Rhodium-catalyzed enantioselective hydrogenation of β,β- disubstituted α-acetamido acrylates using cheap monodentate P-ligands

Article abstract of DOI:10.1055/s-2005-918460

The asymmetric Rh-catalyzed hydrogenation of β,β-disubstituted α-acetamido acrylates, which are notoriously difficult substrates, is possible using readily available BINOL-derived monodentate phosphites or phosphonites. Essentially quantitative conversion

Full text of DOI:10.1055/s-2005-918460

SHORT PAPER
3183
Rhodium-Catalyzed Enantioselective Hydrogenation of b,b-Disubstituted
a-Acetamido Acrylates Using Cheap Monodentate P-Ligands
Asymmetric
H
ydrogen
a
a
tion of
b
,
b
n
-Disubstitut
f
a
-
Ace
r
tamido
A
e
crylate
s
d T. Reetz,* Xiaoguang Li
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim/Ruhr, Germany
Fax +49(208)3062985; E-mail: reetz@mpi-muelheim.mpg.de
Received 28 September 2005
Dedicated to Professor Steven Ley on the occasion of his 60th birthday
enantioselectivities of 95–99% in the hydrogenation of
many different types of olefins seems to signal a change
in paradigm regarding the long-held view that chelating
bidentate ligands are required. This suggests that novel ef-
Abstract: The asymmetric Rh-catalyzed hydrogenation of b,b-di-
substituted a-acetamido acrylates, which are notoriously difficult
substrates, is possible using readily available BINOL-derived
monodentate phosphites or phosphonites. Essentially quantitative
conversion and enantioselectivities of 95–97% ee are readily fects may be involved. Indeed, our recent mechanistic
achieved, making the process industrially viable.
study regarding Rh-catalyzed hydrogenation using phos-
phites 1 which includes kinetics, non-linear effects and
quantum mechanical calculations shows, inter alia, that
two P-ligands 1 are attached to Rh in the transition state,
and that an anti-Halpern system is operating.7
Key words: amino acids, asymmetric catalysis, hydrogenations,
rhodium, chiral auxiliaries
Asymmetric transition metal catalyzed hydrogenation of
olefins is well established.1 Although several thousand
chiral P-ligands have been prepared and tested for this
purpose, the number of truly practical catalyst systems is
actually limited. Two reasons can be advanced for con-
tinuing research in such a mature area. Firstly, for a broad-
er industrial application, readily accessible ligands based
on cheap chiral auxiliaries are desirable while maintaining
or even increasing enantioselectivity and/or activity.2 Sec-
ondly, new effects and phenomena can be discovered,
which is important in basic research. Ideally, a given new
asymmetric catalyst system combines these two features.
On the practical side, compounds 1–3 are modular. This is
of great advantage when hydrogenating those olefins
which are not converted with the desired degree of enan-
tioselectivity, because new derivatives are readily acces-
sible which may function better. This pertains especially
to the phosphites 1, because the alcohol component in the
synthesis, ROH, can be varied with almost no limit. Thus,
if the ee in the hydrogenation of a given olefin is poor
when using ‘standard’ phosphites 1, new analogues for
testing are easily prepared.3,8 Finally, the concept of using
mixtures of two different monodentate P-ligands leads to
high catalyst diversity without the need to prepare new
ligands. In other words once a collection of such ligands
has been prepared, the process of mixing provides struc-
turally new catalysts (hetero-combinations) which often
display higher activity and dramatically enhanced enan-
tioselectivities.9 The underlying reason for these novel
effects remain to be revealed.
The independent discovery in the year 2000 by three
groups concerning the use of BINOL-derived phosphites
1,3 phosphonites 2,4,5 and phosphoramidites 36 (Figure 1)
as ligands in Rh-catalyzed olefin-hydrogenation appears
to constitute such a case. BINOL is currently one of the
cheapest chiral auxiliaries available. Moreover, the obser-
vation that these monodentate P-ligands often lead to
O
O
O
R
P
R
P
OR
P
O
O
O
a) R = CH
b) R = CH2Ph
c) R = CH2C(CH3)3
d) R = CH(CH3)2
e) R = c-C6H11
a) R = CH
a) R = N(CH )
3
1
2
3
3
3 2
b) R = CH(CH3)2
c) R = c-C6H11
d) R = Ph
b) R =
c) R =
N
e) R = C(CH3)3
f) R = CH2CH(CH2CH3)2
HN
Ph
Figure 1
SYNTHESIS 2005, No. 19, pp 3183–3185
x
x.
x
x
.
2
0
0
5
Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918460; Art ID: C08905SS
© Georg Thieme Verlag Stuttgart · New York

3184
M. T. Reetz, X. Li
SHORT PAPER
We have previously shown that compounds 1 or 2 (or As shown in Table 1, enantioselectivity varies between
mixtures thereof) are ideally suited as ligands in the Rh- 4% and 96% ee depending upon the nature of the substit-
catalyzed hydrogenation of various a-acetamido acry- uent at phosphorus. In the phosphite series 1a–f, the best
lates.3 However, b,b-disubstituted derivatives, which are ligand is the neopentyl derivative 1c, which leads to an ee
known to be ‘difficult’ substrates because hydrogenation of 96.4% (Table 1, entry 3). Other phosphites such as 1a,
is notoriously slow and only a few bidentate ligands lead 1b, and 1f are considerably less effective (entries 1, 2, 6).
to ee values higher than 90%,10 were not tested thus far us- Among the phosphonites 2a–d, only the methyl derivative
ing our ligands. In the present study we report that appro- 2a leads to an acceptable enantioselectivity (ee = 94%;
priate BINOL-derived monodentate P-ligands are in fact Table 1, entry 7). Although only three phosphoramidites
ideal ligands in the Rh-catalyzed hydrogenation of such 3a–c were tested, none of them turned out to be effective
olefins, equaling and sometimes surpassing the most ligands under the conditions used (Table 1, entries 12–
enantioselective ligands previously described in the liter- 14).
ature.10 Since the BINOL-derived ligands are cheap, the
methodology which we describe is industrially viable.
Rather than optimizing the system further, we turned to
two other notoriously difficult substrates, namely 6 and 8.
In exploratory experiments, we studied the hydrogenation As shown in Table 2, excellent results were obtained once
of the tetra-substituted olefin 4 using ligands 1–3 in more.
CH2Cl2. As delineated above, Rh-catalyzed hydrogena-
tion of olefins of this type proceeds sluggishly with any
previous10 or present ligand, and the Rh/4 ratio was there-
fore adjusted to 1:50. Several solvents were tested,
CH2Cl2 or a mixture of CH2Cl2 and toluene being well-
suited. MeOH and acetone each led to poor results.
Table 2 Rh-Catalyzed Asymmetric Hydrogenation of Olefins 6 and
8a
CO2CH3
NHAc
CO2CH3
NHAc
6
8
7
9
Table 1 Rh-Catalyzed Asymmetric Hydrogenation of Olefin 4a
CO2CH3
NHAc
CO2CH3
NHAc
H3C
CO2CH3
H3C
CO2CH3
H3C
NHAc
H3C
NHAc
4
5
Entry
1
Ligand
1a
Conversion (%)
ee (%)
59.4
86.8
96.4
93.0
94.4
93.4
94.0
74.4
17.2
14.2
44.8
3.8
Entry Olefin
Ligand
1c
Conversion (%)
ee (%)
93.4
94.4
95.8
96.8
93.2
95.2
1b
2b
3
6
6
6
6
8
8
100
100
100
100
100
100
90
100
100
98
2
1b
1c
2a
3
1c
4
1d
1e
4
2a
5
100
100
100
78
5
1c
6
1f
6
2a
7
2a
a Reaction conditions: 60 bar H2; 30 °C, 20 h; toluene and CH2Cl2
(3:1); [Rh(COD)2]BF4:ligand = 1:2; substrate:Rh = 50:1. (R)-Ligand
leads to (S)-product.
8
2b
2c
9
5
b CH2Cl2 as solvent.
10
11
12
13
14b
2d
2e
22
100
44
In summary, BINOL-derived monophosphites 1 and
phosphonites 2 are cheap compounds, which are superbly
suited as chiral ligands in the Rh-catalyzed asymmetric
hydrogenation of b,b-disubstituted a-acetamido acrylates.
These substrates are known to pose problems, and only
few ligands are known to deliver high enantioselectivity
(ee > 90%)10 which, however, require multistep syntheses.
Since the present ligands are unusually cheap, the process
constitutes an industrially viable approach to the asym-
metric synthesis of a variety natural and unnatural a-ami-
no acids. Further optimization, if necessary, may be
possible by using mixtures of appropriate monodentate P-
ligands.9
3a
3b
3c
4
27.0
45.6
85
a Reaction conditions: 60 bar H2, 30 °C, 20 h; toluene and CH2Cl2
(3:1) as solvent mixture; [Rh(COD)2]BF4:ligand = 1:2; substrate:Rh =
50:1. R-Ligand leads to (S)-5.
b (S)-BINOL is used.
Synthesis 2005, No. 19, 3183–3185 © Thieme Stuttgart · New York

SHORT PAPER
Asymmetric Hydrogenation of b,b-Disubstituted a-Acetamido Acrylates
3185
A. J.; Mehler, G.; Reetz, M. T.; de Vries, J. G.; Feringa, B.
L. J. Org. Chem. 2005, 70, 943. (d) Reetz, M. T.; Ma, J.-A.;
Goddard, R. Angew. Chem. Int. Ed. 2005, 44, 412; Angew.
Chem. 2005, 117, 416.
General Procedure
Eight dry 10-mL glass vials were placed in an autoclave, vacuum
was applied and the vials were purged three times with Ar. Then un-
der an atmosphere of Ar, the vials were charged with a 4.0 mM so-
lution of ligand (1.0 mL) and a 4.0 mM solution of [Rh(cod)2]BF4
(0.5 mL) in anhydrous CH2Cl2. The reaction mixture was stirred at
r.t. for 5 min and substrate 4 (or 6, 8) (0.10 mmol) in toluene (4.5
mL) was added. After purging with H2 three times, the autoclave
was pressurized with H2 to 60 bar and the reactions were magneti-
cally stirred at r.t. for 20 h. 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 abso-
lute configuration was determined by comparison with known com-
pounds described in the literature.
(7) Reetz, M. T.; Meiswinkel, A.; Mehler, G.; Angermund, K.;
Graf, M.; Thiel, W.; Mynott, R.; Blackmond, D. G. J. Am.
Chem. Soc. 2005, 127, 10305.
(8) Further examples and other types of monodentate P-ligands:
(a) Junge, K.; Hagemann, B.; Enthaler, S.; Oehme, G.;
Michalik, M.; Monsees, A.; Riermeier, T.; Dingerdissen, U.;
Beller, M. Angew. Chem. Int. Ed. 2004, 43, 5066; Angew.
Chem. 2004, 116, 5176. (b) Komarov, I. V.; Börner, A.
Angew. Chem. Int. Ed. 2001, 40, 1197; Angew. Chem. 2001,
113, 1237. (c) Ostermeier, M.; Prieß, J.; Helmchen, G.
Angew. Chem. Int. Ed. 2002, 41, 612; Angew. Chem. 2002,
114, 625. (d) Chi, Y.; Zhang, X. Tetrahedron Lett. 2002, 43,
4849. (e) Chen, W.; Xiao, J. Tetrahedron Lett. 2001, 42,
8737. (f) Huang, H.; Zheng, Z.; Luo, H.; Bai, C.; Hu, X.;
Chen, H. J. Org. Chem. 2004, 69, 2355. (g) Hu, A.-G.; Fu,
Y.; Xie, J.-H.; Zhou, H.; Wang, L.-X.; Zhou, Q.-L. Angew.
Chem. Int. Ed. 2002, 41, 2348; Angew. Chem. 2002, 114,
2454. (h) Pakulski, Z.; Demchuk, O. M.; Frelek, J.;
Luboradzki, R.; Pietrusiewicz, K. M. Eur. J. Org. Chem.
2004, 3913. (i) Jerphagnon, T.; Renaud, J.-L.; Bruneau, C.
Tetrahedron: Asymmetry 2004, 15, 2101. (j) Lagasse, F.;
Kagan, H. B. Chem. Pharm. Bull. 2000, 48, 315. (k)Ansell,
J.; Wills, M. Chem. Soc. Rev. 2002, 31, 259.
(9) (a) Reetz, M. T.; Sell, T.; Meiswinkel, A.; Mehler, G.
Angew. Chem. Int. Ed. 2003, 42, 790; Angew. Chem. 2003,
115, 814. (b) Reetz, M. T.; Li, X. Tetrahedron 2004, 60,
9709. (c) Reetz, M. T.; Mehler, G.; Meiswinkel, A.; Sell, T.
Tetrahedron: Asymmetry 2004, 15, 2165. (d) Reetz, M. T.;
Li, X. Angew. Chem. Int. Ed. 2005, 44, 2959; Angew. Chem.
2005, 117, 3019. (e) Reetz, M. T.; Sell, T.; Meiswinkel, A.;
Mehler, G. Pat. Appl., DE-A 10247633.0, 2002; Chem.
Abstr. 2004, 140, 381359. (f) See also: Peña, D.; Minnaard,
A. J.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G.;
Feringa, B. L. Org. Biomol. Chem. 2003, 1, 1087.
Acknowledgment
We thank the Fonds der Chemischen Industrie for generous support.
References
(1) (a) Knowles, W. S. Angew. Chem. Int. Ed. 2002, 41, 1998;
Angew. Chem. 2002, 114, 2096. (b) Noyori, R. Angew.
Chem. Int. Ed. 2002, 41, 2008; Angew. Chem. 2002, 114,
2108.
(2) Blaser, H. U.; Spindler, F.; Studer, M. Appl. Catal. A: Gen.
2001, 221, 119.
(3) (a) Reetz, M. T.; Mehler, G. Angew. Chem. Int. Ed. 2000, 39,
3889; Angew. Chem. 2000, 112, 4047. (b) Reetz, M. T.;
Mehler, G.; Meiswinkel, A.; Sell, T. Tetrahedron Lett. 2002,
43, 7941. (c) Reetz, M. T.; Goossen, L. J.; Meiswinkel, A.;
Paetzold, J.; Feldthusen Jensen, J. Org. Lett. 2003, 5, 3099.
(d) Reetz, M. T. In Perspectives in Organometallic
Chemistry; Screttas, C. G.; Steele, B. R., Eds.; Royal Society
of Chemistry: Cambridge, 2003, 265–274. (e) Reetz, M. T.;
Bondarev, O. G.; Gais, H.-J.; Bolm, C. Tetrahedron Lett.
2005, 46, 5643. (f) Reetz, M. T.; Mehler, G.; Meiswinkel, A.
Pat. Appl., DE-A 10027505.2, 2000; Chem. Abstr. 2002,
136, 20159.
(4) Reetz, M. T.; Sell, T. Tetrahedron Lett. 2000, 41, 6333.
(5) Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D.
J.; Martorell, A.; Orpen, A. G.; Pringle, P. G. Chem.
Commun. 2000, 961.
(6) (a) van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van
Esch, J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. J.
Am. Chem. Soc. 2000, 122, 11539. (b) Minnaard, A. J.; van
den Berg, M.; Schudde, E. P.; van Esch, J.; de Vries, A. H.
M.; de Vries, J. G.; Feringa, B. L. Chim. Oggi 2001, 19, 12.
(c) Bernsmann, H.; van den Berg, M.; Hoen, R.; Minnaard,
(10) (a) Burk, M. J.; Gross, M. F.; Martinez, J. P. J. Am. Chem.
Soc. 1995, 117, 9375. (b) Sawamura, M.; Kuwano, R.; Ito,
Y. J. Am. Chem. Soc. 1995, 117, 9602. (c) Imamoto, T.;
Watanabe, J.; Wada, Y.; Masuda, H.; Yamada, H.; Tsuruta,
H.; Matsukawa, S.; Yamaguchi, K. J. Am. Chem. Soc. 1998,
120, 1635. (d) Ohashi, A.; Kikuchi, S.-I.; Yasutake, M.;
Imamoto, T. Eur. J. Org. Chem. 2002, 2535. (e) Evans, D.
A.; Michael, F. E.; Tedrow, J. S.; Campos, K. R. J. Am.
Chem. Soc. 2003, 125, 3534. (f) Hoge, G.; Wu, H.-P.;
Kissel, W. S.; Pflum, D. A.; Greene, D. J.; Bao, J. J. Am.
Chem. Soc. 2004, 126, 5966.
Synthesis 2005, No. 19, 3183–3185 © Thieme Stuttgart · New York