Enantioselective Iridium-Catalyzed Hydrogenation of α-Keto Amides to α-Hydroxy Amides

Article abstract of DOI:10.1021/acs.orglett.7b02912

A highly enantioselective iridium-catalyzed hydrogenation of α-keto amides to form α-hydroxy amides has been achieved with excellent results (up to >99% conversion and up to >99% ee, TON up to 100?000). As an example, this protocol was applied to the synthesis of (S)-4-(2-amino-1-hydroxyethyl)benzene-1,2-diol, the enantiomer of norepinephrine, which is widely used as an injectable drug for the treatment of critically low blood pressure. Density functional theory (DFT) calculations were also carried out to reveal the reaction mechanism.

Full text of DOI:10.1021/acs.orglett.7b02912

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Enantioselective Iridium-Catalyzed Hydrogenation of α‑Keto Amides
to α‑Hydroxy Amides
Guoxian Gu,† Tilong Yang,† Ouran Yu,† Hua Qian,† Jiang Wang,† Jialin Wen,† Li Dang,*,†,‡
and Xumu Zhang*,†
†Department of Chemistry, Southern University of Science and Technology, 1088 Xueyuan Road, Nanshan District, Shenzhen,
Guangdong 518055, P. R. China
‡Department of Chemistry and Key Laboratory for Preparation and Application of Ordered Structural Materials of Guangdong
Province, Shantou University, Shantou, Guangdong 515063, P. R. China
S
* Supporting Information
ABSTRACT: A highly enantioselective iridium-catalyzed
hydrogenation of α-keto amides to form α-hydroxy amides
has been achieved with excellent results (up to >99%
conversion and up to >99% ee, TON up to 100 000). As an
example, this protocol was applied to the synthesis of (S)-4-(2-
amino-1-hydroxyethyl)benzene-1,2-diol, the enantiomer of
norepinephrine, which is widely used as an injectable drug for the treatment of critically low blood pressure. Density functional
theory (DFT) calculations were also carried out to reveal the reaction mechanism.
Scheme 1. Asymmetric Hydrogenation of α-Keto Amides
Catalyzed by Ir/f-Amphox
nantioenriched α-hydroxy carboxylic acids and their
Ederivatives are an important class of compounds that
widely exist in many pharmaceuticals.1 Hence, significant effort
has been devoted to the synthesis of chiral α-hydroxy acids and
their derivatives, including enantioselective reduction of α-keto
acids,2 α-keto esters,3 and α-keto amides.4 Among these three
types of substrates, asymmetric hydrogenation of α-keto acids
has a relative high enanioselectivity and high turnover
numbers.2a In addition, a broad range of α-hydroxy acids
with high enanioselectivity have been realized through
biocatalysis.2b Enantioselective reduction of α-keto esters was
also quite common. Biomimetic catalysis,3h asymmetric
Meerwein−Ponndorf−Verley (MPV) reaction,3a asymmetric
hydrosilylation,3b Ru-catalyzed asymmetric hydrogenation,3c,d,g
and catalytic asymmetric transfer hydrogenation3e,f have been
established to prepare chiral α-hydroxy esters, with modest ee’s
and turnovers achieved. In contrast, there is no excellent
solution for asymmetric hydrogenation of α-keto amides.4
Transition metal catalyzed asymmetric hydrogenation of α-
keto amides provided an efficient approach to prepare
enantioenriched α-hydroxy amides. Herein, we are delighted
to report a highly enantioselective and active asymmetric
hydrogenation of α-keto amides with a broad substrate scope
using an Ir-catalyst (Scheme 1) and utilities of this method for
making related pharmaceutical products in a concise manner.
Recently, we reported that iridium/f-amphox (ferrocence-
aminophosphine oxazoline),5a iridium/f-amphol (ferrocence-
aminophosphine alcohol),5b and iridium/f-ampha (ferrocence-
aminophosphine acid)5c complexes could catalyze the
enantioselective hydrogenation of simple aromatic ketones to
form chiral alcohols. Considering the success of these
protocols, we envisioned that these catalyst systems could
also promote the asymmetric hydrogenation of α-keto amides.
Initially, we targeted α-keto amide 1a as the standard
substrate for asymmetric hydrogenation. Three tridentate
ligands were examined (Figure 1), and the results are
summarized in Table 1. Although all three ligands are excellent
for asymmetric hydrogenation of simple ketones, they behave
differently in this reaction. f-Ampha and f-amphol exhibited
excellent activity, but with poor to moderate enantioselectiv-
ities. It is interesting that full conversion and 99%
Figure 1. Ligands screening in Ir-catalyzed hydrogenation of 1a.
Received: September 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02912
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
With the optimized reaction conditions in hand, we turned
our attention to study the substrate scope. As shown in the
Scheme 2, excellent ee’s were achieved for a wide range of α-
Table 1. Ligands Screening for Asymmetric Hydrogenation
of α-Keto Amides 1a
a
Scheme 2. Scope Study for the Asymmetric Hydrogenation
a
of α-Keto Amides with Ir/f-Amphox
b
c
entry
ligand
solvent
iPrOH
conv (%)
ee (%)
1
2
3
4
5
6
7
8
9
f-ampha
f-ampha
f-ampha
f-ampha
f-ampha
f-ampha
f-ampha
f-amphox
f-amphol
>99
trace
>99
nr
76
nd
74
nd
84
84
85
99
54
MeOH
THF
1,4-dioxane
DCM
>99
>99
>99
>99
>99
EtOAc
toluene
iPrOH
iPrOH
a
Reaction conditions: 0.2 mmol of substrate, 0.01 mmol %
t
[Ir(COD)Cl]2, 0.021 mmol % ligand, 0.2 mmol % BuONa, solvent
b
c
volume = 1.0 mL. Determined by 1H NMR analysis. Determined by
HPLC analysis.
enantioselectivity were obtained when f-amphox was used as
the chiral ligand.
Subsequently, the effect of solvent and base was examined in
detail when f-amphox was used as ligand (Table 2). Toluene
Table 2. Screening Solvents and Bases for the Asymmetric
a
Hydrogenation of α-Keto Amide 1a with Ir/f-Amphox
b
c
entry
solvent
toluene
base
conv (%)
ee (%)
1
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
tBuOLi
tBuOK
>99
>99
nr
99
98
nd
nd
97
93
99
99
99
99
nd
nd
99
99
2
DCM
a
Reaction conditions: 0.2 mmol of substrate, 0.01 mmol %
3
THF
[Ir(COD)Cl]2, 0.021 mmol % ligand, 0.2 mmol % Cs2CO3, 1.0 mL
b
i
4
1,4-dioxane
EtOAc
MeOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
nr
of PrOH, 10 atm H2. Ee’s were determined by HPLC analysis. 40
c
5
>99
>99
>99
>99
>99
>99
trace
nr
atm of H2. All the yields are isolated yield.
6
keto amides and were found to be insensitive to the nature of
substituents on the aromatic rings. Both electron-donating
(2b−2e) and electron-withdrawing (2i) substituents were
tolerable for the substrates. The position of the substituent
groups on the aromatic core of the substrates shows little
influence on the reactions (2b vs 2d, 2f vs 2g). Increasing the
steric hindrance of the aromatic ring also provided superior
results (2l). Particularly, the challenging heterocyclic substrates
(2m) also proceeded smoothly affording the desired hydro-
genation product with >99% conversion and >99% ee. In
addition, the substrates (2n, 2o, 2p) without the benzyl group
but with an alkyl on the N-atom can also work efficiently with
>99% conversion and ≥99% ee. However, secondary α-keto
amides did not work (2q, 2r). Some particular examples (2b,
2d, and 2k) to be noted required a higher H2 pressure for
completion.
7
8
9
10
11
12
13
KOH
K2CO3
Na2CO3
Cs2CO3
Cs2CO3
>99
>99
d
14
a
Reaction conditions: 0.2 mmol of substrate, 0.01 mmol %
[Ir(COD)Cl]2, 0.021 mmol % ligand, 0.2 mmol % base, solvent
b
c
volume = 1.0 mL. Determined by 1H NMR analysis. Determined by
d
HPLC analysis. 10 atm of H2. The absolute configuration of 2a was
determined by comparing the HPLC with those reported in the
literature.4e
and isopropanol were found to achieve both excellent yield and
enantioselectivity (Table 2, entry 1 and entry 7), while THF or
1,4-dioxane is not a good choice for the reaction (Table 2,
entries 3 and 4). Cs2CO3 and tert-butoxides were found equally
efficient while neither K2CO3 nor Na2CO3 works. Here,
Cs2CO3 was chosen for further study because it could tolerate
more functional groups compared to strong bases.
As we expected, this Ir/f-amphox catalytic system is highly
efficient in this asymmetric hydrogenation (Table 3). The
turnover number was up to 50 000 with a low loading of base at
low H2 pressure (Table 3, entry 2). After increasing the base
loading and H2 pressure, the TON was even up to 100 000 with
98% ee.
B
DOI: 10.1021/acs.orglett.7b02912
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
used as an injectable drug for the treatment of critically low
blood pressure.
Table 3. Asymmetric Hydrogenation of α-Keto Amide 1a
Catalyzed by Ir/f-Amphox in High TON
a
We carried out density functional theory (DFT) calculations
to study the detailed mechanism for enantioselective hydro-
genation of 1a catalyzed by Ir/f-amphox with a base such as
tBuONa.7 Ir(III) Na−amidato complex I can be formed by Ir/f-
amphox in the presence of tBuONa [see Supporting
Information (SI)].8 As shown in Figure 2, this catalytic
reaction takes place with (1) hydride transfer from the Ir center
of complex I to the α-keto carbon of 1a and (2) protonation of
the alkoxide anion to yield 2a and regenerate the active
complex I. The second step is calculated to be the rate-
determining step with less than 14 kcal/mol activation energy9
while the first step controls the enantioselectivity. The hydride
transfer leading to the (S)-alkoxide anion has a transition state
(TS1S) which is more stable than the one leading to the (R)-
alkoxide anion by 3.2 kcal/mol, indicating an ee value of 99.1%,
which is consistent with the experimental value of 99%. The
energy difference between these two transition states comes
from the C−H−π interaction and π−π stacking between the f-
amphox ligand and the phenyl group in TS1S as shown in
Figure 3,10 together with the steric repulsion5 between the f-
amphox ligand and benzyl amide group in TS1R. The
electrostatic interaction stabilizes TS1S and the steric repulsion
destabilizes TS1R, resulting in enantioselective hydrogenation.
Other possible but unfavorable reaction mechanisms were also
studied and shown in the SI.
b
c
entry
s/c
H2 (atm)
base (equiv)
conv (%)
ee (%)
1
2
3
4
10 000
50 000
10
10
10
40
0.001
0.001
0.02
>99
>99
70
99
99
98
100 000
100 000
0.02
>99
98
a
i
Reaction conditions: 0.2 mmol of substrate, 1.0 mL of PrOH.
b
c
Conversion was determined by 1H NMR analysis. The ee was
determined by HPLC analysis.
In addition, the asymmetric hydrogenation of 1k in gram-
scale proceeded smoothly under the optimized reaction
conditions (S/C = 10 000, 1.5 g of 1k, 0.11 mg of
[Ir(COD)Cl]2, and 0.19 mg of f-amphox). Full conversion
and 98% ee were obstained within 24 h (Scheme 3). The
Scheme 3. Asymmetric Hydrogenation of N-Benzyl-2-(3,4-
bis(benzyloxy)phenyl)-2-oxoacetamide 1k on Gram Scale
In summary, we have successfully developed the iridium/f-
amphox-catalyzed asymmetric hydrogenation of a wide range of
α-keto amides to prepare the corresponding chiral α-hydroxy
amides with excellent results (>99% conversion and up to
>99% ee). Our catalytic system is extremely reactive; the TON
was up to 100 000. DFT data revealed that the noncovalent
interactions between the ligand and substrate played an
important role in high enantioselectivity. This will be helpful
for chemists to understand the role that the ligand plays in the
desired chiral α-hydroxy amide 2k can be further reduced to
prepare chiral β-amino alchol 3k. 3k was a candidate start
material to prepare (S)-4-(2-amino-1-hydroxyethyl)benzene-
1,2-diol, the enantiomer of norepinephrine, which is widely
t
Figure 2. Solvent corrected Gibbs free energy profile for the iridium-catalyzed enantioselective hydrogenation of 1a in BuONa.
C
DOI: 10.1021/acs.orglett.7b02912
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) (a) Wu, W.; Zou, S.; Lin, L.; Ji, J.; Zhang, Y.; Ma, B.; Liu, X.;
Feng, X. Chem. Commun. 2017, 53, 3232. (b) Ren, X.; Du, H. J. Am.
Chem. Soc. 2016, 138, 810. (c) Sun, Y.; Wan, X.; Wang, J.; Meng, Q.;
Zhang, H.; Jiang, L.; Zhang, Z. Org. Lett. 2005, 7, 5425. (d) Sun, X.;
Zhou, L.; Li, W.; Zhang, X. J. Org. Chem. 2008, 73, 1143. (e) Yang, J.
W.; List, B. Org. Lett. 2006, 8, 5653. (f) Yin, L.; Shan, W.; Jia, X.; Li,
X.; Chan, A. S.C. J. Organomet. Chem. 2009, 694, 2092. (g) Enders, D.;
̈
StOckel, B. A.; Rembiak, A. Chem. Commun. 2014, 50, 4489.
(h) Kanomata, N.; Nakata, T. J. Am. Chem. Soc. 2000, 122, 4563.
(i) Paule, S. D.; Jeulin, S.; Virginie, R.-V.; Genet, J. P.; Champion, N.;
Dellis, P. Eur. J. Org. Chem. 2003, 2003, 1931.
(4) (a) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825.
́
(b) Concellon, J. M.; Bardales, E. Org. Lett. 2003, 5, 25. (c) Pasquier,
C.; Naili, S.; Pelinski, L.; Brocard, J.; Mortreux, A.; Agbossou, F.
Tetrahedron: Asymmetry 1998, 9, 193. (d) Stella, S.; Chadha, A. Catal.
Today 2012, 198, 345. (e) Mamillapalli, N. C.; Sekar, G. Chem. - Eur. J.
́
2015, 21, 18584. (f) Pasquier, C.; Pelinski, L.; Brocard, J.; Mortreux,
Figure 3. Geometry information on TS1S and TS1R.
A.; Agbossou-Niedercorn, F. Tetrahedron Lett. 2001, 42, 2809.
(g) Chiba, T.; Miyashita, A.; Nohira, H. Tetrahedron Lett. 1993, 34,
2351. (h) Zhao, Q.; Zhao, Y.; Liao, H.; Cheng, T.; Liu, G.
ChemCatChem 2016, 8, 412. (i) Cederbaum, F.; Lamberth, C.;
Malan, C.; Naud, F.; Spindler, F.; Studer, M.; Blaser, H.-U. Adv. Synth.
Catal. 2004, 346, 842.
reaction and will be useful to guide the design of ligand
synthesis.
ASSOCIATED CONTENT
* Supporting Information
(5) (a) Wu, W.; Liu, S.; Duan, M.; Tan, X.; Chen, C.; Xie, Y.; Lan, Y.;
Dong, X.-Q.; Zhang, X. Org. Lett. 2016, 18, 2938. (b) Yu, J.; Long, J.;
Yang, Y.; Wu, W.; Xue, P.; Chung, L. W.; Dong, X.-Q.; Zhang, X. Org.
Lett. 2017, 19, 690. (c) Yu, J.; Duan, M.; Wu, W.; Qi, X.; Xue, P.; Lan,
Y.; Dong, X.-Q.; Zhang, X. Chem. - Eur. J. 2017, 23, 970.
(6) Barlow, J. J.; Main, B. G.; Snow, H. M. J. Med. Chem. 1981, 24,
315.
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02912.
General information, typical experimental procedures,
HPLC, NMR spectra of the compounds, and computa-
tional details (PDF)
(7) Please see the computational details in the Supporting
Information. DFT calculations were carried out by using the Gaussian
09 package. Geometric structures of all species in the gas phase were
optimized with the M06-2X functional, which has good performance
for noncovalent interactions. On the basis of the gas-phase optimized
AUTHOR INFORMATION
Corresponding Authors
■
i
geometries, the solvation effect of PrOH was incorporated with the
PCM solvent model at the M06-L/6-311++G** level of theory.
(8) (a) Alkali cations (Na+, K+, Cs+) are necessary for the high
activity asymmetric hydrogenation. We choose the Na−amidato
complex in this calculated mechanism to save computational cost.
(b) Dub, P. A.; Henson, N. J.; Martin, R. L.; Gordon, J. C. J. Am.
Chem. Soc. 2014, 136, 3505. (c) Dub, P. A.; Gordon, J. C. ACS Catal.
2017, 7, 6635.
(9) IIS is the TOF-determining intermediate and TS2S is the TOF-
determining transition state, according to the energetic span concept
introduced by Kozuch and Shaik: (a) Kozuch, S.; Shaik, S. J. Am.
Chem. Soc. 2006, 128, 3355. (b) Uhe, A.; Kozuch, S.; Shaik, S. J.
Comput. Chem. 2011, 32, 978. (c) Kozuch, S.; Shaik, S. Acc. Chem. Res.
2011, 44, 101. (d) Kozuch, S.; Martin, J. M. L. ACS Catal. 2012, 2,
2787.
*E-mail: zhangxm@sustc.edu.cn.
*E-mail: ldang@stu.edu.cn.
ORCID
Guoxian Gu: 0000-0003-3216-0933
Tilong Yang: 0000-0002-9126-8840
Li Dang: 0000-0003-2666-7607
Xumu Zhang: 0000-0001-5700-0608
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a start-up fund from Southern
University of Science and Technology, Shenzhen Peacock Plan
(KQTD2015071710315717) and Shenzhen Research Grants
(JSGG20160608140847864).
(10) (a) The noncovalent interaction energy between these two
moieties is evaluated as −3.3 kcal/mol by topology analysis of electron
density by using Multiwfn program packages: Lu, T.; Chen, F. J.
Comput. Chem. 2012, 33, 580. (b) The 3D molecular structures were
generated by using CYL-view: CYLview, 1.0b; Legault, C. Y.,
́
Universite de Sherbrooke, 2009 (http://www.cylview.org).
REFERENCES
■
(1) (a) Hanessian, S. Total Synthesis of Natural Products: The Chiron
Approach; Pergamon: Oxford, 1983. (b) Coppola, G. M.; Schuster, H.
F. α-Hydroxy Acids in Enantioselective Synthesis; VCH: Weinheim,
Germany, 1997. (c) Pfaltz, A.; Yamamoto, H. Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Ed.; Springer: Berlin, Germany,
1999, Vol. I−III. (d) Catalysis Asymmetric Synthesis, 2nd ed.; Ojima, I.,
Ed.; Wiley-VCH: New York, 2000. (e) Zhang, Q.-L.; Zhuang, Z.-Y.;
Liu, Q.-D.; Zhang, Z.-M.; Zhan, F.-X.; Zheng, G.-X. Org. Process Res.
Dev. 2016, 20, 1993.
(2) (a) Yan, P.-C.; Xie, J.-H.; Zhang, X.-D.; Chen, K.; Li, Y.-Q.; Zhou,
Q.-L.; Che, D.-Q. Chem. Commun. 2014, 50, 15987. (b) Xue, Y.-P.;
Zheng, Y.-G.; Zhang, Y.-Q.; Sun, J.-L.; Liu, Z.-Q.; Shen, Y.-C. Chem.
Commun. 2013, 49, 10706.
D
DOI: 10.1021/acs.orglett.7b02912
Org. Lett. XXXX, XXX, XXX−XXX