backbone. Transition-metal complexes of these ligands afford
excellent results in asymmetric hydrogenation reactions.
Scheme 1. Synthesis of BoPhoz Ligands 2
The design of effective nonsymmetrical chiral ligands such
as phosphine-aminophosphines is challenging, as these
species lack the stereochemical redundancy implicit in their
2
C -symmetrical cousins. For this reason, the ferrocenylethyl
scaffold, which has a rich history of affording effective
nonsymmetrical ligands such as the BPPFA7 and the
6
8
Josiphos systems, was chosen to provide a large three-
dimensional steric shield to help enforce the ligand stereo-
selectivity. In addition, the simple preparation of single
9
enantiomer N,N-dimethyl-1-ferrocenylethylamine, its ready
tion of either the amine or the chlorophosphine allows ready
optimization of the electronic and steric properties of the
ligands.
7
one-step conversion to phosphine 3, and the transformation
of the dimethylamino substituent of these R-ferrocenylethyl
systems into a variety of other functionalities with retention
of configuration10 allows the necessary functional group
transformations required for our systems. Thus, our ligand
synthesis involved the transformation of the dimethylamino
species of monophosphine 3 into a variety of secondary
amines that could then be converted to the desired amino-
phosphines. This strategy was accomplished as shown in
Scheme 1 through the intermediacy of acetate 4, prepared
Unlike many phosphines, the BoPhoz ligands display
outstanding air stability: Ligand 2b held at ambient tem-
perature open to the air for more than 1 year retained
complete activity and enantioselectivity for asymmetric
hydrogenation reactions, even at very low (10000:1 substrate/
catalyst) loadings. This stability serves to enhance the
practical appeal of these species, as it allows the use of
nondegassed solvents and reaction mixtures for asymmetric
hydrogenation screening reactions using 2b complexed to
rhodium as the catalyst.
These ligands were first examined in asymmetric hydro-
genation reactions of a variety of dehydro-R-amino acid
derivatives. The reactions were performed, often in a
screening protocol in high-throughput fashion, by in situ
preparation of the ligand-metal complex from the desired
ligand and bis(1,5-cyclooctadiene)rhodium(I) trifluoromethane-
sulfonate followed by substrate introduction and hydrogena-
tion. The results of reactions using the rhodium complex of
7
by reaction of 3 with acetic anhydride. Reaction of 4 with
a variety of primary amines led to the secondary amines 5.
Coupling of the amino substituent with the desired chloro-
phosphine afforded ligands 2.11 Thus, a series of simple
transformations involving no pyrophoric or even air-sensitive
intermediates led to the desired ligands in expedient fashion.
Indeed, the facile nature of the reactions (innocuous and
inexpensive reagents, no low temperature or pyrophoric
chemistry, and high yields) results in eminently practical
ligands that are readily scaled up (>100 g of ligand 2b was
prepared within a few months of its discovery), an elusive
goal that has generally hampered the wider use of asymmetric
catalysis in industrial settings. In addition, simple modifica-
2
with a variety of dehydro-R-amino acid substrates at low
hydrogen pressure (10 psig) are shown in Table 1. Entries
-7 indicate that the N-methyl ligand 2b provides excellent
1
enantioselectivity regardless of the distal, amino, or carboxyl
substitutents. Thus, a wide range of highly enantiopure
R-amino acids with a variety of desired protection strategies
(
5) Due to the rather lengthy systematic names for these compounds (e.g.,
the chemical name for 2b is R-N-methyl-N-diphenylphosphino-1-[S-2-
diphenylphosphino)ferrocenyl]ethylamine), we have given the core structure
(
the trivial name “BoPhoz”. BoPhoz is a trademark of Eastman Chemical
Co.
(Boc, Cbz, acetamide, ester, acid) can be readily obtained
(
6) Richards, C. J.; Locke, A. J. Tetrahedron: Asymmetry 1998, 9, 2377-
407.
7) Hayashi, T.; Mise, T.; Fukushima, M.; Kagotani, M.; Nagashima,
through the use of this ligand. The high enantioselectivities
with the highly desirable Boc and Cbz groups are particularly
noteworthy, as the performance of some ligands suffers in
these cases. The viability of the parent carboxylic acid
substrates with ligand 2b was unexpected, as cleavage of
the nitrogen-phosphorus bond might have been anticipated.
2
(
N.; Hamada, Y.; Matsumoto, A.; Kawakami, S.; Konishi, M.; Yamamoto,
K.; Kumada, M. Bull. Chem. Soc. Jpn. 1980, 53, 1138-1151.
12
(8) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.; Tijani,
A. J. Am. Chem. Soc. 1994, 116, 4062-4066.
(
9) (a) Gokel, G. W.; Ugi, I. K. J. Chem. Ed. 1972, 49, 294-296. (b)
Boaz, N. W. Tetrahedron Lett. 1989, 30, 2061-2064. (c) Brieden, W. U.S.
Patent 5,760,264, 1998.
(
10) Gokel, G. W.; Marquarding, D.; Ugi, I. K. J. Org. Chem. 1972, 37,
052-3058.
11) The same sequence using the opposite enantiomer of 3 afforded
the enantiomeric ligands to 2.
(12) (a) Kreuzfeld, H.-J.; D o¨ bler, C.; Krause, H. W.; Facklam, C.
Tetrahedron: Asymmetry 1993, 4, 2047-2051. (b) Ojima, I.; Yoda, N.;
Yatabe, M.; Tanaka, T.; Kogure, T. Tetrahedron 1984, 40, 1255-1268.
(c) Achiwa, K. Chem. Lett. 1977, 777-778.
3
(
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