A bisphosphepine ligand with stereogenic phosphorus centers for the practical synthesis of β-aryl-β-amino acids by asymmetric hydrogenation

Article abstract of DOI:10.1002/anie.200351465

Excellent enantioselectivities and reactivities were observed in the hydrogenation of a variety of methyl (Z)-β-aryl-β-(acetyl-amino)acrylates in the presence of a rhodium catalyst with the chiral ligand binapine (see scheme). This bisbinaphthophosphepine

Full text of DOI:10.1002/anie.200351465

Angewandte
Chemie
Asymmetric Hydrogenation
A Bisphosphepine Ligand with Stereogenic
Phosphorus Centers for the Practical Synthesis of
b-Aryl-b-Amino Acids by Asymmetric
Hydrogenation**
Wenjun Tang, Weimin Wang, Yongxiang Chi, and
Xumu Zhang*
Enantiomerically pure b-amino acids are important chiral
building blocks for the synthesis of b-peptides, b-lactam
antibiotics, and many other important chiral drugs.[1]
Although chiral b-amino acids have been synthesized through
several stoichiometric and catalytic methods,[2] an efficient
and practical synthetic method is still needed. The Rh-[3] or
Ru-catalyzed[4] asymmetric hydrogenation of b-(acylamino)-
acrylic acid derivatives to make chiral b-amino acids has
recently attracted much attention. Although many Rh[3] and
Ru[4a,c] complexes with chiral phosphane ligands exhibited
high enantioselectivities in the hydrogenation of b-alkyl-b-
(acylamino)acrylic acid derivatives, the asymmetric hydro-
genation of b-aryl-b-(acylamino)acrylic acid derivatives has
met with much less success. Heller and co-workers recently
reported that the use of a Rh–Et–ferrotane catalyst can give
rise to ee values of over 99% in the asymmetric hydro-
genation of a set of (E)-b-aryl-b-(acylamino)acrylic acid
derivatives.[3b] However, the preparation of (E)-b-aryl-b-
(acylamino)acrylic acid derivatives requires their separation
from the corresponding thermodynamically more stable
Z isomers, and low yields are generally observed.[3b] On the
other hand, (Z)-b-aryl-b-(acylamino)acrylic acid derivatives
can be preferentially formed over their E isomers under
suitable conditions, and high yields for the synthesis of
Z substrates are attainable.[4b] A highly enantioselective
asymmetric hydrogenation of (Z)-b-aryl-b-(acylamino)acrylic
acid derivatives would allow the practical synthesis of chiral
b-aryl-b-amino acids. In previous work we developed a set of
Ru–o-binapo complexes,[4b] which gave rise to ee values of up
to 99% in the asymmetric hydrogenation of (Z)-b-aryl-b-
(acylamino)acrylic acid derivatives.[5] However, the reactiv-
ities of the Ru complexes were moderate. A Rh–TangPhos
catalyst promoted both high enantioselectivities (up to
98.5% ee) and high reactivities in the hydrogenation of a
series of Z substrates, with the exception of those with ortho-
substituted b-aryl groups.[3e] Herein we present a new chiral
catalyst for the hydrogenation of (Z)-b-aryl-b-(acylamino)-
acrylic acid derivatives. The Rh complex of the chiral
bisphosphepine ligand 1 (abbreviated as (S,S,S)-binapine),
[*] Prof. X. Zhang, W. Tang, Dr. W. Wang, Dr. Y. Chi
Department of Chemistry, The Pennsylvania State University
University Park, PA 16802 (USA)
Fax: (+1)814-863-8403
E-mail: xumu@chem.psu.edu
[**] This workwas supported by the National Institute of Health.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 3509 –3511
DOI: 10.1002/anie.200351465
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3509

Communications
Table 1: Rh-catalyzed hydrogenation of methyl (E)- and (Z)-3-acetyl-
which has stereogenic phosphorus centers, promoted excel-
amino-2-butenoate with binapine and TangPhos ligands.[a]
lent enantioselectivities and reactivities in the asymmetric
hydrogenation of a wide range of (Z)-b-aryl-b-(acylamino)-
acrylic acid derivatives.
Ligand design has played a pivotal role in the develop-
ment of new efficient metal-catalyzed asymmetric reactions.
We recently reported an efficient chiral bisphospholane
ligand, TangPhos, with stereogenic P centers, for the asym-
metric hydrogenation of various functionalized olefins.[6] In
our ongoing efforts toward the development of efficient chiral
bisphosphane ligands, we have designed a more rigid chiral
bisbinaphthophosphepine ligand, binapine, for use in asym-
metric hydrogenation. The structure of ligand 1 not only
contains diaxial chirality but also has stereogenic P and
C centers. To our knowledge, no chiral bisbinaphthophosphe-
pine ligands with stereogenic P centers have been reported
previously.[7] The synthesis of ligand 1 is straightforward
(Scheme 1). Double metalation of enantiomerically pure (S)-
2,2’-dimethylbinaphthyl with nBuLi/TMEDA followed by
Ligand
Bite angle of
ee [%]
Rh complex [8][b] from E isomer from Z isomer
(S,S,R,R)-TangPhos 75.1
77.4
99.6
32.7
98.5
99.2
1
[a] The absolute configurations of the products were determined as R by
comparison of their optical rotation data with reported values. The
reactions were carried out at room temperature under H2 (20 psi
(138 kPa)) in THF for 24 h. Substrate/[Rh(ligand)nbd]SbF6 =100:1. The
ee values were determined by GC on a chiral phase (Chiralselect 1000
column). [b] Molecular simulations were performed on a CaChe model
with MM2 calculations; see Supporting Information for further details.
Rh–binapine catalyst led to superior enantioselectivity for the
hydrogenation of the Z substrate. However, a low ee value
was observed for the hydrogenation of the E isomer.
Molecular simulation on a CaChe model showed that the
Rh–binapine complex has a larger P–Rh–P angle (bite angle)
than the Rh–TangPhos complex. This difference leads to a
sterically more hindered chiral environment in the Rh–
binapine complex.
Many chiral b-aryl-b-amino acids are important inter-
mediates for drug synthesis.[9] As a series of (Z)-b-aryl-b-
(acylamino)acrylic acid derivatives can be obtained in mod-
erate to high yields through the amination of aryl b-keto
esters with NH4OAc, followed by acetylation with acetic
anhydride and pyridine at reflux (Scheme 2),[10] the highly
Scheme 1. Synthesis of ligand 1: a) 1) nBuLi, TMEDA, Et2O;
2) tBuPCl2, S, THF, 61%; b) tBuLi, TMEDA, HMPA/THF, CuCl2, 25%;
c) Si2Cl6, benzene, 90%. HMPA=hexamethyl phosphoramide,
TMEDA=N,N,N’,N’-tetramethylethylenediamine.
Scheme 2. Synthesis of methyl (Z)-b-aryl-b-(acetylamino)acrylates:
a) 1) NH4OAc, CH3OH; 2) Ac2O, pyridine, THF, reflux, 50–70% yield
of isolated products.
reaction with tBuPCl2 and sulfur provided the binaphtho-
phosphepine sulfide 2 in 61% yield.[7c,d] Deprotonation of 2
with tBuLi/TMEDA at À788C in HMPA/THF followed by
coupling mediated by CuCl2 yielded 3 as a single isomer in
25% yield, along with recovered starting material 2 (50%).
The absolute configuration of 3 was confirmed by its X-ray
crystallographic structure.[8] Desulfurization of 3 with hexa-
chlorodisilane[6a] in benzene provided ligand 1 in 90% yield.
In its solid state this electron-rich bisphosphane is remarkably
insensitive to air. No oxidation product was observed after
exposure of the ligand to air for several days. Both isomers of
binapine can be synthesized by this simple synthetic route.
Ligand 1 was then used in the Rh-catalyzed hydrogena-
tion of b-(acylamino)acrylic acids. The cationic Rh complex
[Rh(1)(nbd)]SbF6 (nbd = 3,5-norbornadiene) was prepared
and used directly for the hydrogenation of both the E and Z
enantioselective hydrogenation of (Z)-b-aryl-b-(acylamino)-
acrylic acid derivatives could provide a practical method for
the synthesis of chiral b-aryl-b-amino acids. We therefore
used binapine in the Rh-catalyzed asymmetric hydrogenation
of a series of methyl (Z)-b-aryl-b-(acetylamino)acrylates. As
shown in Table 2, a wide array of chiral b-aryl-b-amino acid
derivatives was obtained with ee values of over 99%, regard-
less of the electronic properties of the aryl group on the
substrate 4. Excellent enantioselectivities were also observed
in the hydrogenation of substrates with ortho-substituted b-
aryl groups (Table 2, entries 8 and 9), in contrast to the
moderate ee values observed when a Rh–TangPhos catalyst
was used.[3e] Excellent enantioselectivity was also observed in
the hydrogenation of a substrate containing a heteroaryl
group. In the presence of HBF4,[11] the hydrogenation of
methyl (Z)-b-(3-pyridyl)-b-(acetylamino)acrylate provided
isomers of methyl 3-acetamido-2-butenoate (Table 1). In the chiral b-(3-pyridyl)-b-amino acid derivative 5j with
contrast to the Rh–TangPhos catalyst, which promoted the 96% ee (Table 2, entry 10). 5j is a key component for the
formation of the hydrogenation products from both the E and
the Z substrates with high enantioselectivities, the use of the
synthesis of the GP IIb/IIIa antagonist RWJ-53308.[9b,c] To
further test the catalytic efficiency of the Rh–binapine
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Angewandte
Chemie
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(acetylamino)acrylates.[a]
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[5] As Heller et. al pointed out in reference [3b], the “E/Z isomeric
mixtures of b-aryl-b-(acylamino)acrylates” referred to in refer-
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(acylamino)acrylates and (Z)-diacetylated products. The authors
have corroborated the mischaracterization.
Entry
Ar (4)
ee [%] (5)
1
2
3
4
5
6
Ph (a)
p-F-Ph (b)
>99 (a)
>99 (b)
>99 (c)
99 (d)
>99 (e)
>99 (f)
>99 (g)
>99 (h)
99 (i)
p-Cl-Ph (c)
p-Br-Ph (d)
p-Me-Ph (e)
p-MeO-Ph (f)
p-BnO-Ph (g)
o-Me-Ph (h)
o-MeO-Ph (i)
3-pyridyl (j)
7[b]
8
9
10[c]
96 (j)
[a] The reactions were carried out at room temperature under H2 (20 psi
(138 kPa)) in THF for 24 h unless otherwise specified. Substrate/
[Rh(1)(nbd)]SbF6 =100:1. The absolute configurations of the products
were determined as S by comparison of their optical rotation data with
reported values. The ee values were determined by GC on a chiral phase
(Chiralselect 1000 column), unless otherwise specified. [b] The ee value
was determined by HPLC on a chiral phase ((S,S)-Whelk-01 column).
[c] The hydrogenation was conducted in MeOH in the presence of HBF4
(1.5 equiv) under H2 (20 psi (138 kPa)).
catalyst for the asymmetric hydrogenation of b-aryl-b-(ace-
tylamino)acrylates, substrate 4g was subjected to hydrogena-
tion in the presence of less [Rh(1)(nbd)]SbF6 catalyst
(0.1 mol%), and the chiral product 5g was obtained in
quantitative yield and with 99% ee.
In conclusion, we have developed a new chiral bisphos-
phepine ligand with stereogenic phosphorus centers for the
asymmetric hydrogenation of (Z)-b-(acylamino)acrylic acid
derivatives. Excellent enantioselectivities and reactivities
were observed in the hydrogenation of a wide array of (Z)-
b-aryl-b-(acylamino)acrylic acid derivatives. As the substrates
for the asymmmetric hydrogenation can be prepared readily,
the new ligand binapine provides an efficient method for the
practical synthesis of chiral b-aryl-b-amino acids.[12]
[6] a) W. Tang, X. Zhang, Angew. Chem. 2002, 114, 1682 – 1684;
Angew. Chem. Int. Ed. 2002, 41, 1612 – 1614; b) W. Tang, L.
Duan, X. Zhang, Org. Lett. 2003, 5, 205 – 207.
[7] Several binaphthophosphepine ligands in which the P atoms are
not stereogenic centers have been reported; see: a) D. Xiao, Z.
Zhang, X. Zhang, Org. Lett. 1999, 1, 1679 – 1681; b) D. Xiao, X.
Zhang, Angew. Chem. 2001, 113, 3533 – 3536; Angew. Chem. Int.
Ed. 2001, 40, 3425 – 3428; c) Y. Chi, X. Zhang, Tetrahedron Lett.
2002, 43, 4849 – 4852; d) K. Junge, G. Oehme, A. Monsees, T.
Riermeier, U. Dingerdissen, M. Beller, Tetrahedron Lett. 2002,
43, 4977 – 4980.
[8] CCDC-204741 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or depost@ccdc.
cam.ac.uk). We thank Dr. H. Yennawar for solving the crystal
structure.
Received: March 24, 2003 [Z51465]
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[10] See Supporting Information for details.
[11] No reaction was observed in the absence of acid. HBF4 was used
to protonate the pyridine nitrogen atom. A similar strategy was
applied in the hydrogenation of pyridyl a-dehydroamino acid
derivatives; see: C. Döbler, H.-J. Kreuzfeld, M. Michalik, H. W.
Krause, Tetrahedron: Asymmetry 1996, 7, 117 – 125.
Keywords: asymmetric synthesis · hydrogenation ·
ligand design · P ligands · rhodium
.
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[12] The Supporting Information includes procedures for the syn-
thesis of and analytical data for binapine, procedures for the
synthesis of substrates, hydrogenation procedures, information
on molecular simulation, and the X-ray crystal structure of 3.
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