Enantioselective synthesis of chiral β-aryloxy alcohols by ruthenium-catalyzed ketone hydrogenation via dynamic kinetic resolution (DKR)

Article abstract of DOI:10.1002/adsc.200900675

A highly efficient enantioselective synthesis of chiral β-aryloxy alcohols by the [RuCl₂[(S)-SDP][(R, R)-DPEN]} [(S_a,R, R)-1a; SDP = 7, 7′-bis-(diarylphosphino)-1,1′-spirobiindane; DPEN = trans-1,2-diphenylethylenediamine] complex-ca

Full text of DOI:10.1002/adsc.200900675

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DOI: 10.1002/adsc.200900675
Enantioselective Synthesis of Chiral b-Aryloxy Alcohols by
Ruthenium-Catalyzed Ketone Hydrogenation via Dynamic
Kinetic Resolution (DKR)
Wen-Ju Bai,a Jian-Hua Xie,a Ya-Li Li,a Sheng Liu,a and Qi-Lin Zhoua,*
a
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, Peopleꢀs Republic
of China
Fax : (+86)-22-2350-6177; e-mail: qlzhou@nankai.edu.cn
Received: September 29, 2009; Published online: December 28, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900675.
Abstract: A highly efficient enantioselective synthe-
sis of chiral b-aryloxy alcohols by the {RuCl2[(S)-
of racemic 2-methoxylcyclohexanone (99% ee, 99%
de) and 2-methoxyl-1,2-diphenylethanone (98% ee,
93% de) with high enantio- and diastereoselectivities.
However, to the best of our knowledge, the synthesis
of chiral b-aryloxy alcohols with two vicinal stereo-
genic centers by asymmetric hydrogenation of racemic
a-aryloxy ketones has not been documented.
SDP]
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
trans-1,2-diphenylethylenediamine] complex-cata-
lyzed asymmetric hydrogenation of racemic a-
aryloxydiACHTUNGTRENNUNGalkyl ketones via dynamic kinetic resolu-
tion (DKR) has been developed. Enantioselectivi-
ties of up to 99% ee with good to high cis/anti-selec-
tivities (up to>99:1) were achieved.
Recently, we developed a highly efficient method
for the synthesis of chiral b-aryloxy primary alcohols
by the RuCl2-SDPs/diamine-catalyzed asymmetric hy-
drogenation of a-aryloxy aldehydes via dynamic ki-
netic resolution (DKR).[7] This success promoted us
to explore efficient methods for the synthesis of chiral
b-aryloxy secondary alcohols with two adjacent chiral
centers. Herein we report the first example of the
asymmetric hydrogenation of racemic a-aryloxydialk-
yl ketones with high enantioselectivities (up to 99.1%
ee) and diastereoselectivities (cis/trans or anti/syn
Keywords: b-aryloxy alcohols; asymmetric hydroge-
nation; dynamic kinetic resolution; ketones; ruthe-
nium
Optically active b-aryloxy alcohols are popular units >99:1) via DKR (Scheme 1).
occurring in the structures of various pharmaceutics
Racemic a-aryloxydialkyl ketones 2 can be easily
and natural products.[1] The importance of these chiral prepared by substitution of a-chloro cyclic ketones or
building blocks continues to stimulate the develop- a-bromo acyclic ketones with phenols.[8] For example,
ment of new effective methods for the synthesis of 2-chlorocyclohexanone reacted with phenol in gently
this type of chiral alcohols in enantiomerically pure
form.[2] The transition metal-catalyzed asymmetric hy-
drogenation of a-aryloxy ketones has provided an ef-
ficient approach to the synthesis of chiral b-aryloxy
alcohols. For example, Rh- or Ru-catalyzed asymmet-
ric hydrogenation of 3-(aryloxy)-2-oxo-1-propyl-
ACHTUNGTRENNUNG
amines (up to 97% ee)[3] and 1-phenoxypropan-2-one
(80% ee)[4] produced the corresponding b-aryloxy al-
cohols in good to high enantioselecivities. However,
only one stereogenic center was generated in these
asymmetric hydrogenation reactions. By using RuCl2-
BINAP/diamine [BINAP=2,2’-bis(diphenylphosphos-
ACHTUNGTRENNUNG
phino)-1,1’-binaphthyl] catalysts Matsumoto[5] and
Ohkuma[6] prepared b-methoxy alcohols with two ste-
reogenic centers from the asymmetric hydrogenation drogenation of racemic a-aryloxydialkyl ketones via DKR.
Scheme 1. ACHTUNRGTENN{GU RuCl2-[(S)-SDPs]CAHTUNGTRENN[UGN (R,R)-DPEN]}-catalyzed hy-
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81

Wen-Ju Bai et al.
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refluxing acetone containing anhydrous K2CO3 for tion, indicating that the configuration of the hydroge-
30 h to provide 2-phenoxycyclohexanone (2a) in 75% nation product was mainly determined by SDPs li-
yield. By using this procedure, a variety of racemic a- gands, instead of DPEN in RuCl2-SDPs/diamine cata-
aryloxy cyclic and acyclic dialkyl ketones were pre- lysts.
pared with moderate yields (see Supporting Informa- {RuCl2[(R)-BINAP]
tion). also evaluated under the same reaction conditions,
The
BINAP-based
ruthenium
catalyst
AHCTUNGTRENNUNG
Primary experiments on the asymmetric hydrogena- and the hydrogenation product 3a was obtained with
tion of a-phenoxycyclohexanone (2a) were performed slightly lower enantioselectivity (95% ee) (entry 7).
with the catalyst {RuCl2[(S)-SDP]
[(Sa,R,R)-1a] [SDP=7,7’-bis(diarylphosphino)-1,1’-spi- able. It can hydrogenate racemic a-aryloxydialkyl
robiindane; DPEN=trans-1,2-diphenylethylenedi- ketone 2a at 5 atm hydrogen pressure (entry 8). When
amine] under the conditions of S/C=1000 at 10 atm the catalyst loading was reduced from 0.1 mol% (S/
A
The reactivity of catalyst (Sa,R,R)-1a was remark-
ACHTUNGTRENNUNG
H2 pressure. The hydrogenation product (1S,2R)-3a C=1000) to 0.01 mol% (S/C=10,000) the selectivities
was obtained in excellent enantioselectivity and cis- of the reaction were maintained (entry 9). The hydro-
selectivity (99% ee, cis/trans 99:1) (Table 1, entry 1). genation reaction can even be carried out with
Systematic ligand screening showed that most of (S)- 0.001 mol% (S/C=100,000) catalyst, albeit the enan-
SDPs ligands, combined with (R,R)-DPEN were com- tioselectivity (91% ee) and the cis/trans selectivity
petent to hydrogenate a-phenoxycyclohexanone with (cis/trans 85:15) were diminished and the reaction
high enantioselectivities and cis-selectivities, with the became slow (entry 10). These results demonstrate
ligands (S)-SDP (1a) and (S)-Tol-SDP (1b) being the that the {RuCl2[(S)-SDP]
most efficient (entries 1–5). The complex {RuCl2[(S)- is a highly efficient catalyst for the asymmetric hydro-
SDP][(S,S)-DPEN]} [(Sa,S,S)-1a] was found to be a genation of racemic a-aryloxycyclohexanones via
mismatched catalyst, which gave the product (1S,2R)- DKR.
ACHTUNGRTEN[NGNU (R,R)-DPEN]} [(Sa,R,R)-1a]
ACHTUNGTRENNUNG
3a with only a moderate enantioselectivity (78% ee)
Under the optimized reaction conditions, a series of
(entry 6). Both catalysts (Sa,R,R)-1a and (Sa,S,S)-1a racemic a-aryloxy cyclic ketones were hydrogenated
gave the product (1S,2R)-3a with the same configura- to the corresponding b-aryloxy alcohols with excellent
enantioselectivities and high cis/trans selectivities. As
showed in Table 2, the substituents on the phenyl ring
of the a-aryloxycyclohexanones 2a–h have little effect
on the enantioselectivity and cis/trans selectivity of
the reaction (Table 2, entries 1–8). A pyridin-2-yl
group in a-(pyridin-2-yloxy)cyclohexanone (2i) could
be tolerated by this catalytic system and the hydro-
genated product 3i was obtained in 91% ee for enan-
tioselectivity and 97:3 for cis/trans selectivity
(entry 9). The ring size of the cyclic ketones imposed
a significant effect on the enantioselectivity of the re-
action. When the size of the cyclic ketone substrate
was changed from a six-membered to five-membered
ring, the ee value of the hydrogenation product was
decreased dramatically from 99% to 78% (entry 10
vs. entry 1). Enlarging the size from a six-membered
to seven-membered ring in the substrate also led to a
drop in both enantioselectivity and cis/trans selectivity
(entry 11 vs. entry 1).
Conformationally flexible substrates such as race-
mic a-aryloxy acyclic dialkyl ketones 2l–p have also
been examined under similar reaction conditions. The
hydrogenation products 3l–o were obtained with high
ee values (94–96% ee) and high anti-selectivities (en-
tries 12–15). However, the acyclic dialkyl ketone sub-
strates with R1 =ethyl instead of methyl gave a lower
enantioselectivity. For example, the hydrogenation of
ethyl ketones such as 2-phenoxypentan-3-one (2p)
and 1-phenoxy-1-phenylbutan-2-one (2q) yielded the
corresponding b-aryloxy alcohols 3p and 3q with only
80% ee and 84% ee, respectively (entries 16 and 17).
Table 1. Optimizing the asymmetric hydrogenation condi-
tions.[a]
Entry
Catalyst
Time [h]
cis/trans[b]
ee [%][c]
1
2
3
4
5
6
7
N
1
1
1
1
1
2
1
2
3
88
>99/1
>99/1
>99/1
97:3
98:2
99:1
98:2
99/1
>99/1
85:15
99
99
98
95
98
78
95
98
99
91
8[d]
9[e]
10[f]
[a]
The reactions were performed at 0.2M of 2a, under
10 atm of H2, at room temperature (25–308C) in i-POH
containing (Sa,R,R)-1a (S/C=1000) and t-BuOK ([t-
BuOK]=0.04M) unless otherwise stated. The conversion
is 100%.
[b]
[c]
Determined by GC, HPLC or SFC.
ee value for cis-isomer, which was determined by HPLC
or SFC, the configuration of the product is (1S,2R).
5 atm.
S/C=10,000, under 25 atm H2.
S/C=100,000, under 60 atm of H2, at 358C.
[d]
[e]
[f]
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Adv. Synth. Catal. 2010, 352, 81 – 84

Enantioselective Synthesis of Chiral b-Aryloxy Alcohols
Table 2. Asymmetric hydrogenation of racemic a-aryloxydialkyl ketones catalyzed by (Sa,R,R)-1a.[a]
Entry
Ar
R1
R2
3
Time [h]
Selectivity[b]
ee [%][c]
1
2
3
C6H5
N
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
1
1
2.5
2
6
2
2
7
2
1
3
2
12
11
6
7
8
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
93:7
99:1
96:4
89:11
98:2
98:2
99
99
99
98
99
99
98
99.1
91
78
93
96
94
95
95
80
84
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
3-MeC6H4
2-MeC6H4
2-Np
2-Py
C6H5
C6H5
C6H5
4
5[d]
6
7
8
9
10
11
12
13
14[d]
15
16
17
Me
Me
Me
Me
Et
Me
Ph
Ph
Ph
Me
Ph
C6H5
4-MeOC6H4
4-BrC6H4
C6H5
96:4
87:13
97:3
C6H5
Et
[a]
The reaction conditions were the same as those in Table 1, entry 1, 100% conversion and 89–99% yields.
Determined by GC, HPLC or SFC.
Determined by HPLC or SFC.
[b]
[c]
[d]
The configurations of the product 3e and 3n are (1S,2R) and (1R,2S) as determined by X-ray diffraction analysis of single
crystals[12] (see Supporting Information).
Furthermore, the anti/syn selectivity in the hydroge- method.[11] This investigation provides a highly effi-
nation of ketone 2p decreased to 87:13. This result cient method for the enantioselective synthesis of the
showed the need for a large difference in sizes be- potential non-steroidal glucocorticoid modulators.
tween two alkyl groups of the ketone to
achieve high enantio- and diastereoselectivity.
In conclusion, we have developed a highly efficient
method for the synthesis of chiral b-aryloxy alcohols
To demonstrate a potential for the application of with two adjacent stereogenic centers by chiral
the RuCl2-SDPs/DPEN-catalyzed asymmetric hydro- RuCl2-SDPs/DPEN-catalyzed asymmetric hydrogena-
genation of racemic a-aryloxy dialkyketones via DKR tion of racemic a-aryloxydialkyl ketones via DKR.
in the synthesis of pharmaceuticals and biologically This catalytic asymmetric hydrogenation has also
active compounds, the hydrogenation of racemic 1- been applied to the enantioselective synthesis of the
aryl-1-indazolyloxypropan-2-one was carried out key chiral intermediate of non-steroidal glucocorti-
(Scheme 2). The product of this reaction, a chiral 1- coid modulators, 1-aryl-1-indazolyloxypropan-2-amine
aryl-1-indazolyloxypropan-2-ol, can serve as a key in- derivatives.
termediate for the synthesis of 1-aryl-1-indazolyloxy-
propan-2-amine (1R,2S)-10, which was reported to be
a new type of non-steroidal glucocorticoid modula-
Experimental Section
tor.[9] We thus prepared 1-[1-(4-fluorophenyl)-1H-in-
dazol-5-yloxy]-1-phenylpropan-2-one (8) from the
General Procedure for Asymmetric Hydrogenation
easily available 5-nitroindazole (5) in 4 steps including
copper-catalyzed coupling reaction[10] in 55% yield.
The racemic a-indazolyloxy ketone 8 was hydrogenat-
ed by catalyst (Sa,R,R)-1a to the chiral a-indazolyloxy
alcohol (1R,2S)-9 in 99% yield with 94% ee and 93:7
anti/syn selectivity. The a-indazolyloxy alcohol
(1R,2S)-9 can be conveniently converted to target
molecule (1R,2S)-10 and other 1-aryl-1-indazolyloxy-
The catalyst [RuCl2-(S)-SDP/ACHTNUGTRENUNG(R,R)-DPEN] (Sa,R,R)-1a)
(2.0 mg, 0.002 mmol) and anhydrous i-PrOH (8.0 mL) was
placed in a 30-mL hydrogenation vessel. The vessel was
placed in an autoclave and purged with hydrogen by pres-
surizing to 10 atm and releasing the pressure. The procedure
was repeated three times and the solution was stirred under
10 atm of H2 for 5 min. After releasing the pressure, the a-
aryloxy ketone 2 (2 mmol) and a solution of t-BuOK in i-
propan-2-amine derivatives by the literature PrOH (0.2 mmolmLÀ1, 2.0 mL, 0.4 mmol) were added. The
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83

Wen-Ju Bai et al.
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Scheme 2. Synthesis of the key intermediate of chiral 1-aryl-1-indazolyloxypropan-2-amines. Regeants and conditions: a) 5
mol% Cu(OAc)2, 4-FC6H4B(OH)2, pyridine, DCM, room temperature, 24 h; b) Raney-Ni, 3 atm H2, acetone/THF/MeOH
ACHTUNGTRENNUNG
(1:1:2), 358C, 2 h, 75% yield for two steps; c) NaNO2, H2SO4/H2O, room temperature to 958C (3 h), 90% yield; d) K2CO3,
18-crown-6, dioxane, 758C, 2 h, 81% yield; e) 0.1 mol% (Sa,R,R)-1a, KO-t-Bu, i-PrOH, 10 atm H2, 308C, 10 h, 99% yield.
autoclave was purged with hydrogen and pressurized to
10 atm. After stirring at room temperature for a certain
number of hours, the reaction was stopped. The reaction
mixture was filtered through a short silica gel column, and
the filtrate was diluted with acetone and analyzed by GC,
HPLC or SFC to determine the conversion and the selectivi-
ty. The enantioselectivity was determined by chiral HPLC
or SFC (see Supporting Information).
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Acknowledgements
We thank the National Natural Science Foundation of China,
the Major Basic Research Development Program (Grant No.
2006CB806106), the “111” project (B06005) of the Ministry
of Education of China, and Merck Research Laboratories for
financial support.
[5] T. Matsumoto, T. Murayama, S. Mutsuhashi, T. Miura,
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84
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Adv. Synth. Catal. 2010, 352, 81 – 84