Rhodium-mediated asymmetric transfer hydrogenation: A diastereo- and enantioselective synthesis of: Syn -α-amido β-hydroxy esters

Article abstract of DOI:10.1039/c7cc08231b

The preparation of syn α-benzoylamido β-hydroxy esters through asymmetric transfer hydrogenation (ATH) with a tethered Rh(iii)-DPEN complex via dynamic kinetic resolution (DKR) has been developed for the first time starting from α-benzoylamido β-keto esters. A variety of α-benzoylamido β-keto esters were converted under mild conditions into the corresponding syn α-benzoylamino β-hydroxy esters with high yields (up to 98%) and diastereomeric ratios (up to >99:1 dr) as well as excellent enantioselectivities (up to >99% ee).

Full text of DOI:10.1039/c7cc08231b

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Rhodium-Mediated Asymmetric Transfer Hydrogenation: a
Diastereo- and Enantioselective Synthesis of syn-
Hydroxy Esters
α
-Amido -
β
Received 00th January 20xx,
Accepted 00th January 20xx
Long-Sheng Zheng, Charlène Férard, Phannarath Phansavath* and Virginie Ratovelomanana-
Vidal*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The preparation of syn α-benzoylamido β-hydroxy esters through
asymmetric transfer hydrogenation (ATH) with a tethered Rh(III)-
DPEN complex via dynamic kinetic resolution (DKR) has been
developed for the first time starting from α-benzoylamido β-keto
esters. A variety of α-benzoylamido β-keto esters were converted
under mild conditions into the corresponding syn α-benzoylamino
β-hydroxy esters with high yields (up to 98%) and diastereomeric
ratios (up to >99:1 dr) as well as excellent enantioselectivities (up
to >99% ee).
Because enantiomerically pure β-amino alcohols bearing two
contiguous stereocenters are valuable building blocks in
natural products and pharmaceuticals, and because they can
be used as ligands in asymmetric catalysis, an efficient
synthesis of these scaffolds is highly desirable.
A
straightforward and atom-economical access to such
compounds involves the dynamic kinetic resolution (DKR) of
racemic α-amino β-keto ester derivatives that can be
performed through either asymmetric hydrogenation (AH) or
asymmetric transfer hydrogenation (ATH), to obtain the syn or
anti reduced products.1 However, although the DKR of
α-
amido β-keto esters through asymmetric hydrogenation is now
well established, the asymmetric transfer hydrogenation of
these compounds is much less documented. Previous work in
this field only focused on
with carbamate, 2,2-dichloro N-acetamido or amino
hydrochloride functional groups in the -position to access the
β-keto esters that were substituted
Scheme 1 ATH of α-amino β-keto ester derivatives
α
anti amino alcohol derivatives using either ruthenium2–8 or
rhodium9 complexes (Scheme 1, previous work). On the other
hand, scarce examples of the production of the syn
compounds through Ru-catalyzed ATH have been described so
far for N-diprotected compounds.5a,10,11 We have previously
observed this reversal of diastereoselectivity from anti to syn
in the Ru-7 or Rh-mediated9 ATH of
α-amino β-keto ester
hydrochlorides, bearing thienyl or furyl substituents on the
ketone functional group. These results clearly indicate that the
stereochemical outcome of the ATH of these α-amino β-keto
ester derivatives is highly dependent on the nature of the
amino group as well as on the ketone substituent. As part of
an ongoing program aimed at developing efficient methods for
the asymmetric reduction of functionalized ketones,12 we
report herein an unprecedented syn diastereoselectivity
obtained in the Rh-catalyzed DKR/ATH of N-monoprotected α-
amino -keto esters, in this case, -benzoylamino -keto
β
esters (Scheme 1, this work). The novelty of this study resides
α
β
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Table 1 Catalyst and solvent screeninga
in the use of a rhodium complex for the ATH-DKR of N-
monoprotected -amino -keto esters to access the
α
β
corresponding syn products, as opposed to the work described
by Wang and coworkers,11 which involved the Ru-catalyzed
ATH of N-diprotected compounds and for which rhodium and
iridium complexes were inefficient.
We started our study with the racemic methyl 2-
benzoylamino-3-oxo-3-phenylpropanoate 1a as the standard
substrate (Table 1). The initial asymmetric transfer
hydrogenation experiments were carried out in CH2Cl2 at 30 °C
using ruthenium complexes (R,R)-A, (S,S)-B and (R,R)-C in the
presence of a 5:2 HCO2H/Et3N azeotropic mixture as the
hydrogen source, and afforded the corresponding anti amino
alcohol derivatives as the major isomers albeit with low
enantiomeric excesses (Table 1, entries 1–3). The sense of
diastereoselectivity observed here was in agreement with the
results reported previously for the ruthenium-catalyzed ATH of
entry
catalyst
solvent
CH2Cl2
time
(h)
96
7
yield
(%)
96
95
94
90
86
89
88
87
89
88
93
dr
(syn/anti)b
15:85
10:90
8:92
eesyn
(%)c
28d
1
2
A
B
C
e
CH2Cl2
36d
e
3
CH2Cl2
9
25d
the parent
our surprise however, we found that with the tethered
rhodium complex (R,R)-D 13,14
the reaction proceeded
α-N-Boc or α-N-Cbz β-keto ester compounds. To
4
D
D
D
D
D
E
CH2Cl2
CH3CN
THF
5
86:14
87:13
87:13
83:17
86:14
86:14
86:14
84:16
>99
>99
>99
>99
>99
>99
>99
>99
5
4.5
23
28
4
,
6
smoothly within 5 h to deliver the reduced syn product (R,S)-
2a in 90% yield with a good 86:14 dr and an excellent
enantiomeric excess of >99% for the syn isomer (Table 1, entry
4). The absolute configuration of the reduced product 2a was
assigned as (2R,3S) by converting the diastereomerically pure
syn 2a into the known (1S,2S)-2-benzoylamino-1-phenyl-
propane-1,3-diol and comparing the optical rotation value with
7
8f
i-PrOH
–
9
CH2Cl2
CH2Cl2
–
7
10
11f
F
7
G
20
a Conditions: 0.8 mmol of 1a, 0.5 mol% of precatalyst, 134
in 4 mL of solvent at 30 °C. Complete conversions in all cases. b Determined by 1
ꢀL of HCO2H/Et3N (5:2)
H
the reported data ([ [α]D +94.6
α]D20 = +80.1 (c 1.0, EtOH), lit.:15
(c 1.0, EtOH)).16 To our knowledge, this reversal of
c
d
NMR of the crude product. Determined by SFC analysis. ee of the anti
compound. e 1.6 mL of solvent was used. f Neat reaction.
diastereoselectivity from anti to syn provided by the use of a
Rh complex has never been reported to date for the ATH of N- hydrogenation reaction was not altered by switching from
monoprotected -amino -keto esters. The use of other (R,R)-
to (R,R)- , (R,R)-
or (R,R)-G17 bearing respectively,
solvents under otherwise identical conditions afforded similar methyl, trifluoromethyl or fluoro groups on the aryl ring, even
α
β
D
E
F
results in terms of yields and stereoselectivities although the though the reactions required more time (Table 1, entries 9–
reaction time was longer in THF and i-PrOH (Table 1, entries 5– 11). Accordingly, we selected complex (R,R)-
D as the pre-
7). The neat reaction also led to an 86:14 dr and >99% ee catalyst and CH2Cl2 as the solvent for further studies (Table 2).
(Table 1, entry 8). The stereochemical outcome of the transfer
Table 2 Catalyst loading and temperature screeninga
entry
catalyst (mol %)
cb
temp (°C)
time (h)
5
yield (%)
90
dr (syn/anti)c
86:14
86:14
86:14
89:11
92:8
eesyn (%)d
>99
1
0.5
0.1
0.5
0.5
0.5
0.2
0.5
0.5
0.2
0.2
0.2
0.2
0.2
0.2
0.4
0.5
30
30
30
18
0
2
23
91
61f
>99
3e
4
24
>99
22
87
>99
5
47
93
>99
6
0
94
73
92:8
>99
7
0
34
94
92:8
>99
8
0
28
93
92:8
>99
a Conditions: 0.8 mmol of 1a, respective mol% of (R,R)-D, 134
ꢀ
L of HCO2H/Et3N (5:2) in 1.6–4.0 mL of CH2Cl2. Complete conversions except where indicated. b Initial
c
d
e
f
concentration of α-amido β-keto ester. Determined by 1H NMR of the crude product. Determined by SFC analysis. 1:1 mixture of HCO2H/Et3N used. 64%
conversion obtained under these conditions.
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Table 3 Substrate scopea
Performing the reaction at 30 °C with a catalyst loading of 0.1
mol% instead of 0.5 mol% resulted only in an extended
reaction time without any noticeable effect on either the yield
or stereoselectivity (Table 2, entries 1–2), whereas using a 1:1
HCO2H/Et3N azeotropic mixture rather than the 5:2 system led
to incomplete conversion after 24 h of reaction (Table 2, entry
3). The temperature effect was then investigated, and the
entry/ATH product 2
time
(h)
yield
(%)
dr
eesyn
(%)c
reaction was run at 18 °C, affording
a slightly higher
(syn/anti)b
OH
O
diastereomeric ratio of 89:11 (Table 2, entry 4). A satisfying
92:8 dr was attained at a temperature of 0 °C after either 47 h
(Table 2, entry 5) or 94 h with a catalyst loading of 0.2 mol%
(Table 2, entry 6). Finally, maintaining a 0.5 mol% catalyst
OMe
NHCOPh
1/2a
2/2b
3/2c
4/2d
28
48
70
48
93
98
96
96
92:8
93:7
93:7
94:6
>99
>99
>99
>99
OH
O
Me
OMe
loading, a variation of the initial concentration of α-amido β-
keto ester from 0.2 to 0.4 and 0.5 M showed a decrease of the
NHCOPh
O
OH
reaction time from 47 h to 34 h and 28 h, respectively (Table 2,
OMe
NHCOPh
entries
5
and 7–8). Accordingly, the optimized reaction
, a 5:2
Me
conditions were set as follows: 0.5 mol% of (R,R)-
D
OH
O
HCO2H/Et3N azeotropic mixture as the hydrogen source, CH2Cl2
as the solvent (0.5 M), and a reaction temperature of 0 °C.
With these conditions in hand, we next investigated the scope
OMe
NHCOPh
O
OH
OMe
5/2e
6/2f
64
45
96
86
92:8
91:9
>99
>99
of the reaction and a series of variously substituted α-
benzoylamino -keto esters were subjected to the ATH.
NHCOPh
O
MeO
β
OH
Compounds bearing substituted phenyl groups on the ketone
functional group generally gave the corresponding reduced syn
products in high yields with high diastereoinductions and
excellent enantioselectivities irrespective of the electron-
donating or electron-withdrawing character of the
substituents (Table 3, entries 1–9). An exception to this trend
was observed for 1j having a sterically hindered ortho-tolyl
substituent on the ketone, which delivered in moderate yield
the anti compound as the major isomer (syn/anti 13:87) albeit
with a low enantiomeric excess (52% ee), whereas the syn
isomer was produced in >99% ee (Table 3, entry 10). On the
other hand, heteroaryl ketones afforded excellent levels of
diastereo- and enantioinductions and the reduced compounds
were obtained in very good yields with the exception of
compound 1l, which produced 2l in 87:13 dr and 96% ee (Table
3, entries 11–15). Furthermore, for the amido ester 1o bearing
a thienyl substituent on the ketone, no temperature effect was
observed because the reaction could be carried out at 30 °C
within only 1 h without any alteration of the dr or ee (Table 3,
entries 15–16). In addition, the reduction of 1o was efficiently
performed on gram-scale demonstrating the usefulness of this
O
O
OMe
NHCOPh
O
OH
7/2g
8/2h
9/2i
23
23
25
98
95
98
92:8
93:7
94:6
>99
>99
>99
OMe
NHCOPh
F
OH
O
OMe
NHCOPh
Cl
OH
O
OMe
NHCOPh
O
Br
Me
OH
10/2j
11/2k
12/2l
72
22
42
15
24
70
96
63
93
96
13:87
97:3
>99
OMe
52anti
NHCOPh
OH
O
>99
96
N
OMe
NHCOPh
O
OH
87:13
98:2
N
OMe
NHCOPh
OH
O
13/2m
14/2n
>99
99
N
OMe
NHCOPh
O
OH
method. The substrate scope was then expanded to α-amido
-keto esters containing an alkyl ketone. For these
>99:1
O
β
OMe
NHCOPh
compounds, the reduced syn products were obtained with
lower diastereomeric ratios while the ee remained >99%
(Table 3, entries 17–18). As for the sterically demanding
substrate 1j, a reversal of diastereoselectivity was observed as
well, with the amido ester 1r having an isopropyl substituent
on the ketone. This time the anti isomer was formed with a
very high level of diastereo- and enantioinductions albeit after
a prolonged reaction time of 10 days (Table 3, entry 19), which
could be reduced to 92 h by working at 30 °C with no loss of
stereoselectivity (Table 3, entry 20). Finally, the Rh-catalyzed
ATH of substrate 1s having an alkyne residue proceeded with
near-perfect diastereo- and enantioselectivities in either
OH
O
15/2o
16/2o
34
1d
98
96
>99:1
>99:1
>99
>99
S
OMe
NHCOPh
OH
O
17/2p
18/2q
46
24
97
98
80:20
75:25
>99
>99
OMe
NHCOPh
O
OH
Ph
OMe
NHCOPh
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19/2r
10d
92
72
74
2:98
3:97
>99
99
OH
O
OMe
NHCOPh
20/2rd
2
M. Perez, P.-G. Echeverria, E. Martinez-Arripe, M. Ez Zoubir,
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OH
O
21/2s
10d
24
86
80
>99:1
>99:1
>99
>99
OMe
NHCOPh
22/2sd
C5H11
3
4
5
2j (CDCC 1581420)
aConditions: 0.8 mmol of 1, 0.5 mol% of (R,R)-D, 134
2l (CCDC 1581421)
2o (CCDC 1581422)
6
7
Z. Liu, C. S. Shultz, C. A. Sherwood, S. Krska, P. G. Dormer, R.
Desmond, C. Lee, E. C. Sherer, J. Shpungin, J. Cuff, F. Xu,
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ꢀ
L of HCO2H/Et3N (5:2) in
1.6 mL of CH2Cl2 at 0 °C. Complete conversions except for compounds 1j and 1r
for which 73–82% conv. were obtained. bDetermined by 1H NMR of the crude
product. cDetermined by SFC or HPLC analysis. dReaction carried out at 30 °C.
P.-G. Echeverria, J. Cornil, C. Férard, A. Guérinot, J. Cossy, P.
5
Phansavath, V. Ratovelomanana-Vidal, RSC Adv., 2015,
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8
9
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37701.
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6
,
10 days at 0 °C (Table 3, entry 21) or in only 24 h at 30 °C
(Table 3, entry 22).
10 B. Mohar, A. Valleix, J. Desmurs, M. Felemez, C. Mioskowski,
Chem. Commun., 2001, 2572.
11 G. Sun, Z. Zhou, Z. Luo, H. Wang, L. Chen, Y. Xu, S. Li, W. Jian,
In summary, the rhodium-catalyzed asymmetric transfer
hydrogenation of
α
-amido
β
an efficient tool for the synthesis of syn
-keto esters via DKR appears to be
-benzoylamido β-
α
J. Zeng, B. Hu, X. Han, Y. Lin, Z. Wang, Org. Lett., 2017, 19
4339.
,
hydroxy esters, which until now were not directly attainable
through ATH. The reaction proceeded under mild conditions
using a low catalyst loading with tolerance for a diverse set of
functional groups, delivering the reduced compounds in good
12 (a) Z. Wu, T. Ayad, V. Ratovelomanana-Vidal, Org. Lett.,
2011, 13, 3782; (b) F. Berhal, Z. Wu, Z. Zhang, T. Ayad, V.
Ratovelomanana-Vidal, Org. Lett., 2012, 14, 3308; (c) D.
Cartigny, F. Berhal, T. Nagano, P. Phansavath, T. Ayad, J.-P.
Genêt, T. Ohshima, K. Mashima, V. Ratovelomanana-Vidal, J.
Org. Chem., 2012, 77, 4544; (d) Z. Wu, M. Perez, M. Scalone,
T. Ayad, V. Ratovelomanana-Vidal, Angew. Chem. Int. Ed.,
2013, 52, 4925; (e) L. Monnereau, D. Cartigny, M. Scalone, T.
yields, high
enantioselectivities for
Furthermore, the usefulness of this method was demonstrated
by the efficient gram-scale reduction of 1o
diastereomeric ratios,
and
excellent
a
wide range of substrates.
.
Ayad, V. Ratovelomanana-Vidal, Chem. Eur. J., 2015, 21
,
11799; (f) T. Ayad, P. Phansavath, V. Ratovelomanana-Vidal,
Chem. Rec., 2016, 16, 2750.
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Ratovelomanana-Vidal, Catal. Commun., 2015, 62, 95; (b) D.
S. Matharu, D. J. Morris, A. M. Kawamoto, G. J. Clarkson, M.
This work was supported by the Ministère de l'Education
Nationale, de l'Enseignement Supérieur et de la Recherche
(MENESR) and the Centre National de la Recherche
Scientifique (CNRS). We gratefully acknowledge the China
Scholarship Council (CSC) for a grant to L.-S. Z. We would like
to thank L.-M. Chamoreau and G. Gontard for the X-ray
analysis. This manuscript is dedicated to Prof. Miguel Yus on
the occasion of his 70th birthday.
Wills, Org. Lett., 2005,
Martins, M. Wills, Chem. Asian J., 2008,
7
, 5489; (c) D. S. Matharu, J. E. D.
, 1374; (d) J.
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14 The Rh-catalyzed ATH of the corresponding N-dibenzyl
compound, using 10 mol% of complex (R,R)-D, resulted in no
Conflicts of interest
conversion, even at 40 °C. This result confirmed what Wang
and co-workers observed with Cp*RhTfDPEN in ref. 11.
There are no conflicts to declare.
15 X.-M. Zhang, H.-L. Zhang, W.-Q. Lin, L.-Z. Gong, A.-Q. Mi, X.
Cui, Y.-Z. Jiang, K.-B. Yu, J. Org. Chem., 2003, 68, 4322.
16 The absolute configuration of 2a was further confirmed by
comparison with authentic samples of compounds (2R,3S)-2a
and (2S,3R)-2a (prepared by ruthenium-catalyzed AH of rac-
Notes and references
1
For selected reviews on DKR through AH/ATH, see: (a) R.
Noyori, M. Tokunaga, M. Kitamura, Bull. Chem. Soc. Jpn.,
1995, 68, 36; (b) S. Caddick, K. Jenkins, Chem. Soc. Rev.,
1996, 25, 447; (c) R. S. Ward, Tetrahedron: Asymmetry, 1995,
1a with
[
{
RuCl((R)-SYNPHOS)
}
2(µ-Cl)3]–[Me2NH2]+ and
[{
RuCl((S)-SYNPHOS)}
2(µ-Cl)3]–[Me2NH2]+, respectively) using
HPLC analysis. The absolute configurations of 2e and 2g were
assigned by using the same method.
6, 1475; (d) V. Ratovelomanana-Vidal, J.-P. Genêt, Can. J.
Chem., 2000, 78, 846; (e) F. F. Huerta, A. B. E. Minidis, J.-E.
Bäckvall, Chem. Soc. Rev., 2001, 30, 321; (f) O. Pàmies, J.-E.
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17 L.-S. Zheng, Q. Llopis, P.-G. Echeverria, C. Férard, G.
Guillamot, P. Phansavath, V. Ratovelomanana-Vidal, J. Org.
Chem., 2017, 82, 5607.
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