Chemo- and Enantioselective Hydrogenation of α-Formyl Enamides: An Efficient Access to Chiral α-Amido Aldehydes

Article abstract of DOI:10.1002/anie.201905263

In order to effectively synthesize chiral α-amino aldehydes, which have a wide range of potential applications in organic synthesis and medicinal chemistry, a highly chemo- and enantioselective hydrogenation of α-formyl enamides has been developed, catalyzed by a rhodium complex of a P-stereogenic bisphosphine ligand. Under different hydrogen pressures, the chiral α-amido aldehydes and β-amido alcohols were obtained in high yields (97–99 %) and with excellent chemo- and enantioselectivities (up to >99.9 % ee). The hydrogenation can be carried out on a gram scale and with a high substrate/catalyst ratio (up to 20 000 S/C), and the hydrogenated products were further converted into several important chiral products. Computations of the catalytic cycle gave a clear description for the R/S pathways, provided a reasonable explanation for the enantioselectivity, and revealed several other specific features.

Full text of DOI:10.1002/anie.201905263

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Chemo- and Enantioselective Hydrogenation of ɑ-Formyl
Enamides: An Efficient Access to Chiral ɑ-Amido Aldehydes
Authors: Jian Zhang, Jia Jia, Xincheng Zeng, Yuanhao Wang,
Zhenfeng Zhang, Ilya D. Gridnev, and Wanbin Zhang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201905263
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10.1002/anie.201905263
Angewandte Chemie International Edition
RESEARCH ARTICLE
Chemo- and Enantioselective Hydrogenation of ɑ-Formyl
Enamides: An Efficient Access to Chiral ɑ-Amido Aldehydes
Jian Zhang,[a] Jia Jia,[b] Xincheng Zeng,[a] Yuanhao Wang,[a] Zhenfeng Zhang,[a] Ilya D. Gridnev,[c] and
Wanbin Zhang*[a,b]
Abstract: In order to effectively synthesize chiral ɑ-amino aldehydes, to the environment. Therefore, an alternative and innovative
which have a wide range of potential applications in organic
synthesis and medicinal chemistry, highly chemo- and
approach is still highly desired.
a
enantioselective hydrogenation of ɑ-formyl enamides has been
developed, catalyzed by a rhodium complex of a P-stereogenic
bisphosphine ligand. Under different hydrogen pressures, the chiral
ɑ-amido aldehydes and β-amido alcohols were obtained in high
yields (97-99%) and with excellent chemo- and enantioselectivities
(up to >99.9% ee). The hydrogenation can be carried out on a gram
scale and under a high substrate/catalyst ratio (up to 20000 S/C),
and the hydrogenated products were further converted to several
important chiral products. Computations of the catalytic cycle gave a
clear description for the R/S-pathways, provided a reasonable
explanation for enantioselectivity, and revealed several other specific
features.
Introduction
In the field of synthetic chemistry, aldehydes play a critical role
not only due to their wide applications as bioactive compounds,
but also because of their ability to be derivatized to various
useful functional groups, such as alcohols, carboxylic acids,
esters, and amines. Similarly, chiral aldehydes are very common
structural units and key intermediates in natural products,
pharmaceuticals, flavors, etc.[1] These important and versatile
uses have made the synthesis of chiral aldehydes attractive
(Scheme 1). The main developing methodologies for the
enantioselective synthesis of such compounds include the
asymmetric hydroformylation of alkenes,[2] ɑ-functionalization of
aldehydes,[3] Michael addition of ɑ,β-unsaturated aldehydes,[4]
and transfer hydrogenation of ɑ,β-unsaturated aldehydes.[5]
However, these methods do not satisfy the requirements for
industrial use because of several shortcomings, such as low
efficiency, high cost, poor atom economy, and being damaging
Scheme 1. Asymmetric synthesis of chiral aldehydes.
Asymmetric hydrogenation (AH) is one of the most practical
methodologies due to its high efficiency and environmental
friendliness.[6] Until now, the AHs of ɑ,β-unsaturated carboxylic
acids, esters, amides, and even ketones have been developed
with considerable success.[7] However, the AH of ɑ,β-
unsaturated aldehydes has not been widely reported. Only a
handful of methodologies have been reported for the AH of β-
branched ɑ,β-unsaturated aldehydes with unsatisfactory
enantioselectivity and efficiency.[8] Furthermore, the AH of ɑ-
branched ɑ,β-unsaturated aldehydes is yet to be divulged. The
difficulty for such reactions arises due to the problem of
obtaining both high chemo- and enantioselectivity in a molecule
containing both vinyl and formyl groups. Another significant
problem concerns the racemization of ɑ-stereogenic aldehydes
in an acidic or basic medium. Over our research endeavors
related to AH reactions,[9] we have successfully achieved
chemo- and enantioselectivity by utilizing conjugated substrates
bearing an amido directing group and an electron-rich
bisphosphine-Rh catalytic system in a neutral medium.[9f,g,i,j]
[a]
J. Zhang, X. Zeng, Y. Wang, Z. Zhang, and W. Zhang
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs
School of Pharmacy
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240, China
E-mail: wanbin@sjtu.edu.cn
[b]
[c]
J. Jia and W. Zhang
School of Chemistry and Chemical Engineering
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240, China
I. D. Gridnev
Department of Chemistry, Graduate School of Science
Tohoku University
Aramaki 3-6, Aoba-ku, Sendai 980-8578, Japan
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201905263
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Inspired by these results, we envisaged that ɑ-stereogenic
aldehydes could be prepared using similar strategies (Scheme
1). Herein, we disclose the first example of a chemoselective AH
of ɑ-amido-substituted ɑ,β-unsaturated aldehydes for the
synthesis of chiral ɑ-amido and ɑ-amino aldehydes. These are
important structural units and key intermediates for the synthesis
of bioactive compounds, natural products and pharmaceuticals
(Figure 1).[10]
Scheme 2. Ligand screening. Conditions: 1a (1.0 mmol), ligand (0.0021 mmol),
[Rh(cod)2]SbF6 (0.002 mmol), H2 (30 atm), DCM (2 mL), rt,
4 h. The
conversions were calculated from 1H-NMR spectra. The proportions of
2a:3a:4a were calculated from 1H-NMR spectra. The ee values of 2a were
determined by HPLC using chiral columns after the isolated aldehyde 2a was
reduced to the corresponding alcohol 4a by NaBH4.
With the optimized reaction conditions in hand (Table 1, entry
19), we investigated the substrate scope for the synthesis of ɑ-
amido aldehydes (Scheme 3). All the reduced products,
regardless of the electronic properties and the steric hindrance
of the substituents, were obtained in excellent yields,
chemoselectivities, and enantioselectivities. For a substrate
bearing an electron-donating methyl substituent at the 4-position,
the desired product 2b was obtained in 94% ee. Increasing the
electron-donating ability of the substitutents by changing the
methyl group to a methoxy group showed a great effect on
enantioselectivity. The product 2c was obtained with higher
enantioselectivity (98% ee). 4-Halogen-substituted compounds
showed an increasing tendency in enantioselectivity with the
corresponding products 2d-2f being obtained with 96%, 98%,
and 99% ee values, respectively. The product 2g bearing a 4-
phenyl group was produced with 99% ee, whereas the 4-CF3-
Figure 1. The importance of chiral ɑ-amido and ɑ-amino aldehydes.
Results and Discussion
Initially, the model substrate 1a was tested in the Rh-catalyzed
asymmetric hydrogenation (Scheme 2). (R)-BINAP showed
almost no reactivity. The desired product 2a could be obtained in
good conversion, good chemoselectivity (2a:3a:4a = 81:0:19)
but poor enantioselectivity by using (R,Sp)-JosiPhos. The
electron-rich bisphosphine ligands (R,R)-Me-DuPhos and (R,R)-
Me-FcPhos afforded excellent chemoselectivities (2a:3a:4a
substituted 2h was obtained with
a
slightly lower
=
>99:0:<1) but still with unsatisfactory conversions and
enantioselectivity of 97% ee. A similar trend was observed for
the products 2i-2m, possessing 3-substituents, with that of the
4-substituted 2b-2f. The products 2n-2q bearing 2-substituents
also gave excellent enantioselectivities, especially 2-methoxy-
substituted 2n which was obtained with >99.9% ee.
Disubstituted substrates bearing a 1-naphthyl or 2-naphthyl
group gave the corresponding products 2r and 2s with
comparable enantioselectivities. Other disubstituted substrates
bearing electron-donating groups gave their desired products
with better ee values than those bearing electron-withdrawing
groups (2t-2y). More specifically, the product 2t, with 2,4-
dimethyl substituents, was obtained with much better ee than 2u
which possesses 2,4-difluoro substituents. A substrate bearing
3,4-dimethyl substituents gave the product 2v with better ee
than a substrate bearing 3,4-dichloro substituents. The product
2x bearing 3,5-dimethoxy substituents was obtained with better
results than 2y which possesses 3,5-dichloro substituents.
Furthermore, substrates processing heteroaryl groups, such as
2-thienyl and 3-thienyl, were also amenable to this catalytic
enantioselectivities. The P-stereogenic ligands (R,R)-MiniPhos,
(R,R)-QuinoxP* and (R,R)-BenzP* promoted the hydrogenation
with complete conversions. The (R,R)-MiniPhos showed
moderate enantioselectivity of 65% ee, while (R,R)-QuinoxP*
gave comparatively lower chemoselectivity (2a:3a:4a = 85:0:15).
To our delight, the rhodium complex of (R,R)-BenzP*[11] showed
the most promising stereocontrol, giving the desired product with
both excellent chemoselectivity (2a:3a:4a = >99:0:<1) and high
enantioselectivity of 92% ee. Subsequently, other reaction
conditions were optimized (see Table S1 in Supporting
Information for details). Most of the solvents gave high
conversions and chemoselectivities, but no further increasing in
enantioselectivity was observed. The hydrogenation was
completed at 10 atm hydrogen pressure with a maintained
enantioselectivity. The over-reduced product 4a was obtained
exclusively when increasing hydrogen pressure and prolonging
reaction time. Under these reaction conditions, the by-product
3a was not observed at all.
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10.1002/anie.201905263
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system, affording 2z and 2aa quantitatively with 95% and
>99.9% ee values, respectively. The absolute configuration of
the chiral α-amido aldehydes were considered to be the same as
2w whose configuration was assigned to be R by X-ray single-
crystal analysis.[12]
Scheme 4. Substrate scope to synthesize β-amido alcohols. [a] Conditions: 1
(1.0 mmol), (R,R)-BenzP* (0.0021 mmol), [Rh(cod)2]SbF6 (0.002 mmol), H2
(30 atm), DCM (2 mL), rt, 12 h. Isolated yields were recorded. The ee values
of 4 were determined by HPLC using chiral columns.
To demonstrate the potential utility of the protocol for the
synthesis of chiral ɑ-amido aldehydes, the hydrogenation was
carried out on a gram scale and under a high substrate/catalyst
ratio; the hydrogenated products were further converted to
several important chiral products (Scheme 5). The reaction was
conducted in DCM with 10 atm H2 at room temperature
catalyzed by (R,R)-BenzP*/[Rh(cod)2]SbF6 under 20000 S/C,
affording the desired products 2a, 2c and 2e in high yields and
excellent enantioselectivities. Compound 2a was subsequently
used to synthesize the chiral ɑ-alkynyl amine 5 employing the
Ohira-Bestmann reagent.[13] The hydrogenated product 2q was
deacetylated under an acidic environment and ring closed to
generate the chiral indoline-2-carbaldehyde 7. Alternatively,
under the conditions of a Pinnick oxidation, the chiral indoline-2-
carbaldehyde was transformed to the chiral indoline-2-carboxylic
acid 8 which is a key intermediate in drug synthesis.[14]
Furthermore, using a Witting reagent, the aldehyde 9 can be
easily converted to chiral olefin 10, which can be transformed to
a novel class of mixed D2/D4 receptor antagonists.[15] The chiral
nitrile 11, which can be utlized for the synthesis of ester
bioisosteres with cardioprotective efficacies,[16] was accessed by
sequential treatment of chiral aldehyde 9 with hydroxylamine
hydrochloride and CDI (1,1’-carbonyldiimidazole). The amido
alcohol 4a, obtained directly under 30 atm H2 pressure and after
Scheme 3. Substrate scope to synthesize α-amido aldehydes. [a] Conditions:
1 (1.0 mmol), (R,R)-BenzP* (0.0021 mmol), [Rh(cod)2]SbF6 (0.002 mmol), H2
(10 atm), DCM (2 mL), rt, 4 h. Isolated yields were recorded. The ee values of
2 were determined by HPLC using chiral columns after the aldehydes were
reduced to the corresponding alcohols by NaBH4.
a
12 h reaction time, was smoothly hydrolyzed to the
coorresponding chiral phenylglycinol 12, followed by
condensation and substitution to obtain a bisoxazoline ligand 14
which has been widely applied in many asymmetric catalyzed
reactions.[17] Compound 1u was reduced to the corrsponding
alcohol directly under 30 atm. A subsequent ring closing reaction
under alkaline conditions gave the chiral product 16, an
important chromane skeleton. The absolute configuration of 16
was assigned to be R by X-ray single-crystal analysis.[12]
β-Amido alcohols can also be obtained by extending the reaction
time under a relatively high hydrogen pressure (Scheme 4). We
chose representative substrates that have different electronic
and steric properties, and possess multiple substituted groups.
All the β-amido alcohols were obtained in excellent yields and
enantioselectivities. Among them, the products 4f, 4j, or 4x
bearing 4-Br, 3-OMe, or 3,5-diOMe groups, respectively, were
obtained in 99% ee, and the product 4aa processing a thienyl
substituent was produced quantitatively with >99.9% ee.
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re-gauche-coordinated complex is not possible, since it would
require formation of the chelate cycle in the hindered quadrant.
Instead, formation of a semi-coordinated complex 18 stabilized
by weak intramolecular interactions is observed (Figure 2).
Normal re- and si-coordinated complexes have stabilities similar
to that of 25, but the oxidative addition of hydrogen to these
complexes is significantly less facile (see SI for details). The
complex 18 was computed to be the most active in the hydrogen
activation step yielding dihydride 20a via TS1. The complex 25
is capable of producing a similar dihydride 20b by oxidative
addition via TS6 and further dissociation of the double bond via
TS7. Via TS8, a reverse transformation of 20b yields 26 instead
of the expected non-chelating molecular hydrogen complex.
Although the dihydride 27 is capable of a feasible migratory
insertion, the resulting monohydride intermediate has the
hydride and carbon ligands in a trans-position, thus excluding
the possibility of reductive elimination, whereas the possible
rearrangement routes are also high in energy (see SI for details).
Scheme 5. Scale-up and applications.
Figure 2. Optimized structures of the intermediates most active in activation of
hydrogen. Up: non-chelating catalyst-substrate complex 18; bottom: si-gauche
coordinated catalyst-substrate complex 25. Note the importance of the CHO
group for stabilization of either 18 or 25 via weak intramolecular interactions:
CH…HC (red), CH…π (violet), and CH…O (blue).
Computations of the catalytic cycle gave a clear description for
the R/S-pathways, provided
a reasonable explanation for
enantioselectivity, and revealed several other specific features
(Scheme 6 and Scheme S1 in Supporting Information). BenzP*-
Rh 17 can form three chelate catalyst-substrate complexes with
similar stabilities. Unlike all previously studied cases,[10b,18,19] in
the resting state, the si-gauche-coordinated catalyst-substrate
complex 25 was computed to be more stable than normally
coordinated re- and si-coordinated complexes by 0.9 and 2.5
kcal/mol respectively (see SI for details). Formation of a similar
The double bond of the substrate is not coordinated in either 20a
or 20b, therefore the absolute configuration of the hydrogenation
product is determined by the preferential mode of the double
bond coordination. Careful scanning of this process afforded the
transition states TS2 and TS9 differing in free energy by 4.0
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10.1002/anie.201905263
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kcal/mol, thus demonstrating a strong bias towards formation of
the R-product due to the preferential formation of the chelate
cycle in a non-hindered quadrant (see SI for the routes via β-
coordination that are characterized by significantly higher barries
for the migratory insertion). However, realization of this scenario
involves facile interconversion of 20a and 20b, whereas
computations show that this interconversion requires
overcoming a barrier approximately 5 kcal/mol higher than that
required for the formation of the R-product (see SI for details).
Hence, we conclude that in this particular case, the
stereoselection may be constrained by the lack of convergence
between the two alternative pathways for hydrogen activation. In
that case the enantioselectivity is determined by a difference of
1.8 kcal/mol between the free energies of TS1 and TS6 that is in
good agreement with the experimental value of 92% ee.
Scheme 6. Computed catalytic cycle. Blue numbers correspond to the energies of the intermediates, while the red numbers are the energies of the transition
states.
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10.1002/anie.201905263
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RESEARCH ARTICLE
hand, the multitude of equilibria comprising the catalytic cycle is
certainly quite susceptible to the changes in the structure of the
substrate and reaction conditions, therefore the examples with
slightly lower selectivities are not surprising.
Conclusion
In summary, we have developed a highly efficient route for the
synthesis of chiral ɑ-amido aldehydes. The desired products
were obtained with high yields and with excellent chemo- and
enantioselectivities (up to 99% yield and >99.9% ee). High
catalytic activities were also observed (up to 20000 S/C). The
reaction could be conducted on a gram scale and was further
applied to the synthesis of several useful chiral compounds. DFT
computations for the catalytic cycle gave a clear description for
the R/S-pathways, provided
a reasonable explanation for
enantioselectivity, and revealed several other specific features.
Experimental Section
Figure 3. Schematic profile of potential energy for the catalytic cycle of
hydrogenation of 1a catalyzed by 17.
(R,R)-BenzP* ligand (0.59 mg, 0.0021 mmol) and [Rh(cod)2]SbF6 (1.11
mg, 0.002 mmol) were dissolved in anhydrous and degassed DCM (2
mL) under nitrogen. The mixture was allowed to stir for 30 min at room
temperature. The substrate (1.0 mmol) was placed in a 5.0 mL tube
equipped with a magnetic stirrer bar. This tube was put into an autoclave.
The pre-prepared solution of catalyst was added under a nitrogen
atmosphere. After purging with hydrogen three times, the hydrogen
pressure was finally pressurized to 10 atm. The reaction mixture was
vigorously stirred at room temperature for 4 h. The conversion of the
One must realize that in view of the sophisticated catalytic cycle,
reversible until the very last stage (Figure 3), accurate
quantitative predictions of the optical yields are problematic. The
highly uniform outcomes of the sense and order of
enantioselection in the Rh-catalyzed asymmetric hydrogenation
must be due to the competition in the process of the chelate
cycle formation immediately prior to the almost barrierless
migratory insertion step.[18] With regards to the hydrogen
activation steps, TS1 and TS6, belonging to different pathways,
are competing, resulting in different rates of formation for 20a
and 20b, respectively. Therefore, if interconversion of 20a and
20b is relatively slow, the optical yield of the product will be
determined by the difference in the free energies of TS1 and
TS6. A relatively facile interconversion of 20a and 20b[19a,p] or
significantly higher stability of TS1 compared to that of TS6[11b]
would change the enantioselective stage to the double bond
coordination in 20a and 20b, and the difference in free energies
of TS2 and TS9 would determine the optical yield of the
hydrogenation product.[18b,c] The path that requires least energy
for the interconversion between 20a and 20b computed for this
catalytic cycle requires overcoming a relative free energy barrier
of 0.5 kcal/mol (formation of a non-chelating molecular hydrogen
complex from 20b). This is higher in energy than TS9, hence
20b is capable of producing some amount of the S-product. It is
1
product was determined by H NMR spectroscopic analysis of the crude
reaction mixture and the yield was calculated after isolation by flash
chromatography. The ee value was determined by chiral HPLC after
transforming the formyl group to the corresponding hydroxymethyl group
by NaBH4.
Acknowledgements
This work was partially supported by Shanghai Municipal
Education Commission (No. 201701070002E00030) and
National Natural Science Foundation of China (No.
21620102003, 21831005, 91856106, and 21572131). We thank
the Instrumental Analysis Center of Shanghai Jiao Tong
University. We acknowledge the generous gifts of the P-
stereogenic bisphosphine ligands from Nippon Chemical
Industrial Co. Ltd.
Keywords: hydrogenation • enantioselective • chemoselective •
α-formyl enamides • ɑ-amido aldehydes
clear that in such
a sophisticated system with various
converging pathways and high level of reversibility, the relative
rates of formation of opposite enantiomers depend on a larger
number of kinetic and thermodynamic parameters. However, the
relative stabilities of TS1 and TS6 are still very important, and if
TS1 is much more stable than TS6, the more reliable
mechanism of stereodiscrimination via the difference in
stabilities of TS2 and TS9[18b,c,19p] remains undisturbed. Thus, the
computational results provide a convincing account for the cases
of perfect enantioselection observed in this study. On the other
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10.1002/anie.201905263
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RESEARCH ARTICLE
K. Katagiri, H. Takahashi, M. Kouchi, I. D. Gridnev, Organometallics
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Title
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Jian Zhang, Jia Jia, Xincheng Zeng,
Yuanhao Wang, Zhenfeng Zhang, Ilya
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Chemo- and Enantioselective
Hydrogenation of ɑ-Formyl
Enamides: An Efficient Access to
Chiral ɑ-Amido Aldehydes
A highly chemo- and enantioselective hydrogenation of ɑ-formyl enamides has
been developed for the synthesis of chiral ɑ-amido aldehydes in high yields (98-
99%), excellent chemo- and enantioselectivities (up to >99.9% ee), and with high
substrate/catalyst ratios (up to 20000 S/C).
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