Modular P-OP ligands in rhodium-mediated asymmetric hydrogenation: A comparative catalysis study

Article abstract of DOI:10.1002/adsc.201200477

Highly efficient and enantioselective hydrogenation reactions for α-(acylamino)acrylates, itaconic acid derivatives and analogues, α-substituted enol ester derivatives, and α-arylenamides (25 substrates) catalyzed by chiral cationic rhodium complexes of a set of P-OP ligands have been developed. The catalytic systems derived from these P-OP ligands provided a straightforward access to enantiomerically enriched α-amino acid, carboxylic acid, amine, and alcohol derivatives that are valuable chiral building blocks. Excellent efficiencies (full conversion in all cases) and extremely high enantiomeric excesses (94-99% ee) were achieved for a wide range of α-substituted enol ester derivatives, regardless of the substitution pattern. The R-oxy group of the ligand (methoxy or triphenylmethoxy) strongly influences the enantioselectivity and catalytic activity. Greater steric bulk around the metal centre correlated to greater (or similar) enantioselectivity, but also to slower hydrogenation. Furthermore, the hydrogenation rates observed with the four model substrates follow the same trend, independently of the R-oxy group of the ligand: methyl 2-acetamidoacrylate>dimethyl itaconate>1-phenylvinyl acetate>N-(1- phenylvinyl)acetamide. A substrate-to-catalyst ratio (S/C) of up to 10,000:1 was sufficient for total hydrogenation of a model substrate of intermediate reactivity (dimethyl itaconate), and did not imply any loss in conversion or enantioselectivity. Copyright

Full text of DOI:10.1002/adsc.201200477

FULL PAPERS
DOI: 10.1002/adsc.201200477
À
Modular P OP Ligands in Rhodium-Mediated Asymmetric
Hydrogenation: A Comparative Catalysis Study
Josꢀ L. NfflÇez-Rico,a Pablo Etayo,a Hꢀctor Fernµndez-Pꢀrez,a
and Anton Vidal-Ferrana,b,*
a
Institute of Chemical Research of Catalonia (ICIQ), Avgda. Països Catalans 16, 43007 Tarragona, Spain
Fax : (+34)-977-920-228; phone: (+34)-977-920-200; e-mail: avidal@iciq.es
Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain
b
Received: May 30, 2012; Revised: August 7, 2012; Published online: November 4, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200477.
Abstract: Highly efficient and enantioselective hy- ic activity. Greater steric bulk around the metal
drogenation reactions for a-(acylamino)acrylates, ita- centre correlated to greater (or similar) enantioselec-
conic acid derivatives and analogues, a-substituted tivity, but also to slower hydrogenation. Further-
enol ester derivatives, and a-arylenamides (25 sub- more, the hydrogenation rates observed with the
strates) catalyzed by chiral cationic rhodium com- four model substrates follow the same trend, inde-
À
plexes of a set of P OP ligands have been devel- pendently of the R-oxy group of the ligand: methyl
À
oped. The catalytic systems derived from these P
2-acetamidoacrylate>dimethyl itaconate>1-phenyl-
OP ligands provided a straightforward access to vinyl acetate>N-(1-phenylvinyl)acetamide. A sub-
enantiomerically enriched a-amino acid, carboxylic strate-to-catalyst ratio (S/C) of up to 10,000:1 was
acid, amine, and alcohol derivatives that are valuable sufficient for total hydrogenation of a model sub-
chiral building blocks. Excellent efficiencies (full strate of intermediate reactivity (dimethyl itaconate),
conversion in all cases) and extremely high enantio- and did not imply any loss in conversion or enantio-
meric excesses (94–99% ee) were achieved for selectivity.
a wide range of a-substituted enol ester derivatives,
regardless of the substitution pattern. The R-oxy Keywords: asymmetric catalysis; enantioselectivity;
group of the ligand (methoxy or triphenylmethoxy) hydrogenation; phosphane ligands; phosphine-phos-
strongly influences the enantioselectivity and catalyt- phite ligands; rhodium
Introduction
rated substrates is now amongst the most efficient
and reliable methodologies in asymmetric catalysis.[2]
Despite the remarkably advanced state of the field,
The high degree of enantiopurity required in life-sci-
ence products implies enormous synthetic challenges many research groups are still actively pursuing new
that have fuelled the development and industrial ap- catalytic systems that show higher activity and/or im-
plications of asymmetric catalysis, which is considered proved enantioselectivity for poorly explored sub-
a priori the best method to introduce chirality into strate classes or for recently discovered biologically
any production process.[1] Starting from the earliest active compounds.[2d,i] In other cases, research is di-
days of asymmetric catalysis, there has been an ever rected towards the development of chiral ligands with
increasing research effort in asymmetric hydrogena- an attractive industrial profile: those which offer high
tion within academia and industry. This work has pro- enantioselectivity, enable efficient catalyst use (i.e.,
vided a deep mechanistic understanding of the high reaction rates and substrate-to-catalyst ratios, as
chemistry and enabled the development of myriad well as catalyst robustness and possibilities for reuse),
chiral Ru-, Rh-, and Ir-coordination compounds and are amenable to industrial manufacturing condi-
(mostly phosphorus-containing derivatives) that can tions. Thus, the design, development, screening, and
mediate the addition of hydrogen to prochiral C=C, optimization of new catalysts for asymmetric hydroge-
C=N, and C=O double bonds with very high enantio- nation reactions remain appealing challenges.[3]
selectivities. Consequently, the transition metal-medi-
ated asymmetric hydrogenation of prochiral unsatu- tion of a library of enantiomerically pure P OP li-
In this context, we recently reported the prepara-
À
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+
À
Scheme 1. Asymmetric hydrogenation of functionalized alkenes catalyzed by [RhACTHNUGRTNEUNG(P OP)] complexes.
gands[4] (phosphine-phosphinites and phosphine-phos- is scarcely described in the literature. Thus, we per-
phites), whose catalytic properties we then assessed in formed a methodological study on the asymmetric hy-
different enantioselective transformations of interest. drogenation of a-substituted enol esters catalyzed by
+
À
On the basis of a highly modular ligand design, and in [Rh
(P OP)] complexes, and then evaluated this ap-
conjunction with a fine-tuning methodology for the proach in the synthesis of industrially attractive chiral
performance of the catalytic systems guided by com- building blocks. Herein we describe our results, which
putational analyses of the diastereomeric transition include findings from a comparative catalysis study of
states, our research group has efficiently developed an the four classes of model substrates indicated in
À
array of enantiopure 1,2-P OP derivatives (mostly Scheme 1.
phosphine-phosphite ligands) for palladium-mediated
asymmetric allylic substitution reactions,[5] iridium-
mediated asymmetric hydrogenations of heteroaro- Results and Discussion
matic compounds,[6] and rhodium-mediated asymmet-
ric hydrogenations of functionalized alkenes.[7]
Enantioselective Hydrogenation of a-Substituted
Regarding the last asymmetric transformation men- Enol Esters
tioned above, our group recently reported the highly
enantioselective hydrogenation of a structurally di- Having considered the structural similarities between
verse array of substrates mediated by cationic rhodi- a-arylenol acetates and a-arylenamides, we decided
um complexes of the ligands L1, L2 or ent-L2.[7c–e] a- to apply our enantiopure P OP ligands in the enan-
À
(Acylamino)acrylates, itaconic acid derivatives and tioselective hydrogenation of a-arylenol acetates. Sys-
analogues, a-substituted enamides, and a-substituted tematic assessment of enol esters as substrates for
enol esters were hydrogenated using [Rh
complexes as precatalysts with high enantioselectivi- Furthermore, the enantioselective hydrogenation of
ties (up to 99% ee) (Scheme 1). a-arylenol acetates paves the way to an alternative
(L1 or L2)]+ Rh-mediated asymmetric hydrogenation is lacking.[9]
ACHTUNGTRENNUNG
The successful application of enantiomerically pure route to enantioenriched a-substituted benzylic alco-
rhodium complexes in asymmetric hydrogenation hol derivatives, which are valuable intermediates for
relies on the ability of the substrate to form a rhodium asymmetric organic synthesis.
chelate involving the C=C double bond and a donor
Therefore, we proceeded to explore the rhodium-
atom, which is generally placed in the g-position of mediated asymmetric hydrogenation of various func-
a substituent attached to the C=C double bond. Che- tionalized a-substituted enol esters (S1–S10,
À
lating assistance of an N-acyl group is the classical Scheme 2), using our P OP ligands L1 and/or L2
paradigm for achieving high reactivity and enantiose- under standard hydrogenation conditions for screen-
lectivity in this transformation.[8] Accordingly, a-sub- ing (1.0 mol%, THF, 20 bar H2, room temperature,
stituted enol esters, whose O-acyl group could be har- overnight).
nessed for chelating assistance, seem ripe with poten-
The corresponding rhodium complexes of phos-
tial for this chemistry; however – and rather surpris- phine-phosphite ligands L1 and L2 (or ent-L2) were
ingly –, their Rh-mediated asymmetric hydrogenation compared for catalytic performance using nine differ-
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À
Modular P OP Ligands in Rhodium-Mediated Asymmetric Hydrogenation
Table 1. Rhodium-mediated asymmetric hydrogenation of a-
[a]
À
substituted enol esters using P OP ligands L1 or L2.
Entry Product Ligand used and
observations
Conv.
[%][b]
ee [%][c]
(config.)[d]
1
2
3
4
5
6
7
8
P1
P1
P2
P2
P3
P3
P4
P4
P5
P5
P6
P6
P7
L1
L2
L1
L2
L1
L2
L1
L2
L1
L2
L1
L2
L1
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
96 (R)
97 (R)
91 (R)
95 (R)
99 (R)
98 (R)
90 (R)[e]
94 (R)[e]
97 (R)[e]
98 (R)[e]
97 (R)
96 (R)
97 (R)
98 (S)
9
10
11
12
13
14
15
16
17
18
19
ent-P7 ent-L2[f]
P8
P8
P9
P10
P10
L1
L2
L1
90 (S)
95 (S)
99 (R)
87 (R)
97 (R)
L1, 2.0 mol% cat.
L2, 2.0 mol% cat.
[a]
À
Reaction conditions: [RhACHTNUGTRNEUNG(nbd)2]BF4/P OP ligand/sub-
strate=1.0:1.1:100, room temperature, 20 bar H2, 18 h,
0.20M in THF, unless otherwise indicated. The values
shown are the average values of at least two independent
runs.
[b]
1
Conversions were determined by H NMR, with the ex-
ception of P9 for which 19F NMR was used. Typical iso-
lated yields were >90%, with the exception of the hydro-
genation products P4–P6, which, due to their volatility,
were isolated in ca. 75% yield; and P9, which, due to its
high volatility, was not isolated.
[c]
[d]
[e]
Determined by GC or HPLC analysis using chiral sta-
tionary phases.
Absolute configuration was assigned by comparison of
the specific rotation with reported data.
Absolute configuration was tentatively assigned by anal-
ogy based on the stereochemical outcome for analogous
substrates.
The enantiomer of ligand L2 (ent-L2) was used in this
case, as it provides the desired (S)-configuration for ent-
P7.
Scheme 2. Rhodium-mediated asymmetric hydrogenation of
+
À
a-substituted enol esters using [Rh
N
ent substrates: seven a-arylenol acetates (S1–S7) and
two a-substituted enol esters (S8 and S10). L1 and L2
(or ent-L2) proved to be outstanding ligands in the
Rh-mediated asymmetric hydrogenation of a-arylenol
acetates S1–S7; full conversions and enantioselectivi-
ties ranging from 90% to 99% ee were achieved.
Whilst rhodium complexes of ligands L1 and L2 (or
[f]
The excellent results summarized in Table 1 prove
ent-L2) mediated the hydrogenation of S1, S3, and the outstanding catalytic performance of the rhodium
S5–S7 with comparable enantioselectivities (Æ1% ee; complexes derived from L1 and L2 (or its enantiomer
see entries 1, 2, 5, 6, and 9–14 in Table 1), ligand L2 ent-L2) in the enantioselective hydrogenation of di-
provided higher enantiomeric excesses in the hydro- verse a-arylenol acetates. In general, regardless of the
genation of S2 and S4 (compare entries 3 and 4, and 7 electronic or positional nature of the substituents on
and 8 in Table 1). Analogously, the Rh complex of the aromatic ring, hydrogenation products P1–ent-P7
ligand L2 led to significantly higher enantioselectivi- were efficiently hydrogenated with full conversion
ties in the hydrogenations of a-substituted enol esters and remarkably high enantioselectivities (94–99% ee).
S8 and S10 (compare entries 15 and 16, and 18 and 19
Interestingly, we have reported here the first ever
in Table 1). These results suggest that the steric hin- published preparation of P4 and ent-P7 by hydrogena-
À
drance of the R-oxy substituent in the P OP ligand is tion. Furthermore, we found only one example of P5
important for enantioselectivity.[10]
being prepared by rhodium-mediated asymmetric hy-
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drogenation by Burk et al.,[9c] who obtained this prod- ditions were used for this comparative catalysis study
uct in 89% ee using Et-DuPhos as the chiral ligand. (1.0 mol% of precatalyst formed in situ, 20 bar H2,
However, our ligand L2 provided a significantly supe- THF as solvent, room temperature, overnight reac-
rior enantioselectivity of 98% ee. In addition, L1 and tions), unless otherwise stated. The results are sum-
L2 afforded products P1–P3 and P6 with levels of marized in Table 2. Fifteen different substrates were
enantioselectivity comparable to the best ones report- assessed (S11–S25; Scheme 3), comprising representa-
ed for the Rh-mediated asymmetric hydrogenation of tive examples of dehydro-a-amino acid derivatives
such a-arylenol acetates.[9e–j] Interestingly, the chiral (leading to the b-unsubstituted [P11 and P12], b-
fluorinated products P4–P6 are valuable synthetic alkyl- [P13 and P14], b-aryl- [P15 and P16] and b-
precursors to numerous pharmaceutically active com- alkoxy- [P17] substituted a-amino acid derivatives);
pounds.[11] The (S)-configured hydrogenation product itaconic acid derivatives and analogues (leading to the
ent-P7 constitutes a key chiral precursor for the prep- succinates P18–P20 and to the 3-hydroxy-2-methyl-
aration of Mitsubishiꢂs compound (S)-MA20565, propanoates P21 and P22); and a-arylenamides [lead-
a broad-spectrum agrochemical agent showing potent ing to the N-(1-arylethyl)acetamides P23–P25].
fungicidal activity against various crop diseases.[12]
In almost all cases conversion was complete and
The asymmetric hydrogenation of 1-(trifluorome- enantioselectivity was very high (83% to 99% ee).
thyl)vinyl acetate (S9) and 1-cyanovinyl acetate (S10) Phosphine-phosphite L2 performed better than L1
is challenging: to the best of our knowledge, there are (see Table 2, entries 4, 6, 9, and 11–13), providing
no reports on preparing P10 by asymmetric hydroge- enantiomeric excesses of up to five percent higher.
nation, and only a few examples for P9.[13] These two
The excellent enantioselectivities achieved upon hy-
functionalized alkenes, together with the enol ester drogenation of the a-(acylamino)acrylates S11–S17 to
phosphonate S8,[9i–k] were all hydrogenated with very give the corresponding a-amino acid derivatives P11–
À
high enantioselectivities (95% to 99% ee) using P
P17 (Table 2, entries 1–7) illustrate the tolerance of
OP ligands L1 or L2 (Table 1, entries 15–19). Whilst the catalytic systems derived from ligands L1 and L2
the more selective catalyst [Rh(L2)]+ was required to to a broad variety of carbamate-type amino protect-
achieve enantioselectivities of at least 95% ee, rhodi- ing groups. Furthermore, the exceptional results ob-
um complexes of L1 already gave the hydrogenated tained for the poorly studied N-Boc- or N-Cbz-pro-
product P9 in 99% ee (Table 1, entry 17), which tected, b-ethyl-substituted, a-amino acid precursors
matches the highest value in the literature by Stephan P13 and P14[16] (Table 2, entries 3 and 4) enable us to
et al.[9i] In the enantioselective hydrogenation of sub- extend use of our P OP ligands to new b-alkyl-substi-
À
strate S10, full conversion required an increase in the tuted dehydro-a-amino acids. In fact, only one synthe-
catalyst loading, from 1.0 to 2.0 mol%; interestingly, sis of P13 by enantioselective hydrogenation has pre-
with this substrate, L2 gave a ten percent higher enan- viously been reported:[17] it requires lower hydrogen
tiomeric excess than did L1 for the corresponding pressures. Preparation of P14 by this method is re-
product (compare entries 18 and 19 in Table 1). To ported for the first time here.
the best of our knowledge, the aforementioned results
represent the highest enantioselectivity ever achieved group known as the Weinreb amide (the N-methoxy-
in the synthesis of (R)-O-acetyl-1-cyanoethanol P10: N-methylcarbamoyl group) as an antecedent of nu-
Despite the synthetic versatility of the functional
AHCTUNGTRENNUNG
the only previously reported route to this compound, merous functional groups,[18] our group has reported,
based on the enzyme-mediated enantioselective hy- to the best of our knowledge, the first example of the
drolysis of racemic 1-cyanoethyl acetate, gives poor preparation of P16 by enantioselective hydrogenation
yield and only moderate enantiomeric excess.[14] Fur- using the dicyclohexylphosphino-substituted analogue
thermore, our approach is synthetically advantageous, of ligand L1.[7f] Diphenylphosphine-phosphite ligands
because the hydrolysis product derived from the pre- L1 and L2 mediated the hydrogenation reaction lead-
vious chiral product [i.e., (R)-1-cyanoethanol] is a val- ing to product P16 with higher enantioselectivity (94–
uable chiral synthon for which we found only two 95% ee; Table 2, entry 6) than the one achieved in
enantioselective methods in the literature, both of our first contribution (91% ee), whereby a higher cat-
which give only moderate enantiomeric excesses.[15]
alyst loading of 2.0 mol% was employed.[7f]
Our group recently synthesized the b-alkoxy-substi-
tuted amino acid derivative P17 by enantioselective
hydrogenation, obtaining excellent results (>99%
conversion, 1% hydrogenated MeOH-elimination
product content, and 96% ee for P17) by using the
rhodium complex of the dicyclohexylphosphino-sub-
Comparative Study on the Catalytic Activity of
P OP Ligands L1 and L2 with Other Classes of
Functionalized Alkenes
À
We extended our comparative study on the catalytic stituted analogue of ligand L1.[7f] Our results for P17
activity of L1 and L2 to encompass a broader scope using the rhodium complex of L1 or L2 were compa-
of substrates. Standard screening hydrogenation con- rable in terms of the enantioselectivity, (97% ee;
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Modular P OP Ligands in Rhodium-Mediated Asymmetric Hydrogenation
Table 2. Rhodium-mediated asymmetric hydrogenation of a-(acylamino)acrylates, itaconic acid derivatives and analogues,
[a]
À
and a-arylenamides using P OP ligands L1 or L2.
Entry
Product
Observations
Results with L1
Conv. [%] ee [%] (config.)
Results with L2
Conv. [%] ee [%] (config.)
1
2
3
4
5
6
7
8
P11
P12
P13
P14
P15
P16
P17
P18
P19
P20
P21
P21
P22
P23
P24
P25
–
–
>99
>99
>99
>99
>99
>99
>99[d]
>99
>99
>99
>99
>99
>99
>99
>99
90
99 (R)[b]
98 (R)
99 (R)
>99
>99
>99
>99
>99
92
99 (R)
98 (R)
99 (R)
97 (R)
99 (R)
95 (R)[c]
97 (R)
98 (S)
99 (S)
93 (S)
95 (S)
97 (S)
98 (S)
98 (R)
99 (R)
83 (R)[g]
80 bar H2
80 bar H2
–
in DCM
in DCM
–
–
96 (R)
99 (R)[b]
94 (R)[c]
97 (R)
>99[d]
>99
>99
>99
>99
>99
>99
>99
>99
>99
99 (S)[e]
95 (S)[e,f]
95 (S)[f]
90 (S)[b]
95 (S)[b]
94 (S)[f]
98 (R)[b]
99 (R)
9
10
11
12
13
14
15
16
–
–
08C, 0.5 mol% cat.
08C, 0.5 mol% cat.
–
–
40 bar H2
83 (R)
[a]
See Table 1 for details.
Results from ref.[7c]
[b]
[c]
Absolute configuration was tentatively assigned by analogy based on the stereochemical outcome for analogous sub-
strates.
[d]
[e]
The amount of the hydrogenated MeOH-elimination product (methyl 2-acetamidopropanoate) observed was 4 mol%
(see ref.[7f] for details).
In previous publications, our group incorrectly reported the configuration of the hydrogenation products P18 and P19 to
be R (see refs.[7a,c,d]): their absolute configurations should be S.
Results from ref.[7d]
[f]
[g]
Results from ref.[7e]
Table 2, entry 7), albeit the selectivity was slightly Substitution of the methoxy group in the ligand back-
lower (4% hydrogenated MeOH-elimination product bone of L1 with a triphenylmethoxy one in L2 modi-
content; Table 2, entry 7).[7f]
fies the geometry of the catalytic site, enabling better
In the present study, the tested substrates also in- adjustment to slight changes in substrate geometry
cluded numerous itaconic acid derivatives and ana- (e.g., CO2H groups in S19 vs. CO2Me substituents in
logues. Excellent enantioselectivities were achieved in S18).
the asymmetric hydrogenations of dimethyl itaconate
(S)-Methyl 3-hydroxy-2-methylpropanoate P21,
S18 and itaconic acid S19 (up to 99% ee; Table 2, en- also known as the Roche ester, is an industrially rele-
tries 8 and 9), whereas the enantioselective hydroge- vant chiral building block.[20] It is used in the total
nations of 2-methylenesuccinamic acid S20[9i] fur- synthesis of several anti-tumour agents.[21] As a liquid,
nished lower enantiomeric excesses (up to 95% ee; its enantiomeric purity cannot be upgraded by crystal-
Table 2, entry 10). The resultant enantioenriched hy- lization; thus, only those synthetic procedures that
drogenated products P18–P20 all showed an absolute provide it with an enantioselectivity of at least 95%
S configuration.[19] This fact is consistent with the di- ee are useful.[20a] We achieved this target ee value at
rection of asymmetric induction indicated in room temperature by using 1.0 mol% of the rhodium
Scheme 1. Whilst in the hydrogenation of a-(acylami- complex of ligand L2 (Table 2, entry 11), and were
no)acrylates enantioselectivity was consistently better able to further increase the ee to 97% by using a reac-
with L2 (see Table 2, entries 4 and 6), with the itacon- tion temperature of 08C, which worked even at
ic acid derivatives S18–S20, it ultimately depended on a lower catalyst loading of 0.50 mol% (Table 2,
the combination of substrate and ligand: for S18 and entry 12). The hydrogenation conditions that we de-
S20, L1 was better; whereas for S19, L2 was better scribe here are, to the best of our knowledge, the
(see Table 2, entries 8–10). These results clearly illus- most attractive ones ever reported for the preparation
trate that the stereoselectivity of this chemistry can of enantiomerically enriched Roche ester. Previously
be fine-tuned according to the size of the substituents reported conditions afforded the hydrogenation prod-
in the pendant ether functionality of the ligand.[7f,10] uct with the same (high) level of enantioselectivity
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P22[9j] under the same reaction conditions (08C,
0.50 mol% of Rh complex derived from L2).
Having evaluated functionalized alkenes as sub-
strates in our comparative study on the catalytic activ-
À
ity of our P OP ligands L1 or L2 in asymmetric hy-
drogenations, we then shifted our focus to a-acyl-
AHCTUNGTRENNUNG
arylenamides[22] (substrates S23–S25). The results of
this chemistry, done under the same (standard) condi-
tions, are summarized in Table 2. The products P23
and P24 were obtained with excellent conversion and
enantioselectivities using either L1 or L2 (Table 2, en-
tries 14 and 15). Contrariwise, the more sterically en-
cumbered 1-naphthyl-substituted enamide S25[23]
proved to be very challenging: the desired product
P25 was obtained in 83% ee, and this required a great-
er hydrogen pressure of 40 bar (Table 2, entry 16).
Rationalization of the Stereochemical Outcome of
the Hydrogenation Reactions Catalyzed by
Rhodium(I) Complexes of Ligand L1 or L2
As previously indicated, cationic rhodium(I) com-
plexes of ligand L1 or L2 catalyze hydrogenations
leading to the (R)-configured products derived from
a-(acylamino)acrylate derivatives, a-arylenamides,
and a-substituted enol esters (with the exception of
product P8),[24] whilst those derived from itaconic acid
derivatives and analogues present the (S)-configura-
tion.[24] The stereochemical outcome of all these hy-
drogenations can be predicted on the basis of simple
analyses of quadrant diagrams (see Scheme 1 for the
chemical equation and Figure 1 for the diagrams).
Computational studies on the origin of enantioselec-
tion in the asymmetric hydrogenation of methyl 2-
acetamidoacrylate catalyzed by rhodium complexes of
L1 have provided the basis for the simple analyses of
quadrant diagrams.[7c] The two right-hand quadrants
are disfavoured by the electronic effects of the
BINOL-derived phosphite group, whereas the upper-
left quadrant is blocked by the steric effects of the bi-
naphthyl unit, which points towards the substrate.
This scenario can be visualized in the quadrant dia-
grams by considering that the two right-hand sites are
electronically disfavoured with respect to the place-
ment of the Ca and Cb olefin carbon atoms (repre-
sented in yellow in Figure 1). The difference with the
placement of Ca in the two left-hand quadrants is as-
sociated with steric effects. Since steric hindrance in
the transition state of the rate- and stereo-determin-
ing step (oxidative addition) is developed in the quad-
rant originally occupied by the Ca olefin carbon,[25] its
Scheme 3. Rhodium-mediated asymmetric hydrogenation of
a-(acylamino)acrylates, itaconic acid derivatives and ana-
+
À
logues, and a-arylenamides using [Rh
N
(98% ee),[20a] but they required lower temperatures placement in the lower-left quadrant, far from the
(À408C instead of 08C) and higher catalyst loadings steric congestion of the binaphthyl group, is strongly
(1.0 mol% instead of 0.50 mol%). We observed even favoured. Therefore, (R)-, (S)-,[24] (R)- and (R)-config-
better enantioselectivity (98% ee, Table 2, entry 13) in ured hydrogenation products are obtained from a-
the hydrogenation leading to ethyl ester analogue (acylamino)acrylate derivatives, itaconic acid deriva-
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À
Modular P OP Ligands in Rhodium-Mediated Asymmetric Hydrogenation
Comparative Conversion Curves in the
Enantioselective Hydrogenation of Model Substrates
Catalyzed by Rhodium(I) Complexes of L1 or L2
Studies to optimize the substrate-to-catalyst (S/C)
ratio were first done under 20 bar hydrogen pressure
for one representative model substrate from each
family of functionalized alkenes studied in the present
work [methyl 2-acetamidoacrylate (S11), dimethyl
itaconate (S18), 1-phenylvinyl acetate (S1) and N-(1-
phenylvinyl)acetamide (S23)]. We reasoned that in-
creasing the S/C ratio but keeping the amount of sub-
strate in the reaction mixture constant, would trans-
late to using only tiny amounts of catalyst. However,
considering that when very small amounts of catalyst
are used, deactivation or poisoning of the catalyst
may occur,[26] we increased the scale of the reaction in
the optimization studies reported in this section (20
times more alkene than in the previously discussed
catalytic screening studies).
Under these new reaction conditions, S/C ratios
were increased up to 1,000:1 without any loss in con-
version or enantioselectivity. These studies revealed
very high catalytic activity for the rhodium complexes
of ligands L1 and L2. Conversion curves for the
model substrate from each alkene family were record-
ed from the gas uptake profiles (see Figure 2 and Ex-
perimental Section for details), and then used to cal-
culate TOF values at ca. 50% conversion (TOF1/2)
(Table 3). Interestingly, the TOF values were very
high in some cases (entries 1 and 2 in Table 3). Two
conclusions can be drawn from direct analysis of the
gas uptake curves (Figure 2) or from the calculated
TOF values (Table 3). Firstly, that the triphenylme-
thoxy-substituted ligand L2 requires longer reaction
times for all studied substrates than does its methoxy-
substituted analogue L1. For any given substrate, the
TOF values for L2 are always lower than those for L1
(see Table 3). Greater steric bulk around the metal
centre correlated to greater (or similar) enantioselec-
tivity, but also to slower hydrogenation rates. Second-
ly, the rate of hydrogenation of the four model sub-
strates follows the same trend independently of the
ligand: methyl 2- acetamidoacrylate (S11)>dimethyl
itaconate (S18)>1-phenylvinyl acetate (S1)>N-(1-
phenylvinyl)-acetamide (S23) (Table 3). Thus, a-(acyl-
Figure 1. Quadrant diagrams for a 3D model of the favoura-
ble transition state of the enantioselective hydrogenations
catalyzed by the rhodium complex of ligand L1, for a general
structure of a functionalized alkene. Colour key: green=
rhodium; orange=phosphorus; red=oxygen; purple=hy-
drido ligand; yellow=Ca and Cb carbon atoms; white=hy-
drogen; and pale blue, green and pink=alkene substituents.
AHCTUNGTREGaNNUN mino)acrylate S11 is the most reactive substrate of
this series, whilst N-(1-phenylvinyl)acetamide S23 is
the least reactive.
The reaction conditions used in the optimization
studies towards the calculation of TOF values (room
temperature, 20 bar H2, 2.0 mmol of substrate in
2.5 mL of THF (0.8M) did not tolerate lower catalyst
tives and analogues, a-arylenamides, and a-substitut- loadings (i.e., higher substrate-to-catalyst [S/C]
ed enol esters (with the exception of the product P8, ratios): only partial conversions were obtained
derived from an enol ester phosphonate),[24] respec- (Table 4, compare entries 1 and 2). We suspect that
tively.
trace amounts of oxygen, water or other unknown
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Josꢀ L. NfflÇez-Rico et al.
FULL PAPERS
Figure 2. Conversion plotted against time for model enantioselective hydrogenation reactions catalyzed by rhodium com-
plexes of ligand L1 (left) or L2 (right).
Table 3. Comparison of the catalytic activity exhibited by
rhodium complexes of ligands L1 and L2 in the enantiose-
lective hydrogenation of model substrates.[a]
Entry
Substrate
TOF1/2 (hÀ1)
Ligand L1
Ligand L2
Scheme 4. Asymmetric hydrogenation of dimethyl itaconate
(S18) catalyzed by [Rh(nbd)(L1)]BF4.
AHCTUNGTRENNUNG
1
2
3
4
S11
S18
S1
>49,000
>14,000
>850
>40,000
>5,000
>500
S23
>550
>250
from our series of studied substrates (S1, S11, S18,
and S23): indeed, we did not observe any differences
in conversion or enantioselectivity in these reactions
compared to those done with an S/C of 100:1 (com-
pare entry 8 in Table 2 with entry 3 in Table 4).
[a]
À
Reaction conditions: [RhACHTNUGTRNEUNG(nbd)2]BF4/P OP ligand/sub-
strate=0.10:0.11:100, room temperature, 20 bar H2,
2.0 mmol of substrate in 2.5 mL of THF (0.8M).
chemicals inside the autoclave sufficed to deactivate
or poison the catalyst. Thus, we envisaged further op- Conclusions
timization studies on the catalyst loading using fixed
amounts of preformed precatalyst {ca. 8 mg of In summary, we have developed highly efficient and
[Rh
ACHTUNGTRENNUNG
reaction, which forced us to work with higher
AHCTUNGTRENNUNG
amounts of substrate at higher concentrations. Much arylenamides, and a-substituted enol esters (S1–
to our delight, we found that an S/C=10,000 sufficed S25)[27] catalyzed by chiral cationic rhodium com-
to fully hydrogenate a model substrate of intermedi- plexes of the enantiopure phosphine-phosphite li-
ate reactivity (i.e., dimethyl itaconate, S18; Scheme 4) gands L1, L2, and ent-L2. The catalytic systems de-
Table 4. Catalyst loading optimization studies in the hydrogenation of dimethyl itaconate (S18) catalyzed by
[Rh
ACHTUNGTRENNUNG
(nbd)(L1)]BF4.[a]
Entry S/C
Reaction conditions
Conv.
[%][b]
ee [%][b]
(config.)
1
1,000 0.32 g S18 (2.0 mmol), 0.8M in THF, 1.9 mg (prepared in situ, 0.2 mmol
[Rh(nbd)(L1)]BF4)
10,000 0.32 g S18 (2.0 mmol), 0.8M in THF, 0.2 mg (0.2 mmol [Rh
10,000 13.6 g S18 (85.7 mmol), ca. 5.0M in THF, 8.1 mg (8.6 mmol [Rh-
(nbd)(L1)]BF4)
>99
99 (S)
ACHTUNGTRENNUNG
2
3
(nbd)(L1)]BF4)
46
>99
99 (S)
99 (S)
ACHTUNGTRENNUNG
[a]
[b]
Reaction conditions: 20 bar H2, 24 h. Autoclave was filled under N2 inside a glove box.
See Table 1 for details.
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À
Modular P OP Ligands in Rhodium-Mediated Asymmetric Hydrogenation
À
excess was determined by GC or HPLC analysis on chiral
stationary phases.
rived from these P OP ligands provided straightfor-
ward access to enantiomerically enriched a-amino
acid, carboxylic acid, amine, and alcohol derivatives
that are valuable chiral building blocks. Excellent effi-
ciencies (full conversion in all cases) and very high
enantioselectivities (94 to 99% ee) were achieved for
a wide range of a-substituted enol ester derivatives,
regardless of the substitution pattern.
General Procedure for Monitoring the
Hydrogenation Reactions by Gas Uptake
Measurements
The gas uptake measurement experiments were performed
in an SPR-16 AMTEC parallel autoclave reactor equipped
with pressure probes and a mass-flow controller that ena-
bled monitoring and recording of gas uptake profiles
throughout the hydrogenation reactions. The required
The R-oxy group of the ligand (methoxy for L1,
and triphenylmethoxy for L2 and its enantiomer)
were found to affect both the catalytic activity and
the enantioselectivity (83 to 99% ee). Greater steric
bulk around the metal centre correlated to greater (or
similar) enantioselectivity, but also to slower hydroge-
nation rates. Furthermore, the hydrogenation rate for
the four model substrates follows the same trend in-
dependently of the R-oxy group of the ligand methyl
2-acetamidoacrylate>dimethyl itaconate>1-phenyl-
vinyl acetate>N-(1-phenylvinyl)acetamide.
amount of [RhACTHNUGTRNEUNG(nbd)2]BF4 (0.90 mg, 2.40 mmol) and ligand
L1 or L2 (10% molar excess with respect to the rhodium
precursor) were dissolved in anhydrous and degassed THF
(1.2 mL) under an N2 atmosphere inside a glove box. This
solution was stirred at room temperature for 30 min in order
to form the desired precatalyst. Separately, another solution
(1.7 mL) of the corresponding model substrate, S1, S11, S18
or S23, (2.27 mmol) in anhydrous and degassed THF was
prepared under an N2 atmosphere inside a glove box.
A substrate-to-catalyst ratio (S/C) up to 10,000:1
sufficed to fully hydrogenate a model substrate of in-
termediate reactivity (dimethyl itaconate), with no
loss in conversion or enantioselectivity.
The stainless steel SPR-16 AMTEC reactor was warmed
up to 1108C and pressurized with N2 to 50 bar, vented (five
cycles) and finally, cooled down to room temperature. After-
wards, the solutions of the precatalyst (1.0 mL, 2.0 mmol,
0.1 mol%) and the substrate (1.5 mL, 2.0 mmol) were subse-
quently added (by syringe) into the reactor, which was fur-
ther flushed with H2 and then pressurized to 20 bar. The stir-
ring rate was adjusted to 1000 rpm and the hydrogen gas
uptake was monitored and recorded automatically. Once
steady hydrogen consumption had indicated that the reac-
tion has reached completion, the reactor was further depres-
surized slowly. The reaction mixture was filtered through
a short pad of SiO2 and eluted with EtOAc (20.0 mL). The
resulting solution was concentrated under vacuum. Full con-
version was confirmed by 1H NMR and enantioselectivity
was determined by GC or HPLC analysis on chiral station-
ary phases; the ee values for the four products (P1, P11,
P18, and P23) corresponding to the four representative sub-
strates (S1, S11, S18, and S23, respectively) are listed in
Table 1 and Table 2.
Experimental Section
General Considerations
Analytical and spectral characterization data for substrates
and products; enantioselectivity analyses for hydrogenation
products; and NMR spectra of newly reported compounds
are provided in the Supporting Information.
General Procedure for the Rhodium-Mediated
Asymmetric Hydrogenations
À
A solution of the required amount of [Rh
(nbd)2]BF4, the P
OP ligand L1, L2 or ent-L2 (10% molar excess with respect
to the rhodium precursor) and the corresponding functional-
ized alkene (any one from S1–S25; 0.10 mmol) in anhydrous
and degassed THF or DCM (0.50 mL) was prepared inside
a glass vessel under an N2 atmosphere in a glove box. In all
cases the molar concentration of the substrate in the reac-
tion medium was adjusted to 0.20M.
Once the reaction mixture had been loaded, the glass
vessel was then placed into one of the holes of a steel auto-
clave reactor (HEL Cat-24 parallel pressure multireactor).
The autoclave was purged three times with H2 gas (at a pres-
sure not higher than the chosen one). Finally, the autoclave
was pressurized under the required pressure of H2 gas (20,
40 or 80 bar H2). The mixture was stirred at the desired tem-
perature (room temperature or 08C) for 18 h (overnight re-
action). The autoclave was then depressurized slowly, at
which point the reaction mixture was filtered through
a short pad of SiO2 and subsequently eluted with EtOAc
(1.0 mL). The resulting solution was concentrated under
vacuum. The conversion was determined by 1H NMR
(19F NMR in the case of substrate S9) and the enantiomeric
Experimental Procedure for Hydrogenation of
Dimethyl Itaconate using S/C Ratios >1,000:1
Working inside a glove box, a solution of the required
amount of dimethyl itaconate (S18) in anhydrous and de-
oxygenated THF (ca. 75% w/w) was added (by syringe) into
a steel liner, followed by the addition of a solution of ca.
8 mg of [RhACHTUNGRTENNG(U nbd)(L1)]BF4 (8.6 mmol) in 2 mL of THF. The
steel liner was closed, and then removed from the glove
box. The final molar concentration of the substrate was ca.
5.0M.
The steel liner was then attached to the liquid filling port
of an adequately sized and dried autoclave (previously
heated overnight at 1108C under 30 bar of N2). Once the re-
actor had reached 258C and the liner had been attached to
the autoclave, the reaction mixture was loaded into the reac-
tor by pressurizing the liner with N2. The reactor was then
purged three times with H2 gas (5 bar) and subsequently
pressurized to 20 bar with H2.The reaction mixture was
stirred at room temperature for 24 h. The autoclave was
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Josꢀ L. NfflÇez-Rico et al.
FULL PAPERS
subsequently depressurized and purged with N2. The result-
ing solution was concentrated under vacuum. Full conver-
sion was confirmed by H NMR analysis and enantioselec-
tivity was determined by GC analysis on a chiral stationary
phase; the ee value for the product P18 (corresponding to
the substrate S18) is listed in Table 4.
2011; m) S. Lühr, J. Holz, A. Bçrner, ChemCatChem
2011, 3, 1708.
1
[4] For a comprehensive review describing the synthesis of
these types of phosphorus ligand and their applications
in asymmetric catalysis, see: H. Fernµndez-Pꢀrez, P.
Etayo, A. Panossian, A. Vidal-Ferran, Chem. Rev.
2011, 111, 2119.
[5] A. Panossian, H. Fernµndez-Pꢀrez, D. Popa, A. Vidal-
Ferran, Tetrahedron: Asymmetry 2010, 21, 2281.
[6] J. L. NfflÇez-Rico, H. Fernµndez-Pꢀrez, J. Benet-Buch-
holz, A. Vidal-Ferran, Organometallics 2010, 29, 6627.
[7] a) H. Fernµndez-Pꢀrez, M. A. Pericàs, A. Vidal-Ferran,
Adv. Synth. Catal. 2008, 350, 1984; b) S. M. A. Donald,
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Acknowledgements
The authors thank the Spanish Ministerio de Economia y
Competitividad (CTQ2011-28512), the Generalitat de Catalu-
nya (2009SGR 00623) and the ICIQ Foundation for financial
support. H. F.-P. acknowledges the “Programa Torres Queve-
do” for financial support. J. L. N.-R. thanks the ICIQ Foun-
dation for a predoctoral fellowship.
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present study as ligand L1 failed to mediate the enan-
tioselective hydrogenation of N-((1-tert-butyl)vinyl)ace-
tamide (see ref.[7d]).
[23] The asymmetric hydrogenation of substrate S25 usually
leads to moderate results in terms of conversion and
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Jia, R. Guo, X. Li, X. Yao, A. S. C. Chan, Tetrahedron
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Yeung, K.-H. Lam, T. W. H. Lo, A. S. C. Chan, Tetrahe-
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Xu, Q. Shi, X. Yao, A. S. C. Chan, J. Org. Chem. 2003,
68, 4539; d) W. Zhang, X. Zhang, Angew. Chem. 2006,
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Am. Chem. Soc. 2012, 134, 1754.
[12] K. Tanaka, M. Katsurada, F. Ohno, Y. Shiga, M. Oda,
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[24] The change to the (S)-configuration in the hydrogena-
tion products of itaconic acid derivatives and analogues
(P18–P22), as well as for the product derived from the
enol ester phosphonate S8 (P8), is due to an inversion
in the CIP priority rules.
[16] Reactions run at hydrogen pressures below 80 bar H2
led to incomplete conversion.
[25] a) C. R. Landis, P. Hilfenhaus, S. Feldgus, J. Am. Chem.
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[18] See: a) S. Balasubramaniam, I. S. Aidhen, Synthesis
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[26] Asymmetric Catalysis on Industrial Scale: Challenges,
Approaches and Solutions, 1st edn., (Eds.: H. U. Blaser,
E. Schmidt), Wiley-VCH, Weinheim, 2004, p 45.
[27] A useful summary on Rh-mediated asymmetric hydro-
genations of substrates S1, S8, S11, S15, S18, S22, and
S23 has been recently provided by Stephan et al. in the
Supporting Information of ref.[9j]
[19] The configuration of the hydrogenation products di-
methyl itaconate (P18) and itaconic acid (P19) was in-
correctly reported to be R in previous contributions by
our group (see refs.[7a,c,d]): the absolute configuration of
these products should be S. For more details, see the
results recently summarized in ref.[4] and in the Sup-
porting Information.
Adv. Synth. Catal. 2012, 354, 3025 – 3035
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3035