Iridium-SYNPHOS-catalyzed hydrogenation through dynamic kinetic resolution of α-amino β-keto ester hydrochlorides

Article abstract of DOI:10.1055/s-0034-1379232

The stereoselective synthesis of anti β-hydroxy α-amino esters by iridium-SYNPHOS-catalyzed asymmetric hydrogenation of α-amino β-keto ester hydrochlorides is reported. The reaction proceeded through dynamic kinetic resolution to afford a variety of β-hyd

Full text of DOI:10.1055/s-0034-1379232

LETTER
▌2761
lIertteirdium–SYNPHOS-Catalyzed Hydrogenation through Dynamic Kinetic
Resolution of α-Amino β-Keto Ester Hydrochlorides
Iridium–SYNPHOS-Catalyzed Hydrogenation
Pierre-Georges Echeverria,a Charlène Férard,a Johan Cornil,b Amandine Guérinot,b Janine Cossy,b
Phannarath Phansavath,*a Virginie Ratovelomanana-Vidal*a
a
PSL Research University, Chimie ParisTech-CNRS, Institut de Recherche de Chimie Paris, 75005 Paris, France
Fax +33(1)44071062; E-mail: phannarath.phansavath@chimie-paristech.fr; E-mail: virginie.vidal@chimie-paristech.fr
b
Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI) – UMR 8231 ESPCI ParisTech/CNRS/PSL*
Research University, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(1)40794662; E-mail: janine.cossy@espci.fr
Received: 21.07.2014; Accepted after revision: 11.09.2014
pand the scope of the [{Ir(H)[(S)-diphosphine]}2(μ-X)3]X
Abstract: The stereoselective synthesis of anti β-hydroxy α-amino
complexes, we report herein an application of these Ir(III)
esters by iridium–SYNPHOS-catalyzed asymmetric hydrogenation
complexes bearing SYNPHOS,10 an atropisomeric ligand
developed by one of us, for the synthesis of anti β-hy-
of α-amino β-keto ester hydrochlorides is reported. The reaction
proceeded through dynamic kinetic resolution to afford a variety of
β-hydroxy α-amino ester derivatives with good yields and high droxy-α-amino esters.
level of diastereo- and enantioselectivities (de up to 99%, ee up to
92%).
The first example of DKR of α-amino-β-keto ester cata-
lyzed by an in situ generated Ir axially chiral phosphine
complex was reported by Hamada et al.11 who showed
that the method was effective for the preparation of aro-
matic anti-β-hydroxy-α-amino acids. The authors used ei-
ther an Ir-(S)-MeOBIPHEP complex (prepared from
[IrCl(cod)]2, (S)-MeOBIPHEP, and NaI prior to the hy-
drogenation) with NaOAc in AcOH under high hydrogen
pressure,11a or the Ir-(S)-MeO-BIPHEP-BARF complex
prepared from [IrCl(cod)]2, (S)-MeOBIPHEP, and
NaBARF in the presence of sodium acetate in acetic acid
under low hydrogen pressure.11b In both cases, the chiral
iridium complex was prepared in situ and the hydrogena-
tion proceeded in good yields and with high levels of
diastereo- and enantioselectivities. In connection with the
work disclosed by the group of Hamada, we describe
herein the results obtained for the hydrogenation of
α-amino β-keto ester hydrochlorides using the cationic
Key words: iridium, hydrogenation, asymmetric catalysis, enantio-
selectivity, amino alcohols
Dynamic kinetic resolution (DKR)1 is a useful and highly
efficient tool to access enantiomerically enriched com-
pounds starting from racemic substrates bearing a labile
stereocenter. Catalytic asymmetric hydrogenation of
α-substituted β-keto esters via DKR in particular, pro-
vides a broad range of functionalized molecules in a high
diastereo- and enantioselective fashion. In this field, the
use of chiral ruthenium complexes for the hydrogenation
of β-keto-α-amino esters via DKR was first reported by
Noyori2 and one of our laboratories3 for the syn-selective
formation of β-hydroxy-α-amino esters. The anti-selec-
tive Ru-mediated asymmetric hydrogenation of α-amino-
β-keto esters via DKR was later described by Hamada,4
Zhang5 and one of our groups.6 As part of our ongoing
studies toward the development of practical and efficient
catalysts for asymmetric hydrogenation of unsaturated
compounds, we have previously reported a convenient
one-pot synthesis of cationic triply halogen-bridged dinu-
clear iridium(III) complexes of general formula
[{Ir(H)[(S)-diphosphine]}2(μ-X)3]X (X = Cl, Br and I).7
These complexes were successfully used for the asym-
metric hydrogenation of quinolines8a,b and quinoxalines
derivatives,8c,d and allowed for the synthesis of the corre-
sponding tetrahydroquinolines and tetrahydroquinoxal-
ines with a high level of enantioselectivity. As an
extension of our previous work on the dynamic kinetic
resolution9 of α-amino-β-keto ester hydrochlorides
through asymmetric hydrogenation, and in an effort to ex-
dinuclear
iridium(III)
catalysts
[{Ir(H)[(S)-
SYNPHOS]}2(μ-X)3]X7 1a–c (Figure 1). These complex-
es are conveniently prepared from [IrCl(coe)2]2 by adding
(S)-SYNPHOS10 and an excess of aqueous HX in toluene
at room temperature, and the isolated catalysts are easy to
handle and can be stored.
+
X
X
X
H
Ph2
P
Ph2
P
H
Ir
Ir
O
PPh2
O
Ph2P
X–
O
O
O
O
O
O
1a: X = Cl
1b: X = Br
1c: X = I
Figure 1 Structures of cationic dinuclear triply halogen-bridged irid-
ium complexes 1a–c
SYNLETT 2014, 25, 2761–2764
Advanced online publication: 16.10.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1379232; Art ID: st-2014-d0614-l
© Georg Thieme Verlag Stuttgart · New York

2762
P.-G. Echeverria et al.
LETTER
The DKR was first performed with 2a as the standard sub- incomplete conversion after 24 hours with a slightly lower
strate using 1.5 mol% of [{Ir(H)[(S)-SYNPHOS]}2(μ-Cl)3]Cl er (Table 1, entry 5). When the hydrogenation was carried
(1a) and NaOAc in acetic acid at 40 °C under 100 bar of out in trifluoroacetic acid instead of acetic acid, poor con-
hydrogen pressure (Table 1). After 24 hours of reaction version was observed (Table 1, entry 6). Lowering the cat-
time, complete conversion of 2a was observed and the re- alyst loading to 1 mol% had no influence on either the
sulting substituted β-hydroxy-α-amino ester 3a (prepared conversion or the diastereo- and enantioselectivities (Ta-
by protection of the corresponding ammonium with ben- ble 1, entry 7). Finally, when the reduction was performed
zoyl chloride) was obtained in good yield with an excel- under 70 bar of hydrogen pressure instead of 100 bar, a
lent anti diastereoselectivity (dr >99:1) and with a high decrease of the diastereomeric ratio was observed (93:7 vs
er (90:10; Table 1, entry 1). Similar results were >99:1, Table 1, entries 8 and 3).
observed under these reaction conditions with
[{Ir(H)[(S)-SYNPHOS]}2(μ-Br)3]Br (1b; Table 1, entry
2).
In an attempt to establish the scope of the Ir–(S)-
SYNPHOS-promoted hydrogenation, a series of α-amino-
β-keto ester hydrochlorides 2a–k13 bearing various substi-
tution patterns were subjected to catalytic asymmetric hy-
drogenation under the optimized reaction conditions
(Table 2).
Table 1 Optimization of the Reaction Conditionsa
OH
O
O
O
1) 1 (1.5 mol%), AcONa
AcOH, H2 (100 bar)
40 °C, 24 h
OMe
OMe
NH2⋅HCl
2a
Table 2 DKR of Various α-Amino-β-Keto Ester Hydrochlorides
NHCOPh
through Ir-SYNPHOS-Czatalyzed Hydrogenationa
2) PhCOCl, Et3N
CH2Cl2, 0 °C to r.t.
3a
1) 1c (1.5 mol%), AcONa
AcOH, H2 (100 bar)
40 °C, 24 h
O
O
OH
O
Entry Ir complex Convb (%) Yield (%) drc anti/syn erd
R
OMe
R
OMe
NH2⋅HCl
2) PhCOCl, Et3N
CH2Cl2, 0 °C to r.t
1
1a
1b
1c
1c
1c
1c
1c
1c
100
100
100
0
80
79
72
–
>99:1
>99:1
>99:1
–
90:10
90:10
–4:6
–
NHCOPh
2
3
2
Entry Substrate
Yield drb
erc
3
(%)
anti/syn
4e
5f
6g
7i
8j
O
O
76
67
99:1
84:16
OMe
NH2⋅HCl
1
2
3
4
5
72
>99:1
>99:1
>99:1
>99:1
>99:1
94:6
h
h
h
13
–
–
–
100
100
72
68
>99:1
93:7
92:8
94:6
2a
2b
2c
2d
O
O
a Reaction conditions: 2 (0.44 mmol), catalyst (1.5 mol%), NaOAc
(0.44 mmol) in AcOH (2 mL) at 40 °C for 24 h under 100 bar of
hydrogen pressure.
OMe
73
72
58
87
94:6
93:7
92:8
95:5
NH2⋅HCl
b Conversions were determined after the hydrogenation reaction by 1H
NMR spectroscopy of the crude product.
O
O
c The dr value was determined by 1H NMR spectroscopy of the crude
product 3a.
OMe
d The er value was determined by SFC or HPLC analysis of 3a.
e The reaction was run in the absence of NaOAc.
f (S)-DIFLUORPHOS ligand was used instead of (S)-SYNPHOS.
g CF3CO2H was used as a solvent instead of AcOH.
h Not determined.
NH2⋅HCl
O
O
i The reaction was carried out with 1 mol% of the Ir complex.
j The reaction was conducted under 70 bar of H2.
OMe
NH2⋅HCl
Pleasingly, the use of [{Ir(H)[(S)-SYNPHOS]}2(μ-I)3]I
complex 1c allowed a higher enantiomeric ratio (94:6)
whereas the dr remained excellent (Table 1, entry 3). In
contrast with the result reported by Hamada et al. with a
mononuclear Ir-(S)-MeOBIPHEP complex, in our case,
no reaction was observed in the absence of sodium acetate
(Table 1, entry 4). Replacing (S)-SYNPHOS by the elec-
tron-deficient (S)-DIFLUORPHOS12 ligand resulted in
O
O
OMe
NH2⋅HCl
MeO
2e
Synlett 2014, 25, 2761–2764
© Georg Thieme Verlag Stuttgart · New York

LETTER
Iridium–SYNPHOS-Catalyzed Hydrogenation
2763
Table 2 DKR of Various α-Amino-β-Keto Ester Hydrochlorides
strate 2e bearing a methoxy group at the 4-position of the
phenyl ring provided high diastereo- and enantioselectiv-
ities (Table 2, entry 5). The introduction at the para posi-
tion on the phenyl ring of electron-withdrawing
substituents such as fluorine, as in 2f, a chlorine as in 2g
or a bromine as in 2h, resulted in a slight decrease of the
enantioselectivity, from 92:8 er for the fluorinated com-
pound 3f to 86:14 for the brominated compound 3h (Table
2, entries 6–8). The DKR of 2i bearing a thiophenyl sub-
stituent afforded the anti-substituted β-hydroxy-α-amino
ester 3i with high enantiomeric ratio and excellent diaste-
reoselectivity as high as >99:1 (Table 2, entry 9). α-Ami-
no β-keto ester hydrochlorides 2j and 2k having alkyl
substituents were also investigated. In the case of com-
pound 2j bearing a sterically demanding cyclohexyl
group, the corresponding anti product 3j was obtained
with high diastereoselectivity (dr 95:5, Table 2, entry 10)
whereas a lower dr of 83:17 was obtained for the hydro-
genation reaction of α-amino-β-keto ester hydrochloride
2k having a linear alkyl chain (Table 2, entry 11).
through Ir-SYNPHOS-Czatalyzed Hydrogenationa (continued)
1) 1c (1.5 mol%), AcONa
AcOH, H2 (100 bar)
40 °C, 24 h
O
O
OH
O
R
OMe
R
OMe
NH2⋅HCl
2) PhCOCl, Et3N
CH2Cl2, 0 °C to r.t
NHCOPh
2
3
Entry Substrate
Yield drb
erc
(%)
anti/syn
O
O
OMe
6
63
>99:1
>99:1
92:8
NH2⋅HCl
F
2f
O
O
OMe
7
72
89:11
NH2⋅HCl
Cl
2g
In summary, we have shown that a cationic dinuclear irid-
ium(III) iodide complex bearing the in-house developed
SYNPHOS ligand is efficient for the hydrogenation reac-
tions of a variety of α-amino-β-keto ester hydrochlorides
via a dynamic kinetic resolution process. The efficiency
of our catalyst system was demonstrated through the sub-
strate scope of the reaction. Indeed, a series of anti-β-hy-
droxy-α-amino ester derivatives was synthesized in good
chemical yields and with high levels of asymmetric induc-
tion. In addition, these compounds are key intermediates
for the synthesis of targets of medicinal interest.
O
O
OMe
8
68
85
60
60
> 99:1
>99:1
95:5
86:14
96:4
NH2⋅HCl
Br
2h
O
O
S
OMe
9
NH2⋅HCl
2i
O
O
Acknowledgment
OMe
10
11
91:9
NH2⋅HCl
We thank the Agence Nationale de la Recherche for financial sup-
port (ANR STIMAS, 2011-2014, P.G.E. and J.C.).
2j
O
O
References and Notes
H31C15
OMe
NH2⋅HCl
83:17
81:19
(1) For selected reviews on dynamic kinetic resolution, see:
(a) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem.
Soc. Jpn. 1995, 68, 36. (b) Ward, R. S. Tetrahedron:
Asymmetry 1995, 6, 1475. (c) Ohkuma, T.; Kitamura, M.;
Noyori, R. Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
Wiley: New York, 2000, 2nd ed. 1. (d) Pàmies, O.; Bäckvall,
J.-E. Chem. Rev. 2003, 103, 3247. (e) Vedejs, E.; Jure, M.
Angew. Chem. Int. Ed. 2005, 44, 3974. (f) Pellissier, H.
Tetrahedron 2008, 64, 1563. (g) Pellissier, H. Tetrahedron
2011, 67, 3769. (h) Pellissier, H. Adv. Synth. Catal. 2011,
353, 659.
2k
a Reaction conditions:14 2 (0.44 mmol), catalyst (1.5 mol%), NaOAc
(0.44 mmol) in AcOH (2 mL) at 40 °C for 24 h under 100 bar of hy-
drogen pressure. Complete conversions were obtained for all com-
pounds.
b Determined by 1H NMR spectroscopy of the crude product 3.
c Determined by SFC or HPLC analysis of 3.
(2) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura,
M.; Takaya, S.; Akutagawa, S.; Sayo, N.; Saito, N.;
Taketomi, T.; Kumobayashi, H. J. Am. Chem. Soc. 1989,
111, 9134.
(3) (a) Genet, J.-P.; Mallart, S.; Jugé, S. Fr. Patent 8911159,
1989. (b) Genet, J.-P.; Pinel, C.; Mallart, S.; Jugé, S.;
Thorimbert, S.; Laffitte, J. A. Tetrahedron: Asymmetry
1991, 2, 555.
(4) (a) Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y. Angew.
Chem. Int. Ed. 2004, 43, 882. (b) Makino, K.; Goto, T.;
Hiroki, Y.; Hamada, Y. Tetrahedron: Asymmetry 2008, 19,
2816.
Thus, the hydrogenation of 2a–k was carried out by using
1.5 mol% of [{Ir(H)[(S)-SYNPHOS]}2(μ-I)3]I 1c and
NaOAc in acetic acid at 40 °C under 100 bar of hydrogen
pressure for 24 hours, affording mainly excellent diaste-
reomeric ratios as high as >99:1 with er ranging from
81:19 to 96:4. The introduction of a methyl group at the
para, meta or ortho positions on the phenyl ring of the
corresponding α-amino-β-keto ester hydrochlorides 2b,
2c and 2d had no influence on either the yield or the dias-
tereo- and enantioselectivities (Table 2, entries 1–4). Sub-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2761–2764

2764
P.-G. Echeverria et al.
LETTER
(5) Lei, A.; Wu, S.; He, M.; Zhang, X. J. Am. Chem. Soc. 2004,
126, 1626.
(12) (a) Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal,
V.; Genêt, J.-P.; Champion, N. Angew. Chem. Int. Ed. 2004,
43, 320. (b) Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-
Vidal, V.; Genêt, J.-P.; Champion, N. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5799. (c) Genet, J.-P.; Ayad, T.;
Ratovelomanana-Vidal, V. Chem. Rev. 2014, 114, 2824.
(13) Substrates 2a–k were prepared according to procedures
reported in ref. 6b and in the references thereafter:
(6) (a) Mordant, C.; Dünkelmann, P.; Ratovelomanana-Vidal,
V.; Genet, J.-P. Chem. Commun. 2004, 1296. (b) Mordant,
C.; Dünkelmann, P.; Ratovelomanana-Vidal, V.; Genet,
J.-P. Eur. J. Org. Chem. 2004, 3017. (c) Labeeuw, O.;
Phansavath, P.; Genet, J.-P. Tetrahedron Asymmetry 2004,
15, 1899. (d) Prevost, S.; Ayad, T.; Phansavath, P.;
Ratovelomanana-Vidal, V. Adv. Synth. Catal. 2011, 353,
3213.
(a) Makino, K.; Okamoto, N.; Hara, O.; Hamada, Y.
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Gordon, T. D.; Earley, W. G.; Morgan, B. A. Tetrahedron
Lett. 1993, 34, 211.
(7) Yamagata, T.; Tadaoka, H.; Nagata, M.; Hirao, T.; Kataoka,
Y.; Ratovelomanana-Vidal, V.; Genet, J. P.; Mashima, K.
Organometallics 2006, 25, 2505.
(14) Typical Procedure for the Ir-SYNPHOS-Catalyzed
Asymmetric Hydrogenation of α-Amino-β-Ketoester
Hydrochlorides: To a Teflon tube charged with α-sub-
stituted β-keto ester 2 (0.44 mmol), NaOAc (36 mg,
0.44 mmol, 1 equiv) and AcOH (2 mL), was added solid
catalyst [{Ir(H)[(S)-SYNPHOS]}2(μ-I)3]I (15 mg, 7 μmol,
1.5 mol%) in one portion and the reaction mixture was
subjected to three vacuum/argon cycles. Under a flow of
argon, the reaction vessel was placed in a stainless steel
parallel hydrogenation system equipped with a central
mechanical stirrer. The atmosphere of the autoclave was
purged three times with argon and twice with H2. The
temperature was adjusted to 40 °C and the autoclave was
filled with H2 (100 bar). After 24 h of reaction, the autoclave
was adjusted to r.t. and atmospheric pressure and finally
purged three times with argon. The resulting mixture was
concentrated under reduced pressure. The conversion was
determined by 1H NMR analysis of the crude product. To a
solution of the previous β-hydroxyester hydrochloride (0.44
mmol, 1 equiv) in anhyd CH2Cl2 (2 mL) were added benzoyl
chloride (67 mg, 55 μL, 1.1 equiv) and Et3N (134 mg, 190
μL, 3 equiv) at 0 °C. The reaction mixture was stirred at 0 °C
for 1.5 h and for 1 h at r.t., then diluted with CH2Cl2,
quenched with sat. aq NH4Cl, extracted with CH2Cl2 and
dried over MgSO4. The crude protected product was purified
by flash chromatography to afford compound 3. The
diastereomeric ratio was determined by 1H NMR analysis of
the crude product, and the enantiomeric ratio was
(8) (a) Deport, C.; Buchotte, M.; Abecassis, K.; Tadaoka, H.;
Ayad, T.; Ohshima, T.; Genet, J.-P.; Mashima, K.;
Ratovelomanana-Vidal, V. Synlett 2007, 2743. (b) Tadaoka,
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J.-P.; Ohshima, T.; Ratovelomanana-Vidal, V.; Mashima, K.
Chem. Eur. J. 2009, 15, 9990. (c) Cartigny, D.; Nagano, T.;
Ayad, T.; Genet, J.-P.; Ohshima, T.; Mashima, K.;
Ratovelomanana-Vidal, V. Adv. Synth. Catal. 2010, 352,
1886. (d) Cartigny, D.; Berhal, F.; Nagano, T.; Phansavath,
P.; Ayad, T.; Genet, J.-P.; Ohshima, T.; Mashima, K.;
Ratovelomanana-Vidal, V. J. Org. Chem. 2012, 77, 4544.
(9) Ratovelomanana-Vidal, V.; Genet, J. P. Can. J. Chem. 2000,
78, 846.
(10) (a) Duprat de Paule, S.; Champion, N.; Ratovelomanana-
Vidal, V.; Genet, J.-P.; Dellis, P. Fr. Patent 830254, 2001.
(b) Duprat de Paule, S.; Jeulin, S.; Ratovelomanana-Vidal,
V.; Genet, J.-P.; Champion, N.; Dellis, P. Tetrahedron Lett.
2003, 44, 823. (c) Duprat de Paule, S.; Jeulin, S.;
Ratovelomanana-Vidal, V.; Genet, J.-P.; Champion, N.;
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J.-P.; Champion, N.; Deschaux, G.; Dellis, P. Org. Process.
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determined by chiral SFC analysis of the purified product
using a Chiralcel OD-H, Chiralpak IA, IC or AD-H column.
Synlett 2014, 25, 2761–2764
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