Asymmetric Hydrogenation of Cationic Intermediates for the Synthesis of Chiral N,O-Acetals

Article abstract of DOI:10.1002/chem.202002930

For over half a century, transition-metal-catalyzed homogeneous hydrogenation has been mainly focused on neutral and readily prepared unsaturated substrates. Although the addition of molecular hydrogen to C=C, C=N, and C=O bonds represents a well-studied paradigm, the asymmetric hydrogenation of cationic species remains an underdeveloped area. In this study, we were seeking a breakthrough in asymmetric hydrogenation, with cationic intermediates as targets, and thereby anticipating applying this powerful tool to the construction of challenging chiral molecules. Under acidic conditions, both N- or O-acetylsalicylamides underwent cyclization to generate cationic intermediates, which were subsequently reduced by an iridium or rhodium hydride complex. The resulting N,O-acetals were synthesized with remarkably high enantioselectivity. This catalytic strategy exhibited high efficiency (turnover number of up to 4400) and high chemoselectivity. Mechanistic studies supported the hypothesis that a cationic intermediate was formed in situ and hydrogenated afterwards. A catalytic cycle has been proposed with hydride transfer from the iridium complex to the cationic sp² carbon atom being the rate-determining step. A steric map of the catalyst has been created to illustrate the chiral environment, and a quantitative structure–selectivity relationship analysis showed how enantiomeric induction was achieved in this chemical transformation.

Full text of DOI:10.1002/chem.202002930

Accepted Article
Accepted Article
Title: Asymmetric Hydrogenation of Cationic Intermediates for the
Synthesis of Chiral N,O-Acetals
Authors: Yongjie Sun, Qingyang Zhao, Heng Wang, Tilong Yang, Jialin
Wen, and Xumu Zhang
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10.1002/chem.202002930
Chemistry - A European Journal
RESEARCH ARTICLE
Asymmetric Hydrogenation of Cationic Intermediates for the
Synthesis of Chiral N,O-Acetals
Yongjie Sun [a], †, Qingyang Zhao [b], †, Heng Wang[a], Tilong Yang[c], Jialin Wen*[a],[d], Xumu Zhang *[a]
Dedication ((optional))
[a]
Y. Sun, H. Wang, Dr. J. Wen and Prof. Dr. X. Zhang
Shenzhen Grubbs Institute and Department of chemistry,
Southern University of Science and Technology,
1088 Xueyuan Road, Shenzhen, 518055, China.
E-mail: wenjl@sustech.edu.cn; zhangxm@sustech.edu.cn
Dr. Q. Zhao
School of Pharmaceutical Sciences (Shenzhen)
Sun Yat-sen University,
Shenzhen, 518107, China.
[c]
[c]
[d]
†
T. Yang
Department of chemistry,
The Hong Kong University of Science and Technology,
Clear Water Bay, Kowloon, Hong Kong, China.
Dr. J. Wen
Academy for Advanced Interdisciplinary Studies
Southern University of Science and Technology
1088 Xueyuan Road, Shenzhen, 518055, China.
Yongjie Sun and Qingyang Zhao contributed equally.
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Over
a
half century, transition-metal-catalyzed
achievements in AH, which demonstrated the recognition of this
method in the community of chemistry. For a long time, the
addition of molecular hydrogen to a prochiral C=C, C=N or C=O
bond has always been the paradigm of AH to generate a
stereogenic sp3-carbon (scheme 1a). This stereotype, as a result,
slowed down the exploration of new reaction patterns. For
instance, AH was normally excluded for the construction of
targeting molecules without a β-hydrogen. On the other hand, a
carbocation could also be reduced to form a stereogenic sp3-
carbon via a hydride transfer from a metal hydride complex to a
sp2-C cationic species (scheme 1b). However, the latter is
challenging because of the incompatibility of conditions that are
homogeneous hydrogenation has been mainly focused on neutral
and readily-prepared unsaturated substrates. While the addition of
molecular hydrogen to C=C, C=N and C=O bonds was a well-
studied paradigm, the asymmetric hydrogenation of cationic species
was an underdeveloped area. In this research, we were seeking for
a breakthrough in asymmetric hydrogenation to include cationic
intermediates as the target and therefore expecting to apply this
powerful tool in the construction of challenging chiral molecules.
Under an acidic condition, both N- or O-acetyl salicylamides undergo
cyclization to generate cationic intermediates, which was
subsequentially reduced by an iridium or rhodium hydride complex.
N,O-acetals
were
synthesized
with
remarkably
high
required to generate a
cationic sp2-carbon intermediate[3]
enantioselectivity. This catalytic strategy exhibited high efficiency
(TON up to 4400) and high chemoselectivities. Mechanistic studies
supported the hypothesis that a cationic intermediate was in situ
(normally in acidic condition) with a reactive metal hydride
complex (normally survives in a non-electrophilic condition).
According to our best knowledge, while the stoichiometric
reduction of carbocations could be achieved by silanes[4] or
metal hydride complexes[5], catalytic hydrogenation of this type
of highly reactive species using molecular hydrogen has been a
far less developed field[1, 6]. The methodology to synthesize
chiral molecules based on enantioselective hydrogenation of
cationic intermediates has been so far a virgin land. A novel
strategy of AH regarding sp2-C cations shall not only broadens
the substrate scope of this method, but also provide an efficient
tool to construct challenging chiral molecules, thus encouraging
practitioners in chemistry to continuously make development in
this field.
formed and hydrogenated afterwards.
A catalytic cycle was
proposed with the hydride transfer from iridium complex to the
cationic sp2-carbon being the rate determining step. A steric map of
the catalyst was depicted to illustrate the chiral environment and a
QSSR analysis showed how the enantiomeric induction was
achieved in this chemical transformation.
Introduction
After a half-century development, transition metal catalyzed
asymmetric hydrogenation (AH) has emerged as one of the
most important methods to construct chiral molecules[1]. This
class of asymmetric catalysis is currently an irreplaceable
method in chemists’ toolbox in pharmaceutical, agrochemical
and fine chemical industries[2]. In 2001, the Nobel Prize was
laurelled to William Knowles and Ryoji Noyori for their
Chiral acetals are common but core structures for many
natural and artificial bioactive molecules[7]. The synthesis of this
family of compounds is therefore of high value for both synthetic
methodology and pharmaceutical industry. However, due to lack
of efficient enantiomeric induction and the easy decomposition
such as hydrolysis, synthetic methodologies based on
asymmetric catalysis have been rarely reported and were mainly
1
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10.1002/chem.202002930
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RESEARCH ARTICLE
limited to Brønsted acid catalysis (scheme 1c) developed by
Antilla, Rueping, List and others[8]. The inherent limitations such
as relatively high catalyst loading (5% ~ 10% for N,X-acetals)
and the sophisticated architecture of catalysts (for O,O-acetals)
impeded their large-scale application[8a]. If a carbocation could
be stabilized by either adjacent heteroatoms or substituents and
therefore exists in a considerable concentration, the feasibility of
being captured and subsequently reduced by a metal hydride
will create an opportunity to form a stereogenic center. This
strategy offers an alternative approach to prepare chiral acetals
via asymmetric hydrogenation. Gratefully, our group has recently
amount of impurities (including alcoholysis product 3a and
isomerization product, N-acetyl salicylamide 4a). While
molecular sieve did not improve this reaction, the yield of acetal
2a was driven up to > 95% with a desired suppression of by-
product when one equivalent of titanium isopropoxide was
applied. A series of modifications on the original Zhaophos were
conducted (L2 - L6). It was found that L4 bearing bulkier and
more electron-rich substituents on the phosphorus atoms gave
the highest enantioselectivity. In addition, catalytic amount of
hydrochloric acid would be sufficient under this condition (see
supporting information). In contrast,
a rapid screening of
developed
a
thiourea containing bisphosphine ligand,
commonly used catalytic system in AH (rhodium, ruthenium and
iridium) failed to yield desired product under the optimized
condition. [For experimental details, see supporting information.]
ZhaoPhos[9], which has the potential ability to bind with ionic
substrates via hydrogen bond. This catalytic system could
tolerate acidic conditions[10] and was successfully applied in the
asymmetric
hydrogenation
of
imines[11]
,
.
quinolines/isoquinolines[12], indoles[10] and conjugate olefins[13]
Table 1. Condition optimization for the preparation of acetal using O-
acetylelectsalicylamide.
Guided by these rationales, we envisioned that this catalytic
system has the potential to achieve AH of a cationic sp2-carbon
to generate a chiral acetal compound.
Entry
1
Ligand
L1
solvent
DCM
additive
-
2a
3a + 4a
65%
23%
55%
58%
31%
12%
4%
ee of 2a
85%
93%
86%
81%
92%
93%
93%
96%
99%
96%
89%
35%
77%
45%
42%
69%
86%
96%
98%
97%
98%
99%
2
L1
iPrOH
toluene
THF
-
3
L1
-
4
L1
-
5 [a]
6 [b]
7 [b]
8 [b]
9 [b]
10 [b]
11 [b]
L1
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
3 Å MS
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
L1
L2
L3
2%
Scheme 1. The strategy of hydrogenation of a cationic sp2-carbon to prepare
chiral acetal. a. The model of classical transition-metal-catalyzed
homogeneous hydrogenation of neutral double bonds. b. Hydride transfer from
a metal hydride complex to a cationic sp2 carbon. c. Chiral-Brønsted-acid
catalyzed acetalization: a case of nucleophilic addition. d. Enantioselective
synthesis of chiral N,O-acetals via hydrogenation of unsaturated cation
intermediates.
L4
3%
L5
2%
L6
1%
Reaction condition: 1a 0.1 mmol in 1.0 mL solvent, 1a/[Ir(COD)Cl]2/ligand =
200/1/2.1, 1.0 eq. HCl (1.0 M in AcOH), 60 atm H2, rt, 24 h, conversion and
yield was determined by 1H NMR analysis of crude product, ee was
Results and Discussion
determined by HPLC on
a stationary phase. Detectable amount of
salicylamide was observed in the reaction mixture. [a] 20 mg 3 Å molecular
sieve was added. [b] 1.0 equivalent of titanium isopropoxide was added.
Optimization of reaction conditions
The investigation was commenced by selecting a proper
model substrate which should comprise both simplicity and
generality. O-acetyl salicylamide was eventually selected
because (1) this family of compounds have simple structures
and therefore are easy to prepare[14]; (2) it undergoes cyclization
in an acidic condition, which facilitates the formation of a cationic
sp2-carbon[15]. Initially, iridium and Zhaophos L1 were applied in
the hydrogenation. In the presence of hydrochloric acid, the
cyclization underwent smoothly and N,O-acetal 2a was obtained
with high conversion. However, the yield of acetal 2a was still
not satisfactory in a variety of solvents, along with a detectable
Interestingly, during the progress of condition optimization,
we observed that the by-product N-acetyl compound 4a could be
consumed eventually when elongating the reaction time.
Considering the migration of acetyl group between O- and N-
position in acetylsalicylamide[15], as well as the fact that the N-
acetyl isomer was also commonly found in both nature and fine
chemicals, imides were selected as another starting material for
this approach to chiral N,O-acetals. The initial assessment with
imide 4a under the same condition did not yield satisfied results
compared to that with 1a. After a systematic optimization of
2
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10.1002/chem.202002930
Chemistry - A European Journal
RESEARCH ARTICLE
condition, chiral N,O-acetal 2a was obtained with a rhodium
catalyst in toluene. It is noteworthy that the alcoholysis product 3
was not found in the crude reaction mixture. During the progress
of condition optimization, we observed that the reaction with 1a
was faster than the reaction with 4a under the same conditions.
This phenomenon may be attributed to the fact that the N-acetyl
isomers are thermodynamically more stable than the O-acetyl
isomers[15]
.
Scheme 2. Substrate scope for synthesis of N,O-acetals via asymmetric hydrogenation. Reaction condition:
1 or 3 (0.2 mmol) in 2.0 mL solvent,
substrate/[Ir(COD)Cl]2/ligand = 100/0.50/1.05, 0.2 mL HCl (1.0 M in AcOH) was added, 1.0 eq. Ti(OiPr)4, rt, 24 h, 60 atm H2. Enantiomeric excesses were
determined by HPLC on a chiral stationary phase. Purification of the crude products on silica led to partial decomposition (hydrolysis product 3) and loss of yields.
Reaction scope for the synthesis of chiral N,O-acetals
with the reaction conditions (2l to 2p). The introduction of
We explored the reaction scope under the optimal conditions. substituents on the amide did not erode either the
The cyclization and the subsequent hydrogenation reaction with
O-acyl salicylamides proceeded smoothly with various
substituents on the fused benzene. Remarkably high
enantioselectivities were obtained regardless of the electronic
and steric properties of these substituents (2a to 2k). Different
acyl groups on the phenol did not significantly change in
enantioselectivity although the isolated yields varied. Many
moieties such as long alkyl chain, ether or ester were compatible
enantioselectivity or the yields dramatically (2q to 2s). Strikingly,
olefin moiety survived in this chemical transformation, which
suggested an excellent chemoselectivity of this catalytic system
(2t). Reactions with N-acyl salicylamides also yielded chiral N,O-
acetals with high enantioselectivities under a slightly modified
condition using a rhodium catalyst. These two approaches
broadened the reaction scope of this method. To our
disappointment, the synthesis of chiral N,O-acetals with seven-
3
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10.1002/chem.202002930
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RESEARCH ARTICLE
member ring failed by using this strategy, probably due to the
difficulty in the cyclization step. The catalyst loading could be
lowered to 0.02% to the substrate, giving a turnover number
(TON) of 4400 (1i, 88% yield, 99% ee). As a showcase, this
reaction was carried out in gram-scale with 0.1% catalyst and no
significant erosion of yield and enantioselectivity was observed
(1i, 73% yield, 97% ee).
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
11
10.5
10
9.5
9
8.5
8
7.5
7
0
1
2
3
4
5
6
0
0.1
0.2
0.3
0.4
NH 1
0.5
0.6
0.7
0.8
0.9
1
NH 2
NH1
Figure 1. The identification of cationic intermediate in hydrogenation reactions. a. Hydrogenation using deuterium gas under the standard condition. b. The
formation the cationic intermediate from both O- and N-acetyl substrates. DFT calculated electrostatic potential surface of this cationic intermediate was depicted
quantitatively, along with C-O and C-N bond lengths. c. Hydrogenation of oxazinonium perchlorate salt, with and without chloride ion. d. Job plot and 1H NMR
titration curve showed a 1:1 binding ratio of the zhaophos L1 with the chloride ion.
Identification of the cationic intermediate
efficiently. This intermediate, oxazinonium, is regarded as
neither an iminium nor an oxonium species and the carbocation
was partially delocalized. In order to verify our assumption of a
cationic sp2-carbon intermediate, the oxazinonium ion was
Control experiments revealed the irreplaceability of both
acetic acid and hydrochloric acid (Table S7). Isotope labelling
experiment with deuterium gas from either O- or N-acetyl
substrate yielded a high abundance of the D isotope on the
chiral sp3-carbon while the hydrogen atoms on the methyl group
were not replaced by deuterium (Figure 1a). This phenomenon
suggested that the hydrogenation undergoes a pathway in which
a direct hydride transfer from Ir-H complex to the cationic sp2-
carbon. Mechanism involving hydrogenation of C=C bonds (via
elimination of β-H) could therefore be excluded. It is noteworthy
that a noticeable H-D scrambling might occur in protic solvent
such as isopropanol (12% H), which could be avoided by using
aprotic solvent (Figure 1a, reaction 2).
independently prepared as
a
perchlorate salt 5. The
hydrogenation of 5 gave the identical N,O-acetal 2a, although
the enantiomeric induction was moderate. After introduction of
external chloride ion, the ee value was increased to 78% (Figure
1c), suggesting the importance of chloride in this catalytic
reaction. The ee value being still lower than 93% (table 1, entry
6) might be due to the interference by weaker hydrogen bond
donor ion, which phenomenon was also observed in previous
studies[11, 17]. NMR titration experiments (Figure 1d) showed a
1:1 binding ratio between ligand and chloride ion, giving an
estimated binding constant of 818 mol-1.
We therefore proposed
a cationic intermediate after
cyclization of both O- and N-acetyl salicylamide under an acidic
condition (Figure 1b). The DFT calculated C-N bond length
(1.316 Å) was between a typical C=N bond (1.26 ~ 1.27 Å for
iminium ions[16]) and a C-N bond, which was similar to the
situation of C-O bond. Due to diluted electron density (phenol
and benzamide moiety), the adjacent oxygen and nitrogen could
only form limited conjugation to stabilize the carbocation and the
delocalization is therefore limited. That is to say, the nitrogen or
oxygen atom fails to donate electron to stabilize carbocation
Catalytic cycle
The kinetic profile of this reaction was obtained with in situ
attenuated total reflectance Fourier-transform infrared (ATR
FTIR) spectroscopy. The graphical rate equation[18] indicated a
first order dependence on the substrate (1a or 4a). The
comparison of the reaction rate with hydrogen and deuterium
gas revealed a pronounced kinetic isotope effect (KIE = 2.12,
Figure 2c). This primary KIE indicated that the rate determining
4
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10.1002/chem.202002930
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RESEARCH ARTICLE
step lies in either the hydride transfer step or the hydrogen
cleavage step. The reaction rates (absolute rates) varied when
substituents with different electronic property was located on the
benzene ring. A Hammett plot was depicted with good linearity
and a negative sensitivity constant (ρpara = -0.78) indicated a
cationic species in transition state of the rate determining step
(either the cationic intermediate formation or the hydride
transfer). This ρ value indicated a medium-level communication
between the substituents on the phenyl ring and the adjacent
cation center[19]. We therefore proposed an intermediate with a
correlation between the reaction rates and σ+ indicated a
partially delocalized carbocation which was stabilized with
limited resonance effect (ρ+ = -0.31, see supporting information).
The KIE and the Hammett analysis together led to a hypothesis
that the rate determining step (RDS) in this reaction is the
hydride transfer. Based on these results, we proposed reaction
pathways in this reaction: acid-catalyzed cyclization occurs from
either kind of starting materials, and the resulting cationic
intermediate (Int. 1) is to be reduced by a metal hydride complex
(Figure 2d).
phenolic-substituted cationic sp2-carbon[20]
.
The negative
0.1
0.0
1.2x10-5
1.0x10-5
8.0x10-6
6.0x10-6
4.0x10-6
2.0x10-6
0.0
-0.1
-0.2
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.0
0.2
[1a] (M)
σ(para)
2.0x10-5
1.5x10-5
1.0x10-5
5.0x10-6
0.0
H2
D2
0.00
0.02
0.04
0.06
0.08
[4a] (M)
Figure 2. Mechanistic studies for the reaction pathway. a. Graphical rate equation suggesting a first order kinetic dependence on substrate. b. Hammett plot
shows a cationic species in the transition state of rate determining step. c. Graphical rate equation of reaction with hydrogen or deuterium gas under the same
conditions. d. Proposed catalytic cycle with the hydride transfer from iridium hydride to sp2-carbon being the rate determining step.
Model for enantioinduction
Ir-P bond of the other phosphorus atom was selected as the x-
axial. Percent buried volume (%Vbur) was chosen as a global
descriptor to analyze the overall steric effects. Buried volumes
for each quadrant and the whole molecule were calculated as
summarized in Figure 3c.
Our curiosity was then drawn by the enantio-induction model
in this chemical transformation. Previous mechanistic studies
revealed an ionic hydrogenation model[21]. DFT calculational
studies revealed the structure of the catalytic iridium species that
would deliver hydride to the cationic sp2-carbon. In this iridium
dihydride complex, the sulfur atom of thiourea is prone to
coordinate the metal center, forming a conformationally stable
chiral pocket. In addition, it is believed that the pronounced π-π
stacking between 3,5-bis(trifluoromethyl)phenyl group on the
thiourea and the phenyl group on the phosphorus atom
The correlation between enantioselectivity and the steric
descriptor was analyzed to establish quantitative structure-
selectivity relationship[23] (QSSR).
A
pronounced linear
relationship (R2 = 0.95) was observed between log(er) and %Vbur
of southeastern quadrant. Increasing the bulkiness of the
substituent on the phosphorus atom leads to a more thorough
occupation of this area. When comparing the steric hindrance of
each quadrant, we found that the northeastern area was almost
fully occupied by the 3,5-bis(trifluoromethyl)phenyl group on the
thiourea and the substitution group on the phosphorus atom. In
the meanwhile, southwestern area remains empty in for each
strengthened the conformation. In order to obtain
a
comprehensive understanding of how the catalyst differentiate
two faces of the prochiral oxazinonium ion, computer-aided
topographical map was drawn[22] (Figure 3b). The Ir-H bond
trans to a phosphorus atom was selected as the z-axial while the
5
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10.1002/chem.202002930
Chemistry - A European Journal
RESEARCH ARTICLE
ligand and the southeastern quadrant is more hindered than the
northwest. In the hydride transfer step, a cationic sp2-carbon
species is prone to approach the reactive pocket, posing the
largest substituent in the southwest and the smallest substituent
in the southeast (Figure 3e, left). The structural models of the
two diastereomeric catalyst-substrate complexes are shown in
Figure 3e.
2.2
2.0
1.8
1.6
1.4
1.2
66
67
68
69
70
SE %_buried_volume
Figure 3. Unveiling the enantiomeric induction model. a. Geometry of proposed reactive iridium hydride complex. b. Topographic steric map of chiral pocket of the
catalyst with L1. c. Buried volume of each quadrant of several ligands in Zhaophos family. d. Relationship of enantioselectivity with the steric hindrance in the
southwestern quadrant. e. Simplified diagram and structural models for enantiomeric induction.
This project was financially supported by the National Natural
Science Foundation of China (21801118 and 21602172), the
Science, Technology and Innovation Commission of Shenzhen
(KQTD20150717103157174 and JCYJ20190807155201669).
Yongjie Sun thanks Miss Xiaonan Yang for her loving company
and spiritual support during this project.
Conclusion
In summary, we reported the asymmetric hydrogenation of
cationic intermediates under an acidic condition. Using this
method, chiral N,O-acetals were prepared with remarkably high
enantioselectivities from salicylamide derivatives. This catalytic
system shows high chemoselectivity. Both N-acetyl and O-acetyl
salicylamides led to the chiral acetals, albeit the reaction
conditions were slightly different. Mechanistic studies revealed
that a cationic sp2-carbon intermediate that was in situ formed
and reduced sequentially. The result of deuterium labelling
experiment favored an outer-sphere hydride transfer model.
Mechanistic studies such as kinetic profile, Hammett plot and
KIE supported our proposed catalytic cycle. By introducing the
steric descriptor, percent buried volume, steric maps were
depicted to illustrate how the enantiomeric induction was
achieved in this catalytic reaction.
Keywords: asymmetric catalysis • cationic intermediate • chiral
N,O-acetal • homogeneous hydrogenation
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