Enantioselective access to chiral drugs by using asymmetric hydrogenation catalyzed by Rh(P-OP) complexes

Article abstract of DOI:10.1002/chem.201103014

P-OP art: Rhodium complexes of P-OP ligands serve as highly efficient and enantioselective catalysts in asymmetric hydrogenation leading to various valuable pharmaceutical building blocks and several direct precursors of chiral drugs such as LY2497282, la

Full text of DOI:10.1002/chem.201103014

DOI: 10.1002/chem.201103014
Enantioselective Access to Chiral Drugs by using Asymmetric Hydrogenation
À
Catalyzed by Rh
N
Pablo Etayo,[a] Josꢀ Luis NfflÇez-Rico,[a] Hꢀctor Fernµndez-Pꢀrez,[a] and
Anton Vidal-Ferran*[a, b]
The synthetic challenges arising from the high degree of
enantiopurity required in life-science products have fuelled
the development and industrial application of asymmetric
catalysis. Indeed, asymmetric catalysis should be considered,
a priori, the best method to introduce chirality into any pro-
duction process.[1] Since the very early days of asymmetric
catalysis, intensive research activities on asymmetric hydro-
genation have been followed by ever more increasing re-
search efforts from both academia and industry. This re-
search has provided a profound mechanistic understanding
of this process and has furthermore facilitated the develop-
ment of a myriad of Ru-, Rh-, and Ir-coordination com-
pounds capable of mediating the hydrogenation of prochiral
C=C, C=N, and C=O double bonds with very high enantio-
selectivities, ensuring that this chemistry has become among
the most efficient and reliable methodologies in asymmetric
catalysis.[2] From a practical perspective, enantioselective hy-
drogenation offers several advantages for the synthesis of
valuable chiral products (optimal atom economy, broad sub-
strate scope, high reactivity and selectivity, as well as opera-
tional simplicity). For all of these reasons, many industrial
methods for the synthesis of optically active products for the
pharmaceutical, agrochemical, advanced material, and fra-
grance sectors rely on catalytic asymmetric hydrogenation
reactions.[3]
phine–phosphites for asymmetric Pd-mediated allylic substi-
tution reactions,[5] Ir-mediated hydrogenations of heteroaro-
matic compounds,[6] and Rh-mediated hydrogenations of
functionalized alkenes.[7] Regarding the latter transforma-
tion, we recently reported the highly enantioselective hydro-
genation (up to 99% enantiomeric excess (ee)) of a structur-
ally diverse array of substrates (a-(acylamino)acrylates, ita-
conic acid derivatives and analogues, and a-arylenamides)
catalyzed by [Rh(L1)]+ complexes.[7d]
Herein, we report on more recent efforts aimed at using
+
À
our enantiomerically pure [Rh
N
lysts for the preparation of key synthetic precursors of sever-
al relevant pharmacologically active compounds, which are
derived mostly from the asymmetric hydrogenation of b-
substituted a-(acylamino)acrylates or a-arylenamides. The
Rh-mediated asymmetric hydrogenation of a-substituted
enol esters has barely been explored in the literature, de-
spite this kind of substrate appearing suitable to undergo
highly enantioselective hydrogenation. The work described
herein also encompasses our efforts to access chiral drugs
from a-arylenol acetates by asymmetric hydrogenation.
The preparation and full characterization of enantiomeri-
cally pure phosphine–phosphite ligands L1[7a,c] and L2[6]
(Scheme 1) have been reported by our group elsewhere.
Phosphine–phosphite L1 (R=Me) was the lead ligand in
previously published studies on the Rh-mediated asymmet-
ric hydrogenation of functionalized alkenes,[7a–d] whereas the
ligand L2 (R=CPh3) was only applied to the Ir-mediated
enantioselective hydrogenation of heteroaromatic com-
pounds.[6] The work described here represents the first time
that L2 has been applied in Rh-mediated enantioselective
We recently reported on the preparation of a library of
enantiomerically pure P OP ligands[4] (phosphine–phosphin-
À
ites and phosphine–phosphites), in which the catalytic prop-
erties were assessed in different enantioselective transforma-
tions. On the basis of a highly modular ligand design, and in
conjunction with a fine-tuning methodology for the perfor-
mance of these catalysts guided by computational analyses
of the diastereomeric transition states, our research group
has efficiently developed an array of enantiopure phos-
[a] Dr. P. Etayo, J. L. NfflÇez-Rico, Dr. H. Fernµndez-PØrez,
Prof. A. Vidal-Ferran
Institute of Chemical Research of Catalonia (ICIQ)
Avgda. Països Catalans 16, 43007 Tarragona (Spain)
Fax : (+34)977920-228
E-mail: avidal@iciq.es
[b] Prof. A. Vidal-Ferran
Catalan Institution for Research and Advanced Studies (ICREA)
Passeig Lluís Companys 23, 08010 Barcelona (Spain)
À
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103014.
Scheme 1. Lead P OP ligands for the asymmetric hydrogenation reac-
tions presented in this study.
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Chem. Eur. J. 2011, 17, 13978 – 13982

COMMUNICATION
Table 1. Rh-mediated asymmetric hydrogenation of b-substituted a-
hydrogenation reactions. The straightforward preparation of
[a]
À
the enantiomer of L2 (ent-L2) is also reported here.[8] The
(acyl
N
Entry
Substrate
Ligand
Cat.
[mol%]
Conv.
[%][b]
ee [%][c]
ACHTUNGTRENNUNG
(config.)[d]
À
availability of both enantiomers of the P OP ligands (L2
U
and ent-L2) enables access to both types of enantiomers of
any pharmacologically relevant hydrogenation product.
Following on from previous studies by our group on the
Rh-mediated asymmetric hydrogenation of a wide range of
model b-substituted a-(acylamino)acrylates,[7a–d] we have ex-
tended the scope of our approach to include a number of b-
aryl- (S1–S8), b-alkyl- (S9 and S10), and b-alkoxy-substitut-
ed (S11) a-(acylamino)acrylic acid derivatives (Scheme 2).
The substrates were carefully selected with the aim of gain-
ing access to pharmaceutically relevant chiral building
blocks. The results obtained for these substrates are sum-
marized in Table 1.
1
2
3
4
5
6
7
8
S1
S1
S2
S2
L1
ent-L2
L1
1.0
1.0
1.0
0.10
1.0
1.0
0.25
1.0
1.0 or 0.50
1.0 or 0.50
1.0
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99[g]
99 (R)
99 (S)
99 (R)[e]
98 (R)[e]
99 (S)
L1
S3
ent-L2
ent-L2
ent-L2
ent-L2
L1
ent-L2
L2
ent-L2
ent-L2
L1
S4[f]
S4[f]
S5
98 (S)
96 (S)
98 (S)[e]
98 (R)[e]
98 (S)
9
S6
S7
S8
S9
S10
S11
10
11
12
13
14
98 (R)
99 (S)
99 (S)
1.0
1.0
1.0
97 (R)
[a] Reaction conditions: Catalyst was generated in situ using [Rh-
À
(nbd)2]BF4 (nbd=norbornadiene) Band 10 mol% excess of P OP ligand
with respect to rhodium precursor. Hydrogenations were carried out at
RT, 18 h, 20 bar H2, and 0.20m in THF, unless otherwise indicated. The
results are the average values of at least two reproducible independent
1
runs. [b] Conversions were determined by H NMR spectroscopy. Typical
isolated product yields were >90%. [c] Determined by GC or HPLC
analysis using chiral stationary phases. [d] Absolute configuration was as-
signed by comparison of the specific rotation with reported data. [e] Ab-
solute configuration was tentatively assigned by analogy based on the
one for analogous substrates. [f] Methanol was employed as solvent.
[g] Selectivity towards P11 was 85%.
(0.10 mol% catalyst loading) without affecting the results
(Table 1, entry 4). The asymmetric hydrogenation of b-alkyl-
substituted substrates S9 and S10 (Table 1, entries 12 and
13) catalyzed by the Rh complex of ligand ent-L2 gave full
conversion and excellent enantioselectivity (i.e., 99% ee)
under standard conditions. Finally, we also studied the Rh-
mediated asymmetric hydrogenation of one b-alkoxy-substi-
tuted a-(acylamino)acrylate (S11). Our methodology
worked efficiently for the hydrogenation reaction of the tail-
ored substrate S11 with full conversion and a very high
enantioselectivity (i.e., 97% ee) obtained on using the Rh
complex of ligand L1 under standard conditions. Although
complete conversion of the starting material was achieved,
the selectivity towards the desired hydrogenated compound
was only 85%, as evidenced in the 1H NMR spectrum,
which revealed the presence of 15 mol% of the MeOH
elimination product (methyl 2-acetamidopropanoate).[9]
Scheme 2. Asymmetric hydrogenation of b-aryl-, b-alkyl-, and b-alkoxy-
substituted a-(acylamino)acrylates.
À
Catalytic systems derived from our P OP ligands provid-
ed straightforward access to valuable building blocks for the
preparation of diverse chiral pharmaceutical drugs. (R)-P1
constitutes a valuable chiral precursor for the synthesis of
rosmarinic acid analogues,[10] whereas (S)-P1 (Scheme 2) is a
fully protected derivative of levodopa, a chiral drug that is
very useful for the treatment of Parkinsonꢁs disease.[11] It
should be noted that thus far no precedent for the enantio-
selective hydrogenation of alkene S1 has appeared in the lit-
erature. Product P2 (Scheme 2) is a key intermediate in the
synthesis of LY2497282[12] (Scheme 4, see later), a promising
prodrug for the treatment of type 2 diabetes.[13] Despite the
In general, regardless of the electronic (NO2, F, Br, OAc,
OBoc, OH, OMe) or positional nature of the substituents
on the aromatic ring, or of the protecting group attached to
the nitrogen (Ac, Cbz, Boc), or whether the carboxyl group
was a free acid or a methyl ester, b-aryl-substituted alkenes,
S1–S8 were all hydrogenated with extremely high enantiose-
lectivity (96–99% ee) and full conversion. Hydrogenation
reactions were all carried out initially under screening con-
ditions (20 bar H2, RT, 1.0 mol% catalyst), and substrate/
catalyst (S/C) ratios could be further increased up to 1000:1
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A. Vidal-Ferran et al.
pharmacological relevance of P2, to the best of our knowl-
edge, the results described here constitute the first reported
enantioselective synthesis of P2 by asymmetric hydrogena-
tion. The present approach also constitutes an efficient
enantioselective entry into (S)-N-acetyl-3-bromo-4-fluoro-
phenylalanine (P4, Scheme 2), a key pharmaceutical build-
ing block used for the preparation of dual CCK1/CCK2 re-
ceptor antagonists[14] (Scheme 4, see later), which have re-
cently been developed for the treatment of various gastroin-
testinal diseases.[15] A precedent for the asymmetric hydro-
genation of alkene S3 was not found in the literature, but
the high level of enantioselectivity achieved for its analogue
S4 (96–98% ee) represents an improvement on the enantio-
meric excess previously obtained for this type of alkene
upon using a Rh complex derived from (N-methyl-N-di-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Scheme 3. Asymmetric hydrogenation of a-arylenamides and a-arylenol
94% ee.[14b] l-m-Tyrosine derivatives have found pharma-
ceutical application in the treatment of a wide range of dis-
eases.[16] In this regard, the N-carboxybenzyl (Cbz)-protected
(S)-m-tyrosine methyl ester P5 (Scheme 2) has been used as
a synthetic intermediate in the preparation of HCV NS3
protease inhibitors[17] and in the total synthesis of the immu-
nosuppressant sanglifehrin A.[18] Aryl-substituted phenylala-
nine derivatives P6, P7, and P8 (Scheme 2) constitute rele-
vant building blocks for the preparation of antimigraine
compounds,[19] non-natural analogues of the N-SMases in-
hibitor scyphostatin,[20] and antihypertensive prodrugs,[21] re-
spectively. The antiseizure agent levetiracetam[22] (Scheme 4,
see later) can be straightforwardly obtained from P9
(Scheme 2) by treatment with NH3.[22b] Alkene S9 has re-
cently proven to be a challenging substrate in Rh-mediated
asymmetric hydrogenation as only moderate enantioselectiv-
ities were achieved even under optimized conditions.[23]
Lastly, the hydrogenation product P11 (Scheme 2) repre-
sents an advanced intermediate used in the total synthesis of
the antiepileptic drug lacosamide[24] (Scheme 4, see later).
Following on from the hydrogenation of substrates S1–
S11, we broadened the scope of the study to include a-aryl-
À
acetates catalyzed by Rh
G
Table 2. Asymmetric hydrogenation of a-arylenamides and a-arylenol
acetates using P OP ligands L2 and ent-L2.
À
Entry
Substrate
Conv.
[%]
ee
[%]
ACHTUNGTRENNUNG(config.)
1
2
3
4
5
S12
>99
>99
>99
>99
>99
98 (S)
83 (R)
98 (S)
97 (R)
99 (R)
S13[b]
S14
S15[c]
S16[c]
[a] See Table 1 for details on the hydrogenation reactions. [b] 40 bar H2.
[c] 0.50 mol% catalyst loading.
entry 3) cleanly afforded P14 with 98% ee, enabling an
enantioselective access to rivastigmine (Scheme 4, see later),
a well-known chiral drug that has been used to treat demen-
tia associated with Alzheimerꢁs disease.[29] To the best of our
knowledge, the enantioselectivity reported here represents a
slight improvement with respect to the sole precedent found
in the literature regarding the asymmetric hydrogenation of
S14.[30] Access to rivastigmine can be more elegantly gained
from the hydrogenation product of a-arylenol acetate S15.
The enantioselective hydrogenation of this substrate pro-
ceeded successfully with full conversion and in 97% ee
(Table 2, entry 4). The resulting product P15 (Scheme 3) has
recently been used as a direct precursor to the pharmaceuti-
cal drug rivastigmine,[29] which can be readily prepared by
an SN2 reaction with excess dimethylamine directly from the
benzylic acetate P15.[29b] The attractiveness of our approach
relies on the exploitation of the acetate group, both for the
creation of chirality (chelation-assisted enantioselective hy-
drogenation) and for the further transformations required to
obtain the target molecule (nucleophilic substitution on the
benzylic acetoxy-substituted carbon). Enantioselective ap-
proaches to P15 are, to the best of our knowledge, very
scarce in the literature, as reported synthetic strategies rely
on lipase-mediated acetylations.[29a,b] The Rh-mediated
asymmetric hydrogenation of a-arylenol acetate S16 also
ACHTUNGTRENNUNGenamides (S12–S14) and a-arylenol acetates S15 and S16, of
which the hydrogenation products are well-established pre-
cursors of several chiral drugs. We first became interested in
gaining access to the (S)-configured product P12
(Scheme 3), which was quantitatively obtained in 98% ee
using ligand ent-L2 (Table 2, entry 1). This enantioenriched
product is a useful synthetic precursor of the compound de-
noted as AZ960[25] and related JAK2 kinase inhibitors[26] cur-
rently in clinical development for cancer therapy. The enan-
tioselective hydrogenation of the sterically encumbered 1-
naphthyl-substituted enamide[27] S13 proved to be very chal-
lenging, with the desired product obtained with full conver-
sion and in 83% ee (Table 2, entry 2). These results provide
an enantioselective entry into the pharmaceutical drug cina-
calcet hydrochloride, which is used for the treatment of sec-
ondary hyperparathyroidism.[28] The successful asymmetric
hydrogenation of 3-acetoxyphenyl-substituted enamide S14
catalyzed by the Rh complex of ligand ent-L2 (Table 2,
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Enantioselective Access to Chiral Drugs
COMMUNICATION
gave excellent results. The desired product of R absolute
configuration (P16, Scheme 3) was obtained with full con-
version and extremely high enantioselectivity (99% ee;
Table 2, entry 5). Our approach efficiently delivers P16,
which can be easily hydrolyzed to the corresponding benzyl
alcohol,[31] which is a key building block used in the synthe-
sis of the antiemetic drug aprepitant (Scheme 4).[32] All re-
ported enantioselective procedures for P16 rely on lipase-
catalyzed acetylations.[33] Herein, we provide an alternative
synthetically useful enantioselective entry into P16, which
represents the first route being based on the Rh-mediated
asymmetric hydrogenation of an a-arylenol acetate.
À
yellow in Figure 1) in the lower-left quadrant (far from the
steric congestion of the binaphthyl group), therefore, (R)-
configured hydrogenation products are obtained from a-
(acylACTHNURTGNEUaGN mino)acrylate derivatives, a-arylenamides, and a-
arylenol acetates when L1 or L2 are used.
In summary, we have developed highly efficient and enan-
tioselective hydrogenation reactions for a number of strate-
gically devised alkenes (S1–S16) catalyzed by chiral cationic
À
rhodium complexes of a set of P OP ligands: enantiopure
phosphine–phosphites L1, L2, and ent-L2. The catalytic sys-
À
tems derived from these P OP ligands provided straightfor-
ward access to enantiomerically enriched amine, alcohol,
and a-amino acid derivatives that are valuable building
blocks for the preparation of diverse chiral pharmaceutical
drugs, and, in several cases, constitute advanced intermedi-
ates or direct precursors towards relevant pharmaceutical
compounds (Scheme 4).
Regarding the stereochemical outcome of the [RhACTHNUTRGNEUNG(P
OP)]+-mediated asymmetric hydrogenations for all reported
substrates, ligands L1 and L2 consistently resulted in (R)-
configured hydrogenation products (Figure 1). This observa-
tion can be further rationalized on the basis of simple analy-
sis of quadrant diagrams. The two right-hand quadrants are
disfavored with respect to the placement of the two olefin
carbon atoms by the electronic effects of the (Sa)-BINOL-
derived phosphite group, whereas the upper-left quadrant is
blocked by the steric effects of the binaphthyl unit, which
points towards the substrate.[7c] An example of a transition
state for the simplest a-(acylamino)acrylate strongly favors
positioning of the olefin carbons (see carbons marked in
Scheme 4. Examples of chiral drugs accessible with our methodology
(fragment marked in black derives from the intermediates prepared in
this work).
Acknowledgements
We thank MICINN (No. CTQ2008-00950/BQU), DURSI (No.
2009GR623), Consolider Ingenio 2010 (No. CSD2006-0003), and the
ICIQ Foundation for financial support. H. F.-P. acknowledges the “Pro-
grama Torres Quevedo” for financial support. J. L. N.-R. thanks the
ICIQ Foundation for a predoctoral fellowship.
Keywords: asymmetric catalysis
·
enantioselectivity
·
functionalized alkenes · hydrogenation · rhodium
Figure 1. Above: Stereochemical outcome of [Rh
(L1 or L2)]+-mediated
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Rh, orange=P, red=O, purple=hydrido ligand, white=hydrogen atom,
and yellow=olefin carbons.
Chem. Eur. J. 2011, 17, 13978 – 13982
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A. Vidal-Ferran et al.
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Received: September 26, 2011
Published online: November 22, 2011
13982
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Chem. Eur. J. 2011, 17, 13978 – 13982