Carboxyl Group-Directed Iridium-Catalyzed Enantioselective Hydrogenation of Aliphatic ?-Ketoacids

Article abstract of DOI:10.1021/acscatal.0c02142

Although the transition metal-catalyzed asymmetric hydrogenation of aromatic ketones has been extensively explored, the enantioselective hydrogenation of aliphatic ketones remains a challenge because chiral catalysts cannot readily discriminate between the re and si faces of these ketones. Herein, we report a carboxyl-directing strategy for the asymmetric hydrogenation of aliphatic ?-ketoacids. With catalysis by iridium complexes bearing chiral spiro phosphino-oxazoline ligands, hydrogenation of aliphatic ?-ketoacids afforded chiral ?-hydroxylacids with high enantioselectivity (up to 99% ee). Mechanistic studies revealed that the carboxyl group of the substrate directs hydrogen transfer and ensures high enantioselectivity. Density functional theory calculations suggested the occurrence of chiral induction involving a hydrogen-hydrogen interaction between a hydride on the iridium atom and the substituent on the oxazoline ring of the ligand, and on the basis of the calculations, we proposed a catalytic cycle involving only Ir(III), which differs from the Ir(III)/Ir(V) catalytic cycle that operates in the hydrogenation of α,β-unsaturated carboxylic acids.

Full text of DOI:10.1021/acscatal.0c02142

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Article
Carboxyl Group-Directed Iridium-Catalyzed
Enantioselective Hydrogenation of Aliphatic #-Ketoacids
Mao-Lin Li, Yao Li, Jia-Bin Pan, Yi-Hao Li, Song Song, Shou-Fei Zhu, and Qi-Lin Zhou
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c02142 • Publication Date (Web): 07 Aug 2020
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Carboxyl Group-Directed Iridium-Catalyzed
Enantioselective Hydrogenation of Aliphatic γ-
Ketoacids
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Mao-Lin Li‡, Yao Li‡, Jia-Bin Pan, Yi-Hao Li, Song Song, Shou-Fei Zhu*, Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry,
Nankai University, Tianjin 300071, China
Keywords
Asymmetric synthesis, iridium catalysts, γ-ketoacids, carboxyl-directing hydrogenation, chiral
spiro ligands
Abstract
Although the transition metal-catalyzed asymmetric hydrogenation of aromatic ketones has
been extensively explored, the enantioselective hydrogenation of aliphatic ketones remains a
challenge because chiral catalysts cannot readily discriminate between the re and si faces of these
ketones. Herein we report a carboxyl-directing strategy for the asymmetric hydrogenation of
aliphatic γ-ketoacids. With catalysis by iridium complexes bearing chiral spiro phosphino-
oxazoline ligands, hydrogenation of aliphatic γ-ketoacids afforded chiral γ-hydroxylacids with
high enantioselectivity (up to 99% ee). Mechanistic studies revealed that the carboxyl group of the
substrate directs hydrogen transfer and ensures high enantioselectivity. Density functional theory
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calculations suggested the occurrence of chiral induction involving a hydrogen–hydrogen
interaction between a hydride on the iridium atom and the substituent on the oxazoline ring of the
ligand; and on the basis of the calculations, we proposed a catalytic cycle involving only Ir(III),
which differs from the Ir(III)/Ir(V) catalytic cycle that operates in the hydrogenation of α,β-
unsaturated carboxylic acids.
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Introduction
Transition-metal-catalyzed enantioselective hydrogenation of ketones is a straightforward
method for the synthesis of optically active alcohols,1,2 and a number of effective chiral catalysts
have been developed for the hydrogenation of aromatic ketones.3-8 However, hydrogenation of
dialkyl ketones proceeds with satisfactory enantioselectivity only when one of the alkyl groups is
bulky,9-11 or under the condition of asymmetric transfer hydrogenation12,13 and the enantioselective
14-18
hydrogenation of ketones with two sterically similar alkyl groups remains a challenge.
Recently, we developed a protocol for highly enantioselective iridium-catalyzed hydrogenation of
19-24
unsaturated carboxylic acids.
By isolating the key intermediates and investigating the
mechanism by means of density functional theory (DFT) calculations, we determined that the
carboxyl group coordinates the catalyst and directs the hydrogenation of the C=C bond.25 Inspired
by these findings, we speculated that the aliphatic ketoacids could be hydrogenated to the chiral
aliphatic hydroxylacids by using carboxyl-directing strategy (Figure 1). It should be pointed out
that aromatic ketoacids26-28 and ketoesters4, 29-31 can be hydrogenated with high enantioselectivity
by a variety of chiral catalysts, however, these catalysts are not effictve for the aliphatic ketoacid
substrates. Herein, we report the details of our investigation on the carboxyl group-directed
iridium-catalyzed enantioselective hydrogenation of aliphatic ketoacids. Under mild conditions, a
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broad range of γ-ketoacids were hydrogenated to the γ-hydroxylacids with excellent
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enantioselectivity (up to 99% ee).
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Figure 1. Carboxyl-directed enantioselective hydrogenation of γ-ketoacids catalyzed by chiral
iridium/spiro phosphine-oxazoline complexes.
Results and Discussion
To evaluate various chiral iridium/spiro phosphine-oxazoline catalysts (Ir-SIPHOX, 4), we
carried out the hydrogenation reactions of 4-oxopentanoic acid (1a) at 65 °C for 24 h (Table 1).
Catalyst (Sa)-4a, which has 3,5-di-tert-butylphenyl groups on the phosphorus atom and no
substituent on the oxazoline ring, afforded desired product 4-hydroxylpentanoic acid (2a) with a
conversion of 70% and an ee of 36% (entry 1). The substituent on the oxazoline ring of catalyst
affected both the conversion and the enantioselectivity of reaction (entries 2–5), with (Sa,S)-4b (R
= iPr) and (Sa,S)-4c (R = Ph) giving the same conversion (88%) and ee values of 75% and 86%,
respectively (entries 2 and 3). The use of catalyst (Sa,S)-4d, which has a benzyl substituent on the
oxazoline ring, improved the conversion markedly (to 97%) and the enantioselectivity slightly (to
87% ee, entry 4). However, the catalyst (Sa,S)-4e, which has an α-naphthylmethyl substituent, gave
the best result (100% conversion, 93% ee; entry 5). When the P-aryl groups of catalyst were less
bulky, like those of (Sa)-4f (Ar = 3,5-dimethylphenyl) and (Sa)-4g (Ar = phenyl), the conversion
decreased relative to that with (Sa,S)-4e, although the enantioselectivity remained good (entries 6
and 7). Changing the solvent from methanol to isopropanol decreased the enantioselectivity from
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93% ee (entry 5) to 82% ee (entry 8), and the conversion dropped to <5% in THF (entry 9). A base
was necessary for the reaction (entry 11), and triethylamine gave higher conversion and
enantioselectivity than Cs2CO3 (entry 10).
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Table 1. Carboxyl-directed enantioselective hydrogenation of γ-ketoacids: condition
optimization.a
entry catalyst
solv. conv. (%)b ee (%)c
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(Sa)-4a MeOH
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−36
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--
(Sa,S)-4b MeOH
(Sa,S)-4c MeOH
(Sa,S)-4d MeOH
(Sa,S)-4e MeOH
(Sa,S)-4f MeOH
(Sa,S)-4g MeOH
(Sa,S)-4e iPrOH
(Sa,S)-4e THF
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100
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100
<5
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10[d] (Sa,S)-4e MeOH
11[e] (Sa,S)-4e MeOH
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--
<5
a Reaction conditions: 0.25 mmol scale, [substrate] = 0.125 mol/L, catalyst 4 (2 mol%), H2 (6 atm),
−
Et3N (0.5 equiv). BArF = tetra[3,5-bis(trifluoromethyl)phenyl]borate, 65 °C, 24 h. The conversion
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and ee value were measured after conversion to lactone 3a. b Determined by 1H NMR spectroscopy.
c Determined by GC analysis on a chiral stationary phase. d Cs2CO3 (0.5 equiv) was used as base.
e Without Et3N.
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Under the optimal reaction conditions (Table 1, entry 5), various aliphatic γ-ketoacids were
hydrogenated to γ-hydroxyacids, which becomes γ-lactones after acidifying with hydrochloric acid
(Figure 2). The nature of the alkyl (R) group attached to the carbonyl carbon of γ-ketoacids had a
negligible impact on the yield and enantioselectivity: all the tested substrates afforded the γ-lactone
products (3a–3o) with excellent yields (91–99%) and enantioselectivities (87 to >99% ee). The
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highest enantioselectivity was obtained in the hydrogenation of 1f (R = Pr, >99% ee, 3f).
Substrates with a benzyloxy group, an ester group, or an internal alkene were tolerated. Notably,
ester-containing substrate 1o showed high enantioselectivity (93% ee, 3o), indicating that the
catalyst discriminated between the ester and the carboxyl group. Current catalytic system highly
sensentive to the length of linkage between carbonyl and carboxyl groups and the hydrogenation
of β, δ, ε-keto acids resulted in poor outcomes (Figure S1). It is worth to mention that the reaction
can be performed at gram scale with well retained yield and ee value (Figure S2).
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Figure 2. Carboxyl-directed enantioselective hydrogenation of γ-ketoacids: substrate scope.
Reaction conditions: 0.25 mmol scale, [substrate] = 0.125 mol/L, (Sa,S)-4e (2 mol%), H2 (6 atm),
Et3N (0.5 equiv). Full conversions were obtained within 24 h. The yield and ee value were
measured after conversion to lactones. The absolute configurations were determined by comparing
the specific rotation with those reported in the literature (see the supporting information for details).
[a] EtOH was used as solvent.
The hydrogenation products, γ-lactones are important building blocks for the syntheses of
flavor compounds, pheromone components, and pharmaceuticals; and the reactions of lactones 3
shown in Figure 332-36 illustrate the potential utility of our hydrogenation protocol for the
constructions of bioactive molecules.
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Figure 3. Applications and transformations of optical γ-lactones.
Mechanistic Studies
Although the mechanism of ruthenium-catalyzed asymmetric hydrogenation of ketones has
been well studied,37-41 the mechanism of the iridium-catalyzed hydrogenation of ketones has not
been thoroughly explored,42,43 especially with respect to the active intermediates. Therefore, we
performed several experiments aimed at elucidating the mechanism of the Ir-SIPHOX-catalyzed
carboxyl-directed enantioselective hydrogenation protocol. The hydrogenation of ester, methyl 4-
oxopentanoate (5), catalyzed by (Sa,S)-4e showed low enantioselectivity (23% ee, Figure 4a). The
hydrogenation of substrates with other directing groups (e.g. amide, urea, and cyano, Figure S3)
also resulted in unsatisfactory results (Figure S3). All the above experiments indicate that the
carboxyl group of substrates 1 played a crucial role in controlling the enantioselectivity of
hydrogenation reaction. When 1a was hydrogenated with D2, deuterium incorporation at the β-
position of hydroxyl group in the product was low (15% D, Figure 4b), which means that the
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hydrogenation mainly proceeds via carbonyl intermediate and the enolate hydrogenation may be
competitive pathway. Next we tried to isolate the reaction intermediates. Specifically, treatment
of (Sa)-4a(OTf) with H2 in methanol at 25 °C produced a quantitative yield of iridium dihydride
species 6, which was then reacted with 1 equiv of sodium 4-oxopentanoate in methanol at 25 °C
to form carboxyl-bridged diiridium intermediate 7 in 97% yield (Figure 4c). The presence of a
doublet at −24.01 ppm in the 1H NMR spectrum of 7 indicated that the hydrides were opposite to
the coordinated acid.25,44,45 In addition, the coupling constant between the phosphorus atom of the
ligand and the hydride (2JP-H = 19.1 Hz) also indicated that these are two axial hydrides, which are
oriented cis to the phosphorus.46,47 Furthermore, the presence of a double doublet at −18.68 ppm
(J = 58.4 and 12.6 Hz) showed that there were two bridged hydrides, one located trans to the
phosphorus atom and one located cis, in accord with the reported data for similar dimeric iridium-
hydride complexes.25,48,49 Direct heating of the intermediate 7 did not yield the hydrogenation
product. However, when treated with 1 atm of H2 at 65 °C, intermediate 7 was slowly converted
to complex 8 (Figure 4c); the presence of H2 was necessary for this conversion. In addition,
complex 7 could be used as catalyst precursors for the hydrogenation of γ-ketoacids and afford
essentially identical results as precatalyst 4a (Figure 4d). These experimental results demonstrated
that the diiridium intermediates were thermodynamically stable and were the resting states of the
active catalysts.
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Figure 4. (a) The hydrogenation of methyl 4-oxopentanoate. (b) Deuterium-labeling study. (c)
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Structural analysis and transformations of hydrogenation intermediates and H NMR monitoring
of the hydrogenation in CD3OD. (d) Reaction conditions: 0.25 mmol scale, [substrate] = 0.125
mol/L, complex 7 (2 mol%), H2 (6 atm), Et3N (0.5 equiv), 65 °C, 36 h.
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DFT Calculations
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To obtain insight into the reaction mechanism, we performed DFT calculations for the
reaction between 4-oxopentanoate acid and the iridium dihydride complex of (Sa,S)-4e (Figure 5)
at the B3LYP-D3(SMD(MeOH))/def2-TZVPP//B3LYP/def2-SVP level of theory. First, we
calculated the configuration-determining step (i.e., the conversion of IntA to IntE; Figure 5a).
Active intermediate IntA may have been generated by dissociation of the corresponding carboxyl-
bridged diiridium complex. From IntA, there are two possible pathways for migratory insertion of
the hydride into the keto group: the R pathway and the S pathway. Owing to a strong trans effect,
by which the phosphorus atom weakens the trans Ir–H bond, both pathways obey the well-
established rule that only the trans hydride takes part in the migratory insertion step;50,51 the two
pathways proceed via different carbonyl coordination models (IntCR and IntCS). The calculated
energy of transition state TSDR was 2.3 kcal/mol lower than that of transition state TSDS, which
suggests that the reaction should afford the R product with perfect enantioselectivity; and this
finding is in accord with the experimental results. The difference in energy between the two
transition states may be attributable to interactions between the hydride and the hydrogen atoms
of the α-naphthylmethyl group of the ligand (the distances between these atoms are 2.15 Å in
TSDS and 2.72 Å in TSDR).25,52,53 We speculate that this interaction is crucial for enantiocontrol
because the enantioselectivity is reversed in the absence of the substituent on the oxazoline ring of
the catalyst (Table 1, entry 1). Furthermore, intermediate IntAR has a lower energy than
migratory-insertion intermediate IntER, which implies that isolation of the migratory-insertion
intermediate is very unlikely according to the microreversibility principle.
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We next calculated the Gibbs energy profile of the steps involved in catalyst regeneration.
We considered many scenarios for this process, including direct hydrogen metathesis of IntER,
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metathesis with methanol, and reductive elimination via Ir(V) intermediates (see the supporting
information for details). Among these scenarios, H–H metathesis followed by deprotonation seems
to be the most likely one.54 Because of the slightly acidic reaction conditions (0.5 equiv of NEt3
and 1.0 equiv of 1a), IntER could easily be protonated to generate IntFR (Figure 5b).
Coordination of H2 would form intermediate IntGR1, which would undergo H–H metathesis via
transition state TSHR1 to afford intermediate IntIR, and then deprotonation would generate
intermediate IntJR. In contrast, the formation of intermediate IntGR2, in which the iridium atom
is coordinated by the hydroxyl group, would present a higher energy barrier to H–H metathesis.
Finally, IntAR was regenerated by a ligand-exchange reaction between IntJR and the ketone
substrate. Our DFT calculations suggested that the carboxyl group not only guides migratory
insertion of hydride into the keto group in the configuration-determining step but also facilitates
regeneration of the active intermediates via H–H metathesis.
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Figure 5. (a) Calculated Gibbs energy profile for the configuration-determining step (kcal/mol).
(b) Calculated Gibbs energy profile for the regeneration of the active intermediates (kcal/mol).
The Catalytic Cycle
Taken together, our results suggest that the hydrogenation reaction may proceed by means of
the catalytic cycle shown in Figure 6. The reaction starts with complexation between the γ-keto
carboxylate and Ir(III) species 6 to afford iridium dihydride IntAR. This dihydride undergoes
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migratory insertion of the Ir–H into the keto group to give intermediate IntER, and subsequent
protonation generates intermediate IntFR. This intermediate undergoes a carboxyl group-
mediated reaction with H2 by means of a metathesis mechanism, and then deprotonation affords
intermediate IntJR. A ligand-exchange reaction of intermediate IntJR with the substrate affords
the product and regenerates iridium dihydride complex IntAR. The carboxyl group of the product
can also serve as a bridging ligand to form diiridium complex 8, which acts as a resting catalyst.
The reaction clearly proceeds via an inner-sphere mechanism. Chelation of the carboxyl group
makes the migratory insertion of hydride into the keto group more enantioselective; and in the
subsequent catalyst-regeneration process, the carboxyl group also promotes the H–H metathesis
reaction.
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Figure 6. Catalytic cycle of the Ir-SIPHOX-catalyzed hydrogenation of γ-ketoacid.
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Conclusion
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We have developed a carboxyl-directed strategy for asymmetric hydrogenation of aliphatic
γ-ketoacids. With catalysis by chiral spiro iridium complexes, γ-ketoacids were hydrogenated to
afford chiral γ-hydroxylacids with high enantioselectivity. Comprehensive mechanistic studies
revealed that the carboxyl group of the substrate acts as an anchor, controlling the direction of
hydrogen transfer and ensuring high enantioselectivity. Further applications of this strategy for
catalytic asymmetric reactions are being explored in our laboratory.
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AUTHOR INFORMATION
Corresponding Author
Shou-Fei Zhu; State Key Laboratory and Institute of Elemento-Organic Chemistry, College of
Chemistry, Nankai University, Tianjin 300071, China. Email: sfzhu@nankai.edu.cn.
Qi-Lin Zhou; State Key Laboratory and Institute of Elemento-Organic Chemistry, College of
Chemistry, Nankai University, Tianjin 300071, China. Email: qlzhou@nankai.edu.cn.
Author Contributions
‡Mao-Lin Li and Yao Li contribute equally to this work.
Funding Sources
This research was funded by the National Natural Science Foundation of China (grant nos.
21625204, 21790332, 21532003).
Notes
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The authors declare no competing financial interest.
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Supporting Information. The Supporting Information is available.
Experimental procedures, computational details, and characterization data for compounds.
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ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (21625204, 21790332, 21532003),
the “111” project (B06005) of the Ministry of Education of China, and the National Program for
Special Support of Eminent Professionals for financial support.
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A carboxyl group-directed strategy has been developed for the catalytic asymmetric
hydrogenation of aliphatic ketoacids. By using this strategy, a variety of γ-ketoacids were
hydrogenated to chiral γ-hydroxyl acids with high yield and enantioselectivity. Mechanistic studies
revealed a constant Ir(III) catalytic cycle.
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