Chiral 1-phenylethylamine-derived phosphine-phosphoramidite ligands for highly enantioselective Rh-catalyzed hydrogenation of β-(acylamino) acrylates: Significant effect of substituents on 3,3′-positions of binaphthyl moiety

Article abstract of DOI:10.1039/c000268b

A series of new chiral phosphine-phosphoramidite ligands with a 3,3′-substituted binaphthyl moiety were prepared from 1-phenylethylamine, and successfully applied in the Rh-catalyzed asymmetric hydrogenation of β-(acylamino)acrylates. The research disclosed that the substituents on the 3,3′-positions of binaphthyl moiety significantly influenced the enantioselectivity.

Full text of DOI:10.1039/c000268b

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Chiral 1-phenylethylamine-derived phosphine-phosphoramidite ligands for
highly enantioselective Rh-catalyzed hydrogenation of b-(acylamino)acrylates:
significant effect of substituents on 3,3¢-positions of binaphthyl moiety†
Xiao-Mao Zhou,a Jia-Di Huang,b Li-Bin Luo,a Chen-Lu Zhang,c Xiang-Ping Hu*b and Zhuo Zhengb
Received 14th January 2010, Accepted 25th March 2010
First published as an Advance Article on the web 7th April 2010
DOI: 10.1039/c000268b
A series of new chiral phosphine-phosphoramidite ligands
with a 3,3¢-substituted binaphthyl moiety were prepared
from 1-phenylethylamine, and successfully applied in the
Rh-catalyzed asymmetric hydrogenation of b-(acylamino)-
acrylates. The research disclosed that the substituents on the
3,3¢-positions of binaphthyl moiety significantly influenced
the enantioselectivity.
Fig. 1 Chiral 1-phenylethylamine derived phosphine-phosphoramidite
Chiral b-amino acids are important building blocks in the
ligand, (Sc,Sa)-PEAPhos 1.
synthesis of natural products, b-peptides, and pharmaceuticals.1
Exploring enantioselective methods for the synthesis of optically
active b-amino acid derivatives has therefore attracted much at-
tention recently. Due to its inherent efficiency and atom economy,
catalytic asymmetric hydrogenation of b-(acylamino)acrylates is
arguably one of the most efficient and straightforward ways to
b-amino acid derivatives. Indeed, in the past few years, many
phosphorus-containing ligands have been reported to exhibit
good to excellent enantioselectivities in the Rh- and Ru-catalyzed
ligand was inefficient in this more challenging hydrogenation in
terms of enantioselectivity, giving only 71% ee (entry 1, Table 1).
We surmised that the relatively flexible features of PEAPhos
1 should answer for this insufficient selectivity, and increasing
its steric hindrance by introduction of substituents onto the
3,3¢-positions of the binaphthyl moiety of this ligand should
improve the enantioselectivity. As a result, we report the synthesis
of new phosphine-phosphoramidite ligands 2a-b with a 3,3¢-
disubstituted binaphthyl fragment and their application in the Rh-
catalyzed asymmetric hydrogenation of b-(acylamino)acrylates, in
which significantly improved enantioselectivities (>99% ee) were
obtained.
The synthesis of new chiral phosphine-phosphoramidite lig-
ands 2a-b was performed as outlined in Scheme 1. Ini-
tially, N-methyl-(S)-1-[2-(diphenylphosphino)phenyl]ethylamine
[(S)-DPPNHCH3 3] was prepared from (S)-1-phenylethylamine
asymmetric hydrogenation of b-(acylamino)acrylates.2 However,
for most catalytic systems, high enantioselectivities were ob-
tained only when b-alkyl-b-(acylamino)acrylates were used as
substrates, whereas the results for the hydrogenation of (Z)-b-
aryl-b-(acylamino)acrylates, are less satisfying.2-3 The search for
an effective catalytic system for enantioselective hydrogenation of
(Z)-b-aryl-b-(acylamino)acrylates remains highly desirable.
In the past decade, unsymmetrical hybrid bidentate phosphine-
phosphoramidite ligands have emerged as a new, effective ligand
class for asymmetric catalysis.4 In our recent study, we have
also found that chiral 1-phenylethylamine-derived phosphine-
phosphoramidite ligand, (Sc,Sa)-PEAPhos 1 (Fig. 1), was highly
efficient in the Rh-catalyzed asymmetric hydrogenation of various
functionalized olefins such as dimethyl itaconate, enamide, and
a-dehydroamino acid esters.5 To further expand its utility in
catalytic asymmetric hydrogenation, we attempted to employ this
ligand in the Rh-catalyzed asymmetric hydrogenation of (Z)-b-
aryl-b-(acylamino)acrylates. However, the result disclosed that this
through
a two-step transformation as we have reported
previously.5-6 The treatment of (S)-DPPNHCH3 3 with (S)-3,3¢-
disubstituted binaphthol derived chlorophosphites 47 in toluene at
0 ◦C in the presence of 3 equiv of Et3N provided the corresponding
phosphine-phosphoramidite ligands 2 in good yields. Similar to
the parent ligand 1, these new ligands 2 also show excellent stability
toward air and moisture, and tolerance of various hydrogenation
conditions.
With these newly developed phosphine-phosphoramidite lig-
ands in hand, we then examined their efficiency in the Rh-catalyzed
asymmetric hydrogenation of (Z)-b-aryl-b-(acylamino)acrylates
5.8 Initially, ethyl (Z)-b-phenyl-b-(acetylamino)acrylate 5a was
used as a model substrate for ligand screening and condition
optimizing experiments. All reactions were carried out at room
temperature for 24 h in the presence of 1 mol% of catalyst with
an Rh : ligand ratio of 1 : 1.1, and the results are summarized in
Table 1.
aInstitute of Pesticide, Hunan Agricultural University, Changsha 410128,
China
bDalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian
116023, China. E-mail: xiangping@dicp.ac.cn; Fax: +86-411-84684746;
Tel: +86-411-84379276
cSchool of Chemistry and Chemical Engineering, Liaoning Normal Univer-
sity, Dalian 116029, China
† Electronic supplementary information (ESI) available: General proce-
dures for the synthesis of ligands and for the hydrogenation; 1H, 31P and
13C NMR spectral data of all ligands; chiral GC and HPLC spectra for
ee-determinations of hydrogenation products. See DOI: 10.1039/c000268b
With the parent ligand (Sc,Sa)-PEAPhos 1, (Z)-b-phenyl-b-
(acetylamino)acrylate 5a was hydrogenated to yield the corre-
sponding amino acid ester 6a in only 71% ee (entry 1). In
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a Rh complex of (S,S,S)-binapine bearing stereogenic phosphorus
centers.8c By use of this catalytic system, excellent enantioselectivi-
ties (>99% ee) and reactivities were obtained in the hydrogenation
of a wide range of (Z)-b-aryl-b-(acylamino)acrylates. Some other
bidentate phosphorus ligands have also been reported to show
good to excellent enantioselectivities in this transformation.4f,9,10
However, no result surpassed that obtained with (S,S,S)-binapine
ligand. Therefore, the high enantioselectivity (>99% ee) obtained
with the present Rh/(Sc,Sa)-PEAPhos-Ph catalytic system rep-
resents one of the best results reported so far.2 Comparison of
the results obtained with 1 and 2a-b suggested that the steric
demand in the 3,3¢-positions of the binaphthyl moiety of this
phosphine-phosphoramidite ligand class is crucial for achiev-
ing high enantioselectivity in this challenging hydrogenation.
Lowering H2 pressure to 10 bar didn’t impact the catalytic
activity and enantioselectivity (entry 4). The nature of solvent
has some influence on the catalytic performance. Thus, the
hydrogenation proceeded smoothly in CH2Cl2 and THF, giving
slightly lower enantioselectivity; while only moderate conversion
and enantioselectivity was observed when hydrogenation was
performed in toluene (entries 5-7). Reducing the catalyst loading to
0.1 mol% resulted in a dramatically decreased conversion even in
a promoted H2 pressure (30 bar), although high enantioselectivity
was maintained (entry 8).
Scheme 1 The synthesis of new chiral phosphine-phosphoramidite
ligands (Sc,Sa)-2a-b.
Table 1 Rh-catalyzed asymmetric hydrogenation of ethyl (Z)-b-phenyl-
b-(acetylamino)acrylate 5aa
Having established the optimal hydrogenation conditions
(1 mol% of catalyst, 10 bar of H2 pressure and the use of MeOH
as solvent), we next investigated the Rh-catalyzed asymmetric hy-
drogenation of various (Z)-b-aryl-b-(acylamino)acrylates 5 with
(Sc,Sa)-PEAPhos-Ph 2b, and the results are summarized in Table 2.
In all cases, full conversions were obtained. The results revealed
that the substitution pattern of the substituent on the aryl ring
of substrates has some effect on the enantioselectivity. For 4-
and 3-methyl substituted substrates 5b and 5c, the hydrogenation
yielded the corresponding b-amino acid esters in over 99% ee
Entry
Ligand
Solvent
H2/bar
Conv (%)
Ee (%)b
1
2
3
4
5
6
7
8
(Sc,Sa)-1
MeOH
MeOH
MeOH
MeOH
CH2Cl2
Toluene
THF
20
20
20
10
10
10
10
30
>99
>99
>99
>99
71
95
>99
>99
98
(Sc,Sa)-2a
(Sc,Sa)-2b
(Sc,Sa)-2b
(Sc,Sa)-2b
(Sc,Sa)-2b
(Sc,Sa)-2b
(Sc,Sa)-2b
>99
69 (73)c
>99
72
96
Table 2 Rh-catalyzed asymmetric hydrogenation of (Z)-b-aryl-b-
(acetylamino)acrylate 5 with (Sc,Sa)-PEAPhos-Ph 2ba
MeOH
53 (48)c
99d
a Hydrogenations were performed in 2 mL of solvent with 0.25 mmol of
substrate 5a and 1 mol% of catalyst prepared in situ from [Rh(COD)2BF4]
and 1.1 equiv of ligand at room temperature for 24 h. b Conversions and
enantiomeric excesses were determined by chiral GC. c Conversions were
determined by GC on a DB-17 capillary column using dimethyl phthalate
as internal standard substance. The data in parentheses were determined
by 1H NMR. d Catalyst loading was 0.1 mol%.
Entry
Substrate (Ar, R)
Ee/% (config)b
comparison, ligand 2a with two methyl groups on 3,3¢-positions
provided an ee-value of 95%, remarkably superior to that ob-
tained with the parent ligand 1 (entry 2). Replacing methyl
groups with phenyl groups on the 3,3-positions of the binaphthyl
moiety further increased the enantioselectivity to over 99% ee
(entry 3). Catalytic asymmetric hydrogenation of (Z)-b-aryl-b-
(acylamino)acrylates 5 remains a difficult task. Although many
ligands have been employed in this transformation, only a few
ligands can provide the product in over 95% ee.2 In 1999,
Zhang et al. reported the first highly enantioselective hydro-
genation of b-(acylamino)acrylates using Rh-BICP and Rh-
DuPhos catalytic systems.8b However, only moderate enantiose-
lectivities (~65% ee) were obtained with an aryl substituent in the
b-(acylamino)acrylates using these catalytic systems. The most
important progress was made by the same group in 2003 by using
1
2
3
4
5
6
7
8
9
5a (Ph, Et)
>99 (S)
>99 (S)
>99 (S)
85 (S)
5b (4-MeC6H4, Me)
5c (3-MeC6H4, Me)
5d (2-MeC6H4, Me)
5e (4-MeC6H4, Et)
5f (4-MeOC6H4, Me)
5g (4-MeOC6H4, Et)
5h (3-MeOC6H4, Et)
5i (4-ClC6H4, Me)
5j (4-ClC6H4, Et)
5k (4-FC6H4, Me)
99 (S)
99 (S)
99 (S)
99 (S)
98 (S)
10
11
99 (S)
>99 (S)
a Hydrogenations were performed in 2 mL of MeOH with 0.25 mmol of
substrate 5 and 1 mol% of catalyst prepared in situ from [Rh(COD)2BF4]
and 1.1 equiv of ligand 2b under a H2 pressure of 10 bar at room
temperature for 24 h. Full conversions were obtained in all cases.
b Enantiomeric excesses were determined by chiral GC (for 6a-e and 6i-k)
and chiral HPLC (for 6f-h).
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(entries 2-3). However, the hydrogenation of 2-methyl substituted
substrate 5d resulted in dramatically decreased enantioselectivity,
providing only 85% ee, which is presumably due to the steric
effect as reported by Zhang et al. by use of a Rh/TangPhos
catalytic system (entry 4).9 A series of 3- or 4-substituted substrates
were then hydrogenated with the present catalytic system, and all
of them gave excellent enantioselectivities (entries 5-11). These
results demonstrated the high efficiency of this newly developed
phosphine-phosphoramidite ligand 2b in this hydrogenation.
High enantioselectivity was also observed in the Rh-catalyzed
asymmetric hydrogenation of (Z)-b-alkyl-b-(acylamino)acrylate
[(Z)-7] with (Sc,Sa)-PEAPhos-Ph 2b (Scheme 2). Unexpectedly,
this ligand is not so effective in the hydrogenation of the
corresponding (E)-b-alkyl-substituted substrate [(E)-7], providing
incomplete conversion (89% conversion).
Team in University (2008T107) and the Knowledge Innovation
Program of the Chinese Academy of Sciences (DICP-S200802) is
acknowledged.
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Scheme
2 Rh-catalyzed asymmetric hydrogenation of b-alkyl-b-
(acylamino)acrylate 7 with ligand 2b.
In summary, we have prepared some new chiral phosphine-
phosphoramidite ligands by the introduction of two substituents
onto the 3,3¢-positions of the binaphthyl moiety of the (Sc,Sa)-
PEAPhos skeleton. These newly developed ligands displayed
excellent enantioselectivity in the Rh-catalyzed asymmetric hydro-
genation of challenging (Z)-b-(acylamino)acrylate substrates, in
particular (Z)-b-aryl-b-(acylamino)acrylates, giving up to >99%
ee. The results also reveal that the presence of the substituents on
the 3,3¢-positions of the binaphthyl moiety significantly improves
the enantioselectivity of this challenging hydrogenation. The
further applications of these new ligands in asymmetric catalysis
will be disclosed in due time.
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Acknowledgements
Financial support from the National Natural Science Foundation
of China (20802076), Program for Liaoning Innovative Research
2322 | Org. Biomol. Chem., 2010, 8, 2320–2322
This journal is
The Royal Society of Chemistry 2010
©