A Catalyst-Controlled Enantiodivergent Bromolactonization

Article abstract of DOI:10.1021/jacs.1c05680

A catalyst-controlled enantiodivergent bromolactonization of olefinic acids has been developed. Quinine-derived amino-amides bearing the same chiral core but different achiral aryl substituents were used as the catalysts. Switching the methoxy substituent in the aryl amide system from meta- to ortho-position results in a complete switch in asymmetric induction to afford the desired lactone in good enantioselectivity and yield. Mechanistic studies, including chemical experiments and density functional theory calculations, reveal that the differences in steric and electronic effects of the catalyst substituent alter the reaction mechanism.

Full text of DOI:10.1021/jacs.1c05680

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A Catalyst-Controlled Enantiodivergent Bromolactonization
Yuk-Cheung Chan,† Xinyan Wang,† Ying-Pong Lam, Jonathan Wong, Ying-Lung Steve Tse,*
and Ying-Yeung Yeung*
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ABSTRACT: A catalyst-controlled enantiodivergent bromolactonization of olefinic acids
has been developed. Quinine-derived amino-amides bearing the same chiral core but
different achiral aryl substituents were used as the catalysts. Switching the methoxy
substituent in the aryl amide system from meta- to ortho-position results in a complete switch
in asymmetric induction to afford the desired lactone in good enantioselectivity and yield.
Mechanistic studies, including chemical experiments and density functional theory
calculations, reveal that the differences in steric and electronic effects of the catalyst
substituent alter the reaction mechanism.
dimethyl to the cyclopropane achiral residue in the tetrapeptide
catalyst (Scheme 1B).5b Recently, Shao et al. have described a
catalyst-controlled Mannich reaction by engineering the achiral
residue of 1,2-diamine catalysts (Scheme 1C).5c Zhang et al.
reported enantiodivergent Michael addition controlled by
dipeptide phosphines with achiral amide substituents in
different solvents (Scheme 1D).5d A highly relevant work was
reported by Zhou et al. in which catalysts with different
hydrogen-bond donors were used to create distinct chiral
pockets for diastereodivergent Michael addition reactions.5e
Among the literature precedent of catalyst-controlled enantio-
divergent catalysis, modifications of the steric and electronic
properties at the achiral residues are the common strategies.
However, to the best of our knowledge, utilization of
regioisomeric catalyst to derive both antipodes of product
efficiently remains unknown. Research on this direction could
also provide a new pathway for catalyst design. Herein, we report
the first case of catalyst-controlled enantiodivergent bromo-
lactonization using a pair of quinine-derived regioisomeric
catalysts (Scheme 1E). Quinine-derived benzamides were used
as the chiral catalysts and altering the achiral methoxy
substituents at the benzamides (i.e., regioisomers that have
equal molecular weight) led to a switch in the enantioselectivity
at synthetically useful level with a broad substrate scope.
INTRODUCTION
■
Asymmetric catalysis is one of the most popular approaches for
the preparation of enantioenriched compounds, which are of
paramount importance in the synthesis of pharmaceuticals and
natural products.1 For comprehensive biological studies, it is
highly desirable to have both antipodes of enantioenriched
bioactive compounds.2 However, it is not trivial to synthesize
both hands of enantiomeric products in high optical purity in
some circumstances because the exact antipodes of chiral
catalyst scaffolds are not always available. A representative
example is cinchona alkaloid-derived catalysts in which
unnatural enantiomers of cinchona alkaloids are not readily
available and their pseudoenantiomeric variants are not useful
for comparison in many circumstances (see also Table S1 in
SI).3 An appealing solution is enantiodivergent catalysis that
enables the access to both antipodes of chiral products by
utilizing catalysts with the same stereogenic element in the
structural architecture. Different factors4 such as metal cations,
reagents, ligand substituent, additives, anions, solvent and
reaction time were identified to be tunable parameters in
enantiodivergent asymmetric catalysis. Catalyst-controlled
enantiodivergency, which involves the variation of the achiral
residues remote from the chiral environment while keeping the
stereogenic components and functional groups unchanged, is
also an attractive approach but their reports are sporadic. A
seminal work by Gong et al. demonstrated an efficient
enantiodivergent Biginelli condensation catalyzed by chiral
phosphoric acid in which the change in the substituents at the
3,3′-positions in the BINOL backbone brought a reversal of
enantioselectivity (Scheme 1A).5a In 2017, Miller et al. reported
a desymmetrizing aromatic bromination of bis(phenols) with
enantiodivergence originating from the alteration of the gem-
Received: June 2, 2021
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regioisomers A2 and B2 that have equal molecular weight, the
only difference is the position of -OMe group (C3 or C6) that is
several atoms away from the stereogenic element of the
cinchona alkaloid skeleton. However, their asymmetric
induction behavior is notably different.
Scheme 1. Examples of Catalyst-Controlled
Enantiodivergent Organocatalysis
Encouraged by this interesting result, we further investigated
catalysts with other substituents in the quinoline system8 and a
steric-matching preference between the benzamide and the
quinoline moiety was observed (Scheme 2). For instance, the
2,3,4-trimethoxyphenyl (2,3,4-OMe) catalyst system favors a
bulky substituent at C(6) with concomitant medium-sized
phenyl group at C(2) on quinoline, making A5 an optimized
catalyst (for the rest of combinations, see Table S2 in SI).
However, the 2,4,6-trimethoxyphenyl (2,4,6-OMe) catalyst
system showed an opposite trend. Raising the steric hindrance
from Me to neo-pentyl at C(6) of quinoline gave a disappointing
result; meanwhile, a very bulky 9-anthracenyl at C(2)
significantly improved the enantiomeric induction to give B5
as another lead catalyst. This matching preference between
2,3,4-OMe/2,4,6-OMe and quinoline residues suggests the
catalysts adopt a different pocket for substrate binding and might
eventually contribute to the enantiodivergence.
Substrate Scope. With the optimized catalysts (A5 and B5)
and reaction conditions (for a brief optimization of solvent and
bromine source, see Tables S1 and S3 in SI) in hand, the scope of
bromolactonization of 1 was evaluated and the results are
summarized in Scheme 3.
(a) Scope of 1,1-disubstituted olefinic acids by catalyst A5:
Lactonization of both electron-neutral and donating
substituents of aryl olefinic acids 1, including heterocycles
(1d, 1e), were catalyzed smoothly to give (R)-2 in good
yield and enantioselectivity catalyzed by the 2,3,4-OMe
catalyst A5. For substrates bearing electron-withdrawing
groups, e.g., halogen, CF3, and NO2, a stronger
brominating agent N,N-dibromohydantoin (DBDMH)
was needed for good conversion.
(b) Scope of 1,1-disubstituted olefinic acids by catalyst B5:
The 2,4,6-OMe catalyst B5 also efficiently promoted the
bromolactonization for a wide range of substrates 1 to give
(S)-2 in good yield and enantioselectivity using either
NBS or DBDMH as the brominating source. The catalytic
performance is comparable to that of A5. The asymmetric
induction was also found to be less influenced by the
electronic and steric properties of the substrates.
Interestingly, our new catalyst of amino-benzamide
works well with substrate bearing para-OMe (1g) and
ortho-Me (1n) substituent, which were either less
selective or reactive in previous bromolactonization
studies.7,9 Within the scope, no substrate-controlled
enantiomeric switch was observed.10
(c) Scope of 1,2-disubstituted olefinic acids: We also
extended the scope to 1,2-disubstitued olefinic substrates
that gave rise to products with two stereogenic centers
(Scheme 4). It was found that the enantiodivergent
methodology could be applied to 1,2-trans- and 1,2-cis-
disubsituted olefinic acids 1q and 1r, giving both
antipodes of 2q and 2r, respectively, in good yield and
enantioselectivity. The excellent endo (for 2q) and exo
(for 2r) selectivity could be attributed to the steric and
electronic effects of the trans- and cis-olefins.6j
Mechanistic studies were also undertaken to shed light on the
origin of enantiodivergence and stereoinduction.
RESULTS AND DISCUSSION
■
Catalyst Study. Catalytic asymmetric halolactonization is an
important approach to access chiral lactones, which are useful
building blocks for medicinal chemistry and natural product
synthesis. In addition, the resultant halogen handles in the
lactone products can easily be manipulated to give various useful
derivatives. Over the past few years, a number of research teams
(including ours) have been devoted to this area and a number of
catalytic systems have been developed.6 During our research
endeavors,7 we identified that 9-epi-aminoquinine-derived
catalyst A0 that contains a benzamide achiral substituent
could catalyze asymmetric bromolactonization of 1a to (R)-2a
using N-bromosuccinimide (NBS) with a promising enantiose-
lectivity (27% ee) (Scheme 2). The enantioselectivity was
improved when the catalyst bearing an electron-donating 2,4-
dimethoxy substituent (i.e., A1) was used, giving (R)-2a in 65%
ee. Unexpectedly, a reversed enantiomeric induction [78% ee of
(S)-2a] was observed with the 2,6-dimethoxyphenyl catalyst B1.
Further survey led us to identify that the 2,3,4-trimethoxyphenyl
catalyst A2 gave (R)-2a in 84% ee while the 2,4,6-
trimethoxyphenyl catalyst B2 gave the antipode (S)-2a in 82%
ee. It is an unusual phenomenon because comparing catalyst
Structural Analysis of the Catalysts. Several studies were
conducted in order to get a better understanding on the
B
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a
Scheme 2. Effect of the Catalyst Substituents
a
1
Reactions were carried out at 0.05 mmol scale under N2 in the absence of light. All conversions were determined to be >95% using H NMR.
Enantiomeric excess (ee) was determined by HPLC on a chiral stationary phase. Positive and negative signs of ee are assigned for (R)-2a and (S)-
2a, respectively.
a
Scheme 3. Substrate Scope of the Enantiodivergent Bromolactonization of 1,1-Substituted Olefinic Acids
a
Reactions were carried out on 0.1 mmol scale under N2 in the absence of light. Enantiomeric excess (ee) was determined by HPLC on a chiral
b
c
d
e
stationary phase. NBS, PhMe/m-xylene (2:1 v/v). DBDMH, PhMe/PhCl (4:1 v/v). One mmol scale, 96 h. DBDMH, PhMe/o-xylene (2:1 v/
v). DBDMH, PhMe. NBS, PhMe/o-xylene (2:1 v/v). NBS, PhMe/CHCl3 (4:1 v/v).
f
g
h
structural differences between the two catalyst regioisomers. We
speculate that the difference associated with the amide group
(both sterically and electronically) of the catalysts might play a
crucial role in dictating the mechanistic pathway. Since cinchona
alkaloids derivatives are known to exist in several conformers,11
the population of conformers might be expected to affect the
enantioselectivity.12 Thus, we analyzed the structural difference
between catalysts A2 and B2. For catalyst A2, strong nuclear
Overhauser effect (NOE) correlations were observed between
H1−H9 and H5−H8, suggesting that A2 exhibited anti-open-1
conformation in majority (Figure 1A). Meanwhile, strong NOE
correlations were observed in H1−H9, H5−H8, and H5−H11 in
the case of B2, indicating that it might also adopt an anti-open-2
conformation. While both A2 and B2 adopted “open”
conformations which were consistent with the conformational
analysis of 9-epi-quinine,13 the slight difference (based on the
NOE correlations) in the catalyst geometry could be attributed
to the difference in the steric demand between the 2,3,4- and
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Scheme 4. Asymmetric Bromolactonization of 1,2-
Disubstituted Olefinic Acids
Scheme 5. Comparison of the N−H and N−Me Benzamide
Catalysts
and B6 are 47.4° and 82.5°, respectively. These values are
considerably higher than that of the N−H catalysts A2 and B2,
attributed to the loss of hydrogen bond and increase in steric
effect. In combination with the results from the structural
analysis of the N−H catalysts (Figure 1), we hypothesize the
origin of enantiodivergence might come from a different binding
model or sequence between catalyst and substrate or reagent (Br
source), which could be strongly influenced by the presence of a
free N−H amide. Indeed, recent studies by Borhan et al. nicely
demonstrated that fragment interaction among halogen source,
catalyst, and olefinic acid is crucial for highly enantioselective
chlorolactonization.14
Theoretical Study. Density functional theory (DFT)
calculations were carried out in order to elucidate the origin of
the distinct difference in asymmetric performance of the two
catalysts. The geometry optimizations and single-point energies
were carried out using Gaussian 09 (ver. D.01) at the levels of
M06-2X-D3/6-311G(d) and M06-2X-D3/6-311++G(d,p), re-
spectively.15 The SMD solvent model16 was used. All the
thermodynamic properties were evaluated at 213 K.
a. Free Energy Profile with Catalyst A2. We found in the
calculated free energy profile with catalyst A2 that the
quinuclidine’s nitrogen in catalyst A2 coordinates with the Br
of NBS while the amide N−H hydrogen bonds with the ortho-
methoxy in the aryl substituent (Figure 2). Concurrently, the
carboxylic acid substrate protonates the succinimide’s carbonyl
oxygen to give the trilateral complex R1. Subsequently, the
succinimide dissociates from Br via TS1 with a free energy
barrier of 17.4 kcal mol−1 to give intermediates IM1. A
conformational change together with the formation of a
hydrogen bond between succinimide oxygen and the N−H in
catalyst’s amide moiety give IM2. Then, formation of the
bromiranium intermediate IM3a proceeds via TS2a. Finally,
cyclization of IM3a via TS3a gives the major product (R)-2a.
The rate-determining step is R1 → TS1 while the
enantiodetermining step is IM2 → TS3a. For the pathway
toward the minor product (S)-2a, the barrier of the
enantiodetermining step from IM2 to TS2b (6.3 kcal mol−1)
is significantly higher than that in the major pathway from IM2
Figure 1. Structural analysis. (A) NOE study of catalysts A2 and B2.
(B) Optimized structures of A2 and B2 by DFT.
2,4,6-trimethoxyphenyl substituents, consistent with the opti-
mized structures of A2 and B2 by density functional theory
(DFT) at the level of M06-2X-D3/6-311G(d,p) (Figure 1B;
also see Figures S2−S3 in SI). The calculated torsion angles
between the amide and phenyl planes in A2 is 14.1°, which is
comparable to the measured value (15.5°) from X-ray
crystallography of A2 single crystal. The calculated torsion
angle in B2 (>48.7°) is much larger, attributed to the steric
hindrance of the two methoxy groups at the ortho-position (also
see Figure S1 in SI). Another key structural difference between
two catalysts is the close contact between N−H···OMe (1.961
Å) in A2. This suggested the N−H in A2 interacts with ortho-
OMe in the benzamide via intramolecular hydrogen bond. The
weak intramolecular H-bond in B2 (indicated by the relatively
longer N−H···OMe 2.20−2.90 Å) could be attributed to the
heavily distorted benzamide geometry. We then speculated the
presence of intramolecular hydrogen bond might be a crucial
factor behind the enantiodivergence since no distinct difference
in conformation of catalyst was observed.
Role of N−H in the Benzamide Catalysts. We prepared
and evaluated the catalytic performance of methylated
benzamide A6 and B6 as analogues of A2 and B2, respectively
(Scheme 5). Albeit the enantioselectivity dropped dramatically
for both N−Me catalysts A6 and B6, presumably due to the
involvement of hydrogen bond from amide’s N−H in the
stereodetermining step. Moreover, the reversal of asymmetric
induction completely disappeared in B6, further highlighting the
crucial role of free N−H amide. On the basis of the DFT
calculation, the torsion angles at the N−Me aryl moieties of A6
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Figure 2. Free energy profile of the A2-catalyzed reaction.
to TS3a (5.4 kcal mol−1). Throughout the free energy profile, it
was observed that the intramolecular hydrogen bond persists. As
compared with TS3a, the hydrogen bond between the
succinimide oxygen and the N−H of catalyst’s amide group is
missing in TS2b. In addition, it was found that the α-C−H of the
ammonium cation moiety stabilizes the carbonyl group of the
substrate in the major pathway more significantly (vide infra),
which could justify the lower free energy of TS3a versus TS2b.
b. Free Energy Profile of System with Catalyst B2. For
catalyst B2, the initial stage R2 involves the complexation of the
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Figure 3. Free energy profile of the B2-catalyzed reaction.
catalyst and NBS via the following: (1) N−Br interaction
between quinuclidine’s nitrogen and NBS; (2) hydrogen bond
interaction between the amide N−H and the succinimide
carbonyl oxygen (Figure 3). This result is consistent with the
structural analysis in which the large torsion angle between the
amide and the aryl moieties restricts the formation of
intramolecular hydrogen bond (Figure 1). The Br is transferred
from succinimide to the quinuclidine. Concurrently, proto-
nation of succinimide gives the carboxylate that interacts with
the Br. The whole process (R2 → IM4 via TS4) has a free energy
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barrier of 17.2 kcal mol−1, which is the rate-determining step.
Next, conformational change of IM4 followed by bromination
gives the bromiranium intermediate IM5a. Cyclization of IM5a
via TS5a furnishes (S)-2a as the major product. The
enantiodetermining step in the major product formation is the
step from IM5a to TS5a (barrier = 7.0 kcal mol−1), whose rate is
significantly faster than that of the minor pathway from IM4 to
TS5b (barrier = 8.4 kcal mol−1). TS5a is substantially stabilized
as compared with TS5b for reasons explained in the next section.
There is a major difference when comparing the two catalytic
systems. In catalyst A2, the intramolecular hydrogen bond
restrains the geometry of the aryl amide. Thus, the 2,3,4-
trimethoxyl benzamide appears to mainly serve as a steric shield
group in the reaction. For catalyst B2, however, the amide’s N−
H is available to interact with NBS throughout the process. The
enantioselectivity is likely to be controlled by both function-
alities (quinuclidine and amide) in the catalyst. This key factor
might govern the enantiodivergent bromolactonization.
c. Stabilization Effect in the Reactions. To get a better
understanding of the enantiodetermining steps in Figures 2 and
3, Natural Bond Orbital (NBO)17 and Atoms In Molecules
(AIM)18 analyses were carried out to understand the
interactions. For TS3a of the A2-catalyzed reaction, the NBO
charge of the α-C−H of the ammonium cation (+0.23 as shown
in Figure 4A inset) is markedly more positive than those of the
typical C−H’s (about +0.20) because of the electropositivity of
the ammonium nitrogen. In addition, the NBO charge of the
carboxylate oxygen is calculated to be −0.82. The relatively
larger difference in the NBO charges between the C−H and C−
O along with the short interatomic distances (2.5 Å), the α-C−
H interacts strongly with the carboxylate oxygen and form what
can be classified as a nonclassical hydrogen bond (NCHB)19 as
indicated by the bond path and critical point (green and orange)
from AIM.20 Such a bond path indicates where the electron
density is maximally concentrated between the two nuclei and
shows the directionality of an interaction. The corresponding
NCHB in TS2b of the minor pathway is considerably weaker
(see SI for detail), and we believe this difference is one of the
major factors for the lower free energy of TS3a than that of TS2b
by about 0.9 kcal mol−1, leading to the enantioselectivity.
Similarly, there are NCHBs in TS5a of the B2-catalyzed
reaction. By also carrying out an AIM analysis, we determined
the bond paths and critical points20 that indicate the directions
and paths of maximal electron density of the significant
intermolecular interactions, which include the π−π interaction
in addition to NCHBs in Figure 4B. There are no such NCHBs
and π−π interaction in TS5b of the minor pathway (Figure 3B),
which can explain why TS5a has a lower free energy than TS5b
by 4.7 kcal mol−1. This free energy difference is larger than that
of the enantiodetermining step in the A2-catalyzed reaction,
plausibly due to the fact that both the NCHBs and π−π
interaction are at play.21
Electronic Effect of the Substituents. Since the ortho-
oxygen was found to be crucial for the high enantioselectivity
with the 2,3,4-trimethoxy catalyst A5 (or A2), it is expected that
the electronic property of the aryl group would affect the
asymmetric performance. On the basis of our calculations on the
catalyst structure (Figure 1), it appears that the hydrogen bond
between the N−H and the ortho-oxygen in the aryl group might
be crucial for the high enantioselectivity. A more detailed study
was conducted by varying the R substituents including methoxy,
methoxymethoxy (OMOM), difluoromethoxy, and triflate
(OTf) at the para-position of the phenyl ring (i.e., catalysts
A7−A10). A slight modification of the catalyst (using 2,3-
methylenedioxy instead of 2,3-dimethoxy) was undertaken to
minimize the steric effect brought by the substituents.22 It is
interesting to observe that a higher ee of product (R)-2a could
be obtained with a more electron-donating substituent at the
para-position (Figure 5). In addition, the ΔΔG‡ and Hammett
σpara coefficient23 could be correlated in which a negative slope
of plot was observed.24 The Hirshfeld atomic charge of the
ortho-oxygen (OA) was calculated and its negative charge was
found to become more positive with the increasing electron-
donating ability of the R substituent at the para-position and
higher enantioselectivity in general. This is consistent with the
result that the ortho-oxygen interacts with the amide via
hydrogen bond and such interaction might restrain the
geometry of the catalyst that is crucial for high ee.
CONCLUSION
■
In summary, we have developed a catalyst-controlled
enantiodivergent bromolactonization with both (R)- and (S)-
products in good yield and optical purity. Mechanistic studies
suggest that the amides in the 2,3,4-trimethoxyphenyl catalyst
A5 and the 2,4,6-trimethyloxyphenyl catalyst B5 might serve
different functions, leading to the enantiodivergent behavior.
This study provides an alternative approach toward asymmetric
halocyclization through catalyst substituent manipulation. This
study also highlights that achiral substituents on chiral catalysts
may serve not only in steric-shielding but also in switching
reaction mechanisms.
Figure 4. (A) Optimized structure of TS3a. (B) Optimized structure of
TS5a. Bond paths and critical points computed by an AIM analysis
(green lines and orange dots) show both the nonclassical hydrogen
bonds (NCHBs) and π−π interaction. NBO charges and NCHB
distances of the atoms involved are shown in the insets.
G
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Hong Kong, Hong Kong, China; orcid.org/0000-0002-
3690-2335
Ying-Pong Lam − Department of Chemistry and State Key
Laboratory of Synthetic Chemistry, The Chinese University of
Hong Kong, Hong Kong, China
Jonathan Wong − Department of Chemistry and State Key
Laboratory of Synthetic Chemistry, The Chinese University of
Hong Kong, Hong Kong, China; orcid.org/0000-0002-
1187-063X
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c05680
Author Contributions
†Y.C.C. and X.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the HKSAR University Grant Council (Grant No.
CUHK 14305520) and The Chinese University of Hong Kong
Direct Grant (Grant No. 4053275, 4053329, 4053203,
4053449), and Innovation and Technology Commission to
the State Key Laboratory of Synthetic Chemistry (GHP/004/
16GD) for financial support. This paper is dedicated to
Professor Henry N. C. Wong on the occasion of his 70th
Birthday.
Figure 5. Relationship between enantioselectivity and σpara of R.
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
Corresponding Authors
■
Ying-Lung Steve Tse − Department of Chemistry and State Key
Laboratory of Synthetic Chemistry, The Chinese University of
Hong Kong, Hong Kong, China; orcid.org/0000-0003-
1187-2296; Email: stevetse@cuhk.edu.hk
Ying-Yeung Yeung − Department of Chemistry and State Key
Laboratory of Synthetic Chemistry, The Chinese University of
Hong Kong, Hong Kong, China; orcid.org/0000-0001-
9881-5758; Email: yyyeung@cuhk.edu.hk
Authors
Yuk-Cheung Chan − Department of Chemistry and State Key
Laboratory of Synthetic Chemistry, The Chinese University of
Hong Kong, Hong Kong, China
Xinyan Wang − Department of Chemistry and State Key
Laboratory of Synthetic Chemistry, The Chinese University of
H
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