Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of Racemic β’-Keto-β-Amino Esters via Dynamic Kinetic Resolution

Article abstract of DOI:10.1002/adsc.202100929

An iridium/f-diaphos catalytic system for the enantioselective hydrogenation of α-substituted β-ketoesters via dynamic kinetic resolution is reported. The desired anti β’-hydroxy-β-amino esters were obtained in moderate to good yields (60–95%) with 72–99% ees and 91:9 to 99:1 drs. This protocol tolerates various functional groups and could be easily conducted on gram scale with lower catalyst loading (TON up to 9100). (Figure presented.).

Full text of DOI:10.1002/adsc.202100929

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doi.org/10.1002/adsc.202100929
Iridium-Catalyzed Enantioselective and Diastereoselective
Hydrogenation of Racemic β’-Keto-β-Amino Esters via Dynamic
Kinetic Resolution
Fei Ling,a,* Yifan Wang,a An Huang,a Ze Wang,a Shiliang Wang,a Jiayin He,a
Xianghua Zhao,a and Weihui Zhonga,*
a
College of Pharmaceutical Science
Zhejiang University of Technology
Hangzhou 310014, People’s Republic of China
E-mail: lingfei@zjut.edu.cn; weihuizhong@zjut.edu.cn
Manuscript received: July 27, 2021; Revised manuscript received: August 22, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100929
DKR is considered as the most atom-economical and
straightforward way.
Abstract: An iridium/f-diaphos catalytic system for
the enantioselective hydrogenation of α-substituted
β-ketoesters via dynamic kinetic resolution is
reported. The desired anti β’-hydroxy-β-amino
Since the pioneering work reported in 2004 by
Hamada[11] and Ratovelomanana-Vidal,[12] numerous
metal-ligand catalytic systems have been developed for
esters were obtained in moderate to good yields
the asymmetric hydrogenation of β-keto-α-amino
(60–95%) with 72–99% ees and 91:9 to 99:1 drs.
esters with a DKR process, achieving the highly
This protocol tolerates various functional groups
enatioselective and diastereoselective construction of
and could be easily conducted on gram scale with
diverse β-hydroxy-α-amino acids (up to >99% ee and
lower catalyst loading (TON up to 9100).
99:1 dr) (Scheme 1-2).[13] However, the DKR-AH of
racemic β’-keto-β-amino esters was far less studied.
The limited examples were reported by Zhang[14]
Keywords: asymmetrical hydrogenation; dynamic
kinetic resolution; iridium; f-diashos; β’-keto-β-amino
esters
and Rimoldi[15] who independently realized the enan-
tio- and diastereoselective synthesis of β’-hydroxy-β-
amino esters using ruthenium-diphosphine ligand
catalysis, albeit with narrow scope and low turnover
numbers. Nevertheless, the development of metal-
The conversion of racemic compounds into enantio- ligand catalysis with high efficiency, good compatibil-
merically enriched products via the dynamic kinetic ity and excellent enantio- and stereo-selectivities for
resolution (DKR) represents one of the most powerful chiral β’-hydroxy-β-amino esters have still remained
approaches to asymmetric synthesis.[1] Particularly, elusive, but highly desirable.
pioneered by Noyori[2] and Genêt,[3] this strategy has
Very recently, our group[16] has developed a series
been widely used in the transition metal catalyzed of tridentate ferrocene-based diamine-phosphine sulfo-
asymmetrical hydrogenation (AH) of configurationally namide ligands (f-diaphos), which showed excellent
labile substrates containing carbon-oxygen double enantioselectivities in the iridium-catalyzed asymmet-
bonds, thus offering versatile chiral alcohols with two ric hydrogenation of various ketones, including aryl
or more stereogenic centers (Scheme 1-1).[4,5] Chiral β- alkyl ketones, diaryl ketones and 2-pyridyl aryl
hydroxy amino acids and derivatives represent a class ketones, providing very useful chiral alcohols with up
of versatile structural motifs or building blocks in the to >99% ee and 100000 TON. Encouraged by these
construction of pharmacological compounds, natural works, we envisioned that the Ir/f-diaphos catalytic
products, and biologically active molecules.[6] system may work well with the hydrogenation of β’-
Although numerous mythologies have been developed keto-β-amino esters. Herein, we wish to report a highly
for the access these important scaffolds,[7–10] asymmet- diastereo- and enantio-selective Ir-f-diaphos catalyzed
ric hydrogenation of racemic β-keto amino esters via DKR-AH of racemic β’-keto-β-amino esters, which led
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Table 1. Optimization of Reaction Conditions.[a]
Entry Ligand Base
Conv. (%)[b] ee (%)[c] dr[c]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L2
L2
L2
L2
L2
L2
L2
L2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
tBuOLi
NaOH
90
99
73
91
94
46
95
80
92
58
À 73
À 70
10
57
90
85
92
78
90
99
99
90/10
88/12
89/11
6/94
5/95
69/31
75/25
92/8
87/13
96/4
88/12
89/11
99/1
NaHCO3 92
K2CO3
9
93
94
99
57
10
11[d]
12[e]
13[f]
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
95
14[f,g] L2
99 (95)[h]
99/1
Scheme 1. Dynamic kinetic resolution (DKR) in the transition-
metal (TM)-catalyzed hydrogenation of α-tethered ketones.
[a] Reactions conditions: 0.5 mmol, scale, 0.2 M substrate,
0.05 mol% [Ir(COD)Cl2]2, 0.105 mol% ligand L, 5 mol%
to a variety of optically active anti-β’-hydroxyesters
(Scheme 1-3).
°
base, 2.5 mL of EA, 45 C, 24 h.
We initially selected 1a as a model substrate to
evaluate various chiral Ir/f-diaphos catalysts generated
in situ by mixing [Ir(COD)Cl]2 with f-diaphos ligands
L1–L5. Delightfully, L1 exhibited inspiring results
with ethyl acetate (EA) as the solvent and Na2CO3 as a
base to produce 2a in 90% conversion with 80% ee
and 90:10 dr (Table 1, entry 1).[17] With an increase in
steric hindrance on the benzene ring of the sulfonyl
group from L1 to L2 by switching 4-methyl to 2,4,6-
trimethyl, the enantiomeric selectivity of the reaction
increased to 92% ee with a slight loss of diastereose-
lectivity (Table 1, entry 2). Unexpectedly, L3 gave a
[b] Determined by GC analysis.
[c] The ee and dr values were determined by HPLC on a chiral
stationary phase.
[d] DCM was used instead of EA.
[e] THF was used instead of EA.
[f] Toluene was used instead of EA.
[g]
°
At 60 C.
[h] Isolated yield.
With the optimized conditions in hand, we then
low yield, presumably owing to its oversized steric turned our focus to the scope and functional group
hindrance (Table 1, entry 3). Notably, L4 and L5, compatibility of the reaction (Table 2). Initially, the
enantiomers of L1 and L2, also showed moderate scope of amide groups was examined. Meta-methyl
performances in the reduction of 1a with opposite substituted amide performed well to give 2b in up to
configuration of the product (Table 1, entries 4 and 5). >99% ee with 91:9 dr, while substrates with electro-
Next, a set of bases were examined, and the results withdrawing amide group delivered the targeted 2c in
revealed that strong gave lower ee and dr than weak a slightly lower ee and dr compared with those with
bases. NaOAc turned out to be optimal, delivering the electron-donating amide scaffolds (2a and 2b). Mod-
desired 2a in 92% ee with 96:4 dr (Table 1, entries 6– erate outcomes were obtained when using naphthali-
10). Moreover, several solvents were screened, and mide (1d) as substrate, owing to its large steric
toluene performed results to afford 2a in 99% ee with hindrance. Benzidine (1e) was hydrogenated well to
excellent diastereoselectivity, albeit in relatively lower offer 2e in good results. Notably, phthalamide was
conversion (Table 1, entries 11–13). It was noteworthy suitable substrate which was reduced efficiently to
°
that elevating the reaction temperature from 45 C to afford 2f in 84% yield with 99% ee and 98:2 dr.
°
60 C gave full conversions of 1a without any loss of Moreover, this DKR-AH reaction also tolerated sub-
ee or dr (Table 1, entry 14).
strate with alkyl amide, leading to the corresponding
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Table 2. Investigation of substrate scope.[a]
[a] Reaction condition: 0.5 mmol scale, 0.2 M substrate 1, 0.05 mol% [Ir(COD)]2, 0.105 mol% ligand L2, 5 mol% base, 2.5 mL of
°
toluene, temperature 60 C, 24 h, H2 3.5 MPa. Isolated yields. The ee and dr values were determined by HPLC on a chiral
stationary phase.
product 2g in moderate ee but with extremely high tivities and diastereoselectivities, providing a further
drs. Next, the focus has been paid on the examination chance for late-stage diversifications. Di-trifluorometh-
of aromatic rings. Substitution factors on the benzene yl benzene (1s) performed well to deliver the desired
rings adjacent to the carbonyl group had a little effect product 2s in >99% ee and 99/1 dr, albeit in
on the enantioselectivities, where ortho substituted β’- moderated isolated yield. It was noteworthy that the
hydroxy-β-amino esters expressed a lower ee than benzene ring could be effectively replaced by other
meta or para substituted amino esters (2h vs 2j and aromatic substituents like benzo[d][1,3]dioxol-5-yl
2m; 2i vs 2p). Benzene rings with strong donating (1t), biphenyl (1u) and naphthyl (1v) to forge the
groups (-OMe and -i-Pr) yielded the targeted products corresponding alcohols in extraordinary outcomes.
(2n and 2o) in higher ees. Halogens were also Finally, the ester group in β’-hydroxy-β-amino esters
compatible in this reaction to generate the targeted was examined. Moderate ee with 99/1 dr was obtained
chiral alcohols (2k, 2p–2r) in excellent enantioselec- when using small methyl ester substrate (1w), while
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tert-butyl ester (1y) reacted smoothly to provide 2y in
98% ee and 96/4 dr.
In order to demonstrate the synthetic utility of the
current methodology, a gram-scale experiment (eq. 1)
was performed using 1a as substrate with 0.01% Ir-f-
diaphos catalysis (S/C=10000). An amount of 1.48 g
of product 2a was obtained from 5 mmol of 1a (91%
yield, 99% ee and 99/1 dr) (eq. 1). In addition,
phenylpropanoate 2a could be easily transformed into
chiral γ-amino alcohol 3a by deesterification (eq. 2).[18]
To further explain the reason for excellent perform-
ance of this catalysis, models for the interactions
between catalyst and substrate were established. Based
on our previous work[16c] and previous literature,[19]
hydrogen bonding interaction plays an important role
in the enantioselective induction (Scheme 2). We
hypothesize that the more acidic hydrogen in the
sulfamide group of the ligand links the substrate with
catalyst, therefore reducing the Gibbs energy and
benefitting the formation of a stable catalyst substrate
complex. Scheme 2 shows four models of transition
states in the stereocontrol step, generating four possible
isomers. TS-I has the lowest free energy than others,
owing to its smallest steric hindrance, thus yielding the
desired (2S, 3R)-2a. This modelling rationale helps to
explain the high stereoselectivities in this transforma-
tion. Detailed mechanistic studies on this issue are
currently underway.
Scheme 2. Proposed transition states.
Experimental Section
In conclusion, we have identified an Ir/f-diaphos
catalysis for stereoselective asymmetric hydrogenation
of β’-keto-β-amino esters. A dynamic kinetic resolu-
tion has been achieved with remarkably high enantio-
selectivities and diastereoselectivities (up to >99% ee
and >99:1 dr), thus leading to a plenty of versatile
chiral anti β’-hydroxy-β-amino esters. This protocol
tolerated various functional groups and could be easily
conducted on gram-scale with up to 9100 TON. Trans-
formations allowed the production of versatile chiral γ-
amino alcohol. The proposed transition states gave a
reasonable explanation for these outstanding results.
General Procedure for the Asymmetric Hydrogena-
tion of β’-Keto-β-Amino Esters 1
Under
argon
atmosphere,
[Ir(COD)Cl]2
(1.68 mg,
0.0025 mmol), L2 (3.63 mg, 0.00525 mmol), and anhydrous
iPrOH (1.0 mL) were added to an oven-dried vial (5.0 mL) and
°
then stirred at 30 C for 1.5 h to give a clear yellow solution. An
aliquot of the catalyst solution (0.1 mL) was transferred into a
5.0 mL hydrogenation vessel, and then ketones 1 (0.5 mmol),
NaOAc in toluene (2.05 mg, 0.025 mmol), and anhydrous
toluene (2.5 mL) were added. The vessel was placed in an
autoclave, which was then charged with 35 atm of H2 and
°
stirred at 60 C for 24 h. After the hydrogen pressure was slowly
released, the solvent was removed, and the mixture was purified
by passing through a short column of silica gel to afford the
corresponding alcohol 2. The ee values of all compounds were
determined by HPLC with a chiral column.
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Procedures and analytical data for all compounds are given in
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Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 22078298, 21978271, 21706234 and 21676253) and the
Natural Science Foundation of Zhejiang Province of China
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Iridium-Catalyzed Enantioselective and Diastereoselective
Hydrogenation of Racemic β’-Keto-β-Amino Esters via
Dynamic Kinetic Resolution
Adv. Synth. Catal. 2021, 363, 1–7
F. Ling*, Y. Wang, A. Huang, Z. Wang, S. Wang, J. He, X.
Zhao, W. Zhong*