Enantioselective and Diastereoselective Ir-Catalyzed Hydrogenation of α-Substituted β-Ketoesters via Dynamic Kinetic Resolution

Article abstract of DOI:10.1021/acs.orglett.8b00433

An iridium/f-amphol catalytic system for the enantioselective hydrogenation of α-substituted β-ketoesters via dynamic kinetic resolution is reported. The desired anti products were obtained in high yields (up to 98%) with good diastereoselectivity (up to 96:4 diastereometic ratio (dr)) and excellent enantioselectivity (up to >99% enantiomeric excess (ee)). A catalytic model is proposed to explain the stereoselectivity.

Full text of DOI:10.1021/acs.orglett.8b00433

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective and Diastereoselective Ir-Catalyzed Hydrogenation
of α‑Substituted β‑Ketoesters via Dynamic Kinetic Resolution
Guoxian Gu,† Jiaxiang Lu,† Ouran Yu,† Jialin Wen,*,†,‡ Qin Yin,*,†,‡ and Xumu Zhang*,†
‡
†Department of Chemistry and Academy of Advanced Interdisciplinary Studies, Southern University of Science and Technology,
1088 Xueyuan Rd., Nanshan District, Shenzhen, Guangdong 518055, People’s Republic of China
S
* Supporting Information
ABSTRACT: An iridium/f-amphol catalytic system for the
enantioselective hydrogenation of α-substituted β-ketoesters
via dynamic kinetic resolution is reported. The desired anti
products were obtained in high yields (up to 98%) with good
diastereoselectivity (up to 96:4 diastereometic ratio (dr)) and
excellent enantioselectivity (up to >99% enantiomeric excess
(ee)). A catalytic model is proposed to explain the
stereoselectivity.
ompared to kinetic resolution, which achieves no more
Cthan 50% transformation of the substrates, dynamic
kinetic resolution (DKR) could theoretically realize 100%
conversion of the substrates to the products. In this chemical
process, each enantiomer of a configurationally labile racemic
substrate has a different reaction rate in a chiral environment. If
the racemization step is fast enough prior to the transformation,
both enantioselectivity and diastereoselectivity would be
achieved.
Transition-metal (TM)-catalyzed hydrogenation of α-sub-
stituted β-ketoesters is an example with DKR. If controlled
hydrogenation is performed, two contiguous stereocenters are
constructed in a single reaction (see Figure 1a). This reaction
has drawn great interest1 since Noyori2 and Genet 3
̂
, who
independently used ruthenium/bisphoshine complexes to
perform the hydrogenation of the keto group, giving chiral β-
hydroxy esters. Many efforts have been made to improve this
reaction. Various ligands were designed to fit this reaction.4 In
the meanwhile, TMs other than ruthenium,5 such as iridium6
and nickel,7 were also surveyed in this reaction. In addition,
transfer hydrogenation8 and biocatalytic reduction9 were also
developed. Note that a cobalt-catalyzed borohydride reduction
could also be applied in this reaction with high efficiency and
stereoselectivity.10 Although enantiomeric control has been
achieved, diastereoselectivity is still historically problematic.
The most applied strategy is substrate control (see Figure 1b),
via either a covalent bond or an intramolecular hydrogen bond.
Therefore, the reaction scope is limited to cyclic substrates or
substrates with hydrogen bond donors. A simple alkyl group at
the α-position remains challenging until Hu11 reported an
iridium-catalyzed hydrogenation via DKR, giving anti products.
In this case, a relatively narrow substrate scope and modest
enantiomeric excess (ee) values for some substrates were
reported. However, the synthesis of chiral β-hydroxyesters is
still in demand.
Our group has developed a series of ferrocene-based
tridentate ligands12 to facilitate iridium-catalyzed enantioselec-
tive hydrogenation of ketones. A bifunctional model (Figure 2,
top) was proposed: with a secondary interaction between a
polar functional group in the ligand and carbonyl group in the
substrate, a hydride could be stereoselectively delivered from
the TM to the unsaturated bond. We envisioned that iridium
with those ligands could catalyze stereoselective reduction of α-
substituted β-ketoesters. If the racemization step is fast enough,
a dynamic kinetic resolution would be achieved.
Figure 1. Dynamic kinetic resolution (DKR) in the transition-metal
(TM)-catalyzed hydrogenation of β-ketoesters: (a) general reaction
pathway and (b) substrate control for high diastereoselectivity.
Received: February 6, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00433
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1). With potassium tert-butoxide as the base, a series of solvents
were screened. Tetrahydrofuran (THF) gave no product while
other aprotic solvents did not bring benefit to the dr value (see
entries 11−15 in Table 1). Methanol gave high dr values but
moderate enantiomeric excess (ee) (entry 9 in Table 1).
Gratifyingly, ethanol provided both high diastereoselectivity
(92/8 dr) and high enantioselectivity (>99% ee) (entry 10 in
Table 1). The reaction proceeded completely by extending the
reaction time (entry 16 in Table 1). Lowering the reaction
temperature slightly increased the dr value but slowed down the
reaction (entry 17 in Table 1). Increasing the catalyst loading
enabled a full conversion in a shorter time (entry 18 in Table
1). This Ir/f-amphol catalyst was demonstrated to be highly
efficient: 97% conversion and >99% ee was achieved at S/C =
5000 (entry 19 in Table 1).
Figure 2. Ferrocene-based tridentate ligands for highly efficient Ir-
catalyzed enantioselective hydrogenation of ketones.
To examine the substrate scope, a series of α-substituted β-
ketoesters are prepared and hydrogenated afterward. The
results were summarized in Scheme 1. Methyl esters (2b, 90/10
dr, >99% ee) and tertiary butyl esters (2c, 91/9 dr, 95% ee)
showed similar reactivities and stereoselectivities to the model
ethyl ester substrate (2a, 92/8 dr, >99% ee). Various α-
substitution groups did not bring significant influence to this
reaction. Substrates with various substituents on the α-benzyl
group (2d−2l) were hydrogenated smoothly under the optimal
condition with both high enantioselectivities (all ≥99% ee) and
diastereoselectivities; those containing ortho-substitiuents,
regardless of electron-donating or electron-withdrawing groups,
on α-benzyl group, gave product in diminished dr values (2f,
84/46 dr; 2j, 88/12 dr; 2k, 83/17 dr); those with an para-
electron-withdrawing group on α-benzyl group provided the
Our investigation was initiated with ethyl 2-benzyl-3-oxo-3-
phenylpropanoate (1a) as the model substrate and [Ir(COD)-
Cl]2 as the metal precursor. Ligands were first tested in
isopropanol with sodium tert-butoxide as the base (Table 1,
entries 1−3). To our surprise, these ligands, which are efficient
for the AH of simple ketones, behaved differently under these
conditions. Iridium complexes with f-amphox and f-ampha did
not show any reactivity, with a substrate-to-catalyst molar ratio
(S/C) of 1000/1. In a sharp contrast, Ir/f-amphol gave the
reduction product with excellent enantioselectivity, albeit with
moderate diastereoselectivity (99% ee, 83/17 dr). In order to
increase the diastereoselectivity, screening of bases and solvents
was undertaken. In isopropanol, inorganic bases with alkali-
metal cations worked well in conversion and enantioselectivity,
but the dr values were not satisfactory (see entries 4−8 in Table
a
Table 1. Optimization of the Reaction Conditions
b
c
c
entry
ligand
base
solvent
conversion (%)
diastereomeric ratio, dr
enantiomeric excess, ee (%)
1
2
L1
L2
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
tBuONa
tBuONa
tBuONa
tBuOK
tBuOLi
Cs2CO3
K2CO3
NaOH
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
MeOH
EtOH
toluene
DCM
0
0
N.A.
N.A.
N.A.
N.A.
99
3
98
83/17
86/14
75/25
86/14
80/20
83/17
93/7
4
>99
96
99
5
98
6
>99
70
99
7
99
8
>99
70
99
9
69
10
11
12
13
14
15
81
92/8
>99
98
70
80/20
80/20
N.A.
40
97
THF
0
N.A.
98
EtOAc
n-hexane
EtOH
EtOH
EtOH
EtOH
50
89/11
80/20
92/8
66
99
d
16
>99
77
>99
>99
>99
>99
e
17
93/7
f
18
>99
97
92/8
g
19
92/8
a
b
t
1
Reaction conditions: 0.10 mmol 1a, 1a/[Ir(COD)Cl]2/ligand = 2000/1.0/2.0, 0.001 mmol BuONa, 1.0 mL solvent. Determined via H NMR
c
analysis. Determined by HPLC on a chiral stationary phase, the absolute configuration of 2a was determined by comparing the HPLC and optical
rotation data with those reported in the literature.13 After 24 h. Conditions: −5 °C, 24 h. 1a/[Ir(COD)Cl]2/ligand = 1000/1.0/2.0, 7 h. 1a/
d
e
f
g
[Ir(COD)Cl2]/ligand = 10 000/1.0/2.0, 96 h.
B
DOI: 10.1021/acs.orglett.8b00433
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b c
, ,
Scheme 1. Substrate Scope for Iridium-Catalyzed Stereoselective Hydrogenation of α-Substituted β-Ketoesters
a
b
c
Reaction conditions: 0.10 mmol 1, 1/[Ir(COD)Cl]2/ligand = 1000/1.0/2.0, 0.001 mmol tBuOK, 1.0 mL solvent. Isolated yields. The ee and dr
d
values were determined by HPLC on a chiral stationary phase. Reaction time of 24 h.
hydrogenated products with higher dr values (2h, 94/6 dr and
2i, 96/4 dr). Substrates bearing various substituents adjacent to
the keto group also work well (2m−2p). It is interesting that
substrates with electron-withdrawing group on benzoyl gave
product in decreased dr values (2p, 85/15 dr, 98% ee), while
substrate with electron-donating groups gave product in
elevated dr values (2o, 96/4 dr, > 99% ee). Allylic groups
(2q−2s) and methyl group (2t) at the α-position were also
tested, giving the corresponding β-hydroxy esters with excellent
yields and stereoselectivities. Heteroaromatic groups, which
usually cause incompatibility in the TM-catalyzed homoge-
neous hydrogenation reactions, did not inhibit this reaction
(2v, 90/10 dr, 94% ee and 2w, 92/8 dr, >99% ee). However,
aliphatic groups gave a high conversion but seriously decreased
enantioselectivity and diastereoselectivity (2x, 60/40 dr, 39%
ee). The system also does not apply to the hydrogenation of
cyclic β-ketoesters (2y, <10% conversion and 45% ee).
Chiral β-hydroxyesters are important synthons that play a
fundamental role as intermediates in total synthesis. In order to
showcase the utility of this method, we selected one substrate
(2r) to demonstrate the easy transformation of β-hydrox-
yesters. In the presence of Lewis acid boron trifluoride, the
purified 2r condensed with salicylaldehyde, giving a complex
chiral tetrahydropyran structure with four stereogenic centers
was obtained14 (see Scheme 2). The broad substrate scope,
high stereoselectivities, and easy transformation of the products
Scheme 2. Elaboration on the Product Transformation
together demonstrate that this method to prepare chiral β-
hydroxyesters is practical in synthetic chemistry.
In order to explain the high stereoselectivities, models of
catalyst−substrate interaction were established. Based on our
computational studies in the case of the Ir/f-amphox-catalyzed
AH of α-ketoamides,15 electrostatic interaction plays an
important role in the enantioselective induction (see Figure
3, top). We hypothesize that the metal cation links the substrate
with catalyst, lowering the Gibbs energy and benefitting the
formation of a stable catalyst−substrate complex. Four models
of transition states in the stereocontrol step are shown in Figure
3, yielding four possible isomers. However, because of steric
hindrance, only one catalyst−substrate complex has lower free
C
DOI: 10.1021/acs.orglett.8b00433
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Shenzhen Tech-Innovation
Program from the Shenzhen Science, Technology and
Innovation Commission, the Shenzhen Free Exploration
Fund (G. Gu) and Shenzhen Research Grants (No.
JSGG20160608140847864, X.Z.).
REFERENCES
(1) For early reviews, see: (a) Ratovelomanana-Vidal, V.; Genet
J. Organomet. Chem. 1998, 567, 163−171. (b) Ratovelomanana-Vidal,
̂
V.; Genet, J.-P. Can. J. Chem. 2000, 78, 846−851.
■
̂
, J.-P.
(2) (a) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura,
M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.;
Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134−9135. (b) Noyori,
R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi,
H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856−5858.
Figure 3. Proposed models to elucidate enantiomeric induction in Ir/
f-amphol catalyzed hydrogenation of 1a via DKR.
(3) J. P., Genet
̂
, Mallart, S.; Juge, S. French Patent No. 8911159,
1989.
(4) (a) Zhang, Z.; Qian, H.; Longmire, J.; Zhang, X. J. Org. Chem.
2000, 65, 6223−6226. (b) Qiu, L.; Qi, J.; Pai, C.-C.; Chan, S.; Zhou,
Z.; Choi, M. C. K.; Chan, A. S. C. Org. Lett. 2002, 4, 4599−4602.
energy. This modeling rationale helps to explain the high
stereoselectivities in this chemical transformation. Another
interesting question is this: why does only f-amphol show
reactivity in the reaction condition with 0.1 mol % catalyst
loading? We failed to give any plausible explanations at this
stage, and mechanistic studies on this issue are currently
underway.
In summary, we have identified a highly efficient Ir/f-amphol
complex for stereoselective hydrogenation of β-ketoesters. A
dynamic kinetic resolution has been achieved with remarkably
high enantioselectivities and diastereoselectivities. Various α-
substituted β-ketoesters were hydrogenated to afford chiral anti
β-hydroxyesters. A model is proposed to explain the origin of
stereoselectivities based on our previous mechanistic studies.
(5) (a) Mordant, C.; Dunkelmann, P.; Ratovelomanana-Vidal, V.;
̈
Genet, J.-P. Eur. J. Org. Chem. 2004, 2004, 3017−3026. (b) Lei, A.;
Wu, S.; He, M.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 1626−1627.
(c) Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y. Tetrahedron:
Asymmetry 2008, 19, 2816−2828. (d) Li, X.; Tao, X.; Ma, X.; Li, W.;
Zhao, M.; Xie, X.; Ayad, T.; Ratovelomanana-Vidal, V.; Zhang, Z.
Tetrahedron 2013, 69, 7152−7156.
(6) (a) Makino, K.; Iwasaki, M.; Hamada, Y. Org. Lett. 2006, 8,
4573−4576. (b) Maeda, T.; Makino, K.; Iwasaki, M.; Hamada, Y.
Chem.Eur. J. 2010, 16, 11954−11962. (c) Echeverria, P.-G.; Fer
́
ard,
C.; Cornil, J.; Guerinot, A.; Cossy, J.; Phansavath, P.; Ratovelomanana-
́
Vidal, V. Synlett 2014, 25, 2761−2764. (d) Makino, K.; Hiroki, Y.;
Hamada, Y. J. Am. Chem. Soc. 2005, 127, 5784−5785.
(7) Hamada, Y.; Koseki, Y.; Fujii, T.; Maeda, T.; Hibino, T.; Makino,
K. Chem. Commun. 2008, 6206−6208.
(8) (a) Seashore-Ludlow, B.; Villo, P.; Hacker, C.; Somfai, P. Org.
̈
ASSOCIATED CONTENT
* Supporting Information
Lett. 2010, 12, 5274−5277. (b) Cartigny, D.; Puntener, K.; Ayad, T.;
̈
■
S
Scalone, M.; Ratovelomanana-Vidal, V. Org. Lett. 2010, 12, 3788−
3791. (c) Liu, Z.; Shultz, C. S.; Sherwood, C. A.; Krska, S.; Dormer, P.
G.; Desmond, R.; Lee, C.; Sherer, E. C.; Shpungin, J.; Cuff, J.; Xu, F.
Tetrahedron Lett. 2011, 52, 1685−1688. (d) Seashore-Ludlow, B.;
Saint-Dizier, F.; Somfai, P. Org. Lett. 2012, 14, 6334−6337.
(e) Seashore-Ludlow, B.; Villo, P.; Somfai, P. Chem.Eur. J. 2012,
18, 7219−7223. (f) Fang, Z.; Wills, M. J. Org. Chem. 2013, 78, 8594−
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00433.
Complete experimental details and characterization data
(PDF)
̀
8605. (g) Zerla, D.; Facchetti, G.; Fuse, M.; Pellizzoni, M.; Castellano,
C.; Cesarotti, E.; Gandolfi, R.; Rimoldi, I. Tetrahedron: Asymmetry
2014, 25, 1031−1037. (h) Echeverria, P.-G.; Cornil, J.; Ferard, C.;
Guerinot, A.; Cossy, J.; Phansavath, P.; Ratovelomanana-Vidal, V. RSC
AUTHOR INFORMATION
Corresponding Authors
■
́
Adv. 2015, 5, 56815−56819. (i) Echeverria, P.-G.; Ferard, C.;
*E-mail: wenjl@sustc.edu.cn (J. Wen).
*E-mail: yinq@sustc.edu.cn (Q. Yin).
*E-mail: zhangxm@sustc.edu.cn (X. Zhang).
Phansavath, P.; Ratovelomanana-Vidal, V. Catal. Commun. 2015, 62,
95−99. (j) Monnereau, L.; Cartigny, D.; Scalone, M.; Ayad, T.;
Ratovelomanana-Vidal, V. Chem.Eur. J. 2015, 21, 11799−11806.
ORCID
́
(k) Llopis, Q.; Ferard, C.; Guillamot, G.; Phansavath, P.;
Ratovelomanana-Vidal, V. Synthesis 2016, 48, 3357−3363. (l) Sun,
G.; Zhou, Z.; Luo, Z.; Wang, H.; Chen, L.; Xu, Y.; Li, S.; Jian, W.;
Zeng, J.; Hu, B.; Han, X.; Lin, Y.; Wang, Z. Org. Lett. 2017, 19, 4339−
4342.
(9) (a) Ohta, H.; Kobayashi, N.; Sugai, T. Agric. Biol. Chem. 1990, 54,
489−493. (b) Rodríguez, S.; Schroeder, K. T.; Kayser, M. M.; Stewart,
J. D. J. Org. Chem. 2000, 65, 2586−2587. (c) Rodríguez, S.; Kayser, M.
M.; Stewart, J. D. J. Am. Chem. Soc. 2001, 123, 1547−1555.
(d) Kaluzna, I. A.; Matsuda, T.; Sewell, A. K.; Stewart, J. D. J. Am.
Guoxian Gu: 0000-0003-3216-0933
Jialin Wen: 0000-0003-3328-3265
Qin Yin: 0000-0003-3534-3786
Xumu Zhang: 0000-0001-5700-0608
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Chem. Soc. 2004, 126, 12827−12832. (e) Hackh, M.; Muller, M.;
̈
̈
D
DOI: 10.1021/acs.orglett.8b00433
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Ludeke, S. Chem.Eur. J. 2013, 19, 8922−8928. (f) Kaluzna, I. A.;
̈
Feske, B. D.; Wittayanan, W.; Ghiviriga, I.; Stewart, J. D. J. Org. Chem.
2005, 70, 342−345. (g) Cuetos, A.; Rioz-Martínez, A.; Bisogno, F. R.;
Grischek, B.; Lavandera, I.; de Gonzalo, G.; Kroutil, W.; Gotor, V. Adv.
Synth. Catal. 2012, 354, 1743−1749.
(10) Yamada, T.; Nagata, T.; Sugi, K. D.; Yorozu, K.; Ikeno, T.;
Ohtsuka, Y.; Miyazaki, D.; Mukaiyama, T. Chem.Eur. J. 2003, 9,
4485−4509.
(11) Hou, C.-J.; Hu, X.-P. Org. Lett. 2016, 18, 5592−5595.
(12) (a) Wu, W.; Liu, S.; Duan, M.; Tan, X.; Chen, C.; Xie, Y.; Lan,
Y.; Dong, X.-Q.; Zhang, X. Org. Lett. 2016, 18, 2938−2941. (b) Yu, J.;
Long, J.; Yang, Y.; Wu, W.; Xue, P.; Chung, L. W.; Dong, X.-Q.;
Zhang, X. Org. Lett. 2017, 19, 690−693. (c) Yu, J.; Duan, M.; Wu, W.;
Qi, X.; Xue, P.; Lan, Y.; Dong, X.-Q.; Zhang, X. Chem.Eur. J. 2017,
23, 970−975.
(13) Li, W.; Wang, J.; Hu, X.; Shen, K.; Wang, W.; Chu, Y.; Lin, L.;
Liu, X.; Feng, X. J. Am. Chem. Soc. 2010, 132, 8532−8533.
(14) Saha, P.; Bhunia, A.; Saikia, A. K. Org. Biomol. Chem. 2012, 10,
2470−2481.
(15) Gu, G.; Yang, T.; Yu, O.; Qian, H.; Wang, J.; Wen, J.; Dang, L.;
Zhang, X. Org. Lett. 2017, 19, 5920−5923.
E
DOI: 10.1021/acs.orglett.8b00433
Org. Lett. XXXX, XXX, XXX−XXX