A dual catalyst system provides the shortest pathway for l-menthol synthesis

Article abstract of DOI:10.1039/c2cc16548a

We have demonstrated that a combination of enantiopure 2- diarylmethylpyrrolidines and heterogeneous Pd/BaSO₄ is an efficient catalytic system for the asymmetric hydrogenation of citral, specifically, a mixture of E-citral and Z-citral in any ratio, and that citronellal is obtained with high enantioselectivity. This dual catalyst system provides a new and more economical route to l-menthol.

Full text of DOI:10.1039/c2cc16548a

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 1772–1774
www.rsc.org/chemcomm
COMMUNICATION
A dual catalyst system provides the shortest pathway for L-menthol
synthesisw
Hironori Maeda, Shinya Yamada, Hisanori Itoh and Yoji Hori*
Received 21st October 2011, Accepted 8th December 2011
DOI: 10.1039/c2cc16548a
We have demonstrated that a combination of enantiopure
2-diarylmethylpyrrolidines and heterogeneous Pd/BaSO4 is an
efficient catalytic system for the asymmetric hydrogenation of
citral, specifically, a mixture of E-citral and Z-citral in any
ratio, and that citronellal is obtained with high enantioselectivity.
This dual catalyst system provides a new and more economical
route to L-menthol.
L-Menthol ((1R,2S,5R)-2-isopropyl-5-methylcyclohexanol), a
stereoisomer of menthol, is an important aroma chemical that
occurs naturally in peppermint oil and is widely used as a
cooling agent. Today, Takasago International Corporation
produces more than 2 ꢀ 106 kg of L-menthol per year by
Scheme 2 BASF L-menthol synthesis.
employing the 2,20-bis(diphenylphosphino)-1,10-binaphthyl
During our continuing efforts to develop more efficient
synthetic routes to synthesize L-menthol, we became interested
in the development of enantioselective catalysis of the hydro-
genation of an E/Z mixture of citral since this provides a new
and more economical route to L-menthol. However, the
enantioselective hydrogenation of E/Z mixtures of prochiral
olefinic substrates remains largely unsuccessful because it is
essential for the substrate to have high geometrical purity for
attaining high enantioselectivity (Scheme 3).2
(BINAP)-Rh complex-catalyzed enantioselective isomerization
of geranylamine to citronellal enamine as the key reaction; this
reaction proceeds in 96–99% ee (Scheme 1).1
Recently, BASF presented a simplified 4-step synthesis
method of L-menthol from citral.2 However, rectification of
E/Z mixtures to obtain high purity Z-citral (neral) is needed in
their method (Scheme 2).
However, MacMillan et al.,3a,b List et al.,3c–e and Kudo et al.3f
have recently reported that the enantioselective organocatalytic
hydride reduction of E- and Z-b-methylcinnamaldehyde using
Hantzsch esters affords an identical enantiomer to b-phenyl-
butyraldehyde with excellent levels of enantioselectivity. Taking
these previous works into consideration, we decided to employ
hydrogen gas as the hydrogen source by performing activation
using a heterogeneous Pd/BaSO4 catalyst; a small amount of
chiral cyclic amine was then used as an asymmetric organocatalyst
for forming the iminium salts. After many attempts, we found that
a dual catalyst system comprising Pd/BaSO4 and chiral 2-diaryl-
methylpyrrolidine is effective for the asymmetric hydrogenation of
citral (eqn (1)). In this communication, we describe our results and
Scheme 1 Takasago L-menthol synthesis.
Takasago International Corporation, 4-11, Nishi-Yawata 1-Chome,
Hiratsuka City, Kanagawa 254-0073, Japan.
E-mail: yoji_hori@takasago.com; Fax: +81 463 25 2093;
Tel: +81 463 25 2033
w Electronic supplementary information (ESI) available: Experimental
procedures, characterisation of all new compounds, copies of 1H
and 13C-NMR spectra. See DOI: 10.1039/c2cc16548a
Scheme 3 New route to L-menthol.
c
1772 Chem. Commun., 2012, 48, 1772–1774
This journal is The Royal Society of Chemistry 2012

View Online
Table 2 Asymmetric hydrogenation of citral: substituent effecta
discuss the mechanism of the newly developed asymmetric dual
catalysis.
ð1Þ
First, we conducted preliminary experiments using several
chiral cyclic amines as the organocatalyst for the asymmetric
hydrogenation of citral. The hydrogenations of citral
(E-citral : Z-citral = 50 : 50) were carried out in the presence
Entry
Amine
Conversionb (%)
Yieldb (%)
% eec
4
of 5%-Pd/BaSO4 (0.1 mol%), chiral amines (1.6–1.9 mol%),
1
2
(R)-1a
(R)-1b
(R)-1b
(R)-1b
(R)-1b
(S)-1c
(S)-1d
(S)-1e
5
79
88
100
99
94
92
79
73
65
74
77
76
63
80
67
57
58
78
77 (R)
84 (R)
84 (R)
85 (R)
83 (R)
84 (S)
80 (S)
77 (S)
89 (R)
88 (R)
and trifluoroacetic acid (TFA) (1.6–1.9 mol%) under atmospheric
pressure of H2 in t-BuOH/H2O (92 : 8 v/v) at 50 1C; the results
are summarized in Table 1. Asymmetric hydrogenations of
isophorone catalyzed by heterogeneous Pd and (S)-proline,5a
and by heterogeneous Pd and 3,5b both without TFA, were
reported. When we used (S)-proline as a catalyst, the hydro-
genation of citral gave low conversion and low optical yield of
citronellal (entries 1 and 2). We carried out hydrogenation of
citral catalyzed by Pd/BaSO4 and 3 without TFA as described
above. Optical purity of corresponding citronellal is much
lower than that of our catalyst system (entries 5 and 6).
In all cases, (S)-pyrrolidine catalysts yielded (S)-citronellal,
and significantly, (S)-2-diphenylmethyl-pyrrolidine (1a) provided
the highest enantioselectivity among the cyclic amines.
3d
4d,e
5d,f
6
7
8
9
84
100
10g
5
a
Unless otherwise noted, the reactions were performed in the same
b
manner as described in Table 1. Determined by gas liquid chromato-
c
graphy (GLC) analysis. Enantioexcess was determined by chiral GLC
d
e
analysis. The hydrogenation reaction was performed at 60 1C. E-citral
(E/Z = 91/9) was used as the substrate. Z-citral (E/Z = 3/97) was used
g
as the substrate. The hydrogenation reaction was performed in the
f
presence of 5 (1.0 mol%) and 5%-Pd/BaSO4 (0.1 mol%) in t-BuOH/H2O
(92 : 8 v/v) (2.0 mL) at 60 1C for 21 h.
Encouraged by the preliminary results, we then prepared a
series of chiral 2-diarylmethylpyrrolidines with different alkyl
substituents on the benzene rings and examined their effec-
tiveness as asymmetric organocatalysts. The results are shown
in Table 2. Interestingly, the introduction of an alkyl group at
the para-positions of the benzene rings in 1 led to a signifi-
cantly enhanced % ee (entries 2–7). For instance, the use of
2-di(p-tert-butylphenyl)methylpyrrolidine (1b) afforded 84%
ee and 74% chemical yield. More interestingly, the introduction
of the hydroxy group at the 4-position of 1b further improved the
enantioselectivity up to 89% ee (entry 9). It should be empha-
sized that the sense and degree of enantioselectivity are essentially
independent of the geometry of the substrate used (entries 3–5).
When we carried out hydrogenation of E- and Z-b-methyl-
cinnamaldehyde, the enantioselectivity of corresponding
(S)-3-phenylbutyraldehyde was 36%.3b,d,6 So we need to design
other suitable chiral 2-diarylmethyl-pyrrolidines for the hydro-
genation (eqn (2)).
Table 1 Scope of amine catalyst for asymmetric hydrogenation of citrala
ð2Þ
Although the high complexity of the dual catalyst system
renders mechanistic analysis difficult, the mechanism is considered
to be similar to that proposed for an enantioselective organo-
catalytic reduction process using Hantzsch esters.3a,d A plausible
reaction mechanism is depicted in Scheme 4; here, the equilibrium
between the two iminium cations (6 and 7) initially formed from
citral and (R)-1a might be rapidly shifted to sterically more stable
E-iminium species 77 that then undergoes hydrogenation onto its
olefinic bond preferentially from Si-face to become (R)-citronellal.
To the best of our knowledge, our work presents the first
successful example of the enantioselective hydrogenation of an
E/Z citral mixture by the cooperation of an organocatalyst
and a heterogeneous palladium catalyst.
Entry
Amine
Conversionb (%)
Yieldb (%)
% eec
1d
2
(S)-Proline
(S)-Proline
(S)-1a
2
3
3
4
100
52
75
82
85
52
96
37
38
62
55
35
39
72
3 (S)
6 (S)
77 (S)
40 (S)
5 (S)
3
4
5d
6
69 (S)
74 (S)
7
a
The hydrogenation of citral (E/Z
= 50/50; 13.1 mmol) was
conducted in the presence of 5%-Pd/BaSO4 (0.1 mol%), chiral amines
(1.6–1.9 mol%), and trifluoroacetic acid (TFA) (1.6–1.9 mol%) under
atmospheric pressure of H2 in t-BuOH/H2O (92 : 8 v/v) (2.0 mL) at
b
50 1C for 21 h. Determined by gas liquid chromatography (GLC)
analysis. Enantioexcess was determined by chiral GLC analysis.
c
In summary, we have developed a new and efficient dual
catalyst system for the asymmetric hydrogenation of citral to
d
Without TFA.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1772–1774 1773

View Online
Notes and references
1 R. Noyori, Asymmetric Catalysis in Organic Synthesis, John Wiley &
Sons, Inc., New York, USA, 1994, pp. 95–96.
2 (a) Asymmetric Catalysis on Industrial Scale, ed. H.-U. Blaser and
H.-J. Federsel, Wiley-VCH, Weinheim, Germany, 2010, pp. 187–205;
(b) G. Heydrich et al., US 2010/0249467 A1, 2010; (c) T.-P. Dang,
P. Aviron-Violet, Y. Colleuille and J. Varagnat, J. Mol. Catal., 1982,
16, 51.
3 (a) S. G. Ouellet, A. M. Walji and D. W. C. MacMillan, Acc. Chem.
Res., 2007, 40, 1327. References are cited therein; (b) S. G. Ouellet,
J. B. Tuttle and D. W. C. MacMillan, J. Am. Chem. Soc., 2005,
127, 32; (c) J. W. Yang, M. T. Hechavarria Fonseca and B. List,
Angew. Chem., Int. Ed., 2004, 43, 6660; (d) J. W. Yang,
M. T. Hechavarria Fonseca, N. Vignola and B. List, Angew. Chem.,
Int. Ed., 2005, 44, 108; (e) S. Mayer and B. List, Angew. Chem., Int.
Ed., 2006, 45, 4193; (f) K. Akagawa, H. Akabane, S. Sakamoto and
K. Kudo, Tetrahedron: Asymmetry, 2009, 20, 461.
4 We tried to use various heterogeneous catalysts, Pd/CaCO3/
Pb(OAc)2, Pd/C/quinoline, Pd/Al2O3, Pd/C, Rh/C, and Pt/Al2O3
etc. and various acids, HCl, HBr, AcOH, ClCH2CO2H etc. and
various solvents, MeOH, EtOH, THF, toluene etc. Consequently,
the combination of Pd/BaSO4, TFA, and t-BuOH/H2O (92 : 8 v/v)
showed the best results for yield and enantioselectivity of citronellal.
5 (a) N. Gyorffy, A. Tungler and M. Fodor, J. Catal., 2010, 270, 2;
(b) E. Sipos, A. Tungler, I. Bitter and M. Kubinyi, J. Mol. Catal.,
2002, 186, 187.
6 The hydrogenation reaction of b-methylcinnamaldehyde (E/Z =
88 : 12, 1.0 g, 6.84 mmol) was performed in the presence of (R)-1a
(1.6 mol%) and 5%-Pd/C (0.17 mol%) in toluene (2.0 mL) at 25 1C
for 21 h.
7 In other words, this asymmetric process involves a dynamic kinetic
resolution of the E- and Z-iminium species. It is interesting to note
that when the reactions using (R)-1b were performed at a lower
temperature (25 1C), % ee’s decreased with a decrease in the
E-purity of the substrate (83% ee from 91%E, 73% ee from
50%E, and 56% ee from 3%E). This observation probably reflects
the scenario in which the isomerization rate of 6–7 is not sufficiently
rapid to complete the dynamic kinetic resolution.
Scheme 4 Plausible reaction mechanism.
afford (R)- or (S)-citronellal in high enantiopurities; the use of
enantiopure 2-diarylmethylpyrrolidines as the organocatalyst
was the key factor for our success. We have thus established
an important basis for the heterogeneous metal-catalyzed
asymmetric hydrogenation of prochiral olefins, including
a,b-unsaturated aldehydes and ketones. Further researches
for more effective chiral organocatalysts are in progress in
our laboratory.
We thank emeritus Prof. Dr Takeshi Nakai of Tokyo
Institute of Technology and Prof. Dr Masahiro Terada of
Tohoku University for their helpful discussions.
c
1774 Chem. Commun., 2012, 48, 1772–1774
This journal is The Royal Society of Chemistry 2012