Efficient Synthesis of Differentiated syn-1,2-Diol Derivatives by Asymmetric Transfer Hydrogenation-Dynamic Kinetic Resolution of α-Alkoxy-Substituted β-Ketoesters

Article abstract of DOI:10.1002/chem.201501884

Asymmetric transfer hydrogenation was applied to a wide range of racemic aryl α-alkoxy-β-ketoesters in the presence of well-defined, commercially available, chiral catalyst Ru^II-(N-p-toluenesulfonyl-1,2-diphenylethylenediamine) and a 5:2 mixture of formic acid and triethylamine as the hydrogen source. Under these conditions, dynamic kinetic resolution was efficiently promoted to provide the corresponding syn α-alkoxy-β-hydroxyesters derived from substituted aromatic and heteroaromatic aldehydes with a high level of diastereoselectivity (diastereomeric ratio (d.r.)>99:1) and an almost perfect enantioselectivity (enantiomeric excess (ee)>99>). Additionally, after extensive screening of the reaction conditions, the use of Ru^II- and Rh^III-tethered precatalysts extended this process to more-challenging substrates that bore alkenyl-, alkynyl-, and alkyl substituents to provide the corresponding syn α-alkoxy-β-hydroxyesters with excellent enantiocontrol (up to 99‰ee) and good to perfect diastereocontrol (d.r.>99:1). Lastly, the synthetic utility of the present protocol was demonstrated by application to the asymmetric synthesis of chiral ester ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)-propanoate, which is an important pharmacophore in a number of peroxisome proliferator-activated receptor α/γ dual agonist advanced drug candidates used for the treatment of type-II diabetes. Ru^II-catalyzed asymmetric transfer hydrogenation with dynamic kinetic resolution was successfully applied to a wide variety of racemic α-alkoxy-β-ketoesters derived from substituted aromatic and heteroaromatic benzaldehydes and cinnamaldehydes (see scheme; PMB=p-methoxybenzyl, S/C=substrate/catalyst ratio).

Full text of DOI:10.1002/chem.201501884

DOI: 10.1002/chem.201501884
Full Paper
&
Asymmetric Synthesis
Efficient Synthesis of Differentiated syn-1,2-Diol Derivatives by
Asymmetric Transfer Hydrogenation–Dynamic Kinetic Resolution
of a-Alkoxy-Substituted b-Ketoesters
Laure Monnereau,[a] Damien Cartigny,[a] Michelangelo Scalone,[b] Tahar Ayad,*[a] and
Virginie Ratovelomanana-Vidal*[a]
Abstract: Asymmetric transfer hydrogenation was applied to
a wide range of racemic aryl a-alkoxy-b-ketoesters in the
presence of well-defined, commercially available, chiral cata-
lyst RuII–(N-p-toluenesulfonyl-1,2-diphenylethylenediamine)
and a 5:2 mixture of formic acid and triethylamine as the hy-
drogen source. Under these conditions, dynamic kinetic res-
olution was efficiently promoted to provide the correspond-
ing syn a-alkoxy-b-hydroxyesters derived from substituted
aromatic and heteroaromatic aldehydes with a high level of
diastereoselectivity (diastereomeric ratio (d.r.)>99:1) and an
almost perfect enantioselectivity (enantiomeric excess (ee)>
99%). Additionally, after extensive screening of the reaction
conditions, the use of RuII- and RhIII-tethered precatalysts ex-
tended this process to more-challenging substrates that
bore alkenyl-, alkynyl-, and alkyl substituents to provide the
corresponding syn a-alkoxy-b-hydroxyesters with excellent
enantiocontrol (up to 99% ee) and good to perfect diaste-
reocontrol (d.r.>99:1). Lastly, the synthetic utility of the
present protocol was demonstrated by application to the
asymmetric synthesis of chiral ester ethyl (2S)-2-ethoxy-3-(4-
hydroxyphenyl)-propanoate, which is an important pharma-
cophore in a number of peroxisome proliferator-activated re-
ceptor a/g dual agonist advanced drug candidates used for
the treatment of type-II diabetes.
work, catalytic asymmetric transfer hydrogenation (ATH)[3] with
propan-2-ol or HCO2H as the hydrogen source has become
a powerful tool for asymmetric reduction of ketones, compara-
ble to classical asymmetric hydrogenation[4] with molecular hy-
drogen and a chiral RuII–biphosphane catalyst. Indeed, thanks
to its simple execution, the use of readily available and less-
sensitive catalysts and the availability of hydrogen sources,
ATH has established itself as an essential and elegant tool for
enantioselective synthesis. In particular, successful ATH applica-
tions that involve dynamic kinetic resolution (DKR),[5] which
combines a kinetic resolution step with in situ racemization of
a configurationally labile center, have been extensively de-
scribed[6] and provide an additional attractive and powerful
tool to control two contiguous stereogenic centers with high
levels of selectivity and high atom economy in a single opera-
tion starting from racemic mixtures.
Introduction
Many processes that control the generation of stereogenic
centers in an elegant manner typically rely on the develop-
ment of enantioselective syntheses by asymmetric catalysis.
This research area has rapidly attracted the interest of the sci-
entific community with regards to the high-value compounds
generated, which can be crucial intermediates for the prepara-
tion of pharmaceutical agents and advanced materials. One of
the most significant examples of asymmetric catalysis ap-
peared in 1995 when Noyori and co-workers discovered that
a chiral catalyst, namely RuII–TsDPEN (TsDPEN=N-p-toluenesul-
fonyl-1,2-diphenylethylenediamine), was able to drive the
transfer hydrogenation of aryl-, alkyl-, and related ketones[1]
and imines[2] to provide the corresponding alcohols and
amines with high levels of selectivity. Since this pioneering
Continuing our ongoing research toward the synthesis of
relevant biologically active compounds by transition-metal-cat-
alyzed asymmetric reduction,[7] in a preliminary communica-
tion,[8] we described a highly efficient procedure for ATH of
prochiral a-alkoxy-b-ketoesters coupled with a DKR process
under mild reaction conditions with HCO2H/NEt3 as the hydro-
gen source and well-defined, commercially available chiral cat-
alyst RuII–TsDPEN. In this earlier effort, we demonstrated that
easily accessible racemic aryl a-alkoxy-b-ketoesters could be ef-
ficiently transformed to the corresponding monodifferentiated
1,2-diols with almost perfect enantioselectivity (enantiomeric
excess (ee) up to 99%) and excellent diastereoselectivity (dia-
[a] Dr. L. Monnereau, Dr. D. Cartigny, Dr. T. Ayad, Dr. V. Ratovelomanana-Vidal
PSL Research University, Chimie ParisTech - CNRS
Institut de Recherche de Chimie Paris, 75005 Paris (France)
Fax: (+33)144-071-062
E-mail: tahar.Ayad@chimie-paristech.fr
virginie.vidal@chimie-paristech.fr
[b] Dr. M. Scalone
Process Research & Development
F. Hoffmann-La Roche AG, Bldg. 62/413, 4070 Basel (Switzerland)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501884. It contains the experimental
procedures and characterization data for all new a-alkoxy-b-hydroxyester
compounds.
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stereomeric ratio (d.r.) up to 99:1) in favour of the syn product
for a wide variety of substrates bearing diverse functionalized
aromatic and heteroaromatic moieties. However, although
highly efficient, the method reported in our preliminary study
suffered from the drawback of a narrow substrate scope limit-
ing its practicality: the reaction was restricted to aryl and het-
eroaryl a-alkoxy-substituted b-ketoesters. Pursuing our efforts,
we decided to study ATH–DKR processes further with the aim
of extending their scope to more-demanding substrates such
as alkenyl-, alkynyl- and alkyl derivatives. After extensive
screening of the reaction conditions, we found that tethered
RhIII–TsDPEN and RuII–TsDPEN complexes, instead of the classi-
cal Noyori RuII–TsDPEN catalyst, proved essential to reduce the
more challenging classes of substrates with both high reactivi-
ty and selectivity. In this contribution, we report the full details
of our investigation, as well as application of the present pro-
tocol to the formal enantioselective synthesis of AZ-242 (Tesa-
glitazar), a drug candidate in development at AstraZeneca for
the treatment of type-II diabetes.[9]
Table 1. Screening of RuII precatalysts for ATH of 2a.[a]
Entry
Ru catalyst
Conv.
[%][b]
d.r.
(syn/anti)[c]
ee (syn)
[%][d]
1
93
90:10
85:15
>99
>99
2
>99
Results and Discussion
3
4
>99
>99
82:18
88:12
>99
>99
Compounds 2–5, required for our study, were readily prepared
on a gram scale from commercially available or easily accessi-
ble aldehydes by a two-step sequence: aldol reaction followed
by oxidation of the resulting alcohol in the presence of 2-io-
doxybenzoic acid (IBX) in THF or EtOAc (Scheme 1). By this pro-
5
6
74
83:17
55:45
50
91
>99
7
8
9
7
77
91:9
93:7
95:5
nd[e]
Scheme 1. General synthesis of racemic a-alkoxy-b-ketoesters.
>99
cedure, a wide range of aryl, heteroaryl, and alkenyl a-alkoxy-
substituted b-ketoester derivatives with both electron-donat-
ing and electron-withdrawing substituents on the aromatic
moiety were obtained in moderate to good overall yields (50–
70%). The above-mentioned protocol was also successfully
used to synthesize diversely functionalized alkynyl- and alkyl a-
methoxy-substituted b-ketoester substrates with a slightly
lower global average yield of 50%.
>99
>99
[a] Reaction concentration=1m solution of substrate (1 mmol). [b] Con-
version was determined by analysis of the H NMR spectrum of the crude
product. [c] Determined by analysis of the H NMR spectrum of the crude
product. [d] Determined by chiral stationary phase supercritical-fluid chro-
1
1
matography (CSP-SCF). [e] nd=not determined.
With substrates 2–5 in hand, we started our investigation by
identifying the most suitable catalytic system for ATH–DKR of
racemic
phenyl-substituted
a-methoxy-b-ketoester
2a
(Table 1). To this end, various tosylated diamine-based RuII cata-
lysts with structural alterations to either the chiral diamine
backbone (A–E) or the h6-arene ligand coordinated to the
ruthenium atom (F–I) were screened. The test reactions were
performed in CH2Cl2 at 308C for 20 h with a substrate/catalyst
ratio (S/C) of 200:1 in the presence of a 5:2 HCO2H/NEt3 azeo-
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tropic mixture as the hydrogen source. The results presented
in Table 1 show that highly disparate catalytic activities were
observed depending on the diamine ligand used. More specifi-
cally, when the ATH reaction of 2a was performed in the pres-
ence of the Noyori’s RuII–TsDPEN catalyst (A), which bears p-
cymene as the h6-arene, the syn product[10] 6a was obtained in
93% conversion with an encouraging 90:10 d.r. and almost
perfect enantioselectivity (>99% ee) (Table 1, entry 1). Addi-
tionally, replacement of the toluene-p-sulfonyl group on the
chiral diamine ligand with the more-electron-withdrawing p-ni-
trobenzene (B) or 3,5-bis(trifluoromethyl)-benzene group (C)
gave 6a in full conversion with similarly high ee values of 99%,
but with a significant drop in the d.r. values from 90:10 to
85:15 and 82:18, respectively (Table 1, entry 1 versus entries 2
and 3). Also, modification of the ethylene bridge of the TsDPEN
Table 2. Screening of reaction conditions for ATH of 2a catalyzed by RuII
catalyst I.[a]
Entry HCO2H/NEt3 Conc.
Solvent
T
Conv. d.r.
ee (syn)
([equiv])
[molLÀ1
]
[8C] [%][b] (syn/anti)[b] [%][c]
1
2
3
4
5
6
7
8:1 (4)
5:2 (4)
5:2 (2)
5:2 (2)
5:2 (2)
5:2 (2)
5:2 (2)
1
1
1
CH2Cl2 30
0
nd[d]
nd
nd
nd
CH2Cl2 30 >99 87:13
CH2Cl2 30 >99 95:5
CH2Cl2 30 >99 95:5
CH2Cl2 30 >99 97:3
CH2Cl2 30 >99 97:3
CH2Cl2 30 >99 97:3
CH2Cl2 30 >99 97: 3
0.5
0.2
0.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
nd
ligand with
a p-nitrobenzene substituent (D) instead of
a phenyl group had little effect on the stereochemical out-
come of the catalytic process (Table 1, entry 1 versus entry 4).
In sharp contrast, the reaction conducted with catalyst E,
which bore a 1,2-diaminocyclohexane diamine ligand afforded
the expected product 6a with a comparable level of diastereo-
selectivity, but with greatly reduced conversion and enantiose-
lectivity (Table 1, entry 5). The data presented in Table 1 also
clearly demonstrates that the nature of the h6-arene ligand co-
ordinated to the ruthenium center strongly influences the re-
activity and selectivity of the reaction, illustrated by the results
obtained with RuII–TsDPEN based catalysts F–I. In the presence
of catalyst F, which has a benzene ligand, full conversion oc-
curred but with almost no diastereoselectivity. (Table 1,
entry 6). Replacement of the h6-arene p-cymene ligand with
sterically hindered hexamethylbenzene (G) or 1,4-dicyclohexyl-
benzene (H) afforded product 6a with good to excellent selec-
tivity. However, use of the above catalysts also resulted in dra-
matically decreased conversions of 7 and 77%, respectively
(Table 1, entries 7 and 8). Finally, from this catalyst survey, the
RuII–TsDPEN precatalyst I, which bears a mesitylene ligand, was
identified as the best candidate for this reaction and yielded
6a quantitatively with an excellent d.r. (95:5) and superior
enantioselectivity (>99% ee, Table 1, entry 9).
8[e] 5:2 (2)
9
10
11
12
13
14
15
16
17
18
5:2 (2)
5:2 (2)
5:2 (2)
5:2 (2)
5:2 (2)
5:2 (2)
5:2 (2)
5:2 (2)
5:2 (2)
5:2 (2)
MeOH
iPrOH
30
30
78 87:13
99 92:8
CH3CN 30 >99 96:4
DMF 30 >99 95:5
toluene 30 >99 95:5
Et2O
THF
30 >99 91:9
30 >99 97:3
dioxane 30 >99 96:4
10 10 nd
50 >99 97:3
CH2Cl2
>99
[a] Substrate (1 mmol), 20 h. [b] Determined by analysis of the 1H NMR
spectrum of the crude product. [c] Determined by CSP-SCF. [d] nd=not
determined. [e] S/C=500:1, 20 h.
and enantioselectivity of the reaction (Table 2, entries 7–16). To
our delight, decreasing the catalyst loading from S/C=200:1
to S/C=500:1 resulted in the formation of 6a with a similarly
high reaction rate and selectivity (Table 1, entry 8). Finally, the
temperature of the reaction was postliminarily considered.
Raising the reaction temperature from 308C to 508C did not
have any repercussion on the catalytic efficiency, but a decrease
to 108C brought the conversion to only 10% (Table 2, en-
tries 17 and 18). Based on this initial screening, the optimized
reaction conditions were: CH2Cl2 (0.2 mol substrate/L, precata-
lyst I (0.5 mol%), 5:2 HCO2H/NEt3 (2 equiv), 308C).
A library of aryl and heteroaryl a-alkoxy-substituted b-ke-
toesters (2a–p) was subjected to the ATH–DKR process under
the optimized conditions. As shown in Table 3, the electronic
nature of the aromatic substituent in the substrate only slightly
influenced the stereochemical outcome of the catalytic trans-
formation. More specifically, electron-donating substituents,
such as methyl and methoxy groups, were tolerated just as
well as electron-withdrawing substituents, such as bromine,
fluorine, and trifluoromethyl groups, leading to the desired
products 6a–k (Table 3, entries 1–11) in excellent conversions
with almost perfect enantioselectivity (ꢀ99% ee) and excellent
d.r. values (up to 97:3). It should be mentioned that sterically
hindered substrates, such as ortho-substituted a-methoxy-b-ke-
toesters 2c and 2g, exhibited lower conversions (80%) and de-
Encouraged by these results and to improve the catalytic ac-
tivity of this process further, the effects of several key parame-
ters, such as the amount and ratio of HCO2H/
NEt3, the reaction concentration, the nature of the solvent, the
catalyst loading, and the temperature were also studied. The
results of these experiments are shown in Table 2. The catalytic
system did not operate properly (no conversion was observed)
if the relative concentration of NEt3 was too low (Table 2,
entry 1). The use of a 5:2 mixture of HCO2H/NEt3 led to com-
pletion of the reaction. Also, diminishing the amount of
HCO2H from 4 to 2 equivalents gave better results, providing
6a with a 95:5 d.r. and >99% ee (Table 2, entries 2 and 3). Fur-
thermore, by decreasing the reaction concentration from 0.5
to 0.2 or 0.1 molLÀ1, the d.r. was improved to 97:3 and the
enantioselectivity remained high (99% ee) (Table 2, entries 4–
6). With the exception of methanol, which led to a conversion
of only 78%, the ATH–DKR process was tolerant of a wide
range of solvents in terms of conversion, diastereoselectivity,
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Table 3. ATH–DKR of aryl and heteroaryl a-alkoxy-substituted b-ketoes-
ters.[a]
Table 3. (Continued)
Entry
16
Product
Conv. d.r.
ee (syn)
Entry
Product
Conv. d.r.
ee (syn)
[%][b]
(syn/anti)[b] [%][c]
[%][b]
(syn/anti)[b] [%][c]
6p
>99
>97:3
>99
1
2
6a
6b
>99
97:3
97:3
>99
>99
[a] Reaction concentration=0.2m; substrate (1 mmol). [b] Determined by
1H NMR spectroscopy of the crude product. [c] Determined by CSP-SCF.
[d] S/C=100:1.
>99
3
4
6c
80
90:10
97:3
>99
>99
creased diastereoselectivity whatever the electronic nature of
the substituent. However, the enantioselectivity remained
>99% ee (Table 3, entries 3 and 7). This lower reactivity is pre-
sumably caused by increased steric hindrance between the
catalyst and ortho-substituent of the substrate during the
course of the reaction. Interestingly, substrates with heteroaro-
matic rings, such as 2-thienyl (2l) and 2-furanyl (2m), were
also quantitatively converted to the corresponding diols (6l
and 6m; Table 3, entries 12 and 13) with similarly impressive
levels of diastereo- (d.r.ꢀ96:4) and enantiocontrol (>99% ee).
The data reported in Table 3 also illustrates that a-substituted
b-ketoester derivatives 2n–p, which have ethyl, benzyl (Bn),
and p-methoxybenzyl (PMB) substituents, respectively, on the
a-oxygen atom were also suitable partners for this process.
Indeed, under the optimized reaction conditions, the expected
products 6n–p were obtained (Table 3, entries 14–16) with full
conversion and high diastereoselectivity (d.r.=97:3 to >99:1)
and excellent enantioselectivity (ꢀ99% ee). Notably, the Bn
and PMB protecting groups could be easily removed to pro-
vide the valuable corresponding diols by using standard re-
ported conditions.[11] For example, hydrogenolysis of the
benzyl ether group of 2p with H2 over Pd/C resulted in the for-
mation of the corresponding diol (not shown) in excellent iso-
lated yield without loss of stereoselectivity (92% yield, 97:3
d.r., >99% ee).[12] This first insight clearly demonstrated the
ability of RuII–TsDPEN catalysts to create two contiguous ste-
reogenic centers with excellent control of both the diastereo-
(up to 99:1 d.r.) and enantioselectivity (up to 99% ee).
6d
>99
5
6
6e
6 f
>99
>99
97:3
97:3
>99
>99
7
8
6g
6h
80
70:30
97:3
>99
>99
>99
9
10
11
6i
6j
6k
>99
>99
>99
97:3
97:3
96:4
>99
>99
98
12
13
6l
>99
>99
96:4
>99
>99
6m[d]
>99:1
To assess the substrate scope of this ATH–DKR process,
a wide range of more challenging alkenyl-, alkynyl- and alkyl-
derived substrates were prepared and tested. We first studied
the reactivity of various cinnamaldehyde derivatives 3a–k
under the optimized conditions with RuII–TsDPEN catalyst I.
The results of these experiments are reported in Table 4. The
reaction worked well in most cases and gave the desired alco-
hols 7a–k with full conversion and very high selectivity
(Table 4, entries 1–3 and 5–11). For example, the a-methoxy-
14
15
6n
6o
>99
>99
>99:1
>98:2
>99
99
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such as methyl (3b–c) and methoxy (3e–f) substitu-
ents, were efficiently converted with excellent dia-
stereo- and enantioselectivity (Table 4, entries 2, 3, 5,
and 6; 97:3 to 99:1 d.r., up to 99% ee). In contrast,
a significant decrease in catalytic performance in
terms of selectivity was observed with substrates
that had electron-withdrawing substituents (Table 4,
entries 7–9) such as fluoro- (3g–h) and nitro groups
(3i). The data presented in Table 4 also demonstrates
that catalytic activity was influenced by a steric
effect, illustrated by the results obtained for the
family of a-methoxy-substituted b-ketoesters 3b–d
bearing a tolyl substituent. No reaction occurred with
ortho-tolyl substrate 3d (Table 4, entry 4), whereas
para- and meta-substituted substrates 3b and 3c
gave full conversion, ꢀ98:2 d.r., and 99% ee (Table 4,
entries 2 and 3). This observation may be attributed
to a mismatched interaction in the transition state,
which probably prevents the approach of the catalyst
to the ortho-substituted substrate, despite the pres-
ence of the alkenyl spacer. Interestingly, naphthyl-
containing substrate 3j, with greater steric demand,
is well tolerated in this process and gives the desired
diol 7j with full conversion, a high d.r. of 97:3, and
up to 98% ee (Table 4, entry 10). Lastly, the presence
of a 2-thienyl heteroaromatic moiety did not impact
the catalytic efficiency and the reduced product 7k
was provided with excellent diastereo- and enantio-
selectivity (Table 4, entry 11; >99:1 d.r., 98% ee).
Table 4. ATH–DKR of alkenyl a-methoxy-substituted b-ketoesters.[a]
Entry
Product
Conv.
[%][b]
d.r.
(syn/anti)[b]
ee (syn)
[%][c]
1
2
7a
7b
>99
>99
99:1
99:1
99
99
3
7c
>99
98:2
99
[d]
[d]
4
5
7d
7e
0
–
–
>99
97:3
97:3
96:4
94:6
93:7
98
99
97
97
94
6
7
8
9
7 f
7g
7h
7i
>99
>99
>99
>99
Based on these findings, we extended the sub-
strate scope of the ATH–DKR process to increasingly
challenging alkynyl- (4) and alkyl- (5) a-methoxy-sub-
stituted b-ketoester derivatives, which, to the best of
our knowledge, have never been used in such a pro-
cess. The data compiled in Table 5 shows that the
stereochemical course of the reaction was highly cat-
alyst dependent. Indeed, alkynyl substrates with
a phenyl (4a) or pentyl chain (4b) attached to the
alkyne function were completely inert under the pre-
viously optimized reaction conditions with RuII–
TsDPEN catalyst I. A possible explanation that may
account for these results is the existence of unfavora-
ble steric hindrance imposed by the rigid linear al-
kynyl unit, which prevents interactions between cata-
lyst I and substrate 4 (Table 5, entries 1 and 4). To cir-
cumvent this reactivity problem, inspired by the work
of Wills and co-workers, we turned our attention to
the use of tethered RuII–TsDPEN catalyst J,[13] known
to be a highly active precatalyst for ATH of hindered
ketones,[13f,14] imines,[14] and acetylenic ketones,[15]
10
11
7j
>99
>99
97:3
98
98
7k
>99:1
[a] Reaction concentration=0.2m; substrate (1 mmol). [b] Determined by analysis of
the 1H NMR spectrum of the crude product. [c] Determined CSP-SCF. [d] No reaction.
substituted b-ketoester 3a bearing an unsubstituted cinnamal-
dehyde moiety was quantitatively transformed to the corre-
sponding reduced adduct 7a (Table 4, entry 1) with almost
perfect diastereo- (99:1 d.r.) and enantiocontrol (99% ee).
The electronic nature of the phenyl-ring substituent also
clearly influenced the stereochemical outcome of the reaction.
For instance, substrates bearing electron-donating groups,
and RhIII–TsDPEN precatalyst K, a complex developed in our
group.[16] Unfortunately, neither J nor K reduced substrate 4a,
presumably due to incompatibility in the spatial arrangement
of the substrate with the tethered catalyst (Table 5, entries 2–
3).
Pleasingly, both J and K led to full conversion of heptynyl-
substituted substrate 4b (Table 5, entries 5 and 6) with good
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control ranging from 50:50 to 90:10 d.r. (Table 5, entries 8, 11,
and 14). When the tethered metal ion in the TsDPEN-based
precatalyst was changed from RuII to RhIII, contrasting results
were obtained. Indeed, the use of catalyst K led to the best
outcome: starting from flexible pentyl substrate 9a full conver-
sion, 81:19 d.r., and 93% ee were obtained, whereas only little,
or no, catalytic efficiency was obtained for the more sterically
demanding substrates 9b and 9c, which contained an isopro-
pyl or cyclohexyl moiety, respectively (Table 5, entries 9, 12,
and 15). These results clearly suggest that our tethered RhIII–
TsDPEN precatalyst K is much more sensitive to steric effects
than the tethered RuII–TsDPEN precatalyst J, probably due to
the presence of its meta-methoxyphenyl-substituted arm. In
the case of substrate 5d possessing a phenylethyl moiety, full
conversion was reached under all the catalytic conditions em-
ployed, but the selectivity of the reaction was strongly catalyst
dependent. Indeed, no diastereoselectivity and poor enantiose-
lectivity (21% ee) was obtained when the reaction was per-
formed in the presence of RuII catalyst I (Table 5, entry 16),
whereas use of tethered RuII–TsDPEN precatalyst J and our
RhIII–TsDPEN precatalyst K led to significantly better selectivity,
with 67:33 and 77:23 d.r. and 74 and 86% ee, respectively
(Table 5, entries 17 and 18).
Table 5. ATH–DKR of alkynyl and alkyl a-methoxy-substituted b-ketoest-
ers catalyzed by I or tethered RuII and RhIII precatalysts J and K.[a]
Entry Product
Cat. Conv. d.r.
ee (syn)
[%][b] (syn/anti)[b] [%][c]
1
2
3
I
J
K
0
0
0
–
–
–
–
–
–
8a
4
5
6
I
J
K
0
–
–
96[d]
>99[d]
>99 85:15
>99 98:2
8b
7
8
9
I
J
K
50 70:30
>99 50:50
>99 81:19
97[e]
97[e]
93[e]
9a
10
11
12
I
J
K
30 65:35
>99 86:14
nd[f]
93[e]
nd
Finally, the ATH–DKR protocol was also applied to the asym-
metric synthesis of chiral ester ethyl (2S)-2-ethoxy-3-(4-hydrox-
yphenyl)-propanoate 10,[17] which is an important intermediate
in a number of peroxisome proliferator-activated receptor a/g
dual agonist advanced drug candidates used for the treatment
of type-II diabetes,[18] such as AZ-242 (Tesaglitazar)[9] and DRF-
2725 (Ragaglitazar; not shown).[19] As shown in Scheme 2, the
9b
35
–
13
14
15
I
J
K
0
–
–
97[e]
–
>99 90:10
9c
0
–
16
17
18
I
J
K
>99 50:50
>99 67:33
>99 77:23
21
74
86
9d
[a] Reaction concentration=0.2m; substrate (1 mmol). [b] Determined by
1
analysis of the H NMR spectrum of the crude product. [c] Determined by
CSP-SCF. [d] Determined from the corresponding fully reduced benzoylat-
ed product by CSP-SCF. [e] Determined from the corresponding benzoy-
lated product by HPLC. [f] nd=not determined.
to high d.r. values (85:15 and 98:2, respectively) and excellent
ee values (96 and >99%, respectively). This success greatly en-
couraged us to extend this ATH–DKR process to more-chal-
lenging alkyl a-methoxy-b-ketoester substrates incorporating,
for instance, pentyl (5a), isopropyl (5b), cyclohexyl (5c), and
phenylethyl (5d) side chains. As can be seen from the data in
Table 5, the stereochemical outcome of the reaction is highly
substrate- and catalyst dependent. For example, when the re-
action was conducted in the presence of RuII–TsDPEN catalyst
I, although high enantiocontrol (97% ee) was induced for sub-
strate 9a (Table 5, entry 7), only poor to moderate conversion
and selectivity was obtained for almost all the alkyl substrates
tested (Table 5, entries 7, 10, and 13). Prolonging the reaction
time to 48 h did not improve the observed conversion. Pleas-
ingly, alkyl a-methoxy-b-ketoester derivatives 5a–c were effi-
ciently transformed into their reduced analogues 9a–c in the
presence of the commercially available tethered RuII–TsDPEN
precatalyst J with excellent enantioselectivity (97, 93, and
97% ee, respectively), but with disparate syn diastereomeric
Scheme 2. Formal asymmetric synthesis of Tesaglitazar, a) I (S/C=200:1), 5:2
HCO2H/Et3N (2 equiv), CH2Cl2, 308C, 20 h, quantitative; b) i) Et3SiH (1.2 equiv),
TFA (5.0 equiv), CH2Cl2, rt, 12 h; ii) H2 (50 bar), Pd(OH)2 (10% w/w), THF, 15 h,
98% over two steps.
hydrogenation reaction of a-ethoxy-b-ketoester 2n was carried
out on a gram scale to provide 6n in high isolated yield with
excellent asymmetric induction (d.r.>98:2, >99% ee). Subse-
quent deoxygenation by using Et3SiH and trifluoroacetic acid
(TFA), followed by removal of the benzyl group provided the
anticipated key intermediate ethyl ester (S)-10 with >95% ee
(Scheme 2).
Chem. Eur. J. 2015, 21, 11799 – 11806
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Full Paper
Conclusion
Acknowledgements
The RuII-catalyzed ATH–DKR reaction was successfully applied
to a wide variety of racemic a-alkoxy-b-ketoesters derived
from substituted aromatic and heteroaromatic benzaldehydes
and cinnamaldehydes. In this reaction, two contiguous stereo-
genic centers were simultaneously controlled with excellent di-
astereo- (up to 99:1 d.r.) and enantioselectivity (up to 99% ee).
The use of tethered RuII and RhIII precatalysts allowed us to
extend this process to more challenging substrates bearing al-
kynyl- and alkyl substituents, which, to the best of our knowl-
edge, have never been used in such a process, to provide the
corresponding syn a-alkoxy-b-hydroxyesters with excellent
enantiocontrol (up to 99% ee) and good to perfect diastereo-
selectivity (up to 99:1 d.r.). Attractive features of this transfor-
mation include the mild reaction conditions, operational sim-
plicity and practicability, broad substrate scope, and high selec-
tivity. Lastly, this strategy was efficiently applied to the synthe-
sis of an important intermediate en route to AZ-242 (Tesaglita-
zar), which exhibits antidiabetic properties.
L.M. and D.C. are grateful to the Minist›re de l’Education Natio-
nale et de la Recherche and CNRS for financial support. We
thank the Groupe de SpectromØtrie de masse de l’UniversitØ
Pierre et Marie Curie (Paris) for performing the HRMS measure-
ments.
Keywords: alpha-alkoxy-beta-ketoesters
·
asymmetric
catalysis · asymmetric transfer hydrogenation · dynamic kinetic
resolution · ruthenium
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Experimental Section
All reactions were run under an argon atmosphere. Reaction ves-
sels were dried under vacuum and cooled under a stream of
argon. CH2Cl2 and THF were distilled prior to use from calcium hy-
dride and sodium/benzophenone, respectively. Solvents, reagents,
and chemicals were purchased from Sigma–Aldrich, Alfa Aesar, TCI,
or Acros Organics and were used as purchased, unless stated oth-
erwise. Substituted cinnamaldehydes and alkynyl derivatives were
obtained according to literature procedures.[20] 1H and 13C NMR
spectra were recorded with a Bruker AVANCE 300 spectrometer
(300 and 75 MHz, respectively). Chemical shifts (d) are reported in
parts per million (ppm) downfield from tetramethylsilane (TMS),
relative to dH =7.26 ppm (s; CHCl3) or dC =77.0 ppm (t; CDCl3).
Coupling constants (J) are reported in Hertz [Hz]. The following ab-
breviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad. 13C NMR spectra were routinely run with
broadband decoupling. Ee values were determined by SFC, per-
formed with a BERGER instrument equipped with a UV detector or
by HPLC performed with a Waters e2695 instrument equipped
with a UV detector. Chiral analyses were performed with Chiralcel
columns, eluting with the solvent mixture indicated. [Ga]D values
[degcm2 gÀ1] were recorded with a PerkinElmer 241 polarimeter at
l=589 nm (sodium lamp).
General procedure for the RuII- or RhIII-catalyzed ATH of a-
alkoxy-b-ketoxyesters 2–5
a-Alkoxy-b-ketoester (1.0 mmol, 1.0 equiv) and chiral RuII or RhIII
catalyst (0.005 mmol, 0.005 equiv) were dissolved in anhydrous
CH2Cl2 (5 mL) and 5:2 HCO2H/NEt3 (170 mL, 2 mmol, 2 equiv) was
added dropwise. The mixture was stirred under argon for 20 h. The
reaction was neutralized by addition of a saturated aqueous solu-
tion of NaHCO3 (10 mL). The solution was decantated and extract-
ed with CH2Cl2 (2”10 mL). The combined organic layers were dried
over MgSO4 and concentrated under reduced pressure. The residue
was passed through a pad of silica gel (pentane/CH2Cl2 50:50) to
afford the desired chiral syn a-alkoxy-b-hydroxyester as the major
product.
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Received: May 13, 2015
Published online on July 2, 2015
Chem. Eur. J. 2015, 21, 11799 – 11806
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11806
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim