The role of fluorine in the stereoselective tandem aza-Michael addition to acrylamide acceptors: An experimental and theoretical mechanistic study

Article abstract of DOI:10.1002/chem.200700393

Aza-Michael additions of αamino esters to fluorinated acceptors take place in a highly stereoselective manner, to give partially modified ψNHCH₂]retropeptides incorporating a hydrolytically stable trifluoroalanine mimic. The reaction mechanism

Full text of DOI:10.1002/chem.200700393

DOI: 10.1002/chem.200700393
The Role of Fluorine in the Stereoselective Tandem Aza-Michael Addition to
Acrylamide Acceptors: An Experimental and Theoretical Mechanistic Study
Santos Fustero,*[a] Gema Chiva,[a] Julio Piera,[a] Alessandro Volonterio,[b]
[d]
Matteo Zanda,[c] Javier Gonzµlez,[d] andAntonio Morµn Ramallal*
Abstract: Aza-Michael additions of a-
amino esters to fluorinated acceptors
take place in a highly stereoselective
manner, to give partially modified Y-
effect of the trifluoromethyl group on
the reactivity and the origins of the ex-
perimentally observed stereocontrol.
The reaction is a two-step process, in-
volving a tandem aza-Michael addition
followed by a stereoselective hydrogen
transfer. Both steps are base-catalyzed.
The high level of stereocontrol is the
result of a combination of electrostatic
interactions and steric effects.
A
Keywords:
density
functional
hydrolytically stable trifluoroalanine
mimic. The reaction mechanism has
been investigated experimentally and
theoretically, in order to explain the
calculations · diastereoselectivity ·
fluorine chemistry
·
Michael
reaction · peptides
Introduction
these moieties are versatile building blocks for the synthesis
of nitrogen-containing compounds such as 1,3-amino alco-
hols, b-amino ketones, b-amino acids, and b-lactams.[3]
The most conventional approaches to accessing these de-
rivatives are the Mannich reaction and the conjugate addi-
tion of amines and their synthetic equivalents to a,b-unsatu-
rated carbonyls. While the classic Mannich-type protocols
often suffer from harsh conditions and long reaction times,[4]
the asymmetric aza-Michael reaction has emerged during
the last five years as a very powerful tool for the creation of
carbon-nitrogen bonds, owing to its simplicity and atom
economy. Furthermore, this reaction is economical and envi-
ronmentally friendly, as no catalyst is generally required in
the process. There are three major strategies to achieving
asymmetric induction: either by using chiral amines or
chiral Michael acceptors or by incorporating chiral ligands
in a stoichiometric or catalytic manner.[5] However, the cata-
lytic enantioselective aza-Michael reaction still poses a big
challenge in synthetic organic chemistry. Although several
efforts have recently been made in this area,[6] to date a gen-
eral method to perform this transformation is practically un-
known.[7]
b-Amino carbonyl functionalities are found in a large
number of alkaloids and polyketides.[1] Among them, b-
amino acids are of crucial importance, as they constitute the
structural units of b-peptides, compounds that have proved
to be promising biostable peptidomimetics,[2] and so the im-
portance of this field has grown exponentially. In addition,
[a] Prof. Dr. S. Fustero, Dr. G. Chiva, Dr. J. Piera
Departamento de Química Orgµnica
Universidad de Valencia
46100 Burjassot, Valencia
and
Laboratorio de MolØculas Orgµnicas
Centro de Investigación Príncipe Felipe
46013 Valencia (Spain)
Fax : (+34)963-544-939
E-mail: santos.fustero@uv.es
[b] Dr. A. Volonterio
Dipartimento de Chimica, Materiali, ed Ingegnieria Chimica
“Giulio Natta Politecnico di Milano via Mancinelli 7
20131 Milano (Italy)
[c] Dr. M. Zanda
On the other hand, a-(trifluoromethyl)acrylic acid[8] rep-
resents an attractive fluorinated building block for the prep-
aration of fluorinated b-amino acid derivatives[9] and several
other classes of biologically active compounds. In this con-
text, in 1991 Ojima described the preparation of fluorinated
captopril analogues by conjugate addition of thiolacetic acid
to the Michael acceptor derived from a-(trifluoromethyl)-
C.N.R.-Istituto di Chimica del Riconoscimento Molecolare (ICRM)
via Mancinelli 7, 20131 Milano (Italy)
[d] Prof. J. Gonzµlez, A. M. Ramallal
Departamento de Química Orgµnica e Inorgµnica
Universidad de Oviedo, 33071 Oviedo (Spain)
E-mail: figf@unioui.es
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
acrylic acid and l-proline.[10] More recently, Pellacani
et al.[11a] have reported a diastereoselective aza-Michael ad-
dition of carbamate derivatives to 2-(trifluoromethyl)acry-
lates, affording different addition products depending on the
reaction conditions. Avenoza and co-workers also published
a two-step non-Michael-type strategy for the preparation of
(S)-a-CF3-isoserine, combining a Sharpless dihydroxylation
with the formation of cyclic sulfamidates or sulfates.[11b]
Finally, the highly diastereoselective aza-Michael addition
of a-amino esters to N-trifluorometacryloyl a-amino acids
has recently been reported to be an extremely valuable
route to partially modified Y[NHCH2]retropeptides incor-
G
porating a hydrolytically stable trifluoroalanine mimic.[12,13]
The reaction features an unusually high 1,4-asymmetric in-
duction, which is strongly dependent on several experimen-
tal factors, such as solvent, catalytic base, R1 and R2 chains,
and relative stereochemistry of the reaction partners
(Scheme 1).
The process might be viewed as a tandem aza-Michael/hy-
drogen transfer in two steps: a nonstereogenic aza-Michael
addition of 1 to 2, which affords an amide enol intermediate,
followed by its tautomerization to 3, which is the actual ste-
reogenic step.
Scheme 1. Stereoselective aza-Michael additions to CF3-containing acryl-
amide acceptors.
The highest 1,4-asymmetric induction (up to 42:1) was ob-
served with apolar solvents (such as CCl4), together with the
use of 1,4-diazabicyclo
A
Results andDiscussion
amine as catalytic bases[14] and bulky R1 and R2 side-chains
(such as isopropyl and isobutyl groupings). The hydrogen
atom of the newly created stereocenter in the major diaste-
reoisomer of 3 is in an anti configuration with respect to the
R2 group (Scheme 1). However, some key aspects, such as
the full scope of the reaction and particularly the detailed
mechanism of the process and the origin of the diastereose-
lectivity have remained unsolved until now.
With regard to the scope of the process, several representa-
tive examples of nucleophiles 1 and Michael acceptors 2 de-
rived from a-amino ester hydrochlorides and aliphatic
amines [such as (S)-a-methylbenzylamine and (S)-a-methyl-
a-naphthylamine] were tested. Table 1 summarizes the re-
sults obtained. We observed that, although the process
works well independently of the nature of the starting mate-
rials, the best results in terms of diastereoselectivity were
obtained with Michael acceptors and nucleophiles derived
from a-amino esters (entries 1–4, Table 1). An absence of
carbonyl groupings in both 1 and 2 considerably reduced the
efficiency of the process (entry 12, Table 1), while intermedi-
ate situations appear in the cases in which only one carbonyl
grouping is present either in the nucleophile (entries 6 and
8, Table 1) or in the Michael acceptor (entries 9–11,
Table 1).
Here we address these two aspects of the process, both
from an experimental and from a theoretical point of view.
Abstract in Spanish: Las adiciones aza-Michael de a-amino
With regard to the nature of the R1 and R2 chains, we
found that the best stereocontrol was achieved with bulky
groups such as isobutyl and isopropyl (that is, with leucine
and valine derivatives: i.e., iBu>iPr>>Me; see, for exam-
ple, entries 1 vs 2 and 3 vs 13, Table 1). In addition, no sig-
nificant effects involving the nature of the ester groupings
were observed (entries 2, 3, and 4, Table 1).
Another important aspect of the process, relating to the
finally obtained stereoselectivity, is the stereochemistry of
the starting partners 1 and 2 (that is, the knowledge of the
matched/mismatched pair). The configurations of 1 and 2
thus had a significant effect, as demonstrated by the use of
matched/mismatched pairs of the nucleophiles l- and d-Ala
methyl esters and the Michael acceptor l-Ala methyl ester
Østeres a aceptores fluorados tienen lugar de un modo alta-
mente
estereoselectivo,para
dar
lugar
a
Y-
ACHTREUNG
poran un mimØtico de trifluoroalanina,estable frente a la hi-
drólisis. El mecanismo de la reacción ha sido investigado ex-
perimental y teóricamente,a fin de explicar el efecto del
grupo trifluorometilo en la reactividad y en los orígenes de
estereocontrol observado experimentalmente. La reacción es
un proceso en dos pasos,que implican una adición aza-Mi-
chael seguida de una transferencia estereoselectiva de hidró-
geno. Ambos pasos estµn catalizados por una base. El origen
del alto grado de estereocontrol radica en una combinación
de interacciones electrostµticas y efectos estØricos.
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S. Fustero, A. M. Ramallal et al.
Table 1. Reactants and conditions in the aza-Michael addition.
In the light of these results,
we can conclude that the pres-
ence of at least one CO group-
ing in 1 and/or 2 (entries 4, 6,
and 10 vs 12), as well as a base
(DABCO or Me3N) as catalyst
(entries 4 vs 5), are necessary in
order to obtain high 1,4-asym-
metric induction. Furthermore,
Entry[a]
3[b]
X1
R1
X2
R2
dr[c]
42:1
Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3a
3b[d]
3c
CO2Bn
CO2Bn
CO2Me
CO2tBu
CO2tBu
CO2tBu
CO2tBu
CO2tBu
a-C10H7
Ph
iBu
iPr
iPr
iPr
iPr
iPr
iPr
iPr
Me
Me
H
CO2Bn
CO2Bn
CO2Me
CO2tBu
CO2tBu
Ph
iBu
iPr
iPr
iPr
iPr
Me
Me
Me
iPr
iPr
iPr
Me
Me
Me
95
95
89
90
82
77
78
84
84
64
95
60
95
70
38:1
33:1
33:1
6:1[e]
17:1[f]
2:1[g]
15:1
6:1
3d[d]
3d
3e
3 f
Ph
3g
3h
3i
3j
3k
3l
a-C10H7
CO2tBu
CO2tBu
CO2tBu
Ph
the
trifluoromethyl
(Tfm)
8:1
8:1
group plays a critical role in the
process.
Ph
Ph
CO2Me
CO2Me
Me
Me
Me
3:1
CO2Me
CO2Me
9:1[f]
2:1[g]
In order to test these mecha-
nistic hypotheses, a theoretical
study was carried out. The po-
tential energy surfaces corre-
sponding to the model reactions
3m
[a] The S,S combination was used unless otherwise indicated. [b] Reaction conditions: DABCO (1 or 2 equiv)
(see Experimental Section), CCl4, 08C to RT. [c] Diastereoisomeric ratio (dr) a/b determined by 19F NMR
spectroscopy. [d] See ref. [12]. [e] Uncatalyzed reaction. [f] Matched pair: (S,S,S/S,R,S). [g] Mismatched pair:
(R,S,S/R,R,S). The R,S combination (nucleophile 1, Michael acceptor 2) was used in this case.
(entries 13 and 14, Table 1), and also with the mixed pair of
l-Val tert-butyl ester and (S)- and (R)-a-methylbenzylamine
as Michael acceptors (entries 6 and 7, Table 1). In both
cases, the like 1/2 combination (S/S or R/R) provided the
higher diastereoselectivity; see, for example, 3e vs 3 f (en-
tries 6 and 7, Table 1), and 3l vs 3m (entries 13 and 14,
Table 1).
In addition, a comparison of the base-catalyzed vs the un-
catalyzed reaction was also studied. Thus, while the diaste-
reoisomeric ratio was 33 to 1 in the case of 3d, it was only 6
to 1 in the uncatalyzed process (entry 4 vs entry 5, Table 1).
Another interesting feature of this process involves com-
parison of the reactivities of the fluorinated counterparts on
the one hand, and the nonfluorinated ones on the other. For
this purpose, acryloyl and metacryloyl Michael acceptors 2
derived from l-valine a-amino tert-butyl ester (R=H, Me)
were treated with different nucleophiles [such as 1 (X1 =
CO2tBu, R1 =iPr and X1 =Ph, R1 =H)] (Scheme 2). In all
of acrylamide acceptors 4a–d
(Figure 1) with methylamine
and trimethylamine as nucleo-
phile and base, respectively,
were explored with the aid of used in the model calculations.
electron density functional
Figure 1. Acrylamide acceptors
theory, with use of the B3LYP/
6-31G* hybrid functional.[15]
The theoretical study of the stereochemical course of the
reaction was carried out with the Michael acceptors (S)-2l
(R2 =Me, X2 =CO2Me, R=CF3) and (S)-2c (R2 =iPr, X2 =
CO2Me, R=CF3), together with the amines (S)-1l, (R)-1l
(R1 =Me, X1 =CO2Me), and (S)-1c (R1 =iPr, X1 =CO2Me)
(see Scheme 1 and Table 1).
Nucleophilic addition step of methylamine to the Michael
acceptors 4a–d: As the starting point of our study, we ana-
lyzed the model systems 4a–d, finding two possible reaction
pathways for the nucleophilic addition of the methylamine
to the Michael acceptors. The first step of the reaction is the
attack of the nucleophilic nitrogen of methylamine at the b-
carbon of the a,b-unsaturated system. In the four cases ana-
lyzed, the addition reaction appears to start through the for-
mation of a ternary complex 5 between the nucleophile, the
Michael acceptor, and the base (trimethylamine) (Figure 2).
Of course, the calculations reported in this work represent
the situation under gas-phase conditions, but the experimen-
tal situation, which involves the use of nonpolar solvents,
such as CCl4, could be quite similar. In nonpolar solvents
such as CCl4 the formation of these type of hydrogen-
bonded complexes can be expected. In all cases, the nucleo-
philic amine forms a hydrogen bond with the oxygen of the
Michael acceptor and the base (that is, the trimethylamine).
The geometries of the four complexes 5a–d are very similar.
These complexes are stabilized with respect to the isolated
reactants by approximately 4–16 kcalmolꢀ1 (Table 2).
Scheme 2. Unsuccessful aza-Michael additions.
cases, however, under the same reaction conditions
(DABCO, CCl4, and rt), the process did not work at all and
the starting materials were recovered. Similar results were
obtained when a-fluoroacryloyl Michael acceptors deriva-
tives 2 (R=F) were used as starting materials (Scheme 2).
The next step in the reaction pathway is the nucleophilic
addition of the methylamine to the acrylamide acceptors 4,
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Stereoselective Aza-Michael Additions
FULL PAPER
Figure 2. Starting ternary complexes on the potential energy surface.
Figure 3. Transition structures for nucleophilic additions of methylamine
to s-trans- and s-cis-Michael acceptor 4a, together with zwitterionic inter-
mediate 7.
Table 2. Energies of the stationary points located for the Michael addi-
tions of methylamine to acrylamides 4a–d.
Stationary point
Relative energy[a]
Relative energy[b]
5a
5b
5c
5d
6a-trans
7
6a-cis
8a
6b-cis
6c-cis
6d-cis
8b
8c
8d
9a
9b
9c
9d
10a
10b
10c
10d
ꢀ10.5
ꢀ4.7
ꢀ16.5
ꢀ10.9
18.2
0.0
0.0
0.0
(methylamine), either to the Ca or to the oxygen of the Mi-
chael acceptor (Figure 3).
On the other hand, when the Michael acceptor reacts in
the s-cis conformation, this results in a different reaction
pathway. Thus, in the case of the acrylamide 4a, the transi-
tion structure 6a-cis shows the trimethylamine hydrogen-
bonded to one of the hydrogens of the methylamine NH2
grouping, and in addition, a hydrogen bond between the car-
bonyl group and one of the hydrogens of the methylamine
(Figure 4).
0.0
28.7
26.8
18.2
8.2
16.3
24.4
6.3
16.3
7.7
ꢀ2.3
14.0
7.9
ꢀ4.5
0.4
5.1
ꢀ1.2
ꢀ9.5
20.3
24.8
17.3
ꢀ15.3
1.4
30.8
29.5
33.7
16.0
ꢀ17.4
ꢀ15.3
ꢀ10.3
ꢀ15.5
5.1
ꢀ27.9
ꢀ20.0
ꢀ26.7
ꢀ26.4
[a] Relative energy [kcalmolꢀ1] with respect to isolated reactants. [b] Rel-
ative energy [kcalmolꢀ1] with respect to ternary complexes 5.
ꢀ
leading to the formation of a C N bond. However, we
reached different results depending on the conformation of
the Michael acceptor (Figure 3).
Thus, when the Michael acceptor 4a (R=H) reacts in the
s-trans conformation, the transition structure 6a-trans is lo-
cated. This transition structure shows an imaginary vibra-
tional normal mode corresponding to the formation of the
Figure 4. Transition structure for the nucleophilic addition of the amine
to the s-cis conformation of the Michael acceptor 4a, together with
amide–enol intermediate 8a.
ꢀ
N Cb bond leading to the zwitterionic intermediate 7. The
transition structure 6a-trans and intermediate 7 are 18.2 and
16.3 kcalmolꢀ1 above the reactants, respectively. In the inter-
ꢀ
mediate 7 the N Cb bond is fully formed, but no hydrogen
atom is transferred from the nitrogen of the nucleophile
The normal mode associated with the imaginary vibra-
tional frequency of 6a-cis corresponds mainly to the stretch-
ꢀ
ing of the forming N Cb bond, with no significant contribu-
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S. Fustero, A. M. Ramallal et al.
[16]
ꢀ
tion from the N H stretching. According to the IRC cal-
culations, the enol–amide intermediate 8a is formed.
The reaction barrier for the nucleophilic addition of the
methylamine to the acrylamide 4a to form 8a is substantial-
ly lowered in relation to the process in which the Michael
acceptor reacts in the s-trans conformation (Table 2). In the
intermediate 8a, one of the hydrogens of the nucleophile is
transferred to the oxygen of the Michael acceptor, and
forms a short hydrogen bond (1.747 Š) with the nitrogen of
the methylamine fragment (Figure 4). According to these re-
sults, the addition of the methylamine to the s-cis conformer
of the Michael acceptor 4a could be considered a concerted,
yet highly asynchronous, reaction.
While the two reaction pathways each involve a charge
separation (due to the charge transfer from the amine to the
electrophilic Michael acceptor), in the case of the addition
to the s-cis conformer of 4a an intramolecular hydrogen
bond is present in the corresponding transition structure 6a-
cis (Figure 4), which is stabilized as a result, relative to 6a-
trans. The role of intramolecular hydrogen bonds in Michael
additions for reactions between enamine derivatives and ni-
troethylene has been described before.[17,18] In addition, it
should be noted that an analysis of the magnitude of the
charge transfer from the methylamine-triethylamine frag-
ment to the Michael acceptor moiety in 6b-cis and 6b-trans,
based on the Mulliken charges, shows that in the case of the
transition structures 6b-trans the charge transfer is greater
than in the transition structure 6b-cis. This is reflected in
the values of the dipole moments of the two transition struc-
tures: 4.152 D in 6b-cis versus 7.126 D in 6b-trans.
ꢀ
Figure 5. Transition structures for the addition to the s-cis Michael ac-
ceptors and neutral enol–amide intermediates.
It is interesting to note that the distance between the N
H hydrogen of the amide grouping and one of the fluorine
atoms of the Tfm grouping in transition structure 6d-cis is
very short (2.121 Š). This interaction, which is absent in all
the other transition structures located and seems to be elec-
trostatic in nature,[19] might contribute in maintaining the ri-
gidity of this moiety, a feature that can be crucial in the con-
trol of the stereoselectivity of the reaction.
havior is in full agreement with the experimental results
showing that the acrylamide acceptors of type 4a–c are un-
reactive in this aza-Michael process, while the reaction with
the Tfm-containing system takes place very easily. This sit-
uation can be interpreted in terms of Frontier Molecular Or-
bital theory,[20] by considering the energies[21] of the LUMOs
of the Michael acceptors.[22] The Tfm group greatly stabilizes
the LUMO of 4d, relative to the other acrylamide deriva-
tives, making this Michael acceptor more electrophilic than
in the case of the methyl group or the hydrogen.[23] On the
other hand, the LUMO of the fluoroacrylamide 4c is low-
ered, but not sufficiently to make this compound a good Mi-
chael acceptor, as can be seen from the values of the activa-
tion energy for the nucleophilic addition (transition struc-
ture 6c-cis, and Table 2); indeed, the corresponding fluoroa-
crylamide proved to be unreactive in this process.
The Michael reactions of acrylamides 4b, 4c, and 4d (see
Figure 1), in the s-cis conformation, were studied at the
same level of theory, resulting in potential energy surfaces
quite similar to the one found in the case of 4a. In Figure 5,
the transition structures 6b-cis, 6c-cis, and 6d-cis, located
for the nucleophilic addition, and the corresponding enol–
amide intermediates 8b–d, formed in the reaction, can be
found.
Another interesting result that can be seen in the previous
data is the great difference in the reactivities of the Michael
acceptors 4a–c and 4d. The presence of the trifluoromethyl
group thus stabilizes the corresponding transition structure
(6d-cis) extraordinarily for the nucleophilic addition, result-
ing in a barrier significantly lower than in the cases of Mi-
chael acceptors 4a–c (Table 2). The difference in the reactiv-
ities of the Michael acceptors 4a–d is also reflected in the
The potential energy surface for the nucleophilic addition
to the s-cis Michael acceptor was also studied at a higher
level of theory. The stationary points for the reaction path-
way in the addition of methylamine to 4a (see Figure 1),
both in the presence and in the absence of ammonia as the
catalytic base, were located at the MP2/6-31G* level of
ꢀ
lengths of the forming N Cb bonds in the corresponding
transition structures: 6c-cis proves to be a late transition
structure in comparison with 6d-cis (see Figure 5). This be-
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Stereoselective Aza-Michael Additions
FULL PAPER
theory (see Supporting Information section, Figure S1). The
results of this study are similar to those obtained with DFT.
Also, as indicated before (see Figure 5, 6d-cis), an electro-
ꢀ
static interaction exists between the hydrogen of the CON
H grouping and one of the fluorine atoms. The distance be-
tween the hydrogen and fluorine atoms is 2.118 Š.[19]
As can be observed from the data in Table 2 and Figure 8,
the Tfm group reduces the activation energy for the intra-
molecular hydrogen transfer step, relative to the cases of
other Michael acceptors. This effect could be explained by
taking account of the fact that the interaction between the
Michael acceptor moiety and the trimethylammonium frag-
ment in the transition structures for the hydrogen transfer is
mainly electrostatic. Consequently, the Michael acceptor
moiety can be regarded as an enolate species. In this situa-
tion, the presence of the strongly electron-withdrawing Tfm
group causes a greater stabilization of transition structure
9d (Figure 6) than in the cases of 9a–c, in which there is no
stabilizing group.
Intramolecular hydrogen transfer in the enol–amide inter-
mediates 8: After the formation of the enol–amide inter-
mediates 8, we located the transition structures for the hy-
drogen transfer from the nucleophile moiety to the a-
carbon atom. This is an important step because it is at this
point that the new stereogenic center is formed. The Mi-
chael adducts 10 (Figure 8) are formed by hydrogen transfer
from the nitrogen of the nucleophile to the a-carbon. The
transition structures for this step are shown in Figure 6.
Catalytic effect of the base: Moreover, the trimethylamine
also acts as a catalyst for the intramolecular hydrogen trans-
fer from the nucleophilic nitrogen to Ca in the Michael ac-
ceptor, also playing a catalytic role in the addition step.
Also in the uncatalyzed reaction, the Michael acceptor and
methylamine form a binary complex 11, and the addition to
Cb in the unsaturated system takes place through a transi-
tion structure 12, very similar to those found in the case of
the catalyzed reaction, resulting in the enol–amide inter-
mediate 13. However, the activation barrier for the addition
step of methylamine to 4d, in the absence of trimethyla-
mine, amounts to 12.0 kcalmolꢀ1, which is twice the corre-
sponding value for the activation barrier of the Me3N-cata-
lyzed reaction (Figure 7). This effect is also reflected in the
Figure 6. Transition structures for the intramolecular hydrogen transfer.
The hydrogen atom that is being transferred is simultane-
ously bonded to the trimethylamine fragment, to the nitro-
gen of the nucleophile, and to the a-carbon atom. There is
also a hydrogen bond between the nitrogen of the nucleo-
phile and the oxygen of the carbonyl in each of the four
transition structures located. Analysis of the normal mode
associated with the imaginary frequency of the transition
structures 9a–d shows that the trimethylammonium frag-
ment acts as a carrier of the hydrogen between the nitrogen
and the carbon atoms. These structures are quite similar to
those found by Houk and co-workers for enol–keto tauto-
merizations.[24]
Figure 7. Uncatalyzed addition of methylamine to 4d (bottom ) in com-
parison with the Me3N-catalyzed reaction (top).
ꢀ
fact that 12 is a late transition structure (R
1.833 Š) in relation to the transition structure 6d-cis (see
A
Figure 5) for the nucleophilic addition in the catalyzed reac-
ꢀ
tion (R
A
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8535

S. Fustero, A. M. Ramallal et al.
The geometries of the transition structures for the hydro-
gen transfer step also help to explain the different results
obtained when triethylamine is used as base, instead of
DABCO or trimethylamine.[12] Because of the great steric
congestion in the transition structure 9d (Figure 6), the use
of a base with higher steric requirements, such as triethyla-
mine (relative to DABCO or trimethylamine), will result in
a severe distortion of the transition structure, which in turn
will cause a decrease in the stereoselection.
step and for the intramolecular hydrogen transfer. This
effect can be specifically attributed to the presence of the
Tfm group, which is critical for the reaction, as discussed in
the previous analysis of the Khon–Sham frontier orbitals.
Origin of the stereoselectivity: The stereogenic center
formed in the aza-Michael addition of an amine derivative
to the acrylamide acceptor 4d is created in the second step
of the reaction: namely, the intramolecular hydrogen trans-
fer from the nucleophile nitrogen to the Ca carbon atom. In
order to understand the factors underlying the stereocontrol
in this step, we studied the aza-Michael reactions of accept-
or (S)-2l with the alanine-derived amines (S)-1l and (R)-1l
to give the Michael adducts 3l and 3m (see Scheme 3 and
Table 1, entries 13 and 14).
In the first case, we have pair-matched reactants, while
the second reaction is an example of a mismatched pair re-
action. According to the experimental data shown in
Table 1, the stereoselection is notably greater in the case of
the pair-matched reaction. In addition, the reaction between
the most sterically demanding Michael acceptor (S)-2c,
bearing an isopropyl group, and the amine (S)-1c, leading to
the product 3c (Table 1, entry 3), was studied in order to
According to the calculations, the addition of a primary
amine derivative to the Michael acceptors 4 is a stepwise
process. The first step corresponds to the formation of the
ꢀ
Cb N bond in a reaction leading to an enol–amide inter-
mediate, undergoing an intramolecular hydrogen transfer
step from the nitrogen to the Ca carbon atom, to generate
the new stereogenic center. The trimethylamine acts as cata-
lyst in the two steps. The different reaction pathways are
compared in Figure 8, and it can be seen that the second
step is rate-determining.
The data shown in Figure 8 and Table 2 indicate that the
increased reactivity shown by the trifluoromethylacrylamide
acceptor 4d, relative to the analogous systems 4a–c, is relat-
ed to the very low barriers both for the nucleophile addition
Figure 8. Reaction pathways for the addition of methylamine to the Michael acceptors 4a–d.
8536
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Chem. Eur. J. 2007, 13, 8530 – 8542

Stereoselective Aza-Michael Additions
FULL PAPER
Figure 9. The three saddle points located for the intramolecular hydrogen
transfer step in the reaction between (S)-2l and (S)-1l. Relative energy
in kcalmolꢀ1
.
Scheme 3. Influence of the steric demand and the absolute configuration
of the reactants on the aza-Michael reaction.
shed light on the steric effects on the asymmetric induction.
In this case, the reaction stereoselectivity showed a great in-
crease when compared with the previous reactions of the
methyl-containing reactants (entries 13 and 14 vs 3, Table 1).
All the stationary points for the reaction between (S)-2l
and (S)-1l were located (see Supporting Information). The
potential energy surface is qualitatively similar to that found
for the simple Tfm-acrylamide model 4d.
In spite of the observed similarities, however, we found
three different saddle points (14-I, 14-II, and 14-III; see
Figure 9) for the intramolecular hydrogen transfer step,
leading to the major diastereoisomer 3la (see Scheme 3).
There are significant differences in the relative positions of
the ester groupings in the three cases. Also, the three saddle
points differ in energy, 14-I being the most stable one, by 3.6
and 5.3 kcalmolꢀ1 respectively, in relation to 14-II and 14-
III.
Figure 10. Transition structures leading to the diastereoisomers 3la and
3lb, respectively. Relative energy in kcalmolꢀ1
.
One of the keys to understanding of these differences lies
in the interactions between the carbonyl groups of the esters
and the hydrogens of the partially positively charged trime-
thylammonium fragment. The oxygen atoms of the carbonyl
groups are able to form hydrogen bonds with the hydrogens
of the Me3HN+ fragment, thus stabilizing its cationic char-
acter.
As can be seen in Figure 10, this transition structure is
1.4 kcalmolꢀ1 less stable than 14-I, thus indicating that dia-
stereoisomer 3la will be formed preferentially.
It should be noted that according to the experimental
data,[12] the polarity of the solvent strongly influences the
diastereomeric ratio of the reaction. The best stereocontrol
is achieved with the least polar solvent (CCl4). This result
can be understood if it is taken into account that the pres-
ence of solvents able to form intermolecular hydrogen
bonds disrupts the network of intramolecular hydrogen
bonds, previously described and depicted in Figures 9 and
10.
The role of this type of O···HCN+ hydrogen bonding has
previously been analyzed by Houk and co-workers,[25] while
its influence on the control of the stereoselectivity of Diels–
Alder reactions has also been described.[26] According to
these results, 14-I is the true transition structure for the for-
mation of 3la. Moreover, the transition structure 15-I, lead-
ing to the diastereoisomer 3lb, was located (Figure 10).
Chem. Eur. J. 2007, 13, 8530 – 8542
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8537

S. Fustero, A. M. Ramallal et al.
It is interesting to note that the difference between the
transition structures leading to the two possible diastereoiso-
mers is reduced in the case of the mismatched approach
(Figure 11), in good agreement with the experimental re-
Figure 12. Diastereoisomeric transition structures for the intramolecular
hydrogen transfer in the reaction between (S)-2c and (S)-1c. Relative
energy in kcalmolꢀ1
.
agreement with the experimental observation showing that
the stereoselectivity strongly decreases if the reaction is car-
ried out in a solvent capable of forming hydrogen bonds
with the reactants.
Figure 11. Transition structures 16 and 17 for the mismatched reaction.
Relative energy in kcalmolꢀ1
.
In addition to the previous considerations, there also
needs to be consideration of i) whether the steric effects of
the two stereocenters on the stereocontrol are additive, and
ii) if this is the case, what is the main factor determining the
differences in energy between the transition structures lead-
ing to the diastereoisomers?
We have analyzed the differences in energy (DE) of the
diastereomeric pairs of transition structures for the reactions
of the Michael acceptors (S)-2l
and (S)-2c with the amines (S)-
1l, (R)-1l, and (S)-1c (see
Scheme 3), and have tried to
correlate them with the geome-
sults. Thus, in the reaction between (S)-2l and (R)-1l
(Scheme 3), the diastereoisomer ratio is reduced to 2:1. In
this case the transition structure 16, leading to the major ste-
reoisomer 3ma, is only 0.8 kcalmolꢀ1 more stable than 17,
which leads to 3mb (Figure 11).[27]
In the case of the reaction of the valine-derived Michael
acceptor (S)-2c (Scheme 3 and Table 1, entry 3), the stereo-
selectivity is significantly higher (33:1). The presence of the
two isopropyl groups, both in the attacking nucleophile and
the Michael acceptor, contributes to the increase in the
degree of stereocontrol. The transition structures corre-
sponding to the two possible modes of intramolecular hy-
drogen transfer (18 and 19, Figure 12) were located.
tries of the systems. It seems
that the values of two dihedrals
The energy difference between the two diastereomeric
transition structures (4.3 kcalmolꢀ1) is now substantially
greater than in the case of the reaction of Michael acceptor
(S)-2l, in good agreement with the experimental observa-
tions.
w1 and w2 (see Figure 13),
which define the relative posi-
tions of the two chiral centers
in the transition structures, in-
fluence the differences in
Figure 13. Dihedral angles w1
In order to understand the origin of the stereoselectivity
in the intramolecular hydrogen transfer step properly, three
common factors have to be taken into account: a) the pres-
ence of a hydrogen bond between the carbonyl oxygen and
the NH group of the attacking nucleophile, b) the strong in-
teraction between one of the fluorine atoms of the Tfm
group and the NH of the Michael acceptor, which forces an
almost planar conformation of the CF3-C-C(=O)-N-H frag-
ment, and c) the interactions between the hydrogens of the
trimethylammonium fragment and some of the carbonyl
groups of the esters. The important role played by these hy-
drogen bonds in the stereocontrol of the reaction is in good
energy (DE) between the dia- and w2 discussed in Table 3.
stereomeric transition struc-
tures (Table 3).
From the data in Table 3 it is possible to envisage a kind
of correlation: in the two reactions—matched and mis-
matched—the more stable transition structure is the one
with the dihedral w1, the one governing the relative position
of the stereogenic center of the Michael acceptor moiety
(Figure 13), closer to 1808. This spatial position decreases
the steric interactions, while in the case of w1 having a low
value, a more sterically gauche disposition is present (see
Figures 14 and 15, and Supporting Information).
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Chem. Eur. J. 2007, 13, 8530 – 8542

Stereoselective Aza-Michael Additions
FULL PAPER
Table 3. Correlation between the dihedral angles in the transition struc-
tures and the relative energy DE (in kcalmolꢀ1).
Reactants[a]
TS[b]
Products[b]
jw1 j [8]
jw2 j [8]
DE
(S)-2l + (S)-1l
14-I
3la
172
89
0.0
A
ACHTREUNG
(S)-2l + (S)-1l
(S)-2l + (R)-1l
(S)-2l + (R)-1l
(S)-2c +(S)-1c
(S)-2c +(S)-1c
15-I
70
175
70
66
62
+1.4
0.0
G
ACHTREUNG
16
G
ACHTREUNG
86
+0.8
0.0
A
ACHTREUNG
169
71
138
61
A
ACHTREUNG
19
+4.3
A
ACHTREUNG
[a] Michael acceptor + nucleophilic amine. [b] The first letter between
the brackets corresponds to the absolute configuration of the stereogenic
center of the Michael acceptor, the second one to the stereogenic center
generated in the reaction, and the third one to the nucleophilic amine.
Figure 15. Dihedral angle w2 in the diastereomeric transition structures
14-I and 15-I.
Figure 14 shows that the anti and gauche dispositions of
groups R and R2 in the transition structures are the result of
different steric interactions, which thus influence the relative
energies of the two diastereomeric transition structures for
the intramolecular hydrogen transfer.
On the other hand, the dihedral w2, which governs the rel-
ative position of the stereogenic center of the nucleophile
moiety (Figure 13) seems to modulate the effect of w1; thus,
as w2 has a lower value for the major diastereoisomeric tran-
sition structure, DE increases, and consequently the diaste-
reoisomeric ratio is reduced, as can be seen in the case of
the mismatched reaction (see Figure 15 and Supporting In-
formation).
Our preliminary results point to a more general scheme:
the effects of the stereogenic centers of the Michael accept-
or and the nucleophile can be considered independent each
from the other, as well as additives. In addition, each chiral
center induces the same configuration in the newly generat-
ed center, the influence of the stereogenic center in the Mi-
chael acceptor being greater than that of the amine. In
order to test this model, a new computational experiment
was carried out. In this experiment, the presence or the ab-
sence of one of the stereogenic centers in the reaction part-
ners is controlled.[28]
Conclusions
We report the mechanistic analysis of a new type of aza-Mi-
chael reaction, involving trifluoromethyl-containing Michael
acceptors. The reactions take place with high degrees of ste-
reocontrol,
leading
to
partially
modified
Y-
AHCTREUNG
trifluoroalanine mimic. According to the theoretical study,
carried out with density-functional theory methods, the reac-
tion is a two-step process, with an initial nucleophilic attack
of the amine on the acceptor double bond, in which a neu-
tral enol–amide intermediate is formed.
The second step corresponds to an intramolecular hydro-
gen transfer catalyzed by the amine present in the reaction
medium. At the same time, a new chiral center is formed.
The role of the Tfm group appears to be critical both in the
reactivity of the Michael acceptor and in the control of the
reaction stereoselectivity. The Tfm grouping makes the Mi-
chael acceptor more electrophilic, dramatically reducing the
activation barrier of the reaction. In addition, the electro-
static interaction between one of the fluorine atoms of the
CF3 fragment with the hydrogen of the amide influences the
conformation of the transition structure.
Figure 14. Dihedral angle w1 and different steric interactions in transition
structures 14-I and 15-I.
Chem. Eur. J. 2007, 13, 8530 – 8542
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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8539

S. Fustero, A. M. Ramallal et al.
+
ꢀ
CDCl3): d=1.65 (d, J=6.8 Hz, 3H), 5.88–5.97 (m, 1H), 6.09 (brs, 1H),
On the other hand, the N CH O hydrogen bonds are
critical in maintaining the rigidity of the transition structure.
This effect, coupled with the steric hindrance of the substitu-
ents in the stereogenic centers of the nucleophile and the
Michael acceptor, determines the high degree of stereocon-
trol observed.
6.14 (q, J
4H), 7.51–7.82 (m, 2H), 7.99 ppm (d, J=8.1 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=20.7 (CH3), 45.5 (CH), 122.1 (Cq, 1J
(C,F)=
271.2 Hz), 122.5 (CH), 123.0 (CH), 125.2 (CH), 125.9 (CH), 126.2 (CH),
A
G
ACHTREUNG
3
126.6 (CH), 128.6 (CH), 129.2 (Cq, J
A
133.9 (Cq, 2J(C,F)=30.4 Hz), 137.4 (C), 159.8 ppm (C); 19F NMR
AHCTREUNG
(282.4 MHz, CDCl3): d=ꢀ64.2 ppm (s, 3F); HRMS: m/z: calcd for
C16H14F3NO: 293.1027; found: 293.1054 [M]+.
General procedure for the preparation of Michael adducts 3: Amine 1
(0.22 mmol) was added at 08C to a stirred solution of 2 (0.22 mmol) in
CCl4 (5 mL). DABCO (0.22 mmol) was then added, and the mixture was
stirred for 2 h at room temperature. The reaction was monitored by thin-
layer chromatography (TLC). The solvent was removed under vacuum,
yielding a diastereoisomeric mixture of 3a/3b which was in turn separat-
ed by flash chromatography with silica gel as stationary phase to afford
the corresponding adducts 3 as white solids.
Experimental Section
General methods: Reactions were carried out under nitrogen unless oth-
erwise indicated. The solvents were purified prior to use: CH2Cl2 and
CCl4 were distilled from calcium hydride. All reagents were used as re-
ceived. The reactions were monitored with the aid of thin-layer chroma-
tography (TLC) on 0.25 mm E. Merck precoated silica gel plates. Visuali-
zation was carried out with UV light and aqueous ceric ammonium mo-
lybdate solution or potassium permanganate stain. Flash column chroma-
tography was performed with the indicated solvents on silica gel 60 (par-
ticle size 0.040–0.063 mm). Melting points were measured on a Bꢁchi B-
540 apparatus and are uncorrected. Optical rotations were measured on
a Jasco P-1020 polarimeter. 1H, 13C, and 19F NMR spectra were recorded
on a 300 MHz Bruker AC 300 spectrometer and a 400 MHz Bruker
Avance instrument. Chemical shifts are given in ppm (d), referenced to
the residual proton resonances of the solvents or fluorotrichloromethane
in 19F NMR experiments. Coupling constants (J) are given in Hertz (Hz).
The letters m, s, d, t, and q stand for multiplet, singlet, doublet, triplet,
and quartet, respectively. The letters br indicate that the signal is broad.
High-resolution mass spectra were carried out on a VGmAutospec instru-
ment (VG Analytical, Micromass Instruments) by the Universidad de Va-
lencia Mass Spectrometry Service.
Benzyl
(S)-2-{(S)-2-[((S)-1-benzyloxycarbonyl-3-methyl-butylamino)-
methyl]-3,3,3-trifluoropropionylamino}-4-methylpentanoate (3aa): This
compound was prepared by the general procedure described above, start-
ing from 2a (30 mg, 0.08 mmol) and (S)-1a (31 mg, 0.08 mmol), to afford
3aa (46 mg, 0.08 mmol) as a white solid after flash chromatography (n-
hexane/diisopropyl ether 2:1) on deactivated silica gel (2% Et3N in n-
hexane); yield 95%; m.p. 53–568C; [a]2D5 =+2.48 (c=0.3 in CHCl3);
1H NMR (300 MHz, CDCl3): d=0.77–0.85 (m, 12H), 1.18 (s, 1H), 1.30–
1.42 (m, 2H), 1.44–1.62 (m, 4H), 2.83–3.00 (m, 3H), 3.24 (dd, J1 =7.9 Hz,
J2 =6.4 Hz, 1H), 4.54–4.62 (m, 1H), 5.03 (d, J=12.2 Hz, 2H), 5.11 (d, J=
10.9 Hz, 2H), 7.27 (d, J=1.3 Hz, 5H), 7.29 (d, J=1.1 Hz, 5H), 7.34 ppm
(d, J=7.7 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=21.7 (CH3), 22.0
(CH3), 22.7 (CH), 24.8 (CH), 40.9 (CH2), 42.5 (CH2), 44.8 (CH2), 50.7
(Cq, 2J
124.3 (Cq, J(C,F)=281.0 Hz), 128.2 (CH), 128.3 (CH), 128.4 (CH), 128.4
A
1
(CH), 128.5 (CH), 135.2 (C), 135.4 (C), 165.9 (C), 172.5 (C), 175.7 ppm
Preparation of fluorinatedacceptors 2
(C); 19F NMR (282.4 MHz, CDCl3): d=ꢀ67.0 ppm (d, J
A
Benzyl (S)-4-methyl-2-(2-trifluoromethylacryloylamino)pentanoate (2a):
This compound was prepared as follows: A solution of (S)-leucine benzyl
ester (1a, 100 mg, 0.25 mmol) and sym-collidine (0.06 mL, 0.5 mmol) in
methylene chloride (3 mL) was added dropwise at 08C to a solution of
trifluoromethylacryloyl chloride (44 mg, 0.28 mmol) in CH2Cl2 (1 mL).
The reaction mixture was stirred at this temperature until TLC revealed
total consumption of the starting material (1 h). The crude mixture was
then quenched with HCl (5%, 15 mL) and extracted with CH2Cl2 (3ꢂ
15 mL). The combined organic layers were dried over anhydrous sodium
sulfate, and solvents were removed under reduced pressure. The crude
reaction mixture was subjected to flash chromatography (n-hexane/ethyl
acetate 7:3) to afford 2a (81 mg, 95%) as a yellow oil. [a]2D5 =ꢀ16.78 (c=
1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.84 (d, J=2.0 Hz, 3H),
0.86 (d, J=2.0 Hz, 3H), 1.49–1.70 (m, 3H), 4.65–4.72 (m, 1H), 5.07 (d,
3F); HRMS: m/z: calcd for C30H39F3N2O5: 565.2889; found: 565.2882
[M+H]+.
Benzyl
(S)-2-{(S)-2-[((S)-1-benzyloxycarbonyl-2-methylpropylamino)-
methyl]-3,3,3-trifluoropropionylamino}-3-methylbutanoate (3ba): This
compound was prepared by the general procedure described above, start-
ing from 2b (30 mg, 0.09 mmol) and (S)-1b (22 mg, 0.09 mmol), to afford
3ba (45 mg, 0.08 mmol) as a white solid after flash chromatography (n-
hexane/diisopropyl ether 1:3) on deactivated silica gel (2% Et3N in n-
hexane); yield 95%; m.p. 48–508C; [a]2D5 =+11.48 (c=1.0 in CHCl3);
1H NMR (300 MHz, CDCl3): d=0.76–0.87 (m, 12H), 1.79 (s, 1H), 1.82–
1.91 (m, 1H), 2.08–2.18 (m, 1H), 2.90–3.02 (m, 4H), 4.56 (dd, J1 =8.6 Hz,
J2 =4.7 Hz, 1H), 5.01–5.13 (m, 4H), 7.26 (s, 5H), 7.28 ppm (s, 5H);
13C NMR (75.5 MHz, CDCl3): d=17.4 (CH3), 18.0 (CH3), 18.9 (CH3),
19.0 (CH3), 30.8 (CH), 31.5 (CH), 45.4 (Cq, 3J
2J
(C,F)=25.3 Hz), 57.3 (CH), 66.6 (CH2), 67.0 (CH2), 67.7 (CH2), 124.3
(Cq, 1J
(C,F)=280.0 Hz), 128.3 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH),
A
J=12.2 Hz, 1H), 5.12 (d, J=12.2 Hz, 1H), 6.16 (q, J
(H,F)=1.3 Hz, 1H),
AHCTREUNG
6.36 (d, J=7.1 Hz, 1H), 6.44 (q, J(H,F)=1.5 Hz, 1H), 7.26 ppm (s, 5H);
AHCTREUNG
13C NMR (75.5 MHz, CDCl3): d=22.3 (CH3), 23.0 (CH3), 25.2 (CH), 41.6
AHCTREUNG
(CH2), 51.7 (CH), 67.7 (CH2), 122.4 (Cq, 1J
(C,F)=273.1 Hz), 128.6 (CH),
128.5 (CH), 135.1 (C), 135.4 (C), 166.1 (C), 171.5 (C), 175.1 ppm (C);
19F NMR (282.4 MHz, CDCl3): d=ꢀ67.1 ppm (d, J
(H,F)=8.2 Hz, 3F);
[M+H]+.
3
2
ACHTREUNG
128.8 (CH), 129.0 (CH), 129.9, (Cq, J
(C,F)=5.7 Hz), 134.0 (Cq, J
(C,F)=
31.0 Hz), 135.5 (C), 160.9 (C), 172.5 ppm (C); 19F NMR (282.4 MHz,
CDCl3): d=ꢀ64.2 ppm (s, 3F); HRMS: m/z: calcd for C17H20F3NO3:
343.1395; found: 343.1390 [M]+.
HRMS: m/z: calcd for C28H35F3N2O5: 537.2576; found: 537.2561
ACHTREUNG
tert-Butyl (S)-3-methyl-2-[(1S)-3,3,3-trifluoro-2-((S)-1-phenylethylcarba-
moyl)propylamino]butanoate (3ea): This compound was prepared by the
general procedure described above, starting from 2e (100 mg, 0.4 mmol)
and (S)-1d (86 mg, 0.4 mmol), to afford 3ea (128 mg, 0.31 mmol) as a
white solid after flash chromatography (n-hexane/ethyl acetate 6:1) on
deactivated silica gel (2% Et3N in n-hexane); yield 77%; m.p. 97–988C;
[a]2D5 =ꢀ0.618 (c=1.6 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.74
(d, J=6.9 Hz, 3H), 0.78 (d, J=6.8 Hz, 3H), 1.39 (s, 9H), 1.43 (d, J=
6.9 Hz, 3H), 1.66 (brs, 1H), 1.75–1.81 (m, 1H), 2.77 (d, J=5.5 Hz, 1H),
2.81–3.03 (m, 3H), 5.03–5.12 (m, 1H), 7.13–7.28 (m, 5H), 7.49 ppm (d,
N-[(1S)-1-Naphthalen-1-yl-ethyl]-2-trifluoromethylacrylamide (2g): This
compound was prepared as follows: A solution of (S)-a-methylnaphthyl-
amine (1e, 490 mg, 2.86 mmol) and sym-collidine (0.37 mL, 2.86 mmol)
in CH2Cl2 (16 mL) was added dropwise at 08C to a solution of trifluoro-
methylacryloyl chloride (500 mg, 3.15 mmol) in CH2Cl2 (8 mL). The reac-
tion mixture was stirred at this temperature until TLC revealed total con-
sumption of the starting material (2 h). The crude mixture was then
quenched with saturated ammonium chloride (15 mL) and extracted with
CH2Cl2 (3ꢂ15 mL). The combined organic layers were dried over anhy-
drous sodium sulfate, and solvents were removed under reduced pressure.
The crude reaction mixture was subjected to flash chromatography (n-
hexane/ethyl acetate 5:1) to afford 2g as a white solid (419 mg, 50%).
M.p. 135–1378C; [a]2D5 =ꢀ63.18 (c=0.9 in CHCl3); 1H NMR (300 MHz,
J=7.5 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=18.1
A
3
21.5 (CH3), 28.0 (CH3), 31.4 (CH), 44.9 (Cq, J
ACHTREUNG
50.9 (Cq, 2J
(C,F)=25.3 Hz), 68.0 (CH), 81.6 (CH), 124.6 (Cq, 1J
AHCTREUNG
8540
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 8530 – 8542

Stereoselective Aza-Michael Additions
FULL PAPER
ꢀ66.7 ppm (d,
C21H31F3N2O3: 416.2286; found: 416.2272 [M]+.
tert-Butyl (S)-3-methyl-2-[(S)-3,3,3-trifluoro-2-((S)-1-naphthalen-1-yl-
ethylcarbamoyl)propylamino]butanoate (3ga): This compound was pre-
J
(H,F)=8.2 Hz, 3F); HRMS: m/z: calcd for
Acknowledgements
The authors thank the CIEMAT (MEC, Spain) for allocating computer
time. A.M.R., G.Ch., and J.P. thank the regional government of the Prin-
cipado de Asturias and the Ministerio de Educacion y Ciencia, respec-
tively, for predoctoral fellowships. The authors thank the MEC
(BQU2003-01610) and the Generalitat Valenciana (GR03-193) for finan-
cial support.
ACHTREUNG
pared by the general procedure described above, starting from 2g
(100 mg, 0.34 mmol) and (S)-1d (72 mg, 0.34 mmol), to afford 3ga
(133 mg, 0.29 mmol) as a white solid after flash chromatography (n-
hexane/ethyl acetate 15:1) on deactivated silica gel (2% Et3N in n-
hexane); yield 84%; m.p. 110–1118C; [a]2D5 =ꢀ14.28 (c=0.9 in CHCl3);
1H NMR (300 MHz, CDCl3): d=0.49 (d, J=6.8 Hz, 3H), 0.56 (d, J=
6.8 Hz, 3H), 1.33 (brs, 1H), 1.35 (s, 9H), 1.50–1.56 (m, 1H), 1.63 (d, J=
6.8 Hz, 3H), 2.48 (d, J=5.3 Hz, 1H), 2.72–3.00 (m, 3H), 5.83–5.93 (m,
1H), 7.33–7.49 (m, 4H), 7.58 (d, J=7.7 Hz, 1H), 7.69–7.80 (m, 2H),
8.01 ppm (d, J=8.3 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=17.8
(CH3), 18.7 (CH3), 20.3 (CH3), 28.0 (CH3), 31.2 (CH), 44.7 (CH), 44.8
[1] Reviews: a) M. Misra, R. Luthra, K. L. Singh, K. Sushil, in Compre-
hensive Natural Products Chemistry,Vol. 4 (Eds.: D. H. R. Barton,
K. Nakanishi, O. Meth-Cohn), Pergamon, Oxford, UK, 1999, p. 25;
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1999, 82, 1774–1783; b) Y. Hamuro, J. P. Schneider, W. F. DeGrado,
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merlin, D. Hoyer, D. Seebach, J. Med. Chem. 2001, 44, 2460–2468;
d) D. Liu, W. F. DeGrado, J. Am. Chem. Soc. 2001, 123, 7553–7559;
e) J.-A. Ma, Angew. Chem. 2003, 115, 4426–4435; Angew. Chem.
Int. Ed. 2003, 42, 4290–4299; f) N. Sewald, Angew. Chem. 2003, 115,
5972–5973; Angew. Chem. Int. Ed. 2003, 42, 5794–5795; g) J. Frack-
enpohl, P. I. Arvidsson, J. V. Schreiber, D. Seebach, ChemBioChem
2001, 2, 445–455; h) G. Lelais, D. Seebach, Biopolymers 2004, 76,
206–243; i) D. Seebach, D. F. Hook, A. Glꢃttli, Biopolymers 2006,
84, 23–37.
[3] S. Kobayashi, K. Kakumoto, M. Sugiura, Org. Lett. 2002, 4, 1319–
1322, and references therein.
[4] a) L.-W. Xu, Ch.-G. Xia, S.-L. Zhou, J.-W. Li, X.-X. Hu, Synlett
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Angew. Chem. 1998, 110, 1096–1122; Angew. Chem. Int. Ed. 1998,
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[5] a) Enantioselective Synthesis of b-Amino Acid (Eds.: E. C. Juaristi,
V. A. Soloshonok), Wiley-VCH, Weinheim, 2nd ed., 2005; b) J. Et-
xebarria, J. L. Vicario, D. Badia, L. Carrillo, N. Ruiz, J. Org. Chem.
2005, 70, 8790–8800 and references therein.
[6] For a recent review, see: L.-W. Xu, Ch.-G. Xia, Eur. J. Org. Chem.
2005, 633–639.
[7] Only one example, to the best of our knowledge, involving a catalyt-
ic enantioselective conjugate addition of carbamates to b-alkyl-sub-
stituted a’-hydroxy enones has recently been described, by Palomo
and co-workers. See, C. Palomo, M. Oiarbide, R. Halder, M. Kelso,
E. Gómez-Bengoa, J. M. García, J. Am. Chem. Soc. 2004, 126, 9188–
9189 and references therein.
[8] a) I. Ojima, Chem. Rev. 1988, 88, 1011–1030; b) T. Kitazume, T.
Ohnogi, H. Miyauchi, T. Yamazaki, J. Org. Chem. 1989, 54, 5630–
5632; c) Y. Hanzawa, M. Suzuki, Y. Kobayashi, T. Taguchi, Y. Iitaka,
J. Org. Chem. 1991, 56, 1718–1725; d) T. Yamazaki, T. Ichige, S.
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2915–2918.
[9] I. Ojima, K. Kato, K. Nakahashi, T. Fuchikami, M. Fujita, J. Org.
Chem. 1989, 54, 4511–4522.
[10] I. Ojima, F. A. Jameison, Bioorg. Med. Chem. Lett. 1991, 1, 581–
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[11] a) D. Colantoni, S. Fioravanti, L. Pellacani, P. A. Tardella, Org. Lett.
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J. M. Peregrina, J. Org. Chem. 2005, 70, 5721–5724.
3
2
ACHTREUNG
(Cq, J
122.7 (CH), 123.2 (CH), 125.1 (CH), 125.7 (CH), 126.4 (CH), 127.4 (Cq,
1J
(C,F)=278.4 Hz), 128.2 (CH), 128.7 (CH), 131.0 (C), 133.9 (C), 137.9
(C), 164.7 (Cq, 3J(C,F)=1.8 Hz), 173.5 ppm (C); 19F NMR (282.4 MHz,
A
ACHTREUNG
ACHTREUNG
CDCl3): d=ꢀ67.7 ppm (d, J (H,F)=9.2 Hz, 3F); HRMS: m/z: calcd for
C25H33F3N2O3: 467.2521; found: 467.2476 [M+H]+.
tert-Butyl
(S)-3-methyl-2-{(S)-3,3,3-trifluoro-2-[((S)-1-naphthalen-1-yl-
ethylamino)methyl]propionylamino}butanoate (3ha): This compound
was prepared by the general procedure described above, starting from 2d
(100 mg, 0.33 mmol) and (S)-1e (57 mg, 54 mL, 0.33 mmol), to afford 3ha
(137 mg, 0.29 mmol) as a white solid after flash chromatography (n-
hexane/ethyl acetate 6:1) on deactivated silica gel (2% Et3N in n-
hexane); yield 84%; m.p. 105–1078C; [a]2D5 =+8.58 (c=1.2 in CHCl3);
1H NMR (300 MHz, CDCl3): d=0.82 (d, J=6.8 Hz, 3H), 0.87 (d, J=
6.8 Hz, 3H), 1.42–1.44 (m, 12H), 1.50 (br, 1H), 2.07–2.17 (m, 1H), 2.81–
2.88 (m, 1H), 2.97–3.00 (m, 1H), 3.01–3.15 (m, 1H), 4.42 (dd, J1 =8.7 Hz,
J2 =4.5 Hz, 1H), 4.59 (q, J=6.6 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 7.37–
7.47 (m, 3H), 7.58 (d, J=6.6 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.79–7.82
(m, 1H), 8.10 ppm (d, J=8.7 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=
3
17.4 (CH3), 18.8 (CH3), 23.6 (CH), 31.1 (CH3), 43.9 (Cq, J
A
51.3 (Cq, 2J
1J
(C,F)=280.5 Hz), 122.6 (CH), 122.7 (CH), 125.4 (CH), 125.6 (CH),
125.8 (CH), 127.4 (CH), 128.9 (CH), 131.1 (C), 133.9 (C), 140.2 (C),
165.6 (Cq, 3J(C,F)=2.3 Hz), 170.6 ppm (C); 19F NMR (282.4 MHz,
A
ACHTREUNG
ACHTREUNG
CDCl3): d=ꢀ70.4 ppm (d, J
C
(S)-2-[((S)-1-Cyclohexa-1,3-dienyl-ethylamino)methyl]-3,3,3-trifluoro-N-
((S)-1-phenylethyl)propionamide (3ka): This compound was prepared by
the general procedure described above, starting from 2e (121 mg,
0.49 mmol) and (S)-1 f (60 mg, 64 mL, 0.49 mmol), to afford 3ka (105 mg,
0.29 mmol) as a white solid after flash chromatography (n-hexane/ethyl
acetate 6:1) on deactivated silica gel (2% Et3N in n-hexane); yield 60%;
m.p. 122–1248C; [a]2D5 =ꢀ38.98 (c=0.9 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=1.31 (d, J=6.6 Hz, 3H), 1.50 (d, J=6.8 Hz, 3H), 1.64 (brs,
1H), 2.71 (dd, J1 =12.5 Hz, J2 =3.4 Hz, 1H), 2.86–2.99 (m, 1H), 3.09–3.13
(m, 1H), 3.70 (q, J=6.6 Hz, 1H), 5.11–5.19 (m, 1H), 7.21–7.40 (m, 10H),
7.76 ppm (d, J=7.3 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=21.5
(CH3), 23.8 (CH3), 43.7 (Cq, 3J
2J(C,F)=24.7 Hz), 58.7 (CH), 124.7 (Cq, 1J
126.5 (CH), 127.3 (CH), 127.4 (CH), 128.6 (CH), 128.6 (CH), 142.7 (C),
144.1 (C), 164.7 ppm (Cq, 3J(C,F)=2.3 Hz); 19F NMR (282.4 MHz,
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
CDCl3) d=ꢀ66.4 ppm (d, J
C
[12] Preliminary communication: M. Sani, L. BruchØ, G. Chiva, S. Fus-
tero, J. Piera, A. Volonterio, M. Zanda, Angew. Chem. 2003, 115,
2106–2109; Angew. Chem. Int. Ed. 2003, 42, 2060–2063.
[13] In the same way, Zanda, Volonterio, and co-workers previously de-
signed a similar protocol for the synthesis of a new class of pseudo-
peptides starting, in this case, from b-trifluoromethyl acrylic acid de-
rivatives and a-amino acid esters. a) A. Volonterio, P. Bravo, M.
Zanda, Org. Lett. 2000, 2, 1827–1830; b) A. Volonterio, S. Bellosta,
P. Bravo, E. Canavesi, E. Corradi, S. V. Meille, M. Monetti, N.
Moussier, M. Zanda, Eur. J. Org. Chem. 2002, 428–438; c) A. Vo-
lonterio, S. Bellosta, F. Bravin, M. C. Belluci, L. BruchØ, G. Colom-
Computational methods: The potential energy surfaces corresponding to
the reactions of the Michael acceptors 4a–c (Figure 1) and (S)-2l and
(S)-2c (Scheme 3) were explored by the density-functional method, at
the B3LYP/6-31G* level of theory.[15] All the geometrical parameters
were fully optimized, and the stationary points located were character-
ized as minima or saddle points, by performing the corresponding vibra-
tional analysis. In addition, some stationary points were also located at
the MP2/6-31G* level[15] (see Supporting Information for details). All the
calculations were carried out with the Gaussian98 programs package.[29]
Chem. Eur. J. 2007, 13, 8530 – 8542
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8541

S. Fustero, A. M. Ramallal et al.
bo, L. Malpezzi, S. Mazzini, S. V. Meille, M. Melli, C. R. de Arella-
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[23] A more detailed study of the concept of the electrophilicity, includ-
ing a quantitative definition relating the energies of the HOMO and
LUMO with a global electrophilicity index, can be found in: L. R.
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6591.
[24] a) C. E. Cannizzaro, T. Strassner, K. N. Houk, J. Am. Chem. Soc.
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[14] Other bases and solvents gave less satisfactory results (see ref. [12]).
[15] For a description of the theoretical methodology, see: F. Jensen, In-
troduction to Computational Chemistry, Wiley, Chichester, 2nd ed.
2007.
[16] An analogous transition structure has previously been described in a
study of the nucleophilic addition of ammonia to acrolein: L. Pardo,
R. Osman, H. Weinstein, J. R. Rabinowitz, J. Am. Chem. Soc. 1993,
115, 8263–8269.
[17] M. Arnó, R. J. Zaragozµ, L. R. Domingo, Tetrahedron: Asymmetry
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[18] The authors would like to thank the referees for clarifying this
point.
[19] For a detailed discussion of fluorine–hydrogen interactions see: K.
Uneyama, Organofluorine Chemistry, Blackwell Publishing Ltd.,
Oxford 2006, Chapter 4.
[20] For a classical presentation of Frontier Molecular Orbital theory,
see: I. Fleming, Frontier Orbitals and Organic Chemical Reactions,
Wiley, New York, 1982.
[21] The LUMO energies (in eV) are as follows: 4a (R=H, ꢀ0.762), 4b
(R=Me, ꢀ0.571), 4c (R=F, ꢀ0.870), 4d (R=CF3, ꢀ1.360).
[22] Strictly speaking, the orbitals used in this work are Khon–Sham or-
bitals: that is, solutions of Khon–Sham density-functional equations
(see ref. [15]), and not molecular orbitals in the most habitual sense
of being solutions of the Hartree–Fock–Roothaan equations.
[25] C. E. Cannizzaro, K. N. Houk, J. Am. Chem. Soc. 2004, 126, 10992–
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[26] D. Suµrez, R. López, J. Gonzµlez, T. L. Sordo, J. A. Sordo, Int. J.
Quantum Chem. 1996, 57, 493–499.
[27] A difference in energy of 0.8 kcalmolꢀ1 at 08C produces a diastereo-
isomeric ratio (dr) of about 5:1.
[28] The full details of this experiment and the corresponding mathemat-
ical analysis can be found in the Supporting Information.
[29] Gaussian 98, Revision A.3, M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, V. G. Zakrzewski,
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M. W. Wong, J. L. Andres, C. Gonzalez, M. Head-Gordon, E. S. Re-
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www.gaussian.com
Received: March 9, 2007
Published online: July 20, 2007
8542
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 8530 – 8542