Enantioselective hydrogenation of tetrasubstituted olefins of cyclic β-(acylamino)acrylates

Article abstract of DOI:10.1021/ja035777h

Hydrogenation of a series of cyclic β-(acylamino)acrylates with tetrasubstituted olefins has been accomplished successfully with the use of Ru catalysts with chiral biaryl ligands such as C3-TunaPhos, and up to over 99% ee's have been achieved. This methodology provides an efficient catalytic method for the synthesis of both cis and trans chiral cyclic β-amino acid derivatives. Copyright

Full text of DOI:10.1021/ja035777h

Published on Web 07/16/2003
Enantioselective Hydrogenation of Tetrasubstituted Olefins of Cyclic
â-(Acylamino)acrylates
Wenjun Tang, Shulin Wu, and Xumu Zhang*
Department of Chemistry, The PennsylVania State UniVersity, UniVersity Park, PennsylVania 16802
Received April 24, 2003; E-mail: Email: xumu@chem.psu.edu
Enantiomerically pure â-amino acids and their derivatives are
key structural elements of many natural products and drugs. They
are also important chiral building blocks for the synthesis of
â-peptides for biomedical research.1,2 Chiral cyclic â-amino acids
have recently gained much attention due to their increasing
importance for the synthesis of â-peptides.3 For instance, trans-
aminocyclopentanecarboxylic acid (1, trans-ACPC, Figure 1) and
trans-4-aminopyrrolidine-3-carboxylic acid (2, trans-APC) have
been successfully used by Gellman and co-workers for constructing
Figure 1. Cyclic â-amino acids.
Table 1. Ru-Catalyzed Hydrogenation of
2-Acetylamino-cyclopent-1-enecarboxylic Acid Ethyl Ester
â-peptide antibiotics,3a while (1R,2S)-cis-aminocyclopentane-
carboxylic acid (3, cispentacin) itself is a strong antifungal
antibiotic.4 Although some stoichiometric asymmetric synthesis or
resolution methods of chiral cyclic â-amino acids and their
derivatives have been reported,5 the development of new, efficient,
entrya
chiral P* ligands
(S,S)-DIOP
(R,R)-Me-DuPhos
(S,S,R,R)-TangPhos
(S)-BINAP
(S)-MeO-BIPHEP
(S)-C1-TunaPhos
(S)-C2-TunaPhos
(S)-C3-TunaPhos
(S)-C4-TunaPhos
(S)-C5-TunaPhos
(S)-C6-TunaPhos
conv. (%)
% ee (config)
and catalytic asymmetric synthetic methods remains an important
goal. Herein we report the first catalytic synthesis of chiral cyclic
â-amino acids via asymmetric hydrogenation of cyclic â-(acyl-
amino)acrylates, and excellent enantioselectivities have been achieved.
Although great success has been achieved in asymmetric
hydrogenation of trisubstituted functionalized olefins, hydrogenation
of tetrasubstituted olefins is generally more difficult, and much
fewer successful results have been reported.6 While many excellent
chiral catalytic systems have been developed for hydrogenation of
trisubstituted olefins of acyclic â-(acylamino)acrylates,7,8 enantio-
selective hydrogenation of tetrasubstituted olefins of cyclic or
acyclic â-(acylamino)acrylates remains an unexplored area. We
were interested in developing an efficient catalyst for hydrogenation
of tetrasubstituted olefins of cyclic â-(acylamino)acrylates. Thus,
a series of cyclic â-(acylamino)acrylates were synthesized from
their corresponding cyclic â-keto esters through amination and
acylation in high yields. 2-Acetylamino-cyclopent-1-enecarboxylic
acid ethyl ester (4) was selected as the hydrogenation substrate for
testing different hydrogenation methods. A Rh-(S,S,R,R)-TangPhos
complex7e was first used as the catalyst for asymmetric hydrogena-
tion. It was found that this catalyst, which was very successful for
hydrogenation of trisubstituted olefins of â-(acylamino)acrylates,7e
exhibited no reactivity under similar conditions. A low conversion
was observed even when a higher hydrogen pressure (50 atm) and
temperature (50 °C) were employed.
Bruneau et al.9a and Rautenstrauch et al.9b have recently reported
hydrogenation of tetrasubstituted enamides and a vinylogous
â-oxoester, respectively, by employing Ru catalysts generated in
situ from a monomeric Ru precursor, a chiral phosphorus ligand,
and HBF4. We thus switched to the use of chiral Ru catalysts for
hydrogenation of the tetrasubstituted olefin of 4. The Ru catalysts
were prepared in situ by protonation of a mixture of Ru(COD)-
(methallyl)2 and a chiral bisphosphorus ligand with two equivalents
of HBF4‚Me2O in CH2Cl2. After evaporation of the solvent, the
residue was directly used for hydrogenation. The reactions were
performed at room temperature under 50 atm of H2 pressure in
MeOH. As shown in Table 1, different chiral ligands exhibited
1
2
3
4
5
6
7
8
9
91
100
100
100
100
100
100
100
100
100
100
34 (1S,2R)
69 (1R,2S)
57 (1R,2S)
99 (1S,2R)
99 (1S,2R)
98 (1S,2R)
99 (1S,2R)
99 (1S,2R)
99 (1S,2R)
99 (1S,2R)
97 (1S,2R)
10
11
a
For a detailed procedure of catalyst preparation, see Supporting
Information. Ru:P*:HBF4:substrate ) 1:1:2:20, The hydrogenations were
performed at room temperature under 50 atm of H2 pressure in MeOH for
18 h.
dramatically different enantioselectivities. While DIOP, DuPhos,
and TangPhos gave only moderate enantioselectivities (entries 1-3),
chiral biaryl ligands such as MeO-BIPHEP and BINAP provided
99% ee’s (entries 4-5). To test the effect of the dihedral angle of
chiral biaryl ligand on enantioselectivity of the reaction, a set of
TunaPhos ligands11 with different dihedral angles was employed.
With the exception of C1-TunaPhos and C6-TunaPhos that provided
slightly lower ee’s, other TunaPhos ligands showed comparably
high enantioselectivities (entry 6-11). The preparation method of
the Ru catalysts is important for the high reactivity. When a Ru
catalyst precursor such as [NH2Me2][{RuCl((S)-C3-TunaPhos)}2-
(µ-Cl)3]11 was applied for hydrogenation under identical conditions,
a lower conversion (80%) was obtained although the high enantio-
selectivity was maintained. Alcoholic solvents such as MeOH and
EtOH are beneficial for the reactivity; lower conversion was
observed when THF, CH2Cl2, or toluene was used as the solvent.
We then used C3-TunaPhos as the ligand for Ru-catalyzed
asymmetric hydrogenation of a series of cyclic â-(acylamino)-
acrylates. As shown in Table 2, over 99% ee was obtained in
hydrogenation of 2-acetylamino-cyclopent-1-enecarboxylic acid
methyl ester (5, entry 2). Excellent enantioselectivity (98% ee) was
also achieved in hydrogenation of substrate 6 containing a BocNH-
9
9570
J. AM. CHEM. SOC. 2003, 125, 9570-9571
10.1021/ja035777h CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Hydrogenation of Cyclic or Acyclic â-(Acylamino)crylates
with a Ru-(S)-C3-TunaPhos Catalyst
hydrogenation. The Ru catalysts combined with chiral biaryl ligands
such as C3-TunaPhos are found to be efficient for hydrogenation
of tetrasubstituted olefins of cyclic â-(acylamino)acrylates and up
to 99% ee’s have been achieved. Since the hydrogenation substrates
are easy to synthesize,11 we believe that this methodology may be
potentially practical for the synthesis of both cis and trans chiral
cyclic â-amino acids.
Acknowledgment. This work was supported by National
Institute of Health. We thank Dr. Mark A. Scialdone in DuPont
for his helpful suggestions.
Supporting Information Available: Detail hydrogenation proce-
dure and spectroscopic data of substrates and products. This material
is available free of charge via the Internet at http://pubs.acs.org.
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a
For a detailed procedure of catalyst preparation, see Supporting
Information. Ru:(S)-C3-TunaPhos:HBF4:substrate ) 1:1:2:20, The hydro-
genations were performed at room temperature under 50 atm of H2 pressure
in EtOH for 18 h. The enantiomeric excesses were determined by chiral
GC on a chiralselect 1000 or γ-dex 225 column. The sign of optical
rotation. The absolute configuration of 6a (entry 3) is determined as (1S,2R).
Scheme 1. Epimerization of 6a
b
c
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group (entry 3). The chiral cis product 6a has been used as a synthon
for the peptide synthesis.5i A heterocyclic â-(acylamino)acrylates
7 is also hydrogenated to give the cis product 7a in excellent
enantioselectivity (entry 4). Hydrogenation of a cyclohexenyl
substrate 8 provided the cis hydrogenation product in 92% ee.
However, lower ee’s were observed in hydrogenation of the
cycloheptenyl and cyclooctenyl substrates 9 and 10. An acyclic
â-(acylamino)acrylate 11 with a tetrasubstituted olefin was also
hydrogenated, and the product 11a was obtained in 72% ee.
Hydrogenation with other biaryl ligands such as BINAP, MeO-
BIPHEP, C2-, C4-, and C5-TunaPhos provided similar hydrogena-
tion results.
To demonstrate the synthetic utility of the chiral cis hydrogena-
tion products for the synthesis of trans cyclic â-amino acid
derivatives, compound 6a was heated in a basic alcoholic solution
to yield its trans epimer trans-(1R,2R)-2-tert-butoxycarbonylamino-
cyclopentanecarboxylic acid methyl ester (6b) in high yield (Scheme
1). The chiral trans product 6b has been frequently used by Gellman
and co-workers for the synthesis of â-peptides.3c
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(11) See Supporting Information.
In conclusion, we have developed the first catalytic asymmetric
synthesis of chiral cyclic â-amino acid derivatives via asymmetric
JA035777H
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J. AM. CHEM. SOC. VOL. 125, NO. 32, 2003 9571