Highly enantio- and s-trans C=C bond selective catalytic hydrogenation of cyclic enones: Alternative synthesis of (-)-menthol

Article abstract of DOI:10.1002/chem.200701505

A highly enantioselective catalytic hydrogenation of cyclic enones was achieved by using the combination of a cationic Rh¹ complex, (S)-5,5′-bis{di(3,5-di-tert-butyl-4-methoxyphenylphosphino)}-4, 4′-bi-1,3-benzodioxole (DTBM-SEGPHOS), and (CH₂CH ₂PPh₃Br)₂. The presence of an s-cis C=C bond isopropylidene moiety on the cyclic enone influenced the enantioselectivity of the hydrogenation. Thus, the hydrogenation of 3-alkyl-6-isopropylidene-2- cyclohexen-1-one, which contains both s-cis and s-trans enones, proceeded in excellent enantioselectivity (up to 98% ee). To obtain high enantio- and s-trans selectivities, the addition of a halogen source to the cationic Rh complex was the essential step. With the key step of the s-trans selective asymmetric hydrogenation of piperitenone, we demonstrated a new synthetic method for optically pure (-)-menthol via three atom-economical hydrogenations. Moreover, we found that the complete s-trans and s-cis C=C bond selective reactions were also realized by the proper choice of both the chiral ligands and halides.

Full text of DOI:10.1002/chem.200701505

DOI: 10.1002/chem.200701505
Highly Enantio- and s-trans C=C Bond Selective Catalytic Hydrogenation of
Cyclic Enones: Alternative Synthesis of (ꢀ)-Menthol
Takashi Ohshima,[a] Hiroshi Tadaoka,[a] Kiyoto Hori,[b] Noboru Sayo,[b] and
Kazushi Mashima*[a]
Abstract:
A
highly enantioselective
isopropylidene-2-cyclohexen-1-one,
selective asymmetric hydrogenation of
piperitenone, we demonstrated a new
synthetic method for optically pure
(ꢀ)-menthol via three atom-economi-
cal hydrogenations. Moreover, we
found that the complete s-trans and s-
cis C=C bond selective reactions were
also realized by the proper choice of
both the chiral ligands and halides.
catalytic hydrogenation of cyclic
enones was achieved by using the com-
bination of a cationic RhI complex, (S)-
which contains both s-cis and s-trans
enones, proceeded in excellent enantio-
selectivity (up to 98% ee). To obtain
high enantio- and s-trans selectivities,
the addition of a halogen source to the
cationic Rh complexwas the essential
step. With the key step of the s-trans
5,5’-bis{di(3,5-di-tert-butyl-4-meth
phenylphosphino)}-4,4’-bi-1,3-benzodi-
oxole (DTBM-SEGPHOS), and
oxy-
ACHTREUNG
ACHTREUNG
(CH2CH2PPh3Br)2. The presence of an
s-cis C=C bond isopropylidene moiety
on the cyclic enone influenced the
enantioselectivity of the hydrogenation.
Thus, the hydrogenation of 3-alkyl-6-
Keywords: asymmetric catalysis
enones · hydrogenation · rhodium
·
Introduction
they require not only more than stoichiometric amounts of
polymethylhydrosiloxane, but also more than stoichiometric
ꢀ
Enantioselective hydrogenation is one of the most powerful
and practical methods in asymmetric catalysis.[1] A variety of
chiral building blocks is synthesized by using chiral RhI or
RuII complexes—some of them are used in the industrial
production of enantiomerically-enriched compounds.[1,2]
Enantioselective hydrogenation of the enone C=C bond,
however, has not been well studied, despite the usefulness
of the resulting chiral ketones, and thus remains a challeng-
ing transformation. Toward this aim, efficient enantioselec-
tive hydrosilylations catalyzed by copper complexes were re-
ported by Buchwald et al.[3] and Lipshutz et al.[4] In terms of
atom-economy[5] and environmental concerns, however,
these catalyses still have much room for improvement, as
amounts of reagents to cleave the Si O bond of the enol
silyl ether intermediate, which causes the formation of more
than stoichiometric amounts of unwanted silicon waste.
Thus, the development of an efficient catalytic asymmetric
hydrogenation of enones is highly desirable. Successful re-
sults of catalytic asymmetric hydrogenation of enones, how-
ever, are limited to the following three Ru-catalyzed reac-
tions. Takaya et al. reported the asymmetric hydrogenation
of the s-cis (exocyclic) C=C bond of cyclopentanone cata-
lyzed by an Ru-BINAP complex, providing a-substituted cy-
clopentanone in 98% ee (one example).[6] Simonneauxet al.
reported that the [HRuCl(tbpc)2] (TBPC=trans-1,2-bis(di-
A
phenylphosphinomethyl)cyclobutane) catalyzed the hydro-
genation of s-trans (endocyclic) enones to afford chiral ke-
tones in up to 62% ee (four examples).[7] GenÞt et al. re-
ported a practical synthesis of (+)-cis-methyl dihydrojasmo-
[a] Prof. Dr. T. Ohshima, H. Tadaoka, Prof. Dr. K. Mashima
Department of Chemistry
nate (88% ee) by catalytic hydrogenation using the Ru–JO-
Graduate School of Engineering Science, Osaka University
Toyonaka, Osaka 560-8531 (Japan)
Fax: ( +81)6-6850-6249
[8]
SIPHOS
complex(one amexple).
The
lower
enantioselectivities of the s-trans enones might be due to the
A
G
A
E-mail: mashima@chem.es.osaka-u.ac.jp
unfavorable s-trans coordination of cyclic enone to transi-
tion metals. These initial results clearly demonstrate the
need for improved substrate generality, enantioselectivity,
and catalyst activity for practical production of highly opti-
cally active chiral ketones. Herein, we report an enantiose-
[b] Dr. K. Hori, Dr. N. Sayo
Takasago International Corporation
Ohta-ku, Tokyo 144-8721 (Japan)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
2060
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Chem. Eur. J. 2008, 14, 2060 – 2066

FULL PAPER
lective catalytic hydrogenation of various cyclic enones. The
presence of an s-cis C=C bond isopropylidene moiety on the
cyclic enone influenced the enantioselection of the hydroge-
nation. Thus, the reaction of 3-alkyl-6-isopropylidene-2-cy-
clohexen-1-one (1), which contains both s-cis and s-trans
enones, proceeded in excellent enantioselectivity (up to
98% ee). Hydrogenation of 1 afforded 26 products via satu-
ration of C=C and/or C=O double bonds [Eq. (1)].[9] To
crease both enantio- and s-trans selectivities.[10] Our catalyst
screening for the hydrogenation of 1a is summarized in
Table 1. The catalytic activity of cationic RhI–diphosphine
complexes in EtOAc[11] was very high. After 18 h treatment
under the conditions shown in Table 1, both C=C bonds of
1a were saturated to give a diastereomixture of 4a (R=Me;
menthone/isomenthone ca. 4:1) as the sole detectable prod-
ucts (entries 1–3). Although shortening the reaction time
partially prevented this over-reaction, in contrast to the pre-
ꢀ
obtain the C2 C3 saturated product 2 out of all the possible
products in a highly selective
manner, the addition of a halo-
gen source to the cationic Rh
complexwas key. Using this
asymmetric catalysis, piperiten-
A
fully converted to (+)-pulegone
(2a: R=Me) in 98% ee with
extremely high catalyst turn-
over (S/C 50000), allowing for
an atom-economical synthesis
of (ꢀ)-menthol by successive
highly diastereoselective cata-
lytic hydrogenations of (+)-2a.
Moreover, complete s-trans
(1!2) and s-cis (1!3) C=C
bond selective reactions were
realized by the proper choice of
both the chiral ligands and hal-
ides.
Table 1. Catalytic asymmetric hydrogenation of piperitenone (1a) by using cationic RhI–(S)-diphosphine com-
plexes.
Results and Discussion
Catalyst discovery by using cat-
ionic Rh complexes: Despite
the usefulness of optically
active 2 as a chiral source, only
a few catalysts that can selec-
tively transform 1 to 2 have
been reported. When a cationic
RhI complexbearing chiral
monodentate phosphine ligands
was used, the highest enantiose-
lectivity (2a, 38% ee) was ob-
tained with moderate s-trans se-
lectivity (2a/3a/4a 61:30:9).[10]
Because (+)-pulegone (2a) is
an attractive intermediate for
the synthesis of (ꢀ)-menthol,
we first performed catalyst
screening for the s-trans C=C
bond selective hydrogenation of
piperitenone (1a). To obtain
high enantioselectivity, we used
Entry
Catalyst
S/C[a]
t [h]
Conv.[b] [%]
Selectivity[c]
2a/3a/4a
ee 2a[d] [%]
1[e]
2[e]
3[e]
4
5
6
[Rh
[Rh
[Rh
[Rh
[Rh
[Rh
[Rh
[Rh
[Rh
C
100
100
100
100
100
100
100
100
1000
18
18
18
1
3
3
1
3
18
>99
>99
>99
91
>99
>99
44
–:–:>99
–:–:>99
–:–:>99
4:83:13
1:76:23
–:80:20
11:79:10
–:14:86
70:4:12
–
–
–
10[f]
–
–
38
–
7
8
>99
97
9[g]
96
+ Et4NCl
[Rh(cod)2]OTf + L5
+ Et3NBnCl
[Rh(cod)2]OTf + L5
+ HexPPh3Br
[Rh(cod)2]OTf + L5
+ HexP{C6H2-2,4,6-(OMe)3}3Br
[Rh(cod)2]OTf + L5
+ (CH2CH2PPh3Br)2
10[g]
11[g]
12[g]
13[g]
A
1000
1000
1000
1000
18
18
18
18
89
83
99
97
79:4:7
72:7:7
68:5:12
77:5:9
96
98
97
98
AHCTREUNG
AHCTREUNG
AHCTREUNG
[a] Substrate catalyst ratio. [b] Conversion yield based on consumed starting material was determined by GC
analysis. [c] Selectivity was determined by GC analysis. [d] The ee of 2a was determined by chiral GC analysis.
The absolute configuration of 2a was determined by comparing the measured optical rotations with the report-
chiral
diphosphine
ligands,
though diphosphine ligands are
reported to dramatically de- ed one. [e] Rh/ligand 1:1. [f] (ꢀ)-Pulegone (2a) was obtained. [g] Rh/ligand/additive 1:1:1.
Chem. Eur. J. 2008, 14, 2060 – 2066
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2061

K. Mashima et al.
vious results using cationic RhI
complexes bearing monoden-
tate phosphine ligands as de-
scribed above,[10] cationic RhI–
diphosphine complexes showed
s-cis selectivity to afford
Table 2. Ligand effects on catalytic asymmetric hydrogenation of piperitenone (1a) by using cationic Rh com-
plexes with bromide source.
piperitone (3a: R=Me) as a
major product (entries 4–7) and
a prolonged reaction time re-
A
Entry
Ligand
S/C[a]
t [h]
Conv.[b] [%]
Selectivity[c]
2a/3a/4a
ee 2a[d] [%]
1
2
3
4
5
6
(S)-BINAP (L1)
(S)-tol-BINAP (L2)
(S)-SEGPHOS (L3)
(S)-DM-SEGPHOS (L4)
(S)-DM-SEGPHOS (L4)
(S)-DTBM-SEGPHOS (L5)
(S)-DTBM-SEGPHOS (L5)
(S)-DTBM-SEGPHOS (L5)
(S)-DTBM-SEGPHOS (L5)
100
100
100
100
100
100
100
20000
50000
3
3
3
3
1
1
1
18
47
26
57
56
92
15
99
>99
98
85:12:3
91:6:3
92:5:3
71:3:26
43:31:26
86:3:11
88:2:10
85:3:6[f]
87:2:5[f]
94
96
91
94
81
97
97
98
98
sulted
in
over-reaction
(entry 8). Compound 3a was
racemic due to rapid epimeriza-
tion of the a’-stereocenter of
the ketone. As compared with
BINAP (L1) (entry 4), (S)-5,5’-
bis{di(3,5-di-tert-butyl-4-meth-
7[e]
8[e]
9[e,g]
98
ACHTREUNG
[a] Substrate catalyst ratio. [b] Conversion yield based on consumed starting material was determined by GC
analysis. [c] Selectivity was determined by GC analysis. [d] The ee of 2a was determined by chiral GC analysis.
The absolute configuration of 2a was determined by comparing the measured optical rotations with the report-
ACHTREUNG
enantioselectivity and slightly ed one. [e] [Rh
better s-trans selectivity
N
G
(entry 7). Assuming that soft
counteranions would appropri-
ately adjust the reactivity,[13] we next examined the effect of
adding various halogen sources using DTBM-SEGPHOS as
a chiral ligand. To our surprise, we observed drastic halogen
effects. The addition of halogen sources to the cationic Rh
complexreversed the selectivity to afford 2a as a major
product with high enantioselectivity (96–98% ee). Ammoni-
um salts and phosphonium salts gave better selectivity and
reproducibility than inorganic salts. Among the various hal-
ogen sources examined, (CH2CH2PPh3Br)2 was the best
(entry 13).
the best catalyst, [Rh(cod)2]OTf/L5/(CH2CH2PPh3Br)2, the
G
hydrogenation of b-alkyl substituted cyclic enones 5a–d pro-
ceeded efficiently to afford the corresponding ketones 6a–d
in up to 88% ee (Table 3, entries 1–4), which is the same
level as the highest enantioselectivity of catalytic hydrogena-
tion of cyclic enone.[8] The introduction of a sterically con-
gested substituent (R=iPr, entry 4) at the b-position did not
have negative effects on either reactivity (99% yield) or se-
lectivity (85% ee). On the other hand, the reaction of b-
phenyl substituted cyclic enone 5e proceeded sluggishly and
a mixture of 6e and an over reduction product, 3-phenyl-2-
cyclohexanol, was obtained, though the enantiomeric excess
of 6e was quite high (entry 5). The addition of a bromide
source was essential for the hydrogenation of simple cyclic
enones 5 as well. In the absence of a bromide source, the hy-
drogenation of 5 proceeded in lower yield with lower enan-
tioselectivity. Next, to determine the effect of the isopropyli-
dene moiety on cyclic enone, we performed the reaction
using several 3-alkyl-6-isopropylidene-2-cyclohexen-1-ones
1a–c as substrates (entries 6–8). In all cases, catalytic hydro-
genation proceeded smoothly with high enantio- and s-trans
selectivities. As compared with the results using simple b-
substituted cyclic enones 5, the obtained enantioselectivities
using 1 were markedly improved (97–98% ee), indicating
the importance of the isopropylidene moiety in the enantio-
face selection. Coupled with the fact that the isopropylidene
moiety of 2 was easily removed via a retro-aldol reaction to
give the corresponding b-substituted ketone 6,[14] a variety
of highly optically active 3-substituted-cyclic ketones can be
synthesized using this catalytic asymmetric hydrogenation of
cyclic enones. To the best of our knowledge, this is the first
example of a highly enantioselective catalytic hydrogenation
of a C=C bond of a cyclic enone with substrate general-
ity.
As the second stage of the catalyst discovery, we further
examined effects of a chiral diphosphine ligand on catalytic
asymmetric hydrogenation by [Rh(cod)2]OTf in the pres-
U
ence of (CH2CH2PPh3Br)2 (Table 2). DM-SEGPHOS (L4)
(entries 4 and 5) and DTBM-SEGPHOS (L5) (entry 6) had
significantly positive effects on catalyst activity as compared
with BINAP (L1), tol-BINAP (L2), and SEGPHOS (L3),
suggesting that the narrower dihedral angle in the chiral
backbone and bulkier substituent on diarylphosphine moiet-
ies induce higher catalyst activity. In particular, when L5
was used as a chiral ligand, the reaction completed within
1 h (S/C 100) (entry 6). When [Rh
(L5)]BF4 (entry 7) was used as an Rh source, almost the
same result was obtained, while acetonitrile complexes, such
as [Rh(cod)(MeCN)]BF4, had lower reactivity and lower s-
A
N
ACHTREUNG
A
ACHTREUNG
trans selectivity. Under the same conditions as entry 7, a
high substrate catalyst ratio (S/C 20000) was realized with
higher enantioselectivity (98% ee, entry 8). The reaction on
a 2-mol scale (S/C 50000) also proceeded with similar effi-
ciency (entry 9) and pure (+)-2a was isolated in 82% yield
by distillation (70–758C, 5 mm Hg).
Substrate scope: We then investigated the scope and limita-
tions of different substrates. In the presence of 1 mol% of
2062
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Selective Catalytic Hydrogenation
FULL PAPER
Table 3. Catalytic asymmetric hydrogenation of various cyclic enones.
sive catalytic hydrogenations,
including the first enantioselec-
tive hydrogenation described
above. To prevent epimeriza-
tion of the a’-stereocenter of
the ketone as described above,
the ketone in pulegone (2a)
was hydrogenated prior to hy-
drogenation of the isopropyli-
dene moiety. Thus, the second
catalytic hydrogenation using
Entry
Substrate
t [h]
Conv.[a] [%]
Selectivity[b]
ee 6[c] or 2[d] [%]
an
RuCl2
G
N
2/3/4
AHCTREUNG
1
2
3
4
5
6
7
8
R=Me (5a)
R=Et (5b)
R=Pr (5c)
R=iPr (5d)
R=Ph (5e)
R=Me (1a)
R=Et (1b)
R=Pr (1c)
1.5
3
3
3
6
1
1
1
>99
>99
>99
99
48
99
–
–
–
88
83
85
85
96
97
98
98
saturated the C=O bond of 2a
in a highly diastereoselective
manner to afford (ꢀ)-pulegol
(7) (98% yield, dr: 97.4:2.6).
The diastereomixture of 7 was
hydrogenated using an Ru-
–
28[e]:72[f]
86:3:11
84:1:15
82:5:13
99
99
A
U
[a] Conversion yield based on consumed starting material was determined by GC analysis. [b] Selectivity was
determined by GC analysis. [c] The ee of 6 was determined by chiral LC analysis after conversion to the corre-
sponding acetal compound. [d] The ee of 2 was determined by chiral GC analysis. [e] Selectivity of 6e. [f] Se-
lectivity of 3-phenyl-1-cyclohexanol.
to afford (ꢀ)-menthol (8) to-
gether with small amounts of
neomenthol (9) and neoisomen-
thol (10) (99% yield, 8/9/10
96:2.3:1.7). Finally, optically
Synthetic application: With the new synthetic method of
highly optically active ketones at hand, we next undertook
transformation of (+)-pulegone (2a) to (ꢀ)-menthol (8)
(Scheme 1). (ꢀ)-Menthol (8) is a major constituent of pep-
and chemically pure (ꢀ)-menthol (8) was obtained in 73%
yield by recrystallization of the mixture. Based on the high
catalyst turnover, high atom-economy, and ease of scale-up,
this process is a potential industrial process for producing
(ꢀ)-8, and demonstrates the efficiency of homogeneous cat-
alytic hydrogenation.[1]
Catalyst discovery using neutral Rh complexes: The addition
of a bromide to a cationic Rh complexmight form a neutral
dimeric Rh–phosphine complex. To investigate the forma-
tion of neutral Rh complexes under the conditions shown in
Table 2, we first synthesized various halogen-bridged dimer-
ic Rh-phosphine complexes [RhX(L)]2 (X=Cl, Br, I). After
mixing [RhX(cod)]2 and chiral diphosphine ligand (S)-
A
BINAP (L1), (S)-tol-BINAP (L2), and (S)-SEGPHOS (L3)
in CH2Cl2, the color of the solution immediately turned
deep red. After stirring for 2 h at room temperature, the re-
action mixture was concentrated under reduced pressure
and the obtained residue was washed with hexane to afford
[RhX(L)]2 in good yield (77–99% yield) as a deep red solid.
The syntheses of [RhX(L4)]2 and [RhX(L5)]2 complexes
were unsuccessful due to the high steric hindrance of DM-
SEGPHOS (L4) and DTBM-SEGPHOS (L5). The structure
of [RhCl(L1)]2 was determined by X-ray crystallographic
analysis (Scheme 2), and was identical to the reported
Scheme 1. Highly atom-economical synthesis of (ꢀ)-menthol (8) by suc-
cessive catalytic hydrogenations of (+)-pulegone (2a).
permint and other mint oils and is widely used in confec-
tions, perfume, liqueurs, cough drops, cigarettes, toothpaste,
and nasal inhalers.[15] In industrial production, (ꢀ)-8 was
synthesized from b-pinene via catalytic asymmetric isomeri-
zation of geranylamine to the corresponding enamine as a
key step.[1,2,16] Although this process is fairly efficient and
practical, the development of an alternative efficient process
for the production of a constant supply of this mass product
(3500 tons per year)[15] is still in high demand. Thus, an alter-
native, atom-economical approach to (ꢀ)-8 is presented in
Scheme 1. Our synthesis was accomplished by three succes-
data.[21] The addition of (CH2CH2PPh3Br)2 to
a [Rh-
A
31P{1H} NMR from d 26.8 (d, J=145 Hz) to d 49.2 (d, J=
195 Hz). The latter signal was identical to that of the
[RhBr(L1)]2 complex. Similarly, the addition of
(CH2CH2PPh3Br)2 to the [Rh
C
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2063

K. Mashima et al.
Scheme 2. Preparation of halogen-bridged dimeric Rh-phosphine complexes [RhX(L)]2.
136 Hz) to d 46.5 ppm (d, J=197 Hz), which was identical
to that of the [RhBr(L3)]2 complex.
while maintaining high selectivity. In the presence of the
RhI–SEGPHOS complex[RhCl( L3)]2 or [RhBr(L3)]2, the
reaction proceeded with quite low selectivity (entries 10 and
11). In sharp contrast with those results, iodo complex
[RhI(L3)]2 selectively saturated only the s-cis C=C bond to
afford piperitone (3a) as the sole product (entry 12). It is
noteworthy that the complete s-trans (entry 9) and s-cis
(entry 12) C=C bond selective reactions were realized by
the proper choice of both the chiral ligands and halides.[12]
Having obtained surprising re-
It is likely that the neutral dimeric Rh–phosphine com-
plex[RhX( L)]2 acts as a stable pre-catalyst and a monomer-
ic complex might act as the active species. Thus, we next ex-
amined the use of neutral halogen-bridged Rh complexes as
catalysts using 1a as a representative substrate. The neutral
complex[RhBr( L1)]2 showed comparable selectivity
(Table 4, entry 2) to the combination of [Rh(cod)2]OTf, L1,
N
sults using Rh-SEGPHOS iodo
Table 4. Asymmetric hydrogenation of 1a by using neutral Rh complexes.
complex[RhI( L3)]2, we further
examined ligand effects of the
combination of [Rh(cod)2]OTf,
U
chiral ligand L, and iodide
source EtPPh3I. In the same
manner as the [RhI(L3)]2 com-
plex(entry 12), the catalyst in
situ prepared from [Rh-
Entry
Catalyst
[RhCl(L1)]2
[RhBr(L1)]2
[RhI(L1)]2
[RhCl(L1)]2
[RhBr(L1)]2
[RhI(L1)]2
[RhCl(L2)]2
[RhBr(L2)]2
[RhI(L2)]2
[RhCl(L3)]2
[RhBr(L3)]2
[RhI(L3)]2
Solvent
Conv.[a] [%]
Selectivity[b] 2a/3a/4a
ee 2a[c] [%]
1
2
3
4
5
6
7
8
N
EtOAc
EtOAc
EtOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
EtOAc
92
96
46
90
96
56
99
>99
96
69
84:3:13
84:3:13
91:5:4
90:3:7
96:2:2
96:3:1
94:–:6
92:–:8
98:–:2
10:15:75
39:3:58
–:>99:–
–:98:2
81
87
98
90
96
97
94
97
97
–
ACHTREUNG
A
G
and EtPPh3I also selectively sa-
turated the s-cis C=C bond,
suggesting the formation of
similar active species, presuma-
bly neutral RhI(L3) complex
(entry 13). Unlike SEGPHOS
ligand (L3), the reaction using
DTBM-SEGPHOS (L5) had
quite high s-trans selectivity,
even in the presence of an
iodide source (entry 14).
U
E
E
N
N
9
E
10
11
12
13[d]
14[d]
H
R
>99
>99
98
–
–
–
98
E
[Rh
[Rh
A
N
>99
85:3:12
[a] Conversion yield based on consumed starting material was determined by GC analysis. [b] Selectivity was
determined by GC analysis. [c] The ee of 2a was determined by chiral GC analysis. The absolute configuration
of 2a was determined by comparing the measured optical rotations with the reported one. [d] Rh/ligand/addi-
tive 1:1:2.
Conclusion
We developed a highly enantio-
and (CH2CH2PPh3Br)2 (Table 2, entry 1), and [RhI(L1)]2 im-
proved both enantio- and s-trans selectivities, though the re-
activity was decreased (entry 3). This low reactivity was
slightly improved by changing the solvent from EtOAc to
CH2Cl2 (entry 6) and greatly improved by changing the
chiral ligand from BINAP (L1) to tol-BINAP (L2) (entry 9),
selective catalytic hydrogenation of cyclic enones promoted
by the combination of a cationic RhI complex, DTBM-SEG-
PHOS, and (CH2CH2PPh3Br)2 with substrate generality. The
presence of an s-cis C=C bond isopropylidene moiety on
cyclic enone influenced the enantioselection of the hydroge-
nation. Thus, the reaction of 3-alkyl-6-isopropylidene-2-cy-
2064
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Chem. Eur. J. 2008, 14, 2060 – 2066

Selective Catalytic Hydrogenation
FULL PAPER
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif
clohexen-1-ones containing both s-cis and s-trans enone moi-
eties proceeded in excellent enantioselectivity (up to 98%
ee). To obtain high enantio- and s-trans selectivities, the ad-
dition of a halogen source to a cationic Rh complexwas es-
sential. With the key step of s-trans selective asymmetric hy-
drogenation of piperitenone, we demonstrated a new syn-
thetic method for optically pure (ꢀ)-menthol via three
atom-economical hydrogenations. Moreover, s-trans and s-
cis C=C bond selective reactions were accomplished by the
proper choice of both the chiral ligands and halides. Further
applications and mechanistic studies for understanding the
effects of the isopropylidene moiety and the exceptional re-
activity of the Rh-SEGPHOS iodo complexare ongoing in
our group.
Two-step conversion of (+)-pulegone (2a) to (ꢀ)-menthol (8)
Diastereoselective hydrogenation of (+)-pulegone (2a) to (ꢀ)-pulegol (7):
A stainless steel autoclave (500 mL) was charged with (+)-pulegone (2a)
(200 g,
1.316 mol),
[RuCl2
A
(50.9 mg,
0.066 mmol), tBuOK (148.1 mg, 1.32 mmol), and 2-propanol (40 mL).
The autoclave was charged with H2 (30 kgcmꢀ2) to displace the argon
and then stirred for 18 h at 308C. After H2 was released, the reaction
mixture was concentrated and distilled (70–728C, 2 mmHg) to afford a
diastereomeric mixture of (ꢀ)-pulegol (7) (198.6 g, 98%) as a colorless
oil. The diastereoselectivity was determined to be 97.4:2.4 by GC analy-
sis. GC analysis [Neutrabond-1 (0.25 mm”30 m), column temperature
108C up per 1 min from 80 to 2208C, injection temperature 2508C, detec-
tion temperature 2508C, tR =7.9 min (pulegone), 8.7 min (pulegol)].
Diastereoselective hydrogenation of (ꢀ)-pulegol (7) to (ꢀ)-menthol (8): A
stainless steel autoclave (100 mL) was charged with the diastereomixture
of (ꢀ)-pulegol (7) (3.09 g, 20 mmol, dr: 97.4:2.4), [Ru
N
N
(6.2 mg, 0.01 mmol), and methanol (3 mL). The autoclave was charged
with H2 (30 kgcmꢀ2) to displace the argon and then stirred for 18 h at
508C. After H2 was released, the reaction mixture was concentrated to
afford a diastereomixture of (ꢀ)-menthol (8) (3.11 g, 99%, menthol (8)/
neomenthol (9)/neoisomenthol (10) 96:1.7:2.3). This mixture was recrys-
tallized from acetonitrile to give pure menthol (2.28 g, 73%) with chemi-
cal purity of >99% (either neomenthol or neoisomenthol was not detect-
ed) and with enantiomeric excess of 99.6% ee. Chemical purity of the
product was determined by GC analysis and optical purity of the product
was determined by chiral GC analysis. GC analysis [Neutrabond-1
(0.25 mm”30 m), column temperature 108C up per 1 min from 80 to
2208C, injection temperature 2508C, detection temperature 2508C, tR =
7.1 (neomenthol), 7.5 (neoisomenthol), 7.6 (menthol), 8.7 min (pulegol)];
Chiral GC analysis [b-DEX225 (0.25 mm”30 m), column temperature
18C up per 1 min from 70 to 1308C, injection temperature 2308C, detec-
tion temperature 2308C, tR =34.6 min ((+)-menthol), 34.9 min ((ꢀ)-men-
thol)].
Experimental Section
General: All reactions and manipulations were performed under argon
by use of standard vacuum line and Schlenk tube techniques. 1H NMR
spectra were recorded on a Varian MERCURY 300 or Bruker DRX500,
and chemical shifts are reported in ppm (d) relative to tetramethylsilane
or referenced to the chemical shifts of residual solvent resonances
(CHCl3 and C6H6 were used as internal standards, d 7.26 and 7.20 ppm,
respectively). 31P{1H} NMR spectra were recorded on a Varian MERCU-
RY 300 at 121 MHz or Bruker DRX500 at 202 MHz, and chemical shifts
were referenced to external 85% H3PO4. Infrared spectra were recorded
on a JASCO FT/IR-230; mass spectra on a JEOL JMS DX-303HF spec-
trometer; GC analyses on a Shimadzu GC-14 A and Shimadzu GC-2014
gas chromatograph with a Shimadzu C-R3A Chromatopac; HPLC Jasco
UV-970 and PU-980 with Shimadzu C-R16 A Chromatopac. Elemental
analyses were recorded on a Perkin Elmer 2400. All melting points were
recorded on a Yanaco MP-52982 and are not corrected. Unless otherwise
noted, reagents were purchased from commercial suppliers and used
without further purification. Dichloromethane (H2O <0.003%) was de-
gassed. Tetrahydrofuran, toluene, hexane, and diethyl ether were distilled
Acknowledgements
over sodium/benzophenone under argon prior to use. Degassed ethyl ace-
This work was supported by Encouragement of Young Scientists (A)
from Japan Society for the Promotion of Science. H.T. express his special
thanks for 21COE program “Creation of Integrated EcoChemistry”, The
Global COE Program “Global Education and Research Center for Bio-
Environmental Chemistry” of Osaka University.
[22]
tate (H2O <0.003%) was used. [Rh
1,5-cyclooctadiene), [Rh
(cod)2]OTf,[23] [Rh
nap}]BF4,[16b] [Rh(m-Cl){(S)-binap}]2,[24] [Ru
[RuCl2
(PPh3)2(propanediamine)][17] were prepared according to the liter-
A
N
A
G
A
A
N
ACHTREUNG
ACHTREUNG
ature methods.
General procedure for the Rh-catalyzed asymmetric hydrogenation of
enones (1) (Table 2, entry 6): A Schlenk flask was charged with [Rh-
[1] For general reviews, see: a) R. Noyori, in Asymmetric Catalysis in
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Asymmetric Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamo-
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Ohkuma, M. Kitamura, R. Noyori, in Catalytic Asymmetric Synthe-
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Chem. 2002, 114, 2108; Angew. Chem. Int. Ed. 2002, 41, 2008;
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A
0.0322 mmol), and (CH2CH2PPh3Br)2 (23.8 mg, 0.0322 mmol) under
argon. To the mixture, ethyl acetate (1.0 mL) and piperitenone (1a)
(484 mg, 3.22 mmol) were added. After stirring at 508C for 2 h, the re-
sulting deep red solution was transferred to a stainless steel autoclave.
The autoclave was charged five times with H2 to displace the argon, and
subsequently the pressure was increased to 30 kgcmꢀ2. After stirring at
508C for 1 h, H2 was released, and the conversion yield and the enantio-
meric excesses were determined by 1H NMR and GC analysis of the
crude products.
Large scale reaction (2-mol scale) (Table 2, entry 9): The crystal coated
with paratone-N was mounted on glass fiber. The crystal structure was
solved by using SHELXS 97 (Sheldrick, 1997). Refinement was carried
out by full-matrixleast squares (on F2) with anisotropic temperature fac-
tors for non-H atoms after omission of redundant and space group for-
bidden data. In all of the structures H atoms were included as their calcu-
lated positions. For refinement of the structure and structure analysis, the
program package SHELXTL was used.
CCDC 269103 (6) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
Chem. Eur. J. 2008, 14, 2060 – 2066
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2065

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Received: September 22, 2007
Published online: December 13, 2007
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Chem. Eur. J. 2008, 14, 2060 – 2066