A simple synthetic route to enantiopure α-hydroxy ketone derivatives by asymmetric hydrogenation

Article abstract of DOI:10.1002/adsc.201200224

High enantioselectivities (up to 99% ee) have been observed for the catalytic asymmetric hydrogenation of the α-ketone enol acetates. DuanPhos has been proved to be the most effective ligand for this reaction. The high yield and enantioselectivity of the asymmetric hydrogenation of the α-ketone enol acetates represents a feasible synthetic route to important pharmaceutical building blocks: α-hydroxy ketones. Copyright

Full text of DOI:10.1002/adsc.201200224

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DOI: 10.1002/adsc.201200224
A Simple Synthetic Route to Enantiopure a-Hydroxy Ketone
Derivatives by Asymmetric Hydrogenation
Tian Suna and Xumu Zhanga,*
a
Department of Chemistry and Chemical Biology & Department of Medicinal Chemistry, Rutgers, The State University of
New Jersey, Piscataway, New Jersey 08854, USA
Fax : (+1)-732-445-6312; e-mail: xumu@rci.rutgers.edu
Received: April 2, 2012; Revised: July 31, 2012; Published online: November 8, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200224.
Abstract: High enantioselectivities (up to 99% ee)
have been observed for the catalytic asymmetric hy-
drogenation of the a-ketone enol acetates. Duan-
Phos has been proved to be the most effective
ligand for this reaction. The high yield and enantio-
selectivity of the asymmetric hydrogenation of the
a-ketone enol acetates represents a feasible syn-
thetic route to important pharmaceutical building
blocks: a-hydroxy ketones.
Recently, we have reported the asymmetric hydro-
genation of a-ketone enamides.[6] Inspired by these
results, we realized that the asymmetric hydrogena-
tion of a-ketone enol acetates might be a direct and
efficient approach to the a-hydroxy ketones
(Figure 1). In addition, the synthesis of a-ketone enol
acetates has proved to be very straightforward
(Scheme 1).[7] Starting from the readily available dike-
tones 4a–4g, the a-ketone enol acetates 1a–1g can be
obtained through a one-step reaction. Herein, we
report the asymmetric hydrogenation of a-ketone
enol acetates catalyzed by Rh-DuanPhos (up to 99%
ee), revealing an efficient approach to synthesize the
enantiomerically pure a-hydroxy ketone derivatives
(2a–2g).
Keywords: alcohols; chirality; hydrogen; rhodium
a-Hydroxy ketones and their derivatives are impor-
Although the enol acetate has a similar structure to
tant structural moieties of pharmacologically useful the enamide (Figure 1), the asymmetric hydrogena-
substances and biologically active natural com- tion of enol acetates is more challenging than that of
pounds.[1] In particular, enantiomerically pure a-hy- enamides.[8] One possible reason is that the acyl group
droxy ketones often serve as the chiral building of the enol acetate has a weaker coordinating ability
blocks for the asymmetric synthesis of natural prod- to the transition metal than the amide group of the
ucts.[2] Several methods have been developed in the enamide. It has been reported that both Rh-phos-
field of chiral a-hydroxy ketone synthesis, including phine and Ru-phosphine catalytic systems have suc-
oxidation of enolates[3a–e] and enol ethers,[3e–g] and ki- cessfully catalyzed the hydrogenation of simple enol
netic resolution of racemic a-hydroxy ketones.[4] In acetates.[5,9,11] Rh-DuPhos is the first effective catalyst
addition, several research groups report that both en- for the asymmetric hydrogenation of enol acetates.[5a,b]
zymes and transition metals can catalyze the reduc- Rh-TangPhos was reported with up to 99% ee for the
tion of a-diketones.[4] The last approach in principle hydrogenation of enol acetates.[5f] Ru-TunePhos and
should be the most straightforward and atom econom-
ical route to a-hydroxy ketones. Unfortunately, it is
often difficult to control the chemoselectivity between
the two ketone groups, and mixtures of a-hydroxy ke-
tones and 1,2-diols are generated.[4] Alternatively, the
asymmetric hydrogenation of enol acetates has been
reported by several groups to avoid the problems
raised by direct hydrogenation of ketones.[5] However,
the asymmetric hydrogenation of the a-ketone enol
acetates remains unexplored. Herein, we would like
to propose a simple synthetic route to substituted
Figure 1. Substrates of enamides and enol acetates and their
enantiomerically pure a-hydroxy ketones.
derivatives.
Adv. Synth. Catal. 2012, 354, 3211 – 3215
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Tian Sun and Xumu Zhang
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the alternative coordination group (Figure 1) would
improve the binding capability of the substrates to the
transition metal, resulting in a good enantioselectivity
of the substrate 1a. In order to find the most efficient
catalyst, several ligands were screened for the pro-
posed reaction: the asymmetric hydrogenation of a-
ketone enol acetates 1.
As shown in Table 1, the chiral phosphine ligands:
TangPhos, DuanPhos, Et-DuPhos, MonoPhos, and C2-
TunePhos (Figure 2) were tested using the standard
substrate 1a. Rh-DuanPhos was found to be the most
efficient with 92% ee. Rh-TangPhos also gave good
enantioselectivity of 89% ee, but the side product 3a
was generated. Ru-TunePhos gave poor conversion
and chemoselectivity (Table 1, entry 5). In the case of
C2-TunePhos, a ruthenium precursor instead of a rho-
dium precursor was tested. The reason is that the
ligand with two phenyl groups on the chiral phos-
phine (like BINAP[13] and TunePhos) is less electron-
rich than the alkyl-substituted phosphine ligands (like
DuPhos, TangPhos, and DuanPhos). Therefore, Tune-
Phos generally has better activity with a ruthenium
Scheme 1. The synthesis of a-ketone enol acetates.
Rh-PennPhos were found to be efficient for the hy- precursor. This also explained why Ru-TunePhos was
drogenation of cyclic enol acetates (up to 99% ee).[5i,9] applied in the hydrogenation of cyclic enol acetates.[5i]
Rh-MonoPhos was also reported with up to 94% ee
Further experiments with Rh-DuanPhos and Rh-
for the more difficult substrates: alkenyl carboxy- TangPhos revealed strong pressure effects. We had
lates.[11] From the above examples, we envision that tried to reduce the hydrogen gas pressure to avoid
Table 1. Ligand screening for the asymmetric hydrogenation of a-ketone enol acetate 1a.
Entry
Precursora
Rh(COD)2BF4
Ligand
(S,S,R,R)-TangPhos
PH [b] [bar]
Conversion[c] [%]
2a:3a
ee[d] [%]
2
1[e]
2[e]
3[e]
4[f]
G
E
10
10
10
10
10
5
100
100
100
0
20
90
80:20
95:5
90:10
n.a.
50:50
85:15
n.a.
80:20
100:0
100:0
89
91
89
n.a.
0
89
n.a.
88
92
92
Rh(COD)2BF4
Rh(COD)2BF4
Rh(COD)2BF4
[RuCl2A
(h6-C6H6)]2
Rh(COD)2BF4
Rh(COD)2BF4
Rh(COD)2BF4
Rh(COD)2BF4
Rh(COD)2BF4
R
ACHTUNGTREN(NGNU S,R)-DuanPhos
N
ACHTUNGTRENNUNG
(S)-Et-DuPhos
(R)-MonoPhos
(S)-C2-TunePhos
R
N
E
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
5[g]
6[e]
7[e]
8[h]
9[h]
10[h]
A
U
N
N
N
U
1
0
20
10
20
100
100
100
N
[a]
Complexes: [Rh
N
ACTHGNUETRNN(UNG Sc,Rp)-DuanPhos]BF4, [RhACHUTNGTERNNUG(COD)AHCNUTGERTG(NNUN S,S,R,R)-TangPhos]BF4, [RhACHTNUGTREN(NUGN COD)(S)-Et-DuPhos]BF4, and
[RuCl(benzene)(S)-C2-TunePhos]Cl are used in the reaction. The Rh-MonoPhos catalyst is generated in situ.
ACHTUNGTRENNUNG
[b]
[c]
PH measures pressure of the hydrogen gas, using ꢁbarꢂ as the unit.
Conversion [%] measures the conversion of starting material 1a and is determined by H NMR spectroscopy of the crude
products.
2
1
[d]
[e]
[f]
The ee [%] measures the enantiomeric excess of 2a.
Reaction conditions: metal-ligand complex:1a=1:100, room temperature,12 h, in EtOAc.
Reaction conditions: [RhACHTGNUTRENNUNG
[g]
AHCTUNGTRENNUNG
tested the ligand C3-TunePhos, resulting in no reaction.
Reation conditions: metal-ligand complex:1a=1:100, room temperature, 5 h, in EtOAc.
[h]
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A Simple Synthetic Route to Enantiopure a-Hydroxy Ketone Derivatives
were highly efficient with over 90% yields. As shown
in Scheme 1, 4g was readily converted into 1g without
generating the side product 5g. The asymmetric hy-
drogenations of 1f and 1g achieved up to 99% enan-
tioselectivities. However, the asymmetric hydrogena-
tions of substituted aromatic a-ketone enol acetates
(1b–1e) had lower enantioselectivities. For the elec-
tron-withdrawing group substituted substrates 1d and
1e, the enantioselectivities dropped to 85% and 88%.
The conversion of 1e to 2e was only 60%. Comparing
aliphatic substrates (1f and 1g) with aromatic sub-
strates (1a–1e), we discovered that the aliphatic sub-
strates significantly outperformed the aromatic sub-
strates. The reason might be that the phenyl substitu-
ent group served as an unnecessary coordinating
group, and disrupted the coordination of the acetyl
Figure 2. Structures of TangPhos,[5f,8a] DuanPhos,[12a] DuPho-
s,[5a] MonoPhos,[11] and C2-TunePhos[12b]
.
generating side product 3a. However, when the hy- group to the transition metal. To the best of our
drogen gas pressure was 5 bar (Table 1, entry 6), 3a knowledge, none of the substrates have been tested in
was still generated using Rh-TangPhos. When the hy- asymmetric hydrogenations before.
drogen gas pressure was reduced to 1 bar, no reaction
In conclusion, we have applied DuanPhos for the
was observed (Table 1, entry 7). We also found out asymmetric hydrogenation of various substituted a-
that if the reaction time was kept within 5 h, we could ketone enol acetates. High enantioselectivities have
guarantee the 100% chemoselectivity of 2a over 3a been observed for most of the tested substrates. The
even under a higher hydrogen gas pressure (20 bar) presented results demonstrate that DuanPhos is
using Rh-DuanPhos (Table 1, entry 10). Therefore, we a very efficient hydrogenation ligand for the synthesis
selected Rh-DuanPhos for further experiments, and of chiral a-hydroxy ketones.
ran the experiments under 10 bar for 5 h. As shown in
Table 2, dramatic solvent effects were observed in this
hydrogenation reaction. The highest enantioselectivity Experimental Section
was obtained when ethyl acetate was used as the sol-
vent.
With optimized reaction conditions, several other
Substrate Preparation
A catalytic amount of an acid (p-toluenesulfonic acid) and
Ac2O (5 mL) was added to a stirred solution of 4 (20 mmol)
in toluene. The mixture was heated in a closed vial at 858C
for 48 h. The reaction mixture was then washed with EtOAc
and water thoroughly. The EtOAc layer was washed with sa-
turated NaHCO3 solution and water, dried over Na2SO4.
After removing the solvent by rotary evaporation, the prod-
uct mixture was purified by flash column chromatography
using 1:4 ethyl acetate/hexane. It is necessary to immediate-
ly refrigerate the pure product to À208C after the solvent
has been removed by rotary evaporation.
a-ketone enol acetates were examined. As shown in
Table 3, the substrates can be classified into two
groups: aromatic a-ketone enol acetates (1a–1e) and
aliphatic a-ketone enol acetates (1f and 1g). To our
delight, the syntheses of aliphatic substrates 1f and 1g
Table 2. Optimization of reaction conditions for Rh-Duan-
Phos-catalyzed hydrogenation of a-ketone enol acetate 1a.
Asymmetric Hydrogenation
The
complex
[Rh
(COD)
G
(3ꢃ
10À4 mmol, 2.04 mg) was loaded with substrate 1a
(0.3 mmol) into a 10.0 mL vial. Ethyl acetate (3 mL) was
added into the vial at room temperature in the glove-box.
The vial was added with a magnetic stirring bar, and was
placed into the Parr bomb (autoclave). The bomb was
purged three times with H2, and the pressure of H2 was set
to 10 bar (measured by the Parr bombꢂs pressure gauge).
The hydrogenation reaction was performed at room temper-
ature for 5 h. After carefully releasing H2, the solvent was
removed under reduced pressure. The crude product was
purified through a silica gel plug, eluting with ethyl acetate,
to afford product 2a. The enantiomeric excess (ee) value
was determined by chiral HPLC.
Entry[a] Ligand
Solvent
DuanPhos EtOAc
Conversion [%][b] ee [%][c]
1
2
3
4
5
>99
DuanPhos methanol >99
DuanPhos THF
DuanPhos CH2Cl2
DuanPhos toluene
92
80
>99
85
0
0
n.a.
n.a.
[a]
[b]
[c]
Reation conditions: [RhACHTUNRTGENNG(U COD)ACHTUNTGNER(NNGU Sc,Rp)-DuanPhos]BF4:1=
1:100, room temperature,10 bar, 5 h.
Conversion is determined by 1H NMR spectroscopy of
the crude products.
The ee is determined by chiral HPLC.
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Tian Sun and Xumu Zhang
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Table 3. Asymmetric hydrogenation of a-ketone enol acetates catalyzed by Rh-DuanPhos.
Substrate[a]
Product
Conversion [%][b]
ee [%][c]
1a
1b
(R)-2a
(R)-2b
>99
>99
92
90
90
1c[b]
1d[d]
1e[b]
(R)-2c
(R)-2d
(R)-2e
>99
>99
60
85
88
1f
1g
(S)-2f
(S)-2g
>99
>99
99
98
[a]
[b]
[c]
Reaction conditions: [RhACHTUNTRGENNUG(COD)ACTHUNGTERN(NGUN Sc,Rp)-DuanPhos]BF4:1=1:100, room temperature,10 bar, 5 h, in EtOAc.
1
Conversion is determined by H NMR spectroscopy of the crude products.
The ee is determined by chiral HPLC and GC.
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Acknowledgements
We gratefully thank the National Science Foundation (CHE
0956784) for the financial support. We would also like to
thank Isadora Zhang for her experimental assistance during
the summer internship (Summer 2011).
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