proposal that does not contradicts
existent data, yielding at the same time useful insights on
the possible mechanism of the process in question. The very
good agreement between the calculated diastereoisomeric
excess (without ZPE corrections) and the experimental
value gives us confidence that we are in the right track.
donate its proton to the C=C double bond to give the desired
products, the (S, R)-6 and (R, R)-6. In the mechanism here
proposed the transferred proton comes from the alkyl
halide used to generate the ketene in situ, since (at least
in the beginning of the reaction) the ammonium salt is
obtained when hydrochloric acid is formed. According
to this mechanism, the amount of amine present in the
reaction medium is a key point for this reaction to work, as
confirmed by experiments.14 There must be enough amine
to promote the enolate formation (first and determinant
step of mechanism B) but not great excess, since it would
dilute the ammonium salt that attacks the planar carbon
(second step of mechanism B). Mechanism B is also able to
explain the role of a chiral hydroxyl, a to a carbonyl group,
a characteristic needed for a good chirality inductor. Our
main conclusion is that the specific side from which the
neutral and protonated dimethylethylamine approaches to
the enol intermediate defines the stereochemical outcome.
The diastereoisomeric ratio is determined by the relative
values of the reaction barriers heights of the protonation
step of the C=C double bond. The theoretically calculated
value for the diastereoisomeric ratio agrees with the
experimental result thereby confirming the soundness of
the proposed mechanism.
Differently from Cannizzaro and Houk’s mechanism
where the stereoselectivity is determined by the addition
step that generates an enol intermediate unable to rotate due
to a high energy barrier, we suggest in mechanism (B) that
the stereoselectivity is defined during the tautomerization,
by the side that the ammonium ion is approached to the
enolate. The use of polar solvents, that could solvate
better the ammonium salt, would certainly decrease the
diastereoselectivity of the Merck process, as in fact was
observed experimentally. This proposition also explains the
kinetic isotopic effect observed for deuterated alcohols31 (in
this case the pantolactone), once its proton is withdrawn
by the neutral amine.
Conclusions
In this work the synthetic route leading to the 1-4
asymmetric induction in the preparation of 2-phenyl-
propionatepantolactonylesterwastheoreticallyinvestigated.
It was experimentally observed that diastereoisomeric ratio
(S, R)-6 / (R, R)-6 is about 99:1. 5,14
Two mechanisms have been considered to study the
stereoselectivity: one assumes the intramolecular proton
transfer, and the other assumes the intermolecular proton
transfer through the assistance of dimethylethylamine
and dimethylethylammonium chloride. A very stable enol
intermediate bearing a seven-member ring, generated
through the addition of the ketene and (R)-pantolactone
was considered as the starting reactant in both cases. The
calculations have been carried out at DFT/B3LYP and MP2
levels with the 6-311G(d,p) basis set.
The results obtained have shown that the intramolecular
mechanism is not able to account for different reaction
barriers that would be consistent with the experimentally
observed diastereoisomeric excess. Due to the small
size of the proton, it cannot be held responsible for the
observed enantioselectivity since in practice the two
possible available faces for the proton transfer cannot be
differentially blocked. Hence this channel was discarded
as a reaction path.
The intermolecular mechanism considers the active
participation of the dimethylethylamine. Firstly, a neutral
dimethylethylamine molecule interacts with the seven-
membered ring of the enol intermediate 7(II), and a specific
acid-base interaction is established between the hydroxyl
group of enol and the nitrogen atom of dimethylethylamine.
The neutral dimethylethylamine is able to remove the proton
to generate an enolate ion 8 and a dimethylethylammonium
ion. In the sequence, another dimethylethylammonium ion
already available in the reaction medium, is considered to
The effects of solvation were also considered and their
results are similar to those in gas-phase for the geometrical
parameters. The noticeable changes occur in the values
of the reaction barriers. The solute-solvent interaction
decreases the reactions barriers of the enolate formation
from 0.95 to 0.41 kcal/mol in the (S, R) diastereoisomer
route, and from 3.97 to 1.23 kcal/mol in the (R, R)
diastereoisomer route. From these results it can be inferred
that the conversion from reactive complexes between amine
and enol intermediate to the transition states is favored in
the solvent medium.
Finally, two possible investigations can be performed
to validate (B) mechanism here proposed, because in it the
proton transferred to the enolate comes from the alkyl halide

766
An Alternative Mechanism for the 1,4-Asymmetric Induction in the Stereoselective Addition
J. Braz. Chem. Soc.
used to generate the ketene in situ. One possibility would be
to deuterate the alkyl halide used and control the formation
of a deuterated product. The other possibility, perhaps
still more efficient, would be to work with a deuterated
pantolactone. If the product and the ammonium salt in
solution are found both deuterated, Cannizzaro and Houk’s
proposition as well as our (B) mechanism, respectively, are
possible channels.
In summary, in this paper we provided an alternative
mechanism for the 1-4 asymmetric induction in the
preparation of 2-phenyl-propionate pantolactonyl ester. The
calculated enantiomeric excess is in excellent agreement
with the experimental results. The singular characteristic of
the present proposal, in contrast to the ones in the literature,
is the utilization of two different amine molecules as proton
acceptor and donor. This brings a more realistic flavor to
the proposed mechanism, since it is an experimental fact
that for the reaction to take place the amine should be in a
definite concentration.
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Acknowledgments
Alexander M. Silva, Clarissa O. Silva and André G. H.
Barbosa thank the Brazilian agency FAPERJ for financial
support given to this work. Clarissa O. Silva thanks also
CNPq. The authors would like to acknowledge Prof. Carlos
Maurício Rabello de Sant’Anna for helpful discussions.
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