Asymmetric hydrogenation of 2-arylated cycloalkanones through dynamic kinetic resolution

Article abstract of DOI:10.1055/s-2004-829093

Asymmetric hydrogenation of 2-arylcycloalkanones with trans-RuCl ₂(binap)(1,2-diamine) and t-C₄H₉OK in 2-propanol selectively gives the corresponding cis-2-arylcycloalkanols in excellent enantiomeric purity and high yield.

Full text of DOI:10.1055/s-2004-829093

LETTER
1383
Asymmetric Hydrogenation of 2-Arylated Cycloalkanones through Dynamic
Kinetic Resolution
Asymmetric
H
y
a
drogenatio
k
n of 2-Aryla
t
e
ed Cycloal
s
kanones hi Ohkuma, Jing Li, Ryoji Noyori*
Department of Chemistry and Research Center for Materials Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
Fax +81(52)7834177; E-mail: noyori@chem3.chem.nagoya-u.ac.jp
Received 1 March 2004
Dedicated to Professor Clayton H. Heathcock in recognition of his significant contribution to organic synthesis and basic science.
O
OH
*
Ru complex
t-C4H9OK
Abstract: Asymmetric hydrogenation of 2-arylcycloalkanones
with trans-RuCl2(binap)(1,2-diamine) and t-C4H9OK in 2-propanol
selectively gives the corresponding cis-2-arylcycloalkanols in ex-
cellent enantiomeric purity and high yield. Two synthetic interme-
diates of biologically active compounds have been prepared by this
method.
Ar
Ar
+
(±)-
H2
*
(CH3)2CHOH
R
R
1: R = CH2
4: R = CH2
2: R = (CH2)2
3: R = (CH2)3
5: R = (CH2)2
6: R = (CH2)3
Key words: 2-arylcycloalkanones, asymmetric hydrogenation,
BINAP, dynamic kinetic resolution, ruthenium complexes
a: Ar = C6H5
d: Ar = 1-naphthyl
b: Ar = 4-CH3OC6H4 e: Ar = 2-naphthyl
c: Ar = 4-CF3C6H4
Under suitable conditions, asymmetric hydrogenation of
certain configurationally labile chiral ketones can lead to
single isomeric alcohols out of four possible stereoiso-
mers.1,2 Thus hydrogenation of a racemic a-substituted
ketone with RuCl2(binap)(1,2-diamine)3,4 and an alkaline
base in 2-propanol gives a single chiral alcohol selectively
and in high yield.5–7 In this reaction, a chiral Ru hydride
species generated from the RuCl2 precatalyst reduces a
ketone enantiomer (kinetic resolution) selectively with a
high cis:trans diastereoselectivity. The slow-reacting ke-
tone enantiomer is facilely racemized due to the protic ba-
sic conditions and both enantiomers consequently serve as
hydrogenation substrates. We describe here the enantio-
and diastereoselective hydrogenation of 2-arylcycloal-
kanones (1–3) to cis-2-arylcyclohexanols (4–6) of high
enantiomeric purity under dynamic kinetic resolution
(Scheme 1).1,8 In addition, this method has been applied to
the synthesis of certain important chiral building blocks.
R1
R4
Ar2
P
H2
N
Cl
R2
R3
Ru
P
N
Ar2 Cl H2
(R,RR)-7a: Ar = 4-CH3C6H4,
R1 = R4 = C6H5, R2 = R3 = H
(R,SS)-7b: Ar = 4-CH3C6H4,
R1 = R4 = H, R2 = R3 = C6H5
(R,R)-8: Ar = 3,5-(CH3)2C6H3,
R1 = R2 = 4-CH3OC6H4,
R3 = H, R4 = (CH3)2CH
Scheme 1
approaches the C=O function from the equatorial direc-
tion,10 resulting in the 1S,2S-product. This reaction is
highly productive. Thus, the reaction of 9.12 g of 2a using
0.5 mg of (R,RR)-7a, viz., substrate:catalyst = 100,000:1,
at 8 atm of H2 and 25 °C was completed in 48 hours to
quantitatively afford (1S,2S)-5a in 99.6% ee.11 The diaste-
reomeric (R)-TolBINAP–(S,S)-DPEN-based Ru complex,
(R,SS)-7b, is even more active than (R,RR)-7a but slightly
less stereoselective, giving (1S,2S)-5a in 97% ee.
First, we selected 2-phenylcyclohexanone (2a) as a stan-
dard substrate. When racemic 2a was hydrogenated in 2-
propanol containing trans-RuCl2[(R)-tolbinap][(R,R)-
dpen] [(R,RR)-7a]4d and t-C4H9OK {[2a] = 0.5 M, [t-
C4H9OK] = 15 mM, ketone:Ru = 10,000:1} at 8 atm of H2
and 25 °C for 24 hours, (1S,2S)-2-phenylcyclohexanol
[(1S,2S)-5a] was obtained in 99.7% ee and 100% yield.
The cis diastereoselectivity was perfect. The bulky
RuH(diamine) intermediate delivers a hydride on Ru and
a proton on nitrogen to the carbonyl function via a six-
membered pericyclic transition state.9 As illustrated in
Scheme 2, the (R)-BINAP–(R,R)-DPEN-combined com-
plex kinetically selects (S)-2a with its stable chair con-
former possessing an equatorial phenyl substituent, and
Various 2-arylated cyclohexanones can be used consis-
tently, although the extent of enantio- and/or diastereose-
lectivity is influenced by the substituents, as exemplified
in Table 1. Hydrogenation of the p-methoxyphenyl deriv-
ative 2b in the presence of (R,RR)-7a resulted (1S,2S)-5b
in 99.5% ee and 100% cis selectivity, while the p-trifluo-
romethylphenyl analogue 2c gave (1S,2S)-5c with a lower
stereoselectivity (98% ee, 99.9% cis) under similar reac-
tion conditions.12 Hydrogenation of 2-(2¢-naphthyl)cyclo-
hexanone (2e) with (R,RR)-7a afforded (1S,2S)-5e in
SYNLETT 2004, No. 8, pp 1383–1386
0
1.
0
7.
2
0
0
4
Advanced online publication: 22.06.2004
DOI: 10.1055/s-2004-829093; Art ID: Y01304ST
© Georg Thieme Verlag Stuttgart · New York

1384
T. Ohkuma et al.
LETTER
perfect cis selectivity.12 However, the enantioselectivity
and rate were significantly enhanced by the use of diaste-
reomeric (R,SS)-7b as a precatalyst, resulting in (S,S)-6a
(100% cis) with 95% ee and 100% yield after 24 hour re-
action. Hydrogenation of the lower homologue, 2-phenyl-
cyclopentanone (1a), with (R,RR)-7a or (R,SS)-7b
(ketone:Ru = 2000:1, 8 atm, 25 °C, 36–48 h) gave
(1S,2S)-2-phenylcyclopentanol [(1S,2S)-4a] in 80% ee
(cis:trans = 94.5:5.5) and 76% ee (cis:trans = 100:0), re-
spectively. Fortunately, however, when an (R)-XylBI-
NAP–(R)-DAIPEN-based Ru complex [(R,R)-8]3,4e was
used, the 1S,2S-alcohol was obtained in 98% ee and 100%
cis selectivity.
H
O
inversion
H
O
(S)-2a: reactive
(R)-2a: unreactive
(R,RR)-RuH(diamine)
-
OH
O
H
H
N
H
Ru
Notably, this asymmetric hydrogenation under dynamic
kinetic resolution is applicable to ketonic substrates pos-
sessing an azacyclohexanone skeleton (Figure 1). Thus,
the hydrogenation of 913 with (R,RR)-7a and t-C4H9OK in
2-propanol {[9] = 0.125 M, [t-C4H9OK] = 19 mM,
ketone:Ru = 500:1, 8 atm, 20 h} produced (2S,3S)-10 in
96% ee and quantitative yield with a 96:4 cis:trans selec-
tivity {[a]D25 +29.9 (c 0.39, CH3OH)}.14 This chiral alco-
hol is convertible to the hNK1 antagonists L-733,06015 and
L-741,671.16 Furthermore, the m-methoxyphenyl ketone
1117 was hydrogenated with (S,SS)-7a {[11] = 0.125 M,
[t-C4H9OK] = 25 mM, ketone:Ru = 500:1, 8 atm, 25 °C,
24 h} quantitatively and stereoselectively to (3S,4R)-12 in
97% ee with a cis:trans selectivity of >99:1 {[a]D25 –55.9
(c 0.40, CH3OH)}.12 This product serves as a synthetic in-
termediate of (–)-precramol, which is known as a D2/D3-
auto and sigma receptor agonist.18
H
H
TS
(1S,2S)-5a
Scheme 2
>99% ee and a cis:trans selectivity of >99:1,12 but the
reaction of the 1¢-naphthyl derivative 2d proceeded less
stereoselectively to give (1S,2S)-5d in 93% ee and with a
cis:trans selectivity of 98:2, due to changes in the steric
parameters.
The skeletal change in ketonic substrates requires the
modification of the catalyst structures (Table 1). Hydro-
genation of 2-phenylcycloheptanone (3a) under the stan-
dard conditions using (R,RR)-7a (ketone:Ru = 2000:1, 8
atm, 25 °C, 27 h) gave (1S,2S)-2-phenylcycloheptanol
[(1S,2S)-6a] in only 84% ee and 90% yield, albeit with
Table 1 Asymmetric Hydrogenation of Racemic 2-Arylated Cycloalkanones 1–3a
Conditions
Alcohol
cis-Isomer
Ketone Complex
Ketone:Ru
[t-C4H9OK] Time
Yieldb
(%)
cis:transb
ee (%)c
Config.d
[a]D (°)e
(mM)
50
15
18
25
5
(h)
96
24
48
4
1a
2a
2ag
2a
2b
2c
2d
2e
3a
(R,R)-8
2,000:1
10,000:1
100,000:1
2,000:1
2,000:1
2,000:1
2,000:1
2,000:1
2,000:1
100
100
100
99.6
100
99.9
>99
>99
100
100:0
100:0
100:0
100:0
100:0
99.9:0.1
98:2
98
1S,2S
1S,2S
1S,2S
1S,2S
1S,2Sh
1S,2Sh
1S,2S
1S,2Sh
1S,2Sh
+79.8 (c 1.01)
–
(R,RR)-7a
(R,RR)-7a
(R,SS)-7b
(R,RR)-7a
(R,RR)-7a
(R,RR)-7a
(R,RR)-7a
(R,SS)-7b
99.7
99.6
97
+103.6 (c 2.02)f
–
4
99.5
98
+85.0 (c 1.60)
+59.6 (c 0.30)
+145.0 (c 0.90)
+47.4 (c 0.20)
+93.3 (c 0.21)
6
4
9
16
4
93
10
25
>99:1
100:0
>99
95
24
a Reactions were conducted at 25 °C under 8 atm of H2 using a 0.5 M solution of the ketone in 2-propanol.
b Determined by GC, HPLC, and 1H NMR analysis.
c Determined by chiral GC or HPLC analysis.
d Determined by the sign of rotation.
e A cis-alcohol purified using a silica-gel column. Measured in CHCl3 at 22–24 °C.
f Measured in CH3OH.
g Reaction using 9.12 g of 2a in 100 mL of 2-propanol.
h Estimated by 1H NMR measurement after conversion to diastereomeric compounds according to ref.12
Synlett 2004, No. 8, 1383–1386 © Thieme Stuttgart · New York

LETTER
Asymmetric Hydrogenation of 2-Arylated Cycloalkanones
1385
Katayama, E.; England, A. F.; Ikariya, T.; Noyori, R. Angew.
Chem. Int. Ed. 1998, 37, 1703. (e) Ohkuma, T.; Koizumi,
M.; Doucet, H.; Pham, T.; Kozawa, M.; Murata, K.;
Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1998, 120, 13529. (f) Ohkuma, T.; Koizumi,
M.; Ikehira, H.; Yokozawa, T.; Noyori, R. Org. Lett. 2000,
2, 659. (g) Ohkuma, T.; Koizumi, M.; Yoshida, M.; Noyori,
R. Org. Lett. 2000, 2, 1749. (h) Ohkuma, T.; Takeno, H.;
Honda, Y.; Noyori, R. Adv. Synth. Catal. 2001, 343, 369.
(5) Ohkuma, T.; Ooka, H.; Yamakawa, M.; Ikariya, T.; Noyori,
R. J. Org. Chem. 1996, 61, 4872.
O
OH
3
2
N
N
1
9
10
(6) Matsumoto, T.; Murayama, T.; Mitsuhashi, S.; Miura, T.
Tetrahedron Lett. 1999, 40, 5043.
OCH3
OCH3
(7) Ohkuma, T.; Ishii, D.; Takeno, H.; Noyori, R. J. Am. Chem.
Soc. 2000, 122, 6510.
O
OH
4
(8) For the kinetic resolution of racemic ketones with RuH(h1-
BH4)(binap)(dpen) under base-free conditions, see:
Ohkuma, T.; Koizumi, M.; Muñiz, K.; Hilt, G.; Kabuto, C.;
Noyori, R. J. Am. Chem. Soc. 2002, 124, 6508.
3
1
N
N
(9) For the mechanism of asymmetric hydrogenation of simple
ketones with the BINAP–DPEN–Ru(II) catalyst, see:
Sandoval, C. A.; Ohkuma, T.; Muñiz, K.; Noyori, R. J. Am.
Chem. Soc. 2003, 125, 13490.
(10) See for example: (a) Brown, H. C.; Krishnamurthy, S.
Tetrahedron 1979, 35, 567. (b) Greeves, N. In
n-C3H7
n-C3H7
11
12
Figure 1
Thus, the asymmetric hydrogenation of racemic 2-arylcy-
cloalkanones through dynamic kinetic resolution, when
coupled with previous methods, provides a practical tool
for the synthesis of cis-2-subsitituted cycloalkanols and
aza-analogues of high enantiomeric purity, which are oth-
erwise difficult to prepare. The optimum conditions are
obtained by the careful selection of structural parameters
in the BINAP–diamine Ru catalysts. The reaction is
achievable with low catalyst loading (ketone:Ru ratio of
up to 100,000:1) and under relatively low hydrogen pres-
sure (8 atm) at room temperature.
Comprehensive Organic Synthesis, Vol. 8; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford, 1991, 1. (c) Davis, A.
P. In Houben-Weyl, 4th ed., Vol. E21d; Helmchen, G.;
Hoffmann, R. W.; Mulzer, J.; Schaumann, E., Eds.; Thieme:
Stuttgart, 1995, 4025.
(11) Experimental Procedure of the Hydrogenation of 2a with
Ketone:Ru = 100,000:1.
Solid (R,RR)-7a (0.5 mg, 0.47 mmol), t-C4H9OK (180 mg,
1.73 mmol), and 2a (9.12 g, 51.2 mmol) were placed in a 500
mL glass autoclave equipped with a Teflon-coated magnetic
stirring bar. Air present in the autoclave was replaced by
argon. 2-Propanol (100 mL), which had been degassed by
three freeze-thaw cycles, was added to the autoclave. The
vessel was pressurized to 8 atm of hydrogen. The reaction
mixture was vigorously stirred at 25 °C for 48 h, during
which time the hydrogen cylinder was kept connected. After
carefully venting the hydrogen gas in the apparatus, the
solvent was removed under reduced pressure. The yield
determined by GC was 100%. Subsequently, the residue was
passed through a silica gel pad, eluted with a 1:4 EtOAc–
hexane mixture giving (1S,2S)-5a (8.61 g, 93% yield,
cis:trans = 100:0, 99.6% ee), [a]D23 +103.6 (c 2.02, CH3OH)
{lit. [a]D27 –106 (c 0.20, CH3OH)}, 1R,2R-Isomer: Verbit,
L.; Price, H. C. J. Am. Chem. Soc. 1972, 94, 5143.
(12) The absolute configuration of (1S,2S)-5b,c,e, and -6a, as
well as (3S,4R)-12 was estimated according to the literature:
Matsugi, M.; Itoh, K.; Nojima, M.; Hagimoto, Y.; Kita, Y.
Tetrahedron Lett. 2001, 42, 6903. The cis alcohols were
converted to the trans-(1R,2S) alcohols by stereoinversion of
the hydroxyl-containing carbon, followed by acylation with
3b-acetoxy-D5-etiocholenic acid chloride. The 1H NMR
chemical shift at C(18)-CH3 of the chiral auxiliary was
higher than that derived from the 1S,2R-enantiomer.
(13) Lee, J.; Askin, D.; Hoang, T. US Pat. Appl. 20020019532,
2002.
Acknowledgment
This work was financially supported by grants-in-aid from the Ja-
pan Society for the Promotion of Science (JSPS) (Nos. 14GS0214
and 15350079).
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