Ru-catalyzed hydrogenation of 3,5-diketo amides: Simultaneous control of chemo- and enantioselectivity

Article abstract of DOI:10.1039/c2cc33695b

By modulating the chelating priorities of the different directing groups in 3,5-diketo amides with the assistance from coordinating solvent, highly chemo- and enantioselective hydrogenation of the C3-carbonyls was achieved in the presence of [RuCl(benzene)(S)-SunPhos]Cl in THF.

Full text of DOI:10.1039/c2cc33695b

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COMMUNICATION
Ru-catalyzed hydrogenation of 3,5-diketo amides: simultaneous control
of chemo- and enantioselectivityw
Wanfang Li,a Weizheng Fan,a Xin Ma,a Xiaoming Tao,a Xiaoming Li,a Xiaomin Xiea and
Zhaoguo Zhang*ab
Received 23rd May 2012, Accepted 17th July 2012
DOI: 10.1039/c2cc33695b
By modulating the chelating priorities of the different directing
groups in 3,5-diketo amides with the assistance from coordinating
solvent, highly chemo- and enantioselective hydrogenation of the
C3-carbonyls was achieved in the presence of [RuCl(benzene)(S)-
SunPhos]Cl in THF.
In contrast to the diverse paths to 3-oxo-5-hydroxy acid
derivatives (B and ent-B), sporadic reduction methods lead to
3-hydroxy-5-oxo acid derivatives (C and ent-C).9 Ru-catalyzed
asymmetric hydrogenation of functionalized ketones has
become a routine method for many advanced chiral alcohols.10
It was also employed for the stereoselective reduction of
3,5-diketo acid esters (A). Saburi11 and Carpentier12 have
independently reported the asymmetric hydrogenation of
3,5-diketo esters but they failed to obtain ideal chemo- and
stereoselectivity. The next two decades witnessed some progress in
this continuing subject,12,13 but hitherto it is still impossible to
achieve simultaneously high chemo-, enantio- and diastereoselectivity.
Herein we present our recent work on highly selective hydrogena-
tion of 3,5-diketo amides at the C3-carbonyls (Scheme 2).
Enantiopure 3,5-dioxygenated acid derivatives are found in
many important molecules or their synthetic intermediates,1
such as Berkeleyamide A2 (high inhibition activity against
MMP-3 and caspase-1), Ixempra (anti-cancer drug),3 and side
chains of atorvastatin and rosuvastatin (HMG-CoA reductase
inhibitors).4 Accordingly, various approaches have been
devised to synthesize these important substructures. For
instance, asymmetric aldol-type reactions5 were extensively
used in acquiring the 3-oxo-5-hydroxy acid derivatives. Alter-
native protocols relied mainly upon Claisen condensation of
acetates with chiral b-hydroxy esters6 or a,b-epoxy carboxylic
derivatives.7
Ru-catalyzed asymmetric hydrogenation of b-keto esters
has been extensively investigated, but far fewer examples have
been reported on the hydrogenation of b-keto amides.14
Kramer and Bruckner14e,f proved that b-keto amides were
¨
hydrogenated faster than b-keto esters in alcohol under specified
conditions. Based on the rate comparison method, we realized
the recognition of similar carbonyls within one molecule and
fulfilled the efficient asymmetric hydrogenation of 3-oxoglutaric
acid derived with ester and amide moieties at the two ends.15
Considering that b-keto amides can be hydrogenated prefer-
entially with faster reaction rate in alcohol than that in THF,
we firstly tried the hydrogenation of 3,5-diketo amides in
MeOH (Scheme 3).
Compared with the aforementioned methods, selective
reduction of the 3,5-diketo acid derivatives (A) is most
straightforward (Scheme 1). However, this transformation is
plagued by the chemoselectivity concern from the similarity in
the 3- and 5-carbonyl. Consequently, even many enzymatic
methods failed to give ideal selectivity.8
Initially, 0.5 mmol of 1b was hydrogenated with [Ru(benzene)-
((S)-SunPhos)Cl]Cl (1 mmol%) in MeOH (20 bar of H2, 70 1C)
Scheme 1 Selective reduction of 3,5-diketo acid derivatives.
a School of Chemistry and Chemical Engineering, Shanghai Jiao Tong
University, 800 Dongchuan Road, Shanghai 200240, China.
E-mail: zhaoguo@sjtu.edu.cn
b State Key laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, 345 Lingling Road,
Shanghai 200032, China
w Electronic supplementary information (ESI) available: Experiment
details of substrates synthesis, NMR and HPLC data. CCDC 888973.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c2cc33695b
Scheme 2 Asymmetric hydrogenation of 3,5-diketo acid derivatives.
c
8976 Chem. Commun., 2012, 48, 8976–8978
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Table 2 Optimization of the reaction conditions with 3aa
Entry Ligand T (1C) H2 (bar) Time (h) Yield (%) ee (%)
1
2
3
4
5
6
L1
L1
L1
L1
L2
L3
50
70
70
80
70
70
20
20
40
20
20
20
18
15
12
8
15
15
51b
91
95.0
94.3
90.7
90.9
88.2
72.3
89c
87c
92
90
a
All reactions were carried out in THF (5 mL) with substrate (1 mmol)
S/C = 200. Isolated yield. Conversion was 100% unless otherwise
Scheme 3 Asymmetric hydrogenation of several 3,5-diketo acid
amides in different solvents.
b
noted. 60% conversion based on recovered 3a. A small amount of
c
over-hydrogenation product was detected.
for 3 h (longer reaction time may lead to over-reduced
product, 5b) in the hope of obtaining 2b as the main product
[eqn (1)]. Unexpectedly, 1b remained almost untouched and
neither 2b nor 5b was detected. When the reaction time was
prolonged to 15 h, 1b was partially alcoholized to form methyl
3,5-dioxohexanoate. Further investigation showed that a trace
amount of freed diethylamine poisoned the catalyst. When 1c
was hydrogenated under the same conditions for 5 h [eqn (2)],
only 64.3% ee and 15% conversion were obtained. The
conversion of 1d under the same conditions for 3 h was less
than 5% (by 1H NMR) and the ee of 2d was only 49.7%.
Longer reaction time leads to the over-hydrogenation product
5d. Anyway, it was considerably difficult to achieve selective
hydrogenation and good enantioselectivities in MeOH (similar
results were obtained in EtOH). Several other solvents were
also tested and the chemoselectivity was not as good as in
THF. For example, hydrogenation of 3r in CH2Cl2 and
2-PrOH under the same conditions gave 3,5-dihydroxy pro-
duct 5r, while in acetone a mixture of 5r and 5r0 [eqn (4)] was
obtained.
the lowest ee (entry 6, Table 1). The ester substrate (1g) can
also be selectively hydrogenated at the C3-carbonyl, but the ee
of 2g was only 55.1% (entry 7, Table 1). Therefore, we focused
our attention on the amide substrates.
The reaction conditions were optimized with 3a (Table 2).
Lower temperature leads to somewhat higher ee but the
reaction became much slower (entries 1, 2 and 4, Table 2).
The higher hydrogen pressure had some negative influence on
the enantioselectivity (entries 2 and 3, Table 2). Other ligands
like (S)-BINAP and (S)-SegPhos were inferior to (S)-SunPhos
in enantioselectivity: the ee’s of 4a were 88.2 and 72.3%
Table 3 Asymmetric hydrogenation of various 3,5-diketo amidesa
Entry
Substrates
R
Yieldb (%)
eec (%)
Next, we performed these hydrogenation reactions in THF
(Table 1). 1b, which was inactive in MeOH, can be smoothly
hydrogenated to 2b with 97.2% ee in THF. Besides, the ee’s of
the hydrogenation products of 1c and 1d (Scheme 3) increased
from 64.3 to 87.2% (entry 3, Table 1) and 49.7 to 93.5% (entry 4,
Table 1), respectively. Generally, secondary amides gave
somewhat higher enantioselectivity. The tert-butyl amide gave
1
3a
3b
3c
3d
3e
3f
3g
3h
3i
n-Pr
n-C8H17
Cy
t-Bu
Ph(CH2)2–
Isobutenyl
C6H5
2-MeC6H4
2-MeOC6H4
2-FC6H4
3-ClC6H4
3-MeC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
4-CF3C6H4
1-Naphthyl
2-Naphthyl
2-Furanyl
2-Thienyl
91
92
93
92
95
94e
95
94
93
96
95
96
95
90
94
91
95
94
95
96
94.3
93.5
92.3
87.8
94.2
91.5
95.6
93.7
80.7
95.2
95.9
94.4
95.5
95.5
92.8
93.5
90.7f
91.8
97.4
96.4
2d
3
4
5
6
7
8
9d
10
11
12
13
14d
15
16
17
18
19
20
3j
3k
3l
Table 1 Screening of the acid derivativesa
3m
3n
3o
3p
3q
3r
3s
3t
Entry
1
Het
Yield (%)
eeb (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
NMe2
NEt2
NBn2
NPh2
N-Morpholinyl
NHBu-t
OBu-t
91
94
92
90
92
93
86
96.8
97.2
87.2
93.5
92.5
87.2c
55.1c
a
All reactions were carried out with 1 mmol of substrate in 5 mL of
THF at 70 1C under 20 bar of H2 for 15 h. S/C = 200. Conversion =
b
c
d
100%. Isolated yields. Determined by HPLC. 8 h, longer reac-
tion time leads to somewhat lower yields due to over-hydrogenation of
the product at C5-carbonyls. For 3n, a trace amount of debromination
1g
e
a
product was detected by HPLC/HRMS. A trace amount of over-
1
hydrogenation of the olefin product was detected by HNMR. ee of
its 2-bromoacetate.
All reactions were carried out in THF (5 mL) with substrate (1 mmol)
at 70 1C under 20 bar of H2 for 15 h. S/C = 200. Conversion: 100%,
isolated yield. Determined by HPLC. ee of its 4-nitrobenzoate.
f
b
c
c
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Chem. Commun., 2012, 48, 8976–8978 8977

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respectively (entries 5 and 6, Table 2). Finally, the optimum
reaction conditions with (S)-SunPhos were set at 70 1C and
20 bar of H2.
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Under the optimized conditions, various diethyl amides
were hydrogenated with very good ee’s (Table 3). Longer alkyl
chains decreased the ee to some extent (entry 2, Table 1 vs.
entries 1 and 2, Table 3). Bulkier substituents like tert-butyl
and cyclohexyl further impaired the enantioselectivity, the ee’s
of 4c and 4d were only 92.3% and 87.8% (entries 3 and 4,
Table 3), respectively. Trisubstituted conjugated olefin (3f) was
also tolerated under the hydrogenation conditions (entry 6,
Table 3).16 The halides on the phenyl rings had little effect on
the enantioselectivity of the reaction. Intriguingly, the intro-
duction of an ortho-methoxy (3i), which might participate in
the coordination to some degree, decreased the ee from 95.6%
to 80.7% (entry 7 vs. 9, Table 3). A similar adverse effect on
enantioselectivity from ortho-methoxy was also observed in
the Rh-catalyzed asymmetric hydrogenations of aryl-substituted
enamides.17
Based on our earlier studies15,18 we reckoned that the
hydrogenation of C3-carbonyl was directed by the amide
carbonyl, which could be validated by the absolute configu-
ration of the hydrogenation product (S)-4s (see the X-ray
crystallography data in the ESIw).
In summary, we have succeeded in the asymmetric hydro-
genation of 3,5-diketo amides with simultaneous control of
high chemo- and enantioselectivity, such precise recognition
has not been accomplished by any other chemical methods.
The excellent C3-selectivity rivalled and supplemented the
delicacy of the biocatalysis and also meet the common criterion
of high selectivity19 and atom-economy20 for efficient organic
synthesis. The resultant products furnished valuable precursors
for the stereoisomers of the 1,3-diol substructures. A more
detailed scenario of the reaction pathway and the 3,5-double
stereo control in this hydrogenation is underway.
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