Asymmetric hydrogenation of β-keto esters using chiral diphosphonites

Article abstract of DOI:10.1002/adsc.200606093

The BINOL-derived diphosphonite having an achiral backbone based on diphenyl ether is a readily accessible and cheap ligand for the enantioselective Ru-catalyzed hydrogenation of β-keto esters (ee = 95-99%).

Full text of DOI:10.1002/adsc.200606093

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DOI: 10.1002/adsc.200606093
Asymmetric Hydrogenation of b-Keto Esters Using Chiral
Diphosphonites
a,
a
Manfred T. Reetz * and Xiaoguang Li
a
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim/Ruhr, Germany
Fax : (+49)-208-306-2985; e-mail: reetz@mpi-muelheim.mpg.de
Received: March 10, 2006; Accepted: May 15, 2006
Abstract: The BINOL-derived diphosphonite
having an achiral backbone based on diphenyl
ether is a readily accessible and cheap ligand for
the enantioselective Ru-catalyzed hydrogenation of
b-keto esters (ee=95–99%).
arylboronic acids[7] and Ru-catalyzed transfer hydro-
[
8]
genation of ketones. In all cases studied so far, the
choice of the appropriate achiral backbone is crucial.
This means that in the class of BINOL-derived di-
phosphonites no single ligand is general. However,
this is not a drawback, since the nature of the back-
bone can be varied readily, while using the same
chiral auxiliary. BINOL in both enantiomeric forms is
one of the cheapest chiral auxiliaries currently com-
Keywords: asymmetric catalysis; hydrogenation;
keto esters; phosphonites; ruthenium
[
9]
mercially available.
Exploratory experiments were carried out with b-
keto ester 1a using [RuCl2(benzene)] and two equiv-
AHCTREUNG
2
b-Hydroxy esters are useful building blocks in the alents of a BINOL-derived diphosphonite under a va-
synthesis of many natural products and/or biologically riety of conditions. Remarkably, four of the ligands,
active compounds.[1] A particular useful synthetic namely 3, 4, 5 and 6, turned out to be poor, whereas
strategy is the asymmetric hydrogenation of b-keto the diphosphonite 7 derived from diphenyl ether led
esters 1 ! 2 (Scheme 1) catalyzed by transition metal to an enantioselectivity of ee=95% (Table 1). In con-
complexes of chiral phosphorus ligands.
trast, transfer hydrogenation with ligand 7 using 2-
Following the work of Noyori regarding the use of propanol as the reductant under basic conditions
[
2]
[3]
BINAP, many other effective chiral diphosphines
have been developed for this important transforma-
turned out to be disappointing.
Ligand 7 was then tested in the Ru-catalyzed hy-
tion, generally in combination with ruthenium as the drogenation of the other b-keto esters (Table 2). It
transition metal. In a number of cases ees>95% were can be seen that following optimization of tempera-
[
2,3]
observed.
3
More recently, research has shown that ture and pressure, ees of 97–99% were achieved in all
[4]
,3’-disubstituted BINAPO-ligands and even certain cases. Here again (S,S)-7 leads to the (S)-configurated
[5]
chiral monodentate phosphines are also well suited. products, except in the case of the phenyl derivative
In spite of these impressive results, research continues 2d (due to a switch in priority within the Cahn–
in this area, fueled by the industrial need for simple Ingold–Prelog nomenclature). Thus, our ligand 7 com-
and thus readily accessible ligands.
pares well with the best previous catalyst systems de-
[
2–-5]
We have previously shown that BINOL-derived di- scribed thus far in the literature.
phosphonites of the types 3–7 (Figure 1) are excellent
Finally, it was of interest to test the present catalyst
ligands in Rh-catalyzed asymmetric olefin hydrogena- system in the hydrogenation of chiral b-keto esters in
[
6]
tion, Rh-catalyzed conjugate addition reactions of racemic form under the conditions of dynamic kinetic
resolution. For this purpose rac-8 was subjected to the
Ru-catalyzed hydrogenation (Scheme 2) under typical
reaction conditions (rac-8:Ru=100:1; 20 h). Essen-
tially only one product, (1S,2S)-9 having the anti-con-
figuration was formed quantitatively (anti:syn=96:4),
the ee being 99%. The configurational assignment
was made by comparison with an authentic sample.
In contrast, upon hydrogenating rac-10 under iden-
tical conditions (Scheme 3), an equimolar mixture of
Scheme 1. Asymmetric hydrogenation of b-keto esters.
the two possible diastereomers was formed [anti
Adv. Synth. Catal. 2006, 348, 1157 – 1160
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1157

Manfred T. Reetz and Xiaoguang Li
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Figure 1. BINOL-derived diphosphonites.
[a]
Table 1. Asymmetric Ru-catalyzed hydrogenation of b-keto ester 1a.
Entry
Ligand
Solvent
C H OH/CH Cl (3:1)
Conversion [%]
ee [%]
1
2
3
4
5
6
7
8
9
3
4
5
6
7
7
7
7
7
51
47
21
91
100
97
97
6
5
8
7
27
95
94
88
71
48
2
5
2
2
C H OH/CH Cl (3:1)
2
5
2
2
C H OH/CH Cl (3:1)
2
5
2
2
C H OH/CH Cl (3:1)
2
5
2
2
C H OH/CH Cl (3:1)
2
5
2
2
C H OH/CH Cl (1:1)
2
5
2
2
C H OH/CH Cl (1:3)
2
5
2
2
CH Cl
2
2
THF
75
[
a]
1
a:Ru=100:1; 608C; 80 bar H ; 20 h. (S,S)-7 leads to (S)-2 in all cases.
2
(
(
2S,3S):syn (2R,3S)=1:1], each in high enantiopurity
ee=95%).
All of the reactions described thus far were per-
formed with relatively high catalyst loading (sub-
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 1157 – 1160

Asymmetric Hydrogenation of b-Keto Esters
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[a]
Table 2. Asymmetric Ru-catalyzed hydrogenation of b-keto esters 1 using ligand 7.
Entry
b-Keto ester
Temperature [8C]
H pressure [bar]
2
Conversion [%]
ee [%]
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1c
1c
1d
1d
1d
60
85
60
60
90
60
60
60
85
80
100
97
95
99
95
95
97
97
93
93
97
50
50
80
50
50
50
80
50
100
100
100
100
100
100
100
[
a]
1
:Ru=100:1; solvent: C H OH/CH Cl (3:1); 20 h.
2 5 2 2
that the nature of the achiral backbone is crucial for
obtaining high levels of enantioselectivity. Defining
the source of enantioselectivity in the present hydro-
genations and in other transition metal-catalyzed re-
[
6–8]
actions
using BINOL-derived diphosphonites con-
stitutes a goal for the future.
Scheme 2. Ru-catalyzed hydrogenation of rac-8.
Experimental Section
General Procedure for Asymmetric Hydrogenation of
b-Keto Esters
A 25 mL Schlenk tube was charged with [Ru
A
H
R
U
G
(
16 mg, 0.032 mmol) and the diphosphonite 7 (0.067 mmol).
The tube was purged with argon three times before dry di-
methylformamide (DMF) (3 mL) was added. The resulting
mixture was heated at 1008C for 30 min and then cooled to
6
08C. The solvent was removed under vacuum to provide
the catalyst as a pale green-yellow solid. This catalyst was
dissolved in dry dichloromethane (8 mL), and distributed
equally to eight vials (1 mL each), which had already been
purged with argon three times. A b-keto ester (0.8 mmol)
Scheme 3. Ru-catalyzed hydrogenation of rac-10.
strate:Ru=100:1). In order to see if less catalyst can was placed in each vial followed by addition of 3 mL etha-
be tolerated, the hydrogenation of 1a was carried out nol. Then these eight vials were transferred to a high pres-
sure autoclave. After purging with H three times, the auto-
at a 1a/Ru ratio of 1000:1 under otherwise similar
conditions [908C; 50 bar H ; 20 h; C H OH/CH Cl
2
2
clave was pressurized with H to 60 bar and the reactions
were magnetically stirred at 608C for 20 h. The autoclave
was then cooled to room temperature and the H carefully
released. Samples were taken out of the reaction solution
and passed through a small amount of silica gel prior to the
GC analysis to determine the conversions and ee values. The
conditions for enantiomer separation were those described
by Knochel.[ The absolute configuration was determined
2
2
2
5
2
(
3:1) as solvent]. A quantitative conversion with for-
2
mation of 2a having an ee value of 93% was ob-
served. Thus, catalyst loading can in fact be reduced
by a factor of 10 without compromising enantioselec-
tivity appreciably. However, other substrates may re-
quire optimization.
10]
In conclusion, we have developed a new catalyst by comparison with known compounds described in the lit-
system for the asymmetric hydrogenation of b-keto erature.
esters with formation of chiral b-hydroxy esters. It
employs the BINOL-derived diphosphonite 7 with an
achiral backbone based on diphenyl ether. Since it is
easily prepared by double lithiation of diphenyl ether
followed by phosphorylation and introduction of the
Acknowledgements
BINOL component,[
6–8]
the catalyst system is industri-
ally viable. Other BINOL-derived diphosphonites Generous support from the Fonds der Chemischen Industrie
such as 3–6 are not at all suited, which demonstrates is gratefully acknowledged.
Adv. Synth. Catal. 2006, 348, 1157 – 1160
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
1159

Manfred T. Reetz and Xiaoguang Li
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Adv. Synth. Catal. 2006, 348, 1157 – 1160