Stereoselective synthesis of ferrocene-based C2-symmetric diphosphine ligands: Application to the highly enantioselective hydrogenation of α-substituted cinnamic acids

Article abstract of DOI:10.1002/anie.200604493

(Chemical Equation Presented) Chirality³: A new ferrocene-based diphosphine ligand is applied to the asymmetric hydrogenation of α-substituted cinnamic acids. The P-centered-, C-centered-, and planar-chiral ligand (R_C,R_C,S_Fc,S _Fc,S_P,S_P)-1 displays unprecedented enantioselectivity in this Rh-catalyzed reaction (see scheme; cod = cycloocta-1,5-diene).

Full text of DOI:10.1002/anie.200604493

Angewandte
Chemie
DOI: 10.1002/anie.200604493
Asymmetric Catalysis
Stereoselective Synthesis of Ferrocene-Based C2-Symmetric
Diphosphine Ligands: Application to the Highly Enantioselective
Hydrogenation of a-Substituted Cinnamic Acids
Weiping Chen,* Peter J. McCormack,* Karim Mohammed, William Mbafor, Stanley M. Roberts,
and John Whittall
Optically active phosphine ligands, especially C2-symmetric
diphosphine ligands, have played an important role in various
metal-catalyzed asymmetric transformations, and numerous
phosphine ligands have been prepared for the development of
effective catalytic asymmetric processes.[1] Dramatic results
from Knowles and co-workers with the C2-symmetric P-chiral
accessibility and derivatization as well as special electronic
and steric properties. Indeed, several families of ferrocene-
based phosphine ligands with subtle structural variations have
been developed in the last fewyears. Most of these ligands
incorporate both C-centered chirality and planar chirality,
and they have proved to be highly effective in numerous
asymmetric reactions. In stark contrast, much less attention
has been paid to P-chiral phosphines that bear ferrocenyl
groups,[3k,l,5] doubtless as a result of the previous difficulties in
their synthesis. Very recently, we reported a highly stereose-
lective and modular synthesis of ferrocene-based P-chiral
phosphine ligands using a simple and straightforward strategy,
that is, reaction of a chiral organometallic reagent with a
dichlorophosphine, followed by a second organometallic
reagent; several families of newferrocene-based P-chiral
phosphine ligands have been developed.[6] Herein, we de-
scribe the highly stereoselective synthesis of a newferrocene-
based C2-symmetric diphosphine ligand 1 (TriFer). To the best
of our knowledge, ligand 1 is the first class of C2-symmetric
diphosphine that combines C-centered, P-centered, and
planar chirality. Most importantly, unprecedented enantiose-
lectivities have been achieved with ligand 1 for the Rh-
catalyzed asymmetric hydrogenation of a-substituted cin-
namic acids, a class of very important substrates for which
efficient asymmetric reduction procedures are eagerly sought.
Both enantiomers of 1 can be prepared from the readily
available R and S enantiomers of Ugiꢀs amine (2) in only one
step, in good yield, and with excellent stereoselectivity
(Scheme 1). Thus, Ugiꢀs amine (R)-2 was lithiated with
tBuLi (ꢀ788C, 10 min, then room temperature, 1.5 h) and
then treated with PhPCl2 (ꢀ788C, 10 min, then room temper-
ligand
1,2-ethanediylbis[(2-methoxyphenyl)phenylphos-
phane] (dipamp) for Rh-catalyzed hydrogenations opened
up this field of asymmetric catalysis.[2] However, it took nearly
two decades for other groups to develop efficient methods to
prepare C2-symmetric P-chiral diphosphine ligands, largely as
a result of the synthetic difficulties in the construction of the
P-chiral P centers.[3,4] Nevertheless, some C2-symmetric P-
chiral diphosphine ligands, such as BisP*,[4a] MiniPhos,[4b]
TangPhos,[4c] DiSquareP*,[4d] DuanPhos,[4e] and QuinoxP*,[4f]
which exhibit almost perfect enantioselectivity in some Rh-
catalyzed asymmetric hydrogenations, have been developed
recently. However, a major drawback in many of the requisite
synthetic methods (developed by the groups of Imamoto,[3a]
JugØ,[3b] Corey,[3c] Evans,[3e] and Livinghouse[3g]) is that either
only one enantiomer of the ligand is readily accessible owing
to the nature of the chiral auxiliaries used in the formation of
the chiral center or there is a need for tedious diastereomeric
derivatization, separation, and deprotection sequences.
Ferrocene-based phosphine ligands are well docu-
mented.[5] They are more amenable to asymmetric catalysis
than many other types of chiral ligands as a result of their easy
[*] Dr. W. Chen,[+] P. J. McCormack,[#] K. Mohammed, W. Mbafor,
Prof. S. M. Roberts, Dr. J. Whittall
StylaCats Ltd.
Chemistry Department
University of Liverpool
Liverpool L69 7ZD (UK)
[+] Present address:
Solvias AG, WRO-1055.6.68B
Mattenstrasse 22, Postfach, 4002 Basel (Switzerland)
Fax : (+41)61-68-66-311
E-mail: weiping.chen@solvias.com
[#] Present address:
Phoenix Chemicals, Thursby Road
Bromborough, Merseyside, CH62 3PW (UK)
Fax: (44)151-334-9045
E-mail: peter.mccormack@phoenixchem.com
Supporting information, including details on the preparation of
ligands and substrates, general hydrogenation procedure, and
determination of ee values, for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 1. Preparation of ligand 1.
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ature, 1.5 h) followed by 1,1’-dilithioferrocene (1,1’-FcLi2)
generated from 1,1’-dibromoferrocene by lithiation
efficiency of ligand 1 in the enantioselective hydrogenation of
a-substituted cinnamic acids catalyzed by Rh complexes was
first investigated using (E)-2-[3-(3-methoxypropoxy)-4-
methoxybenzylidene]-3-methylbutanoic acid (5) as the sub-
strate, as this is an industrially relevant compound which is
known to be difficult to hydrogenate with high enantioselec-
tivity.[7,12c] Hydrogenation of 5 in the presence of a Rh
(ꢀ788C!RT, overnight) to afford
a
mixture of
compound
(RC,RC,SFc,SFc,SP,SP)-1
and the
meso
(RC,RC,SFc,SFc,SP,RP)-1 ( ꢁ 95:5 ratio as judged by 1H NMR
and 31P NMR spectroscopy) in 84% yield. Pure
(RC,RC,SFc,SFc,SP,SP)-1 could be easily obtained by crystalliza-
tion from MeOH. Its enantiomer, (SC,SC,RFc,RFc,RP,RP)-1, w as catalyst, generated in situ from [Rh(cod)2]BF4 (0.1 mol%;
obtained from Ugiꢀs amine (S)-2. The absolute configuration
of the product (SC,SC,RFc,RFc,RP,RP)-1 was confirmed by
single-crystal X-ray diffraction analysis. Ligand 1 shows
good air stability; (RC,RC,SFc,SFc,SP,SP)-1 did not showany
changes in its 1H or 31P NMR spectra even after being stored
for about two years under air at room temperature.
cod = cycloocta-1,5-diene) and ligand 1 (1.1 equiv with
respect to Rh) in MeOH, gave optically active (R)-6, a key
intermediate in the synthesis of renin inhibitor Aliskiren, with
unprecedented enantioselectivities of up to 99.6% ee
(Table 1). Importantly, for reactions at higher substrate
The prescribed generation of 1,1’-FcLi2 from 1,1’-dibro-
moferrocene is crucial for the highly stereoselective synthesis
of (RC,RC,SFc,SFc,SP,SP)-1, as the configuration of the P centers
could be reversed by changing the reaction conditions, namely
by replacement of 1,1’-FcLi2 with 1,1’-FcLi2–TMEDA com-
Table 1: Enantioselective hydrogenations on butanoic acid 5 using
(RC,RC,SFc,SFc,RP,RP)-1.[a]
plex
(TMEDA = N,N,N’,N’-tetramethylethylenediamine).
Thus, following lithiation of Ugiꢀs amine (R)-2 and treatment
of the Li compound with PhPCl2 as described above and
subsequent addition of 1,1’-FcLi2–TMEDA complex and
stirring for 1 h at room temperature, a mixture of diastereo-
mer (RC,RC,SFc,SFc,RP,RP)-1 and the meso compound
(RC,RC,SFc,SFc,SP,RP)-1 was obtained in about 9:1 ratio in
93% yield.
The stereochemistry and high stereoselectivity in the
formation of ligand 1 under the standard reaction conditions
are consistent with our proposed reaction mechanism,[6a]
which involves the cyclic intermediate 3 (Figure 1). The
Entry
S/C
T [8C]
[Substrate] [m]
t [h]
ee [%]
1
2
3
4
500
500
1000
2000
40
65
40
60
0.16
0.16
0.55
0.55
13
5
4
99.6
99.3
98.6
98.4
4
[a] The reactions were carried out under 50 bar H2 pressure withover
99% conversion in all cases.
concentrations, substrate-to-catalyst (S/C) ratios and temper-
ature seem to have only a marginal effect on ee values. The
enantioselectivities obtained here for product 6 exceed the
reported values for Rh-catalyzed hydrogenations using Wal-
phos (95% ee)[7] and Monophos (90% ee).[12c] Thus, TriFer is
the most enantioselective ligand in the asymmetric hydro-
genation of 5 so far reported.
Figure 1. Intermediates in the formation of 1.
Recently, the synthesis of optically enriched a-alkoxy
dihydrocinnamic acids has attracted significant attention as a
result of their potential usefulness as PPAR agonists in the
treatment of type 2 diabetes and dislepedimia.[11] Investiga-
tions have been carried out on the synthesis of these materials
through resolution[13] and enzymatic[14] and enantioselective
catalytic procedures.[15] The Rh-catalyzed enantioselective
hydrogenation of 3-aryl-2-ethoxyacrylic acids 7 is usually
extremely difficult.[15] However, gratifyingly, TriFer is highly
effective in the Rh-catalyzed enantioselective hydrogenation
of these acrylic acids, displaying unprecedented enantiose-
lectivities and leading to products with 95–98% ee (Table 2).
A secondary interaction of the ligand with the substrate[16]
could account for the high enantioselectivity and activity of
TriFer in the Rh-catalyzed asymmetric hydrogenation of a-
substituted cinnamic acids. The generally accepted mecha-
nism of enantioselective hydrogenation catalyzed by a Rh
complex involves coordination of a substrate to the solvated
Rh complex to form a chelate catalyst–substrate complex 9
influence of using the 1,1’-FcLi2–TMEDA complex on the
resultant stereochemistry of ligand 1 is also accommodated by
this mechanism. Hence, when 1,1’-FcLi2 is replaced with 1,1’-
FcLi2–TMEDA complex, the more basic TMEDA breaks the
ring intermediate 3 to form intermediate 4. For the reactions
at ambient temperature, the intermediate 4 is fully formed
and leads to (RC,RC,SFc,SFc,RP,RP)-1 highly stereoselectively.
Chiral a-substituted dihydrocinnamic acid derivatives are
key intermediates in the synthesis of several bioactive
compounds, including renin inhibitors,[7] b-secretase inhibi-
tors,[8] enkephalinase inhibitors,[9] opioid antagonists,[10] and
peroxisome proliferator-activated receptors (PPAR) ago-
nists.[11] Nowadays, significant progress has been achieved in
asymmetric hydrogenation of a wide range of unsaturated
substrates, but the enantioselective hydrogenation of a-
substituted cinnamic acids remains a challenge.[12] Thus, the
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Chemie
Table 2: Enantioselective hydrogenations on 3-aryl-2-ethoxyacrylic acids
7 using (RC,RC,SFc,SFc,RP,RP)-1.[a]
ethyl)ferrocen-1-yl groups shield the second and the fourth
quadrants. During a reaction, a substrate approaches the
metal so as to minimize steric interactions with the equatorial
2-(dimethylaminoethyl)ferrocen-1-yl groups. Figure 3 illus-
Entry Aryl group
S/C
T
[Substrate] ee
[8C] [m]
[%]
1
2
3
4
5
6
7
8
3-methoxyphenyl
500 40
0.41
0.82
0.50
0.50
0.41
0.41
0.50
0.40
95.2
94.6
98.0
96.5
95.0
96.5
97.6
96.2
3-methoxyphenyl
4-cyanophenyl
4-cyanophenyl
2-thienyl
3-thienyl
3-benzyloxy-4-methoxyphenyl
1000 40
500 35
500 55
500 50
1000 55
500 50
3-benzyloxy-4-methoxyphenyl 2000 50
[a] Over 99% conversion for all reactions.
=
(Figure 2), in which the C C bond and the carbonyl O atom at
the b position interact with the RhI center.[17] To obtain high
enantioselectivity and activity, it is essential that there is a
Figure 3. Transition-state models for the asymmetric hydrogenation of
a-substituted cinnamic acids catalyzed by the (RC,RC,SFc,SFc,SP,SP)-1–Rh
complex.
Figure 2. Substrate–catalyst complex in the asymmetric hydrogenation.
trates the favored and disfavored transition states for the
asymmetric hydrogenation of a-substituted cinnamic acids
catalyzed by the (RC,RC,SFc,SFc,SP,SP)-1–Rh complex. Transi-
tion state TS-2 suffers from steric repulsion between the aryl
group of the substrate and an equatorial 2-(dimethylamino-
ethyl)ferrocen-1-yl group. In transition state TS-1, this steric
repulsion is avoided and allows the reaction to proceed,
yielding the enantiomer as shown in Figure 3 as the major
product.
In conclusion, a newclass of ferrocene-based C2-symmet-
ric P-chiral diphosphine ligand (Trifer) has been developed
and applied in the highly enantioselective hydrogenation of a-
substituted cinnamic acids with ee values of up to 99.6%
obtained. TriFer is the most enantioselective ligand so far
reported, probably owing to an influential secondary electro-
static interaction of the dimethylamino group of the ligand
with the carboxylate unit of the substrate.
second functional group such as carbonyl group at the
=
b position to the C C bond that is capable of chelation with
the metal and result in a ring system that stabilizes the
reactive intermediate. Unlike enamides, enol acetates, and
itaconates, a-substituted cinnamic acids lack such function-
ality at the b position to coordinate with the metal, and so
most known chiral diphosphine ligands give low enantiose-
lectivities and activities for the Rh-catalyzed asymmetric
hydrogenation of a-substituted cinnamic acids. However, in
the 1–Rh–substrate complex 10, the dimethylamino moiety
would serve to have a secondary interaction with the
substrate, that is, an electrostatic interaction with the
carboxylate unit of the substrate, and establish the multisite
recognition of the substrate by the Rh complex that leads to
high enantioselectivity and activity. In accord with this
postulate, ligand 1 is almost inactive for the Rh-catalyzed
hydrogenation of the corresponding esters of 5 or 7.
Received: November 2, 2006
Published online: April 19, 2007
The origin of the enantioselectivity is accounted for on the
basis of the well-known quadrant rule.[18] When looking at the
1–Rh complex from the side, the two equatorial 2-(dimethyl-
aminoethyl)ferrocen-1-yl groups spatially occupy and thus
block two opposite quadrants. In the case of
(RC,RC,SFc,SFc,SP,SP)-1, two equatorial 2-(dimethylamino-
Keywords: asymmetric catalysis · chirality · ferrocenes ·
.
phosphane ligands · transition states
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Communications
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