Synthesis of versatile building blocks through asymmetric hydrogenation of functionalized itaconic acid mono-esters

Article abstract of DOI:10.1002/adsc.200700307

The rhodium-catalyzed asymmetric hydrogenation of several β-substituted itaconic acid monoesters, using a library of monodentate phosphoramidite and phosphite ligands is described. Two β-alkylsubstituted substrates were readily hydrogenated by the rhodium complex Rh(COD) ₂BF₄ in combination with (S)-PipPhos as a ligand resulting in ees of 99 %. In contrast, the corresponding more hindered β-arylsubstituted substrates did not exhibit acceptable enantioselectivities under these conditions. However, the use of a 48-membered ligand library led to the identification of several suitable ligands for these substrates, resulting in ees of 89-99%. The resulting optically active succinic acid derivatives are potentially useful building blocks for more elaborate compounds, because of the ability to differentiate between the carboxylic acid and the ester groups on either side of the molecule.

Full text of DOI:10.1002/adsc.200700307

FULL PAPERS
DOI: 10.1002/adsc.200700307
Synthesis of Versatile Building Blocks through Asymmetric
Hydrogenation of Functionalized Itaconic Acid Mono-Esters
Koen F. W. Hekking,a Laurent Lefort,b AndrØ H. M. de Vries,b Floris L. van Delft,a
Hans E. Schoemaker,b Johannes G. de Vries,b,* and Floris P. J. T. Rutjesa,*
a
Institute for Molecules and Materials, Radboud University Nijmegen, Toernooiveld 1, 6525 ED Nijmegen,
The Netherlands
Fax : (+31)-24-365-3393; e-mail: F.Rutjes@science.ru.nl
DSM Pharmaceutical Products, Advanced Synthesis, Catalysis & Development, P.O. Box 18, 6160 MD Geleen,
b
The Netherlands
Received: June 26, 2007; Published online: November 23, 2007
Abstract: The rhodium-catalyzed asymmetric hydro- identification of several suitable ligands for these
genation of several b-substituted itaconic acid mono- substrates, resulting in ees of 89–99%. The resulting
esters, using a library of monodentate phosphorami- optically active succinic acid derivatives are poten-
dite and phosphite ligands is described. Two b-alkyl- tially useful building blocks for more elaborate com-
substituted substrates were readily hydrogenated by pounds, because of the ability to differentiate be-
the rhodium complex RhACHTRE(UNG COD)2BF4 in combination tween the carboxylic acid and the ester groups on
with( S)-PipPhos as a ligand resulting in ees of 99%. either side of the molecule.
In contrast, the corresponding more hindered b-aryl-
substituted substrates did not exhibit acceptable Keywords: asymmetric catalysis; asymmetric hydro-
enantioselectivities under these conditions. However, genation; itaconic acid; monodentate phosphorami-
the use of a 48-membered ligand library led to the dite ligands; rhodium; succinic acid
Introduction
cinic diesters (4) and diacids (5) is however limited,
since it is virtually impossible to differentiate between
Over the past decades, homogeneous asymmetric hy- the two acid/ester groups. On the other hand, the use
drogenation of prochiral olefins has proven to be one of itaconic acid monoesters (e.g., 3) would result in
of the most powerful methods for the synthesis of succinic acid derivatives of type 6. These compounds
enantiomerically pure building blocks. Today, this would be considerably more useful than 4 or 5, since
clean and atom-efficient reaction has a broad scope carboxylic acids can normally be reduced selectively
and is amongst the most studied catalytic transforma- in the presence of ester groups, thereby discriminating
tions. Numerous new catalyst systems are reported between the two parts of the molecule.[2] These bi-
each year, thereby continuously increasing the effi- functional, enantiomerically pure compounds could
ciency and scope of this reaction.[1] Dimethyl itaco- thus be transformed into useful building blocks for a
nate (1) and – to a lesser extent – itaconic acid (2) are range of (pharmaceutically relevant) natural prod-
commonly used model substrates in the development ucts.[3]
of new catalyst systems for asymmetric hydrogenation
Surprisingly, the use of such itaconic acid monoest-
(Scheme 1). The synthetic value of the resulting suc- ers in asymmetric hydrogenation research has re-
ceived only moderate attention[4] and particularly ex-
amples of substrates witha carboxylic acid moiety in
the conjugated position are rare.[3,4b,5] In addition, the
asymmetric hydrogenation of substituted itaconate
derivatives has remained relatively unexplored.[4a,c,6]
In this paper we wish to report the rhodium-cata-
lyzed asymmetric hydrogenation of b-substituted ita-
conic acid monoesters, using a monodentate phos-
phoramidite ligand library, developed by Feringa,
Minnaard, de Vries et al. in collaboration withDSM
Scheme 1. Asymmetric hydrogenation of itaconic acids and
its mono- and diesters.
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Figure 1. General structure of phosphoramidite ligands and
structure of MonoPhos.
Pharmaceutical
Products
(e.g.,
MonoPhos,
Figure 1).[7,8] Over the past years, these phosphorus li-
gands have been successfully applied in the asymmet-
ric hydrogenation of a range of prochiral olefins, in-
cluding a- and b-dehydroamino acids and esters,[9] ita-
conic acid and its dimethyl ester,[9b–e] enol acetates
and enol carbamates,[10] enamides,[11] acrylic acids[12]
and imines.[13] Besides asymmetric hydrogenation, this
class of ligands has also been successfully applied in
the enantioselective copper-catalyzed conjugate addi-
tion of dialkylzinc reagents,[14] in asymmetric hydrosi-
lylation,[15] in asymmetric hydrovinylation,[16] in asym-
metric cyclopropanation,[17] in allylic substitution,[18] in
the asymmetric Phauson–Khand reaction,[19] in the
asymmetric Heck reaction,[20] in asymmetric cycloiso-
merization,[21] in asymmetric allyl alcohol isomeriza-
tion,[22] in asymmetric [2+2+2]cycloaddition[23] and
in asymmetric arylations using arylboronic acids.[24]
Scheme 2. Synthesis of unsubstituted and ethyl-substituted
itaconates.
Results and Discussion
We chose to focus our attention on four different ita-
conic acid derivatives. Besides the unsubstituted
monoester 3a, an ethyl-substituted analogue (3b) and
two aryl-substituted substrates (3c and d) were select-
ed as starting points. The preparation of the itaconate
derivatives 3 was carried out via several methods. The
Scheme 3. Synthesis of aryl-substituted itaconates via
Stobbe condensation.
a
unsubstituted monoester 3a could be readily synthe- ous, because it would require the preparation of the
sized from itaconic acid (2) itself. Reaction of 2 in the corresponding nitroalkane reagents, which are not
presence of Amberlyst 15 in methanol under reflux commercially available. Therefore, we chose to pre-
conditions afforded pure 3a in 94% yield, accompa- pare 3c and 3d through a Stobbe condensation[26] of
nied by only trace amounts of the corresponding die- dimethyl succinate (9) withaldeyhdes
ster (Scheme 2). The synthesis of the b-substituted (Scheme 3).
10a and b
itaconates required a somewhat larger effort. First of
Condensation of dimethyl succinate with benzalde-
all, ethyl-substituted monoester 3b was readily synthe- hyde and 4-methoxybenzaldehyde in refluxing tert-
sized using a reported procedure.[25] Hence, dimethyl butyl alcohol resulted in the formation of monoesters
maleate (7) was reacted with1-nitropropane in the
11a and b as single (E)-geometrical isomers. Next, the
presence of one equivalent of DBU, resulting in se- monoesters were hydrolyzed with 2M NaOH and the
quential conjugate addition and elimination of HNO2. resulting diacids were again monoesterified withAm-
The formed (E)-diester 8 was then hydrolyzed with berlyst 15 in methanol, leading to the desired hydro-
aqueous NaOH, followed by selective monoesterifica- genation precursors 3c and d.
tion with Amberlyst 15 in methanol, resulting in the
formation of 3b in 53% from 7 (Scheme 2).
As already pointed out in the introduction, asym-
metric hydrogenations of the four itaconates were
Synthesis of aryl-substituted itaconic acid monoest- performed using a phosphoramidite ligand library.
ers via the previously described route is more labori- Their good accessibility and modular nature makes
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Asymmetric Hydrogenation of Functionalized Itaconic Acid Mono-Esters
FULL PAPERS
tives and dimethyl itaconate,[9b] and enol acetates/car-
bamates.[10] For this reason we decided to start our in-
vestigations into the hydrogenation of 3a–d with L1
(Table 1). The hydrogenations were carried out in an
Endeavor apparatus,[28] which is essentially an auto-
clave witheight parallel reaction vessels capable of
accommodating 5 mL of solvent. In addition, it allows
the continuous monitoring of hydrogen uptake, there-
by enabling the reactions to be followed in time. The
Figure 2. General synthetic route for phosphoramidite li-
gands.
these ligands particularly suitable for combinatorial hydrogenations in Table 1 were carried out at a pres-
applications.[27] Phosphoramidites are essentially built sure of 5 bar with0.5 mmol of substrate, using 2
up from two fragments, bothof whichcan be varied
to a large extent. In a common synthetic procedure, a
mol% of [Rh
ACHTRE(UNG COD)2]BF4 and 4 mol% of ligand.
We were pleased to find that the hydrogenation of
(non-)chiral diol is converted into the corresponding 3a and 3b in dichloromethane proceeded nearly quan-
chlorophosphite by refluxing in an excess of PCl3. titatively and withexcellent ees of 97 and 94% (en-
This chlorophosphite is then reacted with the appro- tries 1 and 2), thus eliminating the need for extensive
priate (non-)chiral amine in the presence of triethyl- optimization for these substrates. On the other hand,
amine, resulting in the phosphoramidite ligand, which the reactions of 3c and 3d under the same conditions
can often be purified by crystallization (Figure 2).
resulted in lower conversions[29] and ees of 52 and
Although MonoPhos (see Figure 1) was the first 46% (entries 3 and 4). A striking difference in reac-
phosphoramidite ligand that was discovered to induce tivity was observed when carrying out the hydrogena-
high enantioselectivities in olefin hydrogenation,[9e] tions of 3a–d in methanol instead of dichloromethane.
follow-up research has shown other analogous ligands No significant hydrogen uptake was observed for 3b–
to be better suited for numerous substrates. For in- d, indicating that no reaction had taken place (en-
stance, PipPhos (L1) was identified as an excellent tries 6–8). The reaction of 3a was found to proceed
ligand for the asymmetric hydrogenations of a range quantitatively, however, hardly any enantiomeric
of compounds, including dehydroamino acid deriva- excess was observed (entry 5). This extreme solvent
Table 1. Asymmetric hydrogenation in Endeavor apparatus.
Entry
Substrate
R
Ligand
Solvent
Product
Conversion [%][a]
ee [%][a,b]
1
3a
3b
3c
3d
3a
3b
3c
3d
3d
3d
H
Et
(S)-L1
(S)-L1
S)-L1
(S)-L1
(S)-L1
(S)-L1
S)-L1
(S)-L1
(S)-L2
(S)-L3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
MeOH
MeOH
MeOH
CH2Cl2
CH2Cl2
6a
6b
6c
6d
6a
6b
6c
6d
6d
6d
>99
98
91
97
94
52
46
2
3[c]
4
Ph(
p-MeOC6H4
H
Et
Ph(
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
60
5
6
7
8
9
10
>99
n.d.[d]
n.d.[d]
n.d.[d]
86
-7
n.d.
n.d.
n.d.
62
78
-51
[a]
Determined by HPLC.
(S)-configuration.
Pressure slowly raised to 25 bar.
No significant H2-consumption was observed; n.d.=not determined.
[b]
[c]
[d]
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Table 2. Influence of lower catalyst loadings.[a]
Entry
Substrate
R
Catalyst [mol%]
Ligand
Concentration [M]
Product
Conversion [%][b]
ee [%][b,c]
1
2
3
4
3a
3b
3a
3b
H
Et
H
0.5
0.5
1
(S)-L1
(S)-L1
(S)-L2
(S)-L2
0.2
0.2
0.1
0.1
6a
6b
6a
6b
>99
>99
>99
>99
99.7
58
98
Et
1
91
[a]
Conditions: RhACHTREUNG(COD)2BF4/ligand (1:2), CH2Cl2, H2 (5 bar), r.t., 18 h.
Determined by HPLC.
(S)-configuration.
[b]
[c]
dependency has been observed before with these cat-
alyst systems and in many cases the use of non-protic
solvents appears to give the best results;[8] known ex-
ceptions are the hydrogenations of (Z)-N-acetyl-b-de-
hydroamino acid esters[9d] and a-substituted cinnamic
acids[12] which proceed best in 2-propanol and 2-prop-
anol/water mixtures, respectively. Additionally, we in-
vestigated whether different ligand backbones had an
influence on the enantioselectivity in the hydrogena-
tion of the aryl-substituted substrate 3d (entries 9 and
10). We employed an octahydro analogue of L1 (i.e.,
L2) and a ligand witha 3,3 ’-dimethylBINOL moiety
(L3). Unfortunately, these two ligands offered only a
slight improvement in terms of enantioselectivity. The
result from entry 10 is remarkable, since the opposite
enantiomer is formed, possibly due to a different co-
ordination mode of substrate and/or ligands to the
rhodium.
Figure 3. Schematic representation of the automated ligand
synthesis and subsequent hydrogenation.
Furthermore, we decided to study the influence of
lower catalyst loadings on the conversion and enan-
tioselectivity of the hydrogenations of 3a and 3b was placed inside a glove-box. Stock solutions of the
(Table 2). Lowering the amount of catalyst from chlorophosphite, triethylamine and the amine or the
2 mol% to 0.5 mol% actually improved the ee of 6a alcohol (for the preparation of phosphites rather than
somewhat (99.7%, entry 1). On the other hand, the ee phosphoramidites) were dispensed into a microtiter
of 6b was found to be surprisingly low (58%, entry 2), plate, which was shaken for 2 h followed by parallel
indicating that for this substrate at least 2 mol% of filtration, affording the different ligands in solution.
catalyst is required to obtain an acceptable ee. This Next, fractions of the ligand solutions were trans-
latter result can probably be ascribed to the presence ferred to 48 vials, alongside withteh solutions of
of minor impurities in the starting material.
(COD)2BF4 and the substrate (3d).[30] The 48 paral-
RhACHTREUNG
The use of ligand L2, which already slightly im- lel hydrogenations were performed in dichlorome-
proved the enantioselectivity for 3c (see Table 1), re- thane in a Premex 96-Multi Reactor,[31] using 4 mol%
sulted in comparable ees for the hydrogenation of 3a of catalyst and 25 bar of H2 at room temperature for
and 3b (entries 3 and 4). It should be noted that these 6 h. Afterwards, conversions and ees were determined
two experiments were performed with1 mol% of cat-
by chiral HPLC.
alyst, making comparison in the case of 3b more com-
The 48 ligands that were selected for the parallel hy-
plicated, in view of the influence of catalyst loading drogenation experiment are depicted in Figure 4 a. Be-
discussed earlier (see above). sides eight secondary amines, we decided to include
Because the hydrogenation experiments conducted five primary amines, because we envisaged that the
so far with 3c and 3d did not result in satisfactory steric hindrance of 3c and d can possibly be compen-
enantioselectivities, we decided to carry out a high- sated for by using less hindered ligands. Phosphorami-
throughput experiment with a solution phase library dite ligands derived from primary amines are generally
of 48 ligands. Figure 3 shows a schematic representa- known to be somewhat unstable, especially towards
tion of the parallel ligand synthesis and subsequent column chromatography purification used in tradition-
hydrogenation. The ligands were prepared in a fully al synthesis. The mild purification used in the automat-
automated fashion by a liquid handling robot, which ed synthesis and the immediate coordination of the
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Asymmetric Hydrogenation of Functionalized Itaconic Acid Mono-Esters
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Figure 4. Asymmetric hydrogenation of 3d. a) List of amines/alcohols and backbones used in ligand library. b) Conversions
and (absolute) ee values.
ligand to the metal makes these ligands easily avail- tion is presented by the ligands based on N-benzylani-
able. We have previously shown that these NH ligands line (entries A5, B5 and C5). Although the conver-
lead to the formation of very fast rhodium catalysts sions obtained withthese ligands are poor (26–34%),
that have hydrogenation rates comparable to or better the observed ees are surprisingly high (99–100%). In
[32]
than the best rhodium bisphosphine complexes.
addition, the isopropyl-substituted phosphite ligand in
In addition, we used three different alcohols instead entry A14 also gave a high conversion (95%) and ee
of amines, resulting in the corresponding phosphite li- (94%), suggesting that monodentate phosphite li-
gands – a class of ligands reported by Reetz and co- gands are also suitable for the hydrogenation of these
workers[33] – which are also excellent ligands for substrates. Finally, the more hindered 3,3’-dimethyl-
asymmetric hydrogenation. Moreover, we chose to BINOL-based ligands (B) were found to be less
study three different BINOL-type ligand backbones suited for this specific substrate, generally exhibiting
(i.e., A–C), whichin combination withthe 16 amine/
alcohol fragments eventually resulted in a library of is again in agreement with the observation that less
48 different ligands. hindered ligands are required for the hydrogenation
Figure 4 b shows the results obtained in the asym- of more hindered substrates.
poor conversions and at best only moderate ees. This
metric hydrogenation of 3d. To our delight, several
In the end, two ligands were selected from the li-
entries resulted in botha conversion and an ee of brary to be scaled up to a 0.5-mmol scale and to test
ꢀ90%. In general, the ligands based on the regular if similar results could be obtained withsubstrate 3c.
BINOL backbone (A) appeared to be the most suita- First of all, phosphoramidite ligand L4[35] was selected
ble. Entries A9, A10, A12 and A14 showed the best based on the results in entry A9 in Figure 4. In addi-
results, withconversions of 90–100% and ees of 94– tion, we chose to use the analogous phosphite ligand
98%.[34] The ligands that were based on the octahy- L5[36] in view of possible instability issues with L4
dro-BINOL backbone (C) gave lower conversions (Figure 5).
and ees, with the exception of those used in entries
Table 3 shows the application of L4 and L5 in the
C9 and C10, which produced data comparable to hydrogenation of 3c and d on a 0.5-mmol scale in the
those from the analogous ligands in entries A9 and Endeavor reactor. The ligands were prepared in a
A10. Clearly, the use of phosphoramidite ligands similar fashion as in the library experiment, namely in
based on primary amines is the key to success for the a glove-box and using the same stock solutions as
hydrogenation of 3d. While these ligands in a number used in the parallel synthesizer. First of all, we were
of cases gave excellent ees and conversions, the li- pleased to see that the behaviour of 3c in terms of re-
gands based on secondary amines led to poor conver- activity and enantioselectivity was almost identical to
sions and in most cases low ees. A noteworthy excep- that of 3d. The use of phosphite ligand L5 resulted in
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Koen F. W. Hekking et al.
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AHCTREUNG
Figure 5. Isopropyl-substituted phosphoramidite (L4) and
phosphite (L5) ligands.
Table 3. Translation of library results to 0.5-mmol Endeavor
experiments.[a]
Entry Substrate L[b]
Product Conversion
[%][c]
ee
[%][c,d]
1
2
3
4
3c
3d
3c
3d
(S)-
L4
(S)-
L4
(S)-
L5
6c
6d
6c
6d
>99
>99
>99
>99
91
92
97
96
For the hydrogenation of 3c and d, a solution of
ligand L5 was synthesized in a glove-box under identi-
cal conditions as employed in the library experiment.
Next, the appropriate amount of this solution, the
(S)-
L5
[a]
[b]
Conditions: RhACHTREUNG(COD)2BF4 (1 mol%), ligand (2 mol%),
RhACHTRE(UNG COD)2BF4 and the dichloromethane were trans-
solvent (0.1M), H2 (25 bar), r.t., 2 h.
Ligands were prepared in a glove box and not further pu-
rified.
Determined by HPLC.
(S)-configuration.
ferred into the high-pressure vessel and the hydroge-
nation was performed under 25 bar of H2 (entries 3
and 4). The conversions of the starting materials were
again quantitative, however, the ees were somewhat
lower than those observed in the library and Endeav-
or experiments. In the end, compounds 6c and 6d
[c]
[d]
quantitative conversions and ees of 96 and 97% (en- were isolated with ees of 94 and 89%, respectively.
tries 3 and 4), which are slightly better than the re-
sults obtained in the library experiment. However,
phosphoramidite ligand L4 was found to give some- Conclusions
what lower ees than those observed in the library ex-
periment (91–92% compared to 96%, entries 1 and Rhodium(I)-catalyzed asymmetric hydrogenation of
2). Preforming the catalyst complex [(L)2Rh- b-substituted itaconic acid monoesters proceeded
Table 4. Autoclave hydrogenations on a gram-scale.
Entry Sub-
strate
R
Catalyst Ligand
[%]
Concentration Pressure [bar]
[M]
Product Conversion ee
[%][a]
[%][b]
1
2
3
4
3a
3b
3c
3d
H
Et
0.5
2
(S)-L1
0.28
0.11
0.10
0.12
10
10
25
25
6a
6b
6c
6d
>99
>99
>99
>99
99 (S)
99 (S)
94 (R)
89 (R)
(S)-L1
Ph2
p-MeOC6H4
(
R)-L5[c]
(R)-L5[c]
2
[a]
[b]
[c]
1
Determined by H NMR.
Determined by HPLC.
Ligand synthesized by hand in a glove-box; (R)-isomer was prepared.
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Asymmetric Hydrogenation of Functionalized Itaconic Acid Mono-Esters
FULL PAPERS
vent was evaporated yielding a white solid. The crude prod-
uct was recrystallized (heptane/toluene, 3:2) affording pure
3a as white crystals; yield: 2.11 g (94%). The analytical data
agreed with those reported in the literature.[38] 1H NMR
(CDCl3, 300 MHz): d=6.48 (m, 1H), 5.84 (m, 1H), 3.71 (s,
3H), 3.35 (s, 2H); 13C NMR (CDCl3, 75 MHz): d=171.2,
171.1, 133.3, 131.1, 52.3, 37.2.
readily and resulted in high ees, using a monodentate
phosphoramidite/phosphite ligand library. Unsubsti-
tuted and b-ethyl-substituted substrates could be con-
verted into the corresponding succinic acid derivatives
on a gram-scale, using (S)-PipPhos as a ligand. Under
5 bar of H2 the conversions were complete within 3 h
with ees of 99%. On the other hand, the reaction of
the corresponding aryl-substituted substrates under
identical conditions proceeded significantly slower
and withlower ees, thus demanding further optimiza-
tion. Investigation of the hydrogenation of one of
these latter substrates with a 48-membered ligand li-
brary, resulted in the discovery of a number of suita-
ble ligands, that exhibited ees up to 99%. Finally,
gram-scale hydrogenation of all itaconates under
25 bar of H2 produced the corresponding succinic acid
derivatives quantitatively and with ees of 94 and
89%, respectively. The resulting optically active suc-
cinic acid derivatives are potentially useful building
blocks for more elaborate compounds, because of the
difference in reactivity between the carboxylic acid
and ester groups on either side of the molecule. An
example from our group illustrating the synthetic use
of these scaffolds is described in the following article
in this issue.[2]
(E)-2-(2-Methoxy-2-oxoethyl)pent-2-enoic Acid (3b)
To a solution of dimethyl maleate (5.03 g, 33.5 mmol) in
MeCN (100 mL) were added 1-nitropropane (3.05 mL,
33.5 mmol) and DBU (5.05 mL, 33.6 mmol). The mixture
was stirred at room temperature for 20 h, after which the
volatiles were removed under vacuum. The crude product
was purified by column chromatography (EtOAc/heptane,
1:6). The resulting diester was dissolved in EtOH (30 mL)
and aqueous NaOH (0.5M, 150 mL) was added. The mix-
ture was stirred at reflux temperature for 1 h, followed by
evaporation of most of the EtOH under reduced pressure.
Extra H2O (100 mL) was added and the mixture was
washed with EtOAc (3”100 mL). Next, the aqueous layer
was acidified (pH~1) with2M HCl, extracted withEtOAc
(2”150 mL) and the organic layers were dried (MgSO4) and
concentrated. The resulting diacid was dissolved in MeOH
(150 mL), Amberlyst-15H+ (3.5 g) was added and the reac-
tion mixture was refluxed for 7 h. The mixture was filtered
over Celite and concentrated under vacuum, resulting in
crude 3b. The product was recrystallized from toluene/hep-
tane, yielding 3b as a white crystalline solid. The overall
yield was 3.06 g (53%). The analytical data agreed with
those reported in the literature.[25a] 1H NMR (CDCl3,
300 MHz): d=7.09 (t, J=7.6 Hz, 1H), 3.68 (s, 3H), 3.34 (s,
2H), 2.22 (m, 2H), 1.07 (t, J=7.6 Hz, 3H); 13C NMR
(CDCl3, 75 MHz): d=172.3, 171.1, 150.0, 124.3, 52.1, 31.7,
22.5, 12.8.
Experimental Section
General
All reactions were carried out under an atmosphere of dry
argon, unless stated otherwise. Argon was dried over SICA-
PENTꢁ, CaCl2 and KOH. Infrared (IR) spectra were ob-
tained using an ATI Mattison Genesis Series FTIR spec-
trometer and wavelengths (n) are reported in cmÀ1. Optical
rotations were measured on a Perkin–Elmer 241 polarime-
ter, using concentrations (c) in g/100 mL in the indicated
solvents. 1H and 13C nuclear magnetic resonance (NMR)
spectra were determined in CDCl3, unless indicated other-
wise, using a Bruker DMX200 (200 MHz) or a Bruker
DMX300 (300 MHz) spectrometer. Chemical shifts (d) are
given in ppm downfield from tetramethylsilane. HR-MS
measurements were carried out using a Fisons (VG) Micro-
mass 7070E or a Finnigan MAT900S instrument. Column
chromatography was performed with Acros Organics silica
gel (0.035Æ0.070 nm) or Merck silica gel 60 (0.040–
0.063 mm). Unless stated otherwise, all commercially avail-
able reagents were used as received. Ligands L1–L3 were
synthesized through a procedure reported in the litera-
ture.[37]
(E)-2-Benzylidene-4-methoxy-4-oxobutanoic Acid
(3c)
To a refluxing suspension of KOtBu (16.5 g, 140.5 mmol) in
t-BuOH (100 mL) was carefully added a solution of dimeth-
yl succinate (23.3 g, 159 mmol) and benzaldehyde (13.6 g,
127 mmol) in t-BuOH (100 mL). The reaction mixture was
stirred at reflux temperature for 18 h, after which the sol-
vent was removed under vacuum. The residue was dissolved
in 1M HCl (100 mL) and this solution was extracted with
EtOAc (3”100 mL). The organic layers were dried
(Na2SO4) and concentrated. The resulting monoacid was dis-
solved EtOH (50 mL) and aqueous NaOH (2M, 100 mL)
was added. The reaction was stirred at reflux temperature
for 1 h, followed by evaporation of most of the EtOH under
reduced pressure. Extra H2O (100 mL) was added and the
mixture was washed with EtOAc (3”100 mL). Next, the
aqueous layer was acidified (pH~1) with2M HCl, extracted
withEtOAc (2”100 mL) and the organic layers were dried
(Na2SO4) and concentrated. The resulting diacid was dis-
solved in MeOH (170 mL), Amberlyst-15H+ (5.8 g) was
added and the reaction mixture was refluxed for 16 h. The
mixture was filtered over Celite and concentrated under
vacuum, resulting in crude 3c. The product was recrystal-
lized from toluene/heptane, yielding 3c as a white solid. The
overall yield was 11.5 g (41%). The analytical data agreed
4-Methoxy-2-methylene-4-oxobutanoic Acid (3a)
Amberlyst-15H+ (2.4 g) was washed to neutral with MeOH
and added to a solution of itaconic acid (2.03 g, 15.6 mmol)
in MeOH (40 mL). After gentle stirring for 6 d at room tem-
perature, the suspension was filtered over Celite and the sol-
vent evaporated. The resulting light brown solid was dis-
solved in CH2Cl2 and filtered over Celite after which the sol-
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91

Koen F. W. Hekking et al.
FULL PAPERS
with those reported in the literature.[39] 1H NMR (CDCl3,
300 MHz): d=8.03 (s, 1H), 7.38 (m, 5H), 3.75 (s, 3H), 3.56
(s, 2H); 13C NMR (CDCl3, 75 MHz): d=172.7, 171.4, 144.3,
134.6, 129.3, 129.2, 128.7, 125.2, 52.3, 33.2.
333 mL, 0.05 mmol),
a
triethylamine solution (0.50M,
100 mL, 0.05 mmol) and solutions of the selected amines and
alcohols (0.15M, 333 mL, 0.05 mmol). The microplate was
shaken for 2 h, after which parallel filtration was performed
to remove the precipitated salts, yielding 48 solutions of the
different ligands (0.065M). The appropriate amounts of the
ligand solutions (93 mL, 8 mol%) were transferred into 48
vials, equipped withstirring bars and the toluene was al-
lowed to evaporate overnight. Next, a stock solution of
(E)-4-Methoxy-2-(4-methoxybenzylidene)-4-
oxobutanoic Acid (3d)
To a refluxing suspension of KO-t-Bu (16.8 g, 150 mmol) in
t-BuOH (60 mL) was carefully added a solution of dimethyl
succinate (17.5 g, 120 mmol) and 4-methoxybenzaldehyde
(13.6 g, 100 mmol) in t-BuOH (60 mL). The reaction mix-
ture was stirred at reflux temperature for 18 h, after which
the solvent was removed under vacuum. The residue was
dissolved in 1M HCl (80 mL) and this solution was extract-
ed withEtOAc (3”75 mL). The organic layers were dried
(Na2SO4) and concentrated. The resulting monoacid was dis-
solved EtOH (40 mL) and aqueous NaOH (2M, 100 mL)
was added. The reaction mixture was stirred at reflux tem-
perature for 2 h, followed by evaporation of most of the
EtOH under reduced pressure. Extra H2O (100 mL) was
added and the mixture was washed with EtOAc (3”
100 mL). Next, the aqueous layer was acidified (pH~1) with
2M HCl, extracted withEtOAc (3”150 mL) and the organ-
ic layers were dried (Na2SO4) and concentrated. The result-
ing diacid was dissolved in MeOH (200 mL), Amberlyst-
15H+ (8.5 g) was added and the reaction mixture was re-
fluxed for 18 h. The mixture was filtered over Celite and
RhACHTER(UNG COD)2BF4 in CH2Cl2 (0.020M, 150 mL, 4 mol%) was
added to each of the vials, allowing the formation the differ-
ent catalysts. A solution of 3d in CH2Cl2 (0.03M, 2.5 mL, 75
mmol) was then added to each vial and the resulting mix-
tures were transferred under a N2 atmosphere to the parallel
hydrogenation apparatus. The mixtures were hydrogenated
under 25 bar of H2 for 6 hand the conversions and ees were
determined by chiral HPLC (Chiralcel OD column; hep-
tane/2-propanol/TFA, 95:5:0.05). The conversions and (ab-
solute) ees are depicted in Figure 4.
General Procedure Afor the Hydrogenation of 3a–d
in an Autoclave Vessel
To a Schlenk tube were added RhACHTRE(UNG COD)2BF4, the ligand
and dry CH2Cl2 (5 mL) under a nitrogen atmosphere. The
resulting orange solution was stirred at room temperature
for 10 min. In a Parr Hastelloy C autoclave were sequential-
ly added 3, CH2Cl2 (45 mL) and the catalyst solution. Next,
concentrated under vacuum, resulting in crude 3d. Th e the vessel was closed and the reaction mixture was stirred
product was recrystallized from toluene/heptane, yielding 3d
by an overhead turbine stirrer at room temperature and
under nitrogen. Then, hydrogen pressure was applied and
the mixture was stirred for the specified time. After that,
as an off-white crystalline solid. The overall yield was 13.1 g
1
(52%). H NMR (CDCl3, 300 MHz): d=7.96 (s, 1H), 7.35
1
(d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 3.83 (s, 3H),
3.74 (s, 3H), 3.59 (s, 2H); 13C NMR (CDCl3, 75 MHz): d=
172.6, 171.6, 160.6, 144.0, 131.2, 127.1, 122.8, 114.2, 55.4,
52.3, 33.3; HR-MS (CI+): m/z=250.0835, calcd. for
C13H14O5, [M]+: 250.0841.
the conversion was measured by H NMR and the ee was
determined by chiral HPLC. The solvent was evaporated
and the product was purified by column chromatography
(EtOAc/heptane, 1:2).
(S)-4-Methoxy-2-methyl-4-oxobutanoic Acid (6a)
Endeavor Experiments
This compound was prepared from 3a (2.01 g, 13.9 mmol)
The substrate, Rh
A
following general procedure A [0.5 mol% RhACHTREU(GN COD)2BF4,
into the glass reaction vessels. The vessels were placed in
the reactors and 5 mL of solvent were added. The reactors
were then purged for 30 min with N2 before applying a hy-
drogen atmosphere. The pressure was kept constant during
the reaction and the hydrogen uptake was monitored. After
completion of the reaction, the reactors were opened and
samples were taken, which were filtered over a short silica
column and subjected to ee determination by GC or HPLC.
1.0 mol% L1, 10 bar H2, 3 h]. The conversion was >99%,
the isolated yield was 1.88 g (92%). The ee was determined
by HPLC to be 98.6% (Chiralpak AD column; heptane/n-
butanol/TFA, 95:5:0.05). Analytical data agreed withthose
reported in the literature.[3] 1H NMR (CDCl3, 300 MHz): d=
3.69 (s, 3H), 3.02–2.91 (m, 1H), 2.75 (dd, J=8.1, 16.7 Hz,
1H), 2.43 (dd, J=6.0, 16.7 Hz, 1H), 1.26 (d, J=7.2 Hz, 3H);
13C NMR (CDCl3, 75 MHz): d=181.5, 172.3, 51.8, 37.1, 35.7,
16.8; [a]2D2: À10.6 (c 0.8, CHCl3).
1
Conversions were determined by H NMR.
Library Synthesis and Hydrogenation
(S)-2-(2-Methoxy-2-oxoethyl)pentanoic Acid (6b)
This compound was prepared from 3b (0.94 g, 5.45 mmol)
General: The library was synthesized using a Zinsser Lissy
liquid handling robot equipped with 4 probes and placed
inside a glove-box. Whatman PKP 2 mL 96-well filter plates
in combination withthe UniVac 3 vacuum manifold were
used to perform the parallel filtration of the ligand library.
The hydrogenation reaction was carried out in a Premex 96-
Multi Reactor[31] that can accommodate 96 reactions vessels
at the same temperature and hydrogen pressure.
following general procedure A [2.0 mol% RhACHTREU(GN COD)2BF4,
4.0 mol% L1, 10 bar H2, 3 h]. The conversion was >99%,
the isolated yield was 0.88 g (93%). The ee was determined
by HPLC to be 98.5% (Chiralpak AD column; heptane/eth-
anol/TFA, 95:5:0.05). Analytical data agreed withthose re-
ported in the literature.[25a] A small amount was converted
into the diacid[40] in order to compare the sign of the optical
rotation and thereby determine the absolute stereochemis-
Conditions: Into 48 wells of the filter plate were trans-
ferred a solution of the desired chlorophosphite (0.15M,
1
try. H NMR (CDCl3, 300 MHz): d=3.68 (s, 3H), 2.87 (m,
92
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Asymmetric Hydrogenation of Functionalized Itaconic Acid Mono-Esters
FULL PAPERS
1H), 2.70 (m, 1H), 2.44(dd, J=5.1, 16.6 Hz, 1H), 1.73–1.46
(m, 2H), 1.43–1.21 (m, 2H), 0.92 (t, J=7.2 Hz, 3H);
13C NMR (CDCl3, 75 MHz): d=180.7, 172.4, 51.9, 40.8, 35.4,
33.8, 20.1, 13.8; [a]2D2: À15.2 (c 0.6, CHCl3).
[2] An example of the application of such optically active
building blocks in the synthesis of biologically relevant
nitrogen heterocycles can be found in the subsequent
paper in the current issue: K. F. W. Hekking, D. C. J
Waalboer, M. A. H. Moelands, F. L. van Delft, F. P. J. T.
Rutjes, Adv. Synth. Catal. following article in this issue.
[3] M. Ostermeier, B. Brunner, C. Korff, G. Helmchen,
Eur. J. Org. Chem. 2003, 3453, and references cited
therein.
[4] For recent examples, see: a) J. Almena, A. Monsees, R.
Kadyrov, T. H. Riermeier, B. Gotov, J. Holz, A.
Bçrner, Adv. Synth. Catal. 2004, 346, 1263; b) S. Wu,
M. He, X. Zhang, Tetrahedron:Asymmetry 2004, 15,
2177; c) W. Tang, D. Liu, X. Zhang, Org. Lett. 2003, 5,
205; d) I. D. Gridnev, Y. Yamanoi, N. Higashi, H. Tsur-
uta, M. Yasutake, T. Imamoto, Adv. Synth. Catal. 2001,
343, 118.
(R)-2-Benzyl-4-methoxy-4-oxobutanoic Acid (6c)
This compound was prepared from 3c (1.11 g, 5.04 mmol)
following general procedure A [2.0 mol% RhACHTREU(GN COD)2BF4,
4.0 mol% L5, 25 bar H2, 16 h]. The conversion was >99%,
the isolated yield was 1.05 g (94%). The ee was determined
by HPLC to be 93.7% (Chiralpak AD column; heptane/eth-
anol/TFA, 95:5:0.05). Analytical data agreed withthose re-
ported in the literature.[41] A small amount was converted
into the diacid,[42] in order to compare the sign of the optical
rotation and thereby determine the absolute stereochemis-
1
try. H NMR (CDCl3, 300 MHz): d=7.33–7.16 (m, 5H), 3.64
(s, 3H), 3.21–3.10 (m, 2H), 2.79 (m, 1H), 2.65 (dd, J=8.8,
16.9 Hz, 1H), 2.41 (dd, J=4.7, 16.9 Hz, 1H). 13C NMR
(CDCl3, 75 MHz): d 179.5, 172.2, 137.9, 129.0, 128.6, 126.8,
51.8, 42.7, 37.3, 34.4; [a]2D2: +11.1 (c 0.5, CH2Cl2).
[5] D. Carmichael, H. Doucet, J. M. Brown, Chem.
Commun. 1999, 261.
[6] a) M. J. Burk, F. Bienewald, M. Harris, A. Zanotti-
Gerosa, Angew. Chem. 1998, 110, 2034; Angew. Chem.
Int. Ed. 1998, 37, 1931; b) Y. Ito, T. Kamijo, H. Harada,
F. Matsuda, S. Terashima, Tetrahedron Lett. 1990, 31,
2731; c) T. Morimoto, M. Chiba, K. Achiwa, Tetrahe-
dron Lett. 1989, 30, 735.
(R)-4-Methoxy-2-(4-methoxybenzyl)-4-oxobutanoic
Acid (6d)
This compound was prepared from 3d (1.49 g, 5.95 mmol)
following general procedure A [2.0 mol% RhACHTREU(GN COD)2BF4,
[7] For reviews on asymmetric hydrogenation with mono-
dentate phosphorus ligands, see: a) M. van den Berg,
B. L. Feringa, A. J. Minnaard, in: The Handbook of
Homogeneous Hydrogenation, Vol. 2, (Eds.: J. G. de
Vries, C. J. Elsevier), Wiley-VCH, Weinheim, 2007,
p 995; b) J. G. de Vries, in: Handbook of Chiral Chem-
icals, 2nd edn., (Ed:. D. J. Ager), CRC (Taylor & Fran-
cis), Boca Raton, 2006, p 269; c) T. Jerphagnon, J.-L.
Renaud, C. Bruneau, Tetrahedron:Asymmetry 2004,
15, 2101.
4.0 mol% L5, 25 bar H2, 2 h]. The conversion was >99%,
the isolated yield was 1.41 g (94%). The ee was determined
by HPLC to be 89.0% (Chiralcel OD column; heptane/2-
1
propanol/TFA, 95:5:0.05). H NMR (CDCl3, 300 MHz): d=
7.09 (d, J=8.7 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 3.78 (s,
3H), 3.64 (s, 3H), 3.17–3.03 (m, 2H), 2.76–2.60 (m, 2H),
2.40 (dd, J=4.8, 16.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz):
d=178.6, 172.3, 158.4, 130.0, 129.8, 114.0, 55.2, 51.8, 42.8,
36.6, 34.4; [a]2D2: +17.4 (c 0.4, CHCl3); HR-MS (CI+): m/z=
252.0988, calcd. for C13H16O5, [M]+: 252.0998.
[8] For a recent review on the use of this ligand library in
asymmetric hydrogenation, see: J. G. de Vries, L.
Lefort, Chem. Eur. J. 2006, 12, 4722.
[9] a) L. Panella, A. M. Aleixandre, G. J. Kruidhof, J. Rob-
ertus, B. L. Feringa, J. G. de Vries, A. J. Minnaard, J.
Org. Chem. 2006, 71. 2026; b) B. Bernsmann, M.
van den Berg, R. Hoen, A. J. Minnaard, G. Mehler,
M. T. Reetz, J. G. de Vries, B. L. Feringa, J. Org. Chem.
2005, 70, 943; c) M. van den Berg, A. J. Minnaard,
R. M. Haak, M. Leeman, E. P. Schudde, A. Meetsma,
B. L. Feringa, A. H. M. de Vries, C. E. P. Maljaars,
C. E. Willans, D. Heytt, J. A. F. Boogers, H. J. W. Hen-
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308; d) D. PeÇa, A. J. Minnaard, J. G. de Vries, B. L.
Feringa, J. Am. Chem. Soc. 2002, 124, 14552; e) M.
van den Berg, A. J. Minnaard, E. P. Schudde, J. van
Esch, A. H. M. de Vries, J. G. de Vries, B. L. Feringa, J.
Am. Chem. Soc. 2000, 122, 11539.
Acknowledgements
This research has been financially supported (in part) by the
Council for Chemical Sciences of the Netherlands Organiza-
tion for Scientific Research (CW-NWO). DSM Research is
kindly acknowledged for their hospitality during the asym-
metric hydrogenations.
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