Conformationally stabilized catalysts by fluorine insertion: Tool for enantioselectivity improvement

Article abstract of DOI:10.1002/chem.201102757

F rigid cats: The power of conformationally stabilized catalysts is demonstrated. By taking appropriate advantage of fluorine insertion (see scheme), purely conformational catalyst design led to a notable improvement in enantioselectivities from around 70% to 91-98.5% ee. The other advantage of this approach is the better understanding of the origin of the stereoselectivity in the given catalytic system. Copyright

Full text of DOI:10.1002/chem.201102757

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DOI: 10.1002/chem.201102757
Conformationally Stabilized Catalysts by Fluorine Insertion: Tool for
Enantioselectivity Improvement
Adrien Quintard, Jean-Baptiste Langlois, Daniel Emery, Jiri Mareda, Laure Guꢀnꢀe, and
Alexandre Alexakis*[a]
In a 21st century in which environmental protection is a
necessity, organic methods that decrease hydrocarbon con-
sumption and thus reduce overall waste are becoming a
standard requirement. In this view, the continuous develop-
ment of increasingly efficient catalysts able to reduce global
waste, notably for the synthesis of optically pure molecules,
is required. Among these, aminocatalysts have recently ap-
peared as systems of choice for carbonyl compounds.[1] This
decade of growth, also called the organocatalytic “gold
rush”, has led to the development of a wide variety of cata-
lysts with different levels of success. The design of the ma-
jority of these catalysts, based on pyrrolidine backbones,
have mostly relied on a set of basic principles, such as bulky
groups or H-bond donor insertions.[2]
In comparison, despite excellent recent published pioneer-
ing works, the essential role of conformational changes in
catalyst structures, notably in pyrrolidine-derived catalysts,
is often neglected.[3] This is relatively surprising given the
known sensitivity of pyrrolidines to conformational equilib-
rium between the Cg-endo and Cg-exo forms (Scheme 1).[4]
This conformational freedom has a dramatic influence on
the different substituents of the pyrrolidine ring and modi-
fies their spatial arrangement (substituent rotation). The
outcome of these subtle modifications has a direct impact
on the nature of the transition state.
This high flexibility in the catalyst, which induces an in-
creased number of possible transition states, can be a real
drawback in view of enantioselectivity control. It would thus
be of high interest to apply tools able to conformationally ri-
gidify the catalytic systems (Scheme 1). In addition to the
positive impact on the selectivity of the reactions, such stud-
ies should also shed light on the origins of the stereocontrol.
The stabilization of one or other conformer of pyrrolidine
by insertion of specific substituents in the 4-position is well-
documented in the literature.[4] This stabilization notably
occurs in natural systems, as exemplified by the collagen
Scheme 1. Proposed conformationally stabilized catalysts.
triple helix, in which insertion of a hydroxyproline increases
the thermal stability.[4,5] With this background in hand, we
hypothesized that insertion of the appropriate substituent
on the pyrrolidine ring should give rise to conformationally
stabilized aminocatalysts, with increasing catalytic efficiency
(Scheme 1). Herein, we present our results on catalyst im-
provement by simple conformation stabilization induced in
fluoroproline, thanks to hyperconjugation.[6]
Aminal-pyrrolidines (APY), modular aminocatalysts
which we recently disclosed, seemed an ideal starting point
for the development of our proposed conformationally sta-
bilized catalysts.[7] Indeed, recent studies have indicated that
insertion of a phenoxy group at the 4-position of the pyrroli-
dine ring induces a dramatic increase in the enantioselectivi-
ty, notably in iminium catalysis.[7c,h] Due to the relatively
remote distance between this bulky substituent and the en-
tering nucleophile, we assumed that the observed beneficial
effect on the enantioselectivity was due to a conformational
readjustment of the intermediate rather than the addition of
another bulky group.
[a] Dr. A. Quintard, J.-B. Langlois, D. Emery, Dr. J. Mareda,
Dr. L. Guꢀnꢀe, Prof. Dr. A. Alexakis
Department of Organic Chemistry, University of Geneva
30 Quai Ernest Ansermet, 1211 Geneva 4 (Switzerland)
Fax : (+41)223-793-215
Given the known stability of the Cg-endo conformer
when substituents, such as N3, OH or F, are placed cis in the
4-position of substituted pyrrolidines, we decided to exacer-
bate this stabilization by inserting a fluorine atom instead of
the phenoxy group. Indeed, fluorine insertion is a perfect
E-mail: alexandre.alexakis@unige.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102757.
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tool for conformation stabilization due to the known gauche
effect (stabilization by hyperconjugation), and this property
has already been exploited by the groups of Marson, Rovis,
List, and particularly Gilmour.[3–6]
Furthermore, such conformation change does not insert
any extra steric hindrance rendering it purely conformation-
ally driven. These newly designed catalysts were then tested
in the reaction involving isovaleraldehyde with vinyl sulfone,
a highly interesting formal alkylation of aldehydes, and di-
rectly compared with the previously reported catalysts.[8]
The results with the different pyrrolidine backbones are
summarized in Scheme 2.
ture for this challenging reaction. With respect to the low
76% ee obtained when using nonsubstituted catalysts these
results confirm our initial hypothesis. Indeed, given the low
steric requirement of fluorine, replacement of the strategi-
cally selected hydrogen by the fluorine at C4 can favor one
single conformation of the pyrrolidine ring.
To confirm this hypothesis, computational investigations
were undertaken on catalysts containing the achiral di-
phenylethane diamine motif (4a, 4d, 4e and FAPYa).[9]
After presenting the relative energies of the four possible
enamines derived from catalysts 4e and FAPYa, our discus-
sion will focus on the properties of the two most stable ones
namely, (E)-trans and (E)-cis.[10] The enamines were chosen
as model since they could reflect the different properties of
the catalysts. Both, (E)-trans and (E)-cis enamines were op-
timized for Cg-endo and Cg-exo conformations of the cata-
lysts 4a, 4e and FAPYa (Table 1). In all the systems, the
Table 1. Relative energies and selected geometry parameters for the dif-
ferent enamines at the B3LYP/6-31G(d) level of theory.
Scheme 2. Catalyst screening in the reaction of aldehyde 1a with vinyl
sulfone 2.
Catalysts 4a and 4b with high conformational freedom,
X=
Enamine
DE
f
[8]
Y
À
led to moderate 76–77% ee. Insertion of the trans free OH
[a]
[kcalmolÀ1
]
[8]
known to stabilize the Cg-exo conformation, did not give
any increase in ee (catalyst 4c, 76% ee).[6] Replacement of
the OH by a trans phenoxy, dramatically reduced the enan-
tiocontrol to 36% ee (catalyst 4d). This decrease in enantio-
selectivity apparently arises from a steric repulsion between
the phenoxy, placed on the bottom face of the enamine, and
the entering electrophile. In contrast, inversion of the C-4
stereocenter in catalysts 4e and 4 f impressively increased
the ee to 94%. The most exciting results arose from the ap-
plication of the fluorinated catalysts FAPYa and FAPYb.
As anticipated high 96% ee was obtained at room tempera-
H
(E)-trans-Cg-endo 4a
(E)-trans-Cg-exo 4a
(E)-cis-Cg-endo 4a
(E)-cis-Cg-exo 4a
(E)-trans-Cg-endo 4e
(E)-trans-Cg-exo 4e
(E)-cis-Cg-endo 4e
(E)-cis-Cg-exo 4e
0
89.8
155.3
86.9
158.3
116.4
150.8
122.2
157.3
106.7
152.8
87.8
74.1
87.4
87.6
78.5
77.1
90.9
89.1
86.9
76.1
0.7
1.5
1.7
0.5
0
1.9
0.9
0
OPh
F
(E)-trans-Cg-endo FAPYa
(E)-trans-Cg-exo FAPYa
1.5
[a] Relative energies (with ZPE corrections) are given in reference to the
most stable enamine for each catalyst.
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Conformationally Stabilized Catalysts
COMMUNICATION
(E)-trans enamines were found to be more stable by at least
0.5 kcalmolÀ1. Interestingly, this enamine geometry prefer-
ence is in line with diarylprolinol silyl ether in which both
(E)-trans and (E)-cis enamines were relatively close in
energy.[11]
Gratifyingly, DFT calculations confirmed the concept of
conformational stabilization and the direct influence of the
exo/endo equilibrium on y angle (aminal rotation). Indeed,
in the endo conformation of (E)-trans enamines, the 2-sub-
stituents readjust their position in order to better accommo-
date the new pyrrolidine ring geometry.[4b] In catalyst 4a,
Cg-exo and Cg-endo are in equilibrium (DE=0.7 kcalmolÀ1,
Table 1). The absence of any notable stabilization in this
system, steric or conformational, led to a greater mobility,
which resulted in a multiplication of the possible reaction
pathways (low enantiocontrol).
As anticipated, insertion of the phenoxy in catalyst 4e,
did stabilize one conformer, however, it was rather the Cg-
exo (DE=0.5 kcalmolÀ1, Table 1). This exo conformer stabi-
lization arises from steric repulsion between the phenoxy
and the aminal. This is confirmed by the similar y angle ob-
served in both conformers (y=78.5 and 77.18 in (E)-trans).
The direct consequence of this repulsion is an increase in
enantioselectivity since the aminal, in all conformations, is
fixed in the appropriate position above the enamine.
As anticipated, fluorine insertion did stabilize the Cg-
endo over the Cg-exo (E)-trans enamine by 1.5 kcalmolÀ1.[12]
This stabilization directly arises from the hyperconjugation
Figure 1. Optimized transition states for the addition of aldehyde to vinyl
sulfone catalyzed by FAPYa.
À
of the adjacent s C H orbitals aligned with the s* of the
À
C F despite the fact that the calculated f values in the endo
enamines (f=106.7 and 105.48, Table 1) are far from the
theoretical 608 required for optimal gauche conformations.
The deformation of dihedral angles can be explained by the
inherent steric strain of the system, reflected by the relative
decreased, allowing for a better enantiocontrol than in 4a.
Indeed, owing to the conformational flexibility of enamine
4a, we did not attempt to locate the transition state for this
system, since it presents quite low enantiocontrol. In addi-
tion, the calculated charges on the active site (C8 atom) are
almost the same in the different catalysts; this confirms that
the insertion of fluorine did not decrease the reactivity, what
would have been detrimental in terms of catalytic activity.[9]
To validate our design, FAPY catalysts were then
screened under known optimized conditions, in a wide varie-
ty of reactions in which APY catalysts had already shown
their efficiency.[7] Satisfyingly, this improvement of enantio-
selectivity is not at all substrate dependent and can also be
observed when applying a wide range of various nucleo-
philes and electrophiles. Indeed, fluorinated catalysts out-
performed the nonfluorinated ones in all the tested reac-
tions. This further demonstrates the power of such a confor-
mation stabilization approach, in which the obtained well-
defined structure does not inhibit the necessary catalyst ad-
justment to accommodate the required transition state.
For instance, the same catalytic trend was observed by
varying the substitution pattern on the aldehyde in the reac-
tion with vinyl sulfone (Table 2). At only 5 mol% catalyst,
enantioselectivities between 96–98.5% ee were obtained
with different sterically demanding aldehydes. These results
highlight the competitive properties of FAPY catalysts.
flattening of the pyrrolidine ring. A slight elongation of the
[13]
À
C F bond in endo conformers, reflects this hyperconjuga-
tion as already reported by Barone et al.[4a] and Markley
et al.[4b] In the (E)-cis enamine (disfavored by 1.0 kcalmolÀ1)
the fluorine stabilization effect is less pronounced. Indeed,
the Cg-endo conformer is more stable by only 1.0 kcalmolÀ1.
The repulsion between the aminal and the enamine increas-
es the y angle for both conformers and thus diminishes the
fluorine effect.
The Cg-endo stabilization, which was established for the
series of enamines (Table 1), has an important consequence
for the location of the aminal in an exquisite position (crea-
tion of a plane with the two N-phenyl groups), efficiently
shielding the upper face of the enamine in the preferred
transition state ((E)-trans/Si face attack, Figure 1). This tran-
sition state is lowered by 3.2 kcalmolÀ1 over the (E)-cis/Re
face attack for the FAPYa system (98.5% ee observed).
This enantiocontrol certainly relies on the fact that the reac-
tive carbon atom (C8) is closer to the aminal in (E)-cis en-
amine. As a result, the approach of the entering sulfone is
disfavored by the significantly higher steric hindrance as
compared to the (E)-trans enamine. Since the endo con-
formers are stabilized, the number of possible pathways are
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A. Alexakis et al.
Table 2. Scope of the aldehyde addition to vinyl sulfones.
Entry
R
t [h], T [8C]
Yield[a]
[%]
ee [%][b]
ACHTUNGTRENNUNG(product)
1
2
3
nPr (1b)
iPr (1a)
tBu (1c)
3, À20
94
96
90
96
98 (83)
98.5 (77)
3, À20
1.33, RT
[a] Isolated yields; [b] determined by super critical fluid chromatography;
values in parentheses refer to the result obtained with 4a.
More interestingly, the creation of a tetra-substituted
carbon center starting from chloroaldehyde 5 could be
achieved in high 95% ee, the best result achieved to date in
this transformation (70% ee for 4a and 93% ee for 4e,
Scheme 3).[7d] It should be pointed out that the remaining al-
dehyde was recovered in 33% ee; this indicates the kinetic
stability of one enantiomer of the starting material.[14]
Scheme 3. Addition of chloroaldehyde to vinyl sulfone.
Scheme 4. Scope of conformationally stabilized catalysts in various ami-
nocatalytic processes.
Gratifyingly, the same increase in enantiocontrol between
4a–b and FAPY catalysts was observed for the addition of
both aldehydes or cyclohexanone to various electrophiles,
such as nitro-olefins or DEAD (increase from 66–68% ee to
91–93% ee, Scheme 4).[15,16] More remarkably, the initial
concept of modularity of APY catalysts was still observed
and both FAPYa and b kept their complementary activity
depending on the reaction. Finally, the conformational stabi-
lization was also effective for iminium catalysis, inducing a
notable improvement from 70 to 94% ee (Scheme 4d). This
is remarkable since it indicates that the remote insertion of
fluorine has long range beneficial effects.
In conclusion, we have demonstrated the power of confor-
mationally stabilized catalysts. By taking advantage of fluo-
rine insertion, a principle widely studied in the literature,[4–6]
purely conformational catalyst design led to an improve-
ment from moderate enantioselectivities of around 70% to
competitive 91–98.5% ee. Furthermore, the fluorine inser-
tion provides a better understanding of the origin of the ste-
reoselectivity in aminal pyrrolidine catalysts. In addition to
these higher enantiocontrols, FAPY catalysts are easier to
prepare than the corresponding phenoxy-based catalysts,
which constitutes a notable practical advantage.[17]
We hope that this study will contribute to future develop-
ment of efficient catalysts. This conformational stabilization
principle, already well-established by the works of Gilmour,
List, Rovis and others,[4–6] should serve as a keystone for fur-
ther improvement of a wide variety of catalytic systems, not
only on the pyrrolidine ring but also on other backbones.
Furthermore, some unexplained behavior of 4-substituted
pyrrolidine catalysts should find their explanations thanks to
such an approach.[2] Further studies aiming at increasing the
scope of conformationally improved catalysts by insertion of
other substituents on different pyrrolidine-based catalysts
are currently ongoing in our laboratory and will be reported
in due course.
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Conformationally Stabilized Catalysts
COMMUNICATION
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[9] See the Supporting Information for details. B3LYP/6-31G(d) level
of theory had already been used in precedent studies of fluorinated
pralines, see for example, refs. [4b,c, 6c]. Comparison with X-ray
analysis of catalyst 4d (the only crystalline one) allowed us to vali-
date our calculation model. CCDC 826006 contains the supplemen-
tary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
[10] The corresponding Z enamines were logically found to be less stable
and are not presented here (e.g., (Z)-trans-Cg-endo enamine of 4e:
DG=8.7 kcalmolÀ1). For a corresponding discussion see ref. [11].
[11] P. Dinꢀr, A. Kjaersgaard, M. A. Lie, K. A. J Jørgensen, Chem. Eur.
J. 2008, 14, 122.
Keywords: asymmetric
organocatalysis · density functional calculations · fluorine ·
organocatalysts
synthesis
·
conformational
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À
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À
[6] For interesting reviews on the role of the C F bond as a conforma-
[17] The insertion of fluorine by SN2 by using DAST, is practically much
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Received: September 4, 2011
Published online: October 31, 2011
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13437