Steric Effect of Protonated Tertiary Amine in Primary-Tertiary Diamine Catalysis: A Double-Layered Sterimol Model

Article abstract of DOI:10.1021/acs.orglett.8b03584

Steric shielding effects are seldom adopted in the stereocontrol with chiral primary amine catalysts. An unexpected steric shielding effect of protonated tertiary amine, a typical hydrogen-bonding moiety, was disclosed. A linear free energy relationship b

Full text of DOI:10.1021/acs.orglett.8b03584

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Steric Effect of Protonated Tertiary Amine in Primary−Tertiary
Diamine Catalysis: A Double-Layered Sterimol Model
‡
,∥
‡,∥
†
†
,†,‡,§
and Sanzhong Luo*,†,‡,§
Yaning Wang, Han Zhou, Kai Yang, Chang You, Long Zhang,*
†
Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing 100084, China
‡
Key Laboratory for Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190,
China
§
Collaborative Innovation center of Chemical Science and Engineering, Tianjin 300071, China
S Supporting Information
*
ABSTRACT: Steric shielding effects are seldom adopted in the
stereocontrol with chiral primary amine catalysts. An unexpected
steric shielding effect of protonated tertiary amine, a typical
hydrogen-bonding moiety, was disclosed. A linear free energy
relationship between structure and enantioselectivity was established
in three reactions when a double-layered Sterimol model was
introduced.
ursuing exquisite stereocontrol is one of the ultimate tasks
The past decade witnessed the blossom of chiral primary−
tertiary diamine catalysts, which showed powerful capabilities
in the enantioselective transformation of carbonyl com-
pounds, especially for the more hindered ketone substrates.
It was found that the hydrogen-bonding effects were mainly
P
in asymmetric catalysis. However, the search for an
optimal catalyst still relies on the evaluation of a considerable
number of catalyst structures, and rational design of chiral
catalysts remains a great challenge. Therefore, understanding
the relationship between enantioselectivity and catalysts
structures is urgently desired but still underdeveloped. The
challenge mainly comes from the small activation energy
difference between two transition states corresponding to two
enantiomers, wherein a 2.7 kcal/mol disparity would give an
9
10
adopted for those privileged catalysts in order to achieve
11
stereocontrol. Recently, we observed an unusual steric effect
caused by the protonated tertiary amine moiety in Robinson
12
annulations, where an dual activation mode was found in this
catalytic process. Later on, a much more obvious steric effect
was observed in the primary amine/palladium-cocatalyzed
1
excellent enantioselectivity, >98% ee. Efforts in this trend by
1
3
using classical physical organic methods, especially linear free
energy relationship analysis, have been proven to be powerful
strategies to understand the intrinsic origin of enantiocontrol
asymmetric allylic alkylation (AAA) reactions. Detailed
studies showed that a novel linear free energy relationship
could be drawn when a double-layered Sterimol model were
introduced. The model could also be applied to two other
reactions (Figure 1).
2
and enable predictive catalyst design. Initial studies along this
line mainly focused on the evaluation of electrostatic characters
3
4
of the catalysts, including Hammett σ parameters, pKa,
13
In the chiral primary amine/Pd-catalyzed AAA reation,
5
polarizability, etc. However, research of the relationship
between steric effects and enantioselectivity has only emerged
in the past decade. Since 2008, Sigman and co-workers have
reported a series of studies on the relationship between steric
bulky primary 3i was identified as the optimal catalyst (Scheme
1
). Surprisingly, the absolute configuration of the newly
formed all-carbon quartnery stereocenter was determined as S,
which could not be explained by the normally occurring H-
bonding model with protonated tertiary amines (Figure 1). A
6
effects and the reaction chiral outcome. Various steric
parameters have been used to elucidate the structure−
enantioselectivity relationships, including Charton steric
6
a,b
parameter
and Winstein−Holness parameter (A value)
1 6d
interference values as well as the Sterimol parameter.
Meanwhile, stepwise regression analysis was also introduced to
deal with the multidimensional parameters. Further successes
were obtained when combined parameters were used in the
7
correlation with the same technique. Along these lines, IR
Figure 1. Enantiocontrol with our catalysts.
Received: November 8, 2018
vibrations, bond lengths, bond angle, atom charges, NMR
shifts, and so on were all selectable parameters, and meaningful
information can be drawn from the analysis of the reaction
8
mechanisms as well as the origin of enantiocontrol.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03584
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Organic Letters
Letter
a
Scheme 1. Catalyst Screening for the Allylic Alkylation
from the measured results (eq 2), indicating this model was
unworkable for an efficient prediction.
a
ΔΔG = 4.67B + 0.21B − 8.19
(1)
(2)
1
5
a
ΔΔG = 2.55B − 3.31
1
The failure mentioned above indicated neither Charton nor
Sterimol parameters were sufficient to describe the nature of
the substituents. Further analysis showed that the inner fine
structure of the substituents was also important for the
stereocontrol; therefore, an additional structure descriptor was
necessary to characterize the nature of the inner structures.
Considering this, we developed a double layered Sterimol
(
DLS) model in which the innersphere was described by an
additional suite of Sterimol parameters (Figure 3). Multivariate
a
Reaction conditions: 1a (0.15 mmol), 2a (0.10 mmol), chiral amine
(
20 mol %), Pd precursor (5 mol %), PPh (20 mol %), CH CN (0.5
3
3
b
c
mL), 40 °C, 36 h. Reaction time: 40 h. The reaction was carried out
with 3 equiv of ketoester 1a, and the reaction time was extended to 72
h.
Figure 3. Double-layered sterimol model.
Si-facial attack transition-state model was thus proposed to
account for the observed stereoselectivity. In this model, steric
effects played a key role in channeling the attack of π-allyl
palladium species, for which a notable H-bonding site is
lacking. The observed bulky substituent effects of the tertiary
amino moiety are clearly in support of this steric model.
In order to elucidate the steric effects of the tertiary amine
moiety, we have tried to determine the linear free energy
relationship between structure and enantioselectivity. As one
type of widely used steric parameters, the Charton values were
evaluated first to account for the observed enantioselectivity;
however, the variance was found to be only 0.57, and no
obvious linear relationships could be drawn (Figure 2A). In
linear least-squares regression analysis with the DLS model
produced an equation shown as eq 3. The equation includes
three statistically significant terms, the minimum width
parameter of the outsphere (B ), the minimum width
1
parameter of the innersphere (B ′), and the offset. The
1
coefficient of these terms indicated that both of the minimum
widths of outspheres and innerspheres showed significant
a
influence on the enantioselectivity, and the predicted ΔΔG
showed good correlation with the experimental results, with an
2
R
= 0.94 (Figure 4). Leave-one-out cross-validation
Figure 4. Double-layered sterimol model and correlation between
Figure 2. Charton (A) and sterimol (B) plot with our catalysts.
computational and experimental results.
(
LOOCV) was implemented to test the predictive perform-
2
view of the huge successes of Sterimol parameter-based
simulation in asymmetric catalysis, we further tried the
multivariate linear least-squares regression analysis using the
three-dimensional Sterimol parameters, and a better result was
ance of this model, and the Q was found to be 0.83, indicating
14
this model is acceptable (see Table S7). We also tried to
omit two pieces of data from the training set and listed them as
the testing set to evaluate the prediction ability; in this case,
the data with catalysts 3d and 3e were selected as testing data
as their catalytic outcomes were moderate. Again, a similar
satisfactory correlation was found (eq 4), and the prediction
was accurate. Omitting the boundary data such as 3h and 3i
also gave a satisfied correlation, and the predicted results with
3h and 3i were in accordance with the experimental
observations (see Figure S3).
2
obtained with R = 0.84 (Figure 2B). It was found that the
minimum width of the substituent played a critical role in this
model, with a large coefficient of 4.67 (eq 1). However, when
we reduced the training set to seven samples and these
catalytic results with 3h and 3i were treated as testing sets,
2
even worse results were obtained with R = 0.71 (Figure 2B).
a
The predicted ΔΔG for the testing sets are much different
B
DOI: 10.1021/acs.orglett.8b03584
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Organic Letters
Letter
a
ΔΔG = 4.15B + 1.88B ′ − 9.45
(3)
(4)
and 3n. Due to the cyclic structure, the orientation of the
larger group on C1 was not directly toward the Re-face; thus,
the space-shielding effect should be much smaller than that for
the N-ethyl-substituted catalyst (Figure 6). The experimental
1
1
a
ΔΔG = 4.20B + 1.84B ′ − 9.49
1
1
With this model in hand, we further predicted the
performance of several new catalysts which were not evaluated
1
5
a
before. As can be seen in Scheme 2, the predicted ΔΔG
Scheme 2. New Catalyst Testing for the Allylic Alkylation
Figure 6. Steric shielding of enamine with catalysts 3m and 3n.
studies showed that catalyst 3m gave similar results with the N-
methyl-substituted catalyst 3h (5% ee with R-configuration); as
for 3n, only 25% ee with S-configuration was obtained, which
is much smaller than that of 3a (Scheme 3).
were similar to the observed ones, with a maximum deviation
of 0.17 kcal/mol; these studies further verified the predictive
power of this model. We then resimulated the equation with
the whole data set; similar results were obtained as shown in eq
Scheme 3. Catalytic Performance of 3m and 3n
5
.
a
2
ΔΔG = 4.08 + 1.89B ′ − 9.33 (R = 0.94)
(5)
1
Why did the minimum width of the innersphere show such a
significant influence on the enantioselective outcome? The
reason could be found in the conformation of the N-
substituents. We have mapped the conformations of the
flexible N-substituents of enamine 3a and enamine 3b with
16
molecular dynamic methods, and the four conformers with
lowest energy of each catalyst were further optimized with
DFT calculations; the most stable conformations are shown in
Figure 5. The orientation of the terminal methyl group was
We have also realized the enantioselective terminal addition
of carbonyl compounds to allenes by synergistic incorporation
17
of primary amines and palladium catalysts in 2017. Similar
allylic alkylation products could be generated which were far
beyond the reach of the reactions with allylic alcohols. A
similar steric effect was found in this system, and multivariate
regression analysis with the DLS model gave a good
2
correlation with a R = 0.89. The produced equation is
presented in eq 6. Again, the outsphere B and innersphere B ′
1
1
showed significant influence on the enantioselectivity (Scheme
4
, eq 6, and Figure S4A). Besides the allylation reactions, such
steric effects could also be found in other important
Scheme 4. Primary Amine Catalyzed Allylic Alkylation and
Sulfuration Reaction
Figure 5. Orientation of the N-substituent in the enamine
intermediate.
found to be on the enamine side, thus making a large
contribution to the steric shielding on the Re face. We have
successfully characterized the enamine structure of 3a by X-ray
analysis, and the configuration of the N-substituent was exactly
the same with our computational results. Further enlarging the
substituent could give more shielding capability, and the
observed increasing trend in enantioselectivity agreed with this
model.
In order to test the validity of this model, we further tested
the pyrrolidine- and piperidine-type primary amine catalyst 3m
C
DOI: 10.1021/acs.orglett.8b03584
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Organic Letters
Letter
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1
(
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primary amine-catalyzed reactions where H-bonding was
absent, indicating the influence of the N-substituent
orientation was general in primary amine-based catalysis.
This finding gave us useful hints toward the development of
new primary amine catalysts.
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ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03584.
Experimental procedures, screening data, steric param-
eters and model development, computational details,
and NMR spectra (PDF)
2
(
2
011, 333, 1875−1878.
8) (a) Milo, A.; Bess, E. N.; Sigman, M. S. Nature 2014, 507, 210−
14. (b) Zhang, C.; Santiago, C. B.; Kou, L.; Sigman, M. S. J. Am.
AUTHOR INFORMATION
Corresponding Authors
■
*
*
E-mail: luosz@tsinghua.edu.cn.
E-mail: zhanglong@tsinghua.edu.cn.
ORCID
Chem. Soc. 2015, 137, 7290−7293. (c) Bess, E. N.; Bischoff, A. J.;
Sigman, M. S. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 14698−14703.
(d) Milo, A.; Neel, A. J.; Toste, F. D.; Sigman, M. S. Science 2015,
3
47, 737−743. (e) Chen, Z.-M.; Hilton, M. J.; Sigman, M. S. J. Am.
Sanzhong Luo: 0000-0001-8714-4047
Author Contributions
Chem. Soc. 2016, 138, 11461−11464. (f) Neel, A. J.; Milo, A.; Sigman,
M. S.; Toste, F. D. J. Am. Chem. Soc. 2016, 138, 3863−3875.
(g) Yamamoto, E.; Hilton, M. J.; Orlandi, M.; Saini, V.; Toste, F. D.;
∥
Y.W. and H.Z. contributed equally to this work.
Notes
Sigman, M. S. J. Am. Chem. Soc. 2016, 138, 15877−15880.
(h) Orlandi, M.; Coelho, J. A. S.; Hilton, M. J.; Toste, F. D.;
Sigman, M. S. J. Am. Chem. Soc. 2017, 139, 6803−6806. (i) Orlandi,
M.; Hilton, M. J.; Yamamoto, E.; Toste, F. D.; Sigman, M. S. J. Am.
Chem. Soc. 2017, 139, 12688−12695. (j) Niemeyer, Z. L.; Pindi, S.;
Khrakovsky, D. A.; Kuzniewski, C. N.; Hong, C. M.; Joyce, L. A.;
Sigman, M. S.; Toste, F. D. J. Am. Chem. Soc. 2017, 139, 12943−
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Natural Science Foundation of China
21390400, 21572232, 21672217, and 21521002) and
Tsinghua University for financial support. S.L. is supported
■
(
12946. (k) Park, Y.; Niemeyer, Z. L.; Yu, J.-Q.; Sigman, M. S.
Organometallics 2018, 37, 203−210. (l) Crawford, J. M.; Stone, E. A.;
Metrano, A. J.; Miller, S. J.; Sigman, M. S. J. Am. Chem. Soc. 2018, 140,
by the National Program of Top-notch Young Professionals.
8
68−871.
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(
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(
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(
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