Catechol-based phosphoramidites: A new class of chiral ligands for rhodium-catalyzed asymmetric hydrogenations

Article abstract of DOI:10.1021/ol049726g

The synthesis and application of a new class of catechol-based phosphoramidites is described. Ees up to 99% were obtained in the rhodium-catalyzed asymmetric hydrogenation of dehydroamino acids and enamides.

Full text of DOI:10.1021/ol049726g

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1433-1436
Catechol-Based Phosphoramidites:
A New Class of Chiral Ligands for
Rhodium-Catalyzed Asymmetric
Hydrogenations
Rob Hoen, Michel van den Berg, Heiko Bernsmann, Adriaan J. Minnaard,*
Johannes G. de Vries, and Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute,
UniVersity of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
b.l.feringa@chem.rug.nl
Received February 16, 2004
ABSTRACT
The synthesis and application of a new class of catechol-based phosphoramidites is described. Ees up to 99% were obtained in the rhodium-
catalyzed asymmetric hydrogenation of dehydroamino acids and enamides.
Rhodium-catalyzed asymmetric hydrogenation of enamides
is a key method for synthesizing enantiomerically pure amino
acids and amines.1 The majority of successful ligands used
in this reaction are bidentate in nature,2 e.g., DUPHOS (1,2-
Bis(-2,5-dimethylphospholano)benzene),3 DiPAMP (1,2-
ethanediylbis[(o-methoxyphenyl)-phenyl-phosphine]),4 DIOP
(2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphos-
phino)butane),5 BINAP (2,2′-bis(diphenylphosphino)-1,1′-
binaphthyl),6 PennPhos (P,P′-1,2-phenylenebis(endo-2,5-
dialkyl-7-phosphabicyclo-[2.2.1]heptane),7 and ferrocenyl-
based ligands.8 With the exception of CAMP (o-anisyl-
methylcyclohexylphosphine),9 limited success was obtained
with monodentate ligands.1c These ligands were considered
not particularly effective since they lack the possibility to
form chelating complexes with the metal. After nearly 30
years of asymmetric hydrogenation, it was unequivocally
demonstrated in 2000 that bidentate chiral ligands are not a
conditio sine qua non to reach high enantioselectivities. Three
groups showed that monodentate phosphonites,10a phosphites,10b
and phosphoramidites10c can be applied successfully as chiral
ligands in rhodium-catalyzed asymmetric hydrogenation
providing excellent enantioselectivities (Figure 1). A major
advantage of these monodentate ligands is that they can be
(1) For reviews see: (a) Chaloner, P. A.; Esteruelas, M. A.; Joo´, F.;
Oro, L. A. Homogeneous Hydrogenation; Kluwer: Dordrecht, 1994. (b)
Brown, J. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 1, Chapter
5.1. (c) Lagasse, F.; Kagan, H. B. Chem. Pharm. Bull. 2000, 48, 315.
(2) For a review, see: Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
(3) Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8515.
(7) (a) Jiang, Q.; Jiang, Y.; Xiao, D.; Cao, P.; Zhang, X. Angew. Chem.,
Int. Ed. 1998, 37, 1100. (b) Zhang, Z.; Zhy, G.; Jiang, Q.; Xiao, D.; Zhang,
X. J. Org. Chem. 1999, 64, 1774.
(8) JosiPhos: Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert,
H.; Tijani, A. J. Am. Chem. Soc. 1994, 116, 4062. FerroPhos: Kang, J.;
Lee, J. H.; Ahn, S. H.; Choi, J. S. Tetrahedron Lett. 1998, 39, 5523.
(9) Knowles, W. S.; Sabacky, M. J.; Vineyard, B. D. Chem. Commun.
1972, 10.
(4) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.;
Weinkauff, D. J. J. Am. Chem. Soc. 1977, 99, 5946.
(5) (a) Dang, T.-P.; Kagan, H. B. Chem. Commun. 1971, 481. (b) Kagan,
H. B.; Dang, T.-P. J. Am. Chem. Soc. 1972, 94, 6429.
(6) (a) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.;
Souchi, T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932. (b) Takaya, H.;
Akutagawa, S.; Noyori, R. Org. Synth. 1988, 67, 20.
(10) (a) Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D. J.;
Martorell, A.; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 961 (b)
Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889 (c) 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.
10.1021/ol049726g CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/01/2004

Figure 1. Monodentate phosphonites, phosphites, and phosphora-
midites.
prepared in one or two steps at low costs, which makes
variations very easy.
All successful monodentate ligands recently introduced
consist of a chiral diol backbone, with another chiral or
achiral moiety attached to phosphorus.11 The chirality of the
backbone dictates, in nearly all cases, the chirality of the
product.10b The chirality of the other moiety at phosphorus
is found to be less important. It is illustrative that one of the
most effective monodentate ligands for hydrogenation reac-
tions, the commercially available12 phosphoramidite Mono-
Phos (3), has, besides the chiral BINOL part, an achiral N,N-
dimethylamine moiety. A few reports on alternative ligands
using chiral backbones such as biphenyls or spiro compounds
have appeared.13
We now describe a new class of monodentate phosphora-
midites for the rhodium-catalyzed asymmetric hydrogenation
of enamides, based on an achiral catechol backbone. In this
case, the chirality of the products must be dictated solely by
the chirality of the amine moiety. Not only is the chiral
moiety the amine instead of the diol but also the bulkiness
Figure 2. Catechol-based phosphoramidites.
of the diol backbone is reduced, as a planar catechol is
present whereas the size of the amine moiety is increased
compared to MonoPhos (3). From earlier results it was
evident that, in the case of BINOL-derived phosphoramidites,
a small amine moiety is favored for the hydrogenation of
dehydroamino acids.10c,11c
The synthesis of the ligands is straightforward, starting
with the commercially available o-phenylene phosphoro-
chloridite (4) and an appropriate amine. A variety of easily
accessible chiral amines, based on 1-phenyl ethylamine, were
used in the preparation of ligands L1-6 (Figure 2). The
cyclic analogue L7 of ligand L1 was obtained from the
corresponding chiral amine.14 For comparison, bidentate
ligands L8 and L9 were also examined.
(11) (a) Komarov, I. V.; Bo¨rner, A. Angew. Chem., Int. Ed. 2001, 40,
1197. (b) Reetz, M. T.; Mehler, G.; Meiswinkel, A.; Sell, T. Tetrahedron
Lett. 2002, 43, 7941. (c) Jia, X.; Li, X.; Xu, L.; Shi, Q.; Yao, X.; Chan, A.
S. C. J. Org. Chem. 2003, 68, 4539. (d) Reetz, M. T.; Sell, T.; Meiswinkel,
A.; Mehler, G. Angew. Chem., Int. Ed. 2003, 42, 790. (e) van den Berg,
M.; Minnaard, A. J.; Haak, R. M.; Leeman, M.; Schudde, E. P.; Meetsma,
A.; Feringa, B. L.; de Vries, A. H. M.; Maljaars, C. E. P.; Willans, C. E.;
Hyett, D.; Boogers, J. A. F.; Henderickx, H. J. W.; de Vries, J. G. AdV.
Synth. Catal. 2003, 345, 308. (f) Li, X.; Jia, X.; Lu, G.; Au-Yeung, T.
T.-L.; Lam, K.-H.; Lo, T. W. H.; Chan, A. S. C. Tetrahedron: Asymmetry
2003, 14, 2687. (g) Jia, X.; Guo, R.; Li, X.; Yao, X.; Chan, A. S. C.
Tetrahedron Lett. 2002, 43, 5541. (h) Chen, W.; Xiao, J. Tetrahedron Lett.
2001, 42, 2897. (i) Junge, K.; Oehme, G.; Monsees, A.; Riermeier, T.;
Dingerdissen, U.; Beller, M. Tetrahedron Lett. 2002, 43, 4977. (j) Pen˜a,
D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2002,
124, 14552. (k) Pen˜a, D.; Minnaard, A. J.; de Vries, A. H. M.; de Vries, J.
G.; Feringa, B. L. Org. Lett. 2003, 5, 475. (l) Doherty, S.; Robins, E. G.;
Pa´l, I.; Newman, C. R.; Hardacre, C.; Rooney, D.; Mooney, D. A.
Tetrahedron: Asymmetry 2003, 14, 1517. (m) Junge, K.; Oehme, G.;
Monsees, A.; Riermeier, T.; Dingerdissen, U.; Beller, M. J. Organomet.
Chem. 2003, 675, 91. (n) Reetz, M. T.; Mehler, G. Tetrahedron Lett. 2003,
44, 4593. (o) Reetz, M. T.; Goossen, L. J.; Meiswinkel, A.; Paetzold, J.;
Jensen, J. F. Org. Lett. 2003, 5, 3099. (p) Pen˜a, 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. (q) Ostermeier, M.; Brunner, B.; Korff, C.; Helmchen,
G. Eur. J. Org. Chem. 2003, 3453. (r) Van den Berg, M.; Haak, R. M.;
Minnaard, A. J.; De Vries, A. H. M.; De Vries, J. G.; Feringa, B. L. AdV.
Synth. Catal. 2002, 344, 1003.
As a benchmark reaction, the ligands were tested in the
rhodium-catalyzed asymmetric hydrogenation of N-acyl
dehydrophenylalanine methyl ester (5) under standard condi-
tions.15 The results are depicted in Table 1.
The catalysts based on ligands L2-6 gave modest to full
conversions, while the ligand L1, based on a sterically
demanding amine, surprisingly gave no conversion at all.
The enantiomeric excesses are disappointing in all cases
(entries 1-6). In sharp contrast, however, is the excellent
yield and enantioselectivity of >92% reached with ligand
L7 (entry 7). Although L1 and L7 have a similar kind of
structure, a remarkable difference in activity was observed
by introduction of a ring structure in the ligand. The bidentate
ligands L8 and L9 gave full conversion but rather poor ees,
although a longer spacer in the ligand resulted in a slightly
higher ee (entries 8 and 9, Table 1).
To expand the scope of the catalytic hydrogenation
employing L7, several substrates were tested. As shown in
(12) MonoPhos (3) is commercially available from Strem chemicals.
(13) (a) Chen, W.; Xiao, J. Tetrahedron Lett. 2001, 42, 8737. (b) Fu,
Y.; Xie, J.-H.; Hu, A.-G.; Zhou, H.; Wang, L.-X.; Zhou, Q.-L. Chem.
Commun. 2002, 480. (c) Hu, A.-G.; Fu Y.; Xie, J.-H.; Zhou, H. Wang,
L-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2002, 41, 2348. (d) Hannen,
P.; Militzer, H.-C.; Vogl, E. M.; Rampf, F. A. Chem. Commun. 2003, 2210.
(e) Hua, Z.; Vassar, V. C.; Ojima, I. Org. Lett. 2003, 5, 3831.
(14) Aldous, D. J.; Dutton, W. M.; Steel, P. G. Tetrahedron: Asymmetry
2000, 11, 2455.
(15) Standard conditions are 0.2 mmol of substrate, 1 mol % catalyst
(L:Rh ) 2:1) in 4 mL of CH2Cl2 at rt and 5 bar of H2 pressure.
1434
Org. Lett., Vol. 6, No. 9, 2004

Table 1. Asymmetric Hydrogenation of N-Acyl
Dehydrophenylalanine Methyl Ester (5) Catalyzed by
Rh-Phosphoramidite Ligand Systems Derived from Catechol
Table 3. Asymmetric Hydrogenation of Enamides by
Rh-Phosphoramidite L7 Catalysta
entry
ligand
conversiona,b
eec
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L8
L9
0
60
45
100
60
90
100
100
100
<3
<3
<3
<3
<3
92d
5d
32d
a Reactions performed under standard conditions.15 b Conversions
1
determined by H NMR; besides product and/or starting material, no side
products were observed. c Ee determined by CSP GC (CP Chiralsil-L-Val).
eeb-e
CH2Cl2
5 bar
eeb-e
CH2Cl2
25 bar
eeb-e
d Product has the (R)-configuration, except when L8 is used.
EtOAc
25 bar
entry
substrate
product
Table 2, other R-amino acid precursors gave full conversions
with modest ees (entries 1 and 2). With full conversions,
isolated yields (Tables 2 and 3) are 99% after filtration. In
contrast, â-amino acid precursor 9 gave no conversion at all
1
2
3
4
5
6
7
8
9
17
18
19
20
10
11
21
22g
23
24
25
26
27f
28
29
15
16
16
16
30
31
32
63
92
95
97
89
99
90
92
70
93
94
97
89
>99
88
93
20 (6)
35 (95)
9 (38)
26
96.5
97
97
94
>99
80
84
<3 (14)
27
Table 2. Asymmetric Hydrogenation of a Variety of Alkenes
Catalyzed by Rh-Phosphoramidite (L7) Catalyst
9 (3.5)
35 (48)
4 (14)
10
11
35 (40)
a Reactions performed in 4 mL of solvent with 0.2 mmol of substrate
and 1 mol % catalyst at rt under a H2 atmosphere for 16 h. b Conversions
1
determined by H NMR; besides product and/or starting material, no side
products were observed. c Ees determined by CSP GC (CP Chiralsil-Dex
CB). d Conversions are given in parentheses if reactions were not run to
completion. e In all cases, the (R)-enantiomer was obtained, except for
products 30 and 31. f Isolated yield for 27 was >99%. g Mixture with a
3:2 ratio of (E)- and (Z)-alkene was used.
in CH2Cl2 (entry 3). When the reaction was performed in
i-PrOH, 80% ee was obtained at 40% conversion (entry 4).
In earlier studies,11j it was shown that i-PrOH is the best
solvent for the Rh-phosphoramidite catalyst system in the
hydrogenation of â-amino acid precursors with a Z-config-
uration. Elimination of the internal hydrogen bond by i-PrOH
has been postulated as the origin of this change in reactivity.16
Enamides 10 and 11 gave full conversion, and the ees were
good to excellent (entries 5 and 6).
This initial study revealed that L7 is comparable to
MonoPhos (3) with respect to selectivity in the hydrogenation
of R-amino acid precursors. In the hydrogenation of enam-
ides, however, higher enantioselectivities are observed with
a remarkable 99% ee for the hydrogenation of 11.10c,11r
entry
substrate
product
conversiona,b
eec,d
1
2
3
4e
5
7
8
9
9
10
11
12
13
14
14
15
16
100
100 (>99)
0
89
66
40
80
89
99
100 (>98)
100 (>99)
6
a Reactions performed under standard conditions.15 b Conversions
1
determined by H NMR. Besides product and/or starting material, no side
products were observed; isolated yields are given in parentheses. c Ees
determined by CSP GC or HPLC (CP Chiralsil-L-Val, CP Chiralsil-Dex
CB, Chiralcel OD). d All products had the (R)-configuration. e Reaction was
performed in i-PrOH.
(16) (a) Lee, S.-g.; Zhang, Y. J. Org. Lett. 2002, 4, 2429 (b) Lubell, W.
D.; Kitamura, M.; Noyori, R. Tetrahedron: Asymmetry 1991, 2, 543.
Org. Lett., Vol. 6, No. 9, 2004
1435

With these results in hand we decided to screen a series
of enamides in two solvents at 5 and 25 bar of H2 pressure
to examine the scope of the asymmetric hydrogenation. The
substrates were synthesized using the methods of Zhang7b
and Burk.17
An increase in the pressure to 25 bar had no influence on
the enantioselectivity, although the conversion did increase.19
Only in the case of the tetrasubstituted alkene and the bicyclic
systems derived from â-tetralone did the ee increase (entries
9 and 11).
With the exception of 23, containing a tetrasubstituted
alkene, and the bicyclic systems 24 and 25 (Table 3, entries
9-11, column 4), all substrates gave full conversion. The
enantioselectivity is lower when R1 is an alkyl group instead
of an aryl group (compare entries 1 and 2, column 4). This
can be due to an increase of steric hindrance, although this
seems to be a common feature of this catalytic system, since
similar results were also observed in the hydrogenation of
the R-amino acid precursors (compare entry 7, Table 1, and
entry 2, Table 2). Favorable π-π interactions between the
aromatic moiety of the substrate and the ligand might be
another reason for this observation. Different substituents
on the aromatic ring seem to have hardly any influence on
the enantioselectivity (entries 2-5, column 4). Trisubstituted
alkenes gave good to excellent enantioselectivities. The best
results were obtained with enamides with a Z-configuration
(entries 6 and 7, column 4), while an E/Z mixture gave the
calculated average of the enantioselectivities for both isomers
(entry 8, column 4). Tetrasubstituted alkenes and bicyclic
systems are not suitable substrates for this new catalytic
system. Low conversions and moderate enantioselectivities
were obtained (entries 9-11, column 4). High enantiose-
lectivities for these substrates have been obtained with a
variety of bidentate phosphines.18 Reasonable enantioselec-
tivities for alkene 24 were obtained using MonoPhos (3) at
-20 °C.11g
The use of EtOAc as solvent resulted in higher enanti-
oselectivities for most of the substrates (Table 3, column
6). Surprisingly, the only exceptions are those with R1 is a
t-Bu group (entry 1) or when R3 is not a hydrogen (entries
7-10).
In conclusion, a new class of monodentate phosphora-
midites has been developed on the basis of an achiral catechol
backbone. Notable features are the excellent levels of
enantioselectivity and high conversions obtained in the
rhodium-catalyzed hydrogenation of enamides. These enan-
tioselectivities are the highest reached so far for monodentate
ligands with this class of substrates and are comparable to
those achieved using bidentate ligands.
Acknowledgment. We thank Mrs. T. D. Tiemersma-
Wegman, Dr. A. H. M. de Vries, Mr. A. Kiewiet, and Mr.
E. P. Schudde for the technical support. Financial support
from the NRSC-C is gratefully acknowledged.
Supporting Information Available: Experimental details
and chromatographic and spectroscopic data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL049726G
(18) Gridnev, I. D.; Yasutake, M.; Higashi, N.; Imamoto, T. J. Am. Chem.
Soc. 2001, 123, 5268.
(19) Reactions were run overnight, although in most cases reactions were
completed in 4 h at 5 bar and in 2 h at 25 bar of hydrogen pressure.
(17) Burk, M. J.; Casy, G.; Johnson, N. B. J. Org. Chem. 1998, 63, 6084.
1436
Org. Lett., Vol. 6, No. 9, 2004