Iridium-catalyzed asymmetric hydrogenation of unfunctionalized, trialkyl-substituted olefins

Article abstract of DOI:10.1002/asia.201000595

Chiral iridium complexes with bicyclic pyridine-based N,P ligands have emerged as efficient catalysts for the enantioselective hydrogenation of unfunctionalized trialkyl-substituted olefins. Optimization of the reaction conditions by variation of the solvent, pressure, and temperature led to enantiomeric excesses of up to 99%. Three pure alkenes, (E)-2-cyclohexyl-2- butene and (E)- and (Z)-3,4-dimethyl-2-pentene were converted into the corresponding chiral alkanes with 97%, 94%, and 93% ee, respectively. Hydrogenation of the three C=C bonds of both α- and γ-tocotrienyl acetate led to α- and γ-tocopheryl acetate with very high diastereoselectivity. The same catalysts were successfully applied in the hydrogenation of trisubstituted alkenes with a carboxylic ester or a keto group in the γ position. This reaction was used as a key step in a highly enantioselective synthesis of the pheromone of the caddisfly Hesperophylax occidentalis. The hydrogenation of a structurally analogous allylic alcohol also gave high enantioselectivities. Unfunctionalized trialkyl-substituted olefins are hydrogenated with high efficiency and excellent enantioselectivity using iridium complexes derived from chiral N,P ligands. In this way, pharmaceutically interesting and industrially relevant compounds with chiral alkyl fragments are easily accessible with high diastereo- and enantioselectivities. Copyright

Full text of DOI:10.1002/asia.201000595

DOI: 10.1002/asia.201000595
Iridium-Catalyzed Asymmetric Hydrogenation of Unfunctionalized, Trialkyl-
Substituted Olefins
Aie Wang, Rui P. A. Fraga, Esther Hçrmann, and Andreas Pfaltz*[a]
Dedicated to Professor Eiichi Nakamura on the occasion of his 60th birthday
Abstract: Chiral iridium complexes
with bicyclic pyridine-based N,P ligands
have emerged as efficient catalysts for
the enantioselective hydrogenation of
2-pentene were converted into the cor-
responding chiral alkanes with 97%,
94%, and 93% ee, respectively. Hydro-
genation of the three C=C bonds of
both a- and g-tocotrienyl acetate led to
a- and g-tocopheryl acetate with very
high diastereoselectivity. The same cat-
alysts were successfully applied in the
hydrogenation of trisubstituted alkenes
with a carboxylic ester or a keto group
in the g position. This reaction was
used as a key step in a highly enantio-
selective synthesis of the pheromone of
the caddisfly Hesperophylax occidenta-
lis. The hydrogenation of a structurally
analogous allylic alcohol also gave high
enantioselectivities.
unfunctionalized
trialkyl-substituted
olefins. Optimization of the reaction
conditions by variation of the solvent,
pressure, and temperature led to enan-
tiomeric excesses of up to 99%. Three
Keywords: asymmetric catalysis
·
hydrogenation
·
iridium
·
N,P
pure
alkenes,
(E)-2-cyclohexyl-2-
ligands · olefins
butene and (E)- and (Z)-3,4-dimethyl-
Introduction
lysts generally show low reactivity and unsatisfactory enan-
tioselectivity.
Asymmetric hydrogenation is one of the most reliable cata-
lytic methods for the preparation of optically active com-
pounds.[1] Since the early 1970s, when the well-known l-
Dopa process was established at Monsanto,[2] hydrogenation
has played a dominant role in industrial asymmetric cataly-
sis.[3] An impressive number of chiral phosphine ligands
have been developed, which induce very high enantioselec-
tivity in rhodium- and ruthenium-catalyzed hydrogenation.
However, the range of olefins that can be hydrogenated
with high enantiomeric excess is limited, because both rho-
dium and ruthenium catalysts require the presence of a co-
ordinating group next to the C=C bond such as an amide or
hydroxy function. With unfunctionalized olefins these cata-
Some years ago, we introduced a new class of hydrogena-
tion catalysts, iridium complexes with chiral N,P ligands,
which overcome these limitations.[4] Various unfunctional-
ized aryl-substituted olefins can be hydrogenated with high
enantioselectivity and high catalytic efficiency using cata-
lysts of this type.[5,6] Nonetheless, satisfactory results in the
hydrogenation of purely alkyl-substituted olefins were elu-
sive until recently, when we found a class of chiral iridium
catalysts with bicyclic pyridine-phosphinites 1 as ligands[7]
that gave high enantioselectivity in the hydrogenation of un-
functionalized, trialkyl-substituted olefins 2 and 3.[8]
The application range of these catalysts is much broader
compared to previously developed catalysts, as they do not
require the presence of any particular substituent near the
C=C bond. The sense of asymmetric induction can be con-
trolled either by selecting the appropriate ligand enantiomer
or by adjusting the double bond geometry in the substrate,
because E and Z isomers are converted into products of op-
posite configuration. In this way, multiple stereocenters can
be introduced in a single hydrogenation step, starting from
substrates containing two or more C=C bonds of defined ge-
ometry. This strategy was recently demonstrated in the hy-
drogenation of g-tocotrienyl acetate 4[8] and the four cis–
trans isomers of farnesol 5.[9,10]
[a] Dr. A. Wang,+ Dr. R. P. A. Fraga, E. Hçrmann, Prof. Dr. A. Pfaltz
Department of Chemistry
University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
Fax : (+41)61-267-1103
E-mail: andreas.pfaltz@unibas.ch
[+] Current address:
Department of Chemistry
College of Chemistry and Chemical Engineering
Xiamen University
Xiamen 361005 (China)
Chem. Asian J. 2011, 6, 599 – 606
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Table 1. Influence of pressure on the hydrogenation of (E)- and (Z)-2.[a]
(E)-2
P [bar]
ee [%]
(Z)-2
P [bar]
ee [%]
50
25
10
5
95 (+)
95 (+)
93 (+)
94 (+)
90 (+)
50
25
10
5
98 (ꢀ)
98 (ꢀ)
98 (ꢀ)
98 (ꢀ)
94 (ꢀ)
1
1
[a] Reaction conditions: 1 mol% of [Ir((S)-1e)
ACHTUNGTRNE(NGNU cod)]BArF, RT, 2 h,
BArF =tetrakis[bis-3,5-(trifluoromethyl)phenyl]borate.
AHCTUNGTRENNUNG
mers of olefin 2, higher enantioselectivities were observed
when the temperature was decreased from room tempera-
ture to ꢀ208C. Up to 96.1% ee and 99.3% ee were obtained
for (E) and (Z)-2 respectively. The reaction was still fast at
ꢀ208C and went to completion within the standard time of
2 h. At ꢀ408C the rate became very slow and only 6% con-
version was observed for (Z)-2.
Herein we report the results of systematic optimization
studies, which have led to improved efficiency and enantio-
selectivity, and describe additional applications that illus-
trate the scope of these catalysts.
Results and Discussion
Table 2. Influence of temperature on the hydrogenation of (E)- and (Z)-
2.[a]
Optimization of the Reaction Conditions
In our previous work on the hydrogenation of trialkyl-sub-
stituted olefins,[8] we had evaluated pyridine-phosphinite li-
gands 1 under standard conditions (1 mol% of catalyst,
50 bar H2 pressure, CH2Cl2, RT). In order to find the opti-
mal conditions for hydrogenations of this type, we carried
out a systematic study of the influence of the temperature,
hydrogen pressure, solvent, and catalyst loading on the
enantioselectivity and conversion. First, the hydrogenation
of test substrates (E)- and (Z)-2 was investigated, using the
Ir complex derived from ligand (S)-1e, which we had previ-
ously identified as the best catalyst for these olefins
(Table 1).
As shown in Table 1, high hydrogen pressures are not es-
sential, as complete reactions and almost the same enantio-
selectivities were obtained with both E and Z isomers of
olefin 2 when the pressure was lowered from 50 bar to 5 bar.
The hydrogenation went smoothly even at 1 bar, although
with somewhat reduced enantioselectivity. Under 5 bar of
H2 at room temperature, other solvents were tested. Besides
dichloromethane, 1,2-dichloroethane and toluene proved to
be effective solvents that gave similar results in the hydroge-
nation of olefin (Z)-2 (1,2-dichloroethane, >99% conv.,
98% ee; toluene, >99% conv., 96% ee).
(E)-2
T [8C]
ee [%]
(Z)-2
T [8C]
ee [%]
23
0
ꢀ20
94.1 (+)
95.6 (+)
96.1 (+)
23
0
ꢀ20
98.0 (ꢀ)
99.0 (ꢀ)
99.3 (ꢀ)
[a] Reaction conditions: 1 mol% of [Ir((S)-1e)
CH2Cl2, >99% conversion.
ACHTUNGTERN(NUNG cod)]BArF, 5 bar H2, 2 h,
Further studies (Table 3) showed that reducing the cata-
lyst loading to 0.5 mol% had no effect on conversion and
enantioselectivity. However, when only 0.1 mol% of catalyst
was used, the reaction became very slow at low hydrogen
pressure, so the pressure had to be increased to 50 bar in
Table 3. Optimized hydrogenation of (E)-2 and (Z)-2.[a]
(E)-2
Cat. loading [mol%]
P [bar]
T [8C]
t [h]
ee [%]
1
5
5
50
50
ꢀ20
ꢀ20
23
ꢀ20
2
3
2
96 (+)
96 (+)
94 (+)
92 (+)
0.5
0.1
0.1
10
(Z)-2
Cat. loading [mol%]
P [bar]
T [8C]
t [h]
ee [%]
1
5
5
50
50
ꢀ20
ꢀ20
23
ꢀ20
2
4
2
99.3 (ꢀ)
99.3 (ꢀ)
98 (ꢀ)
0.5
0.1
0.1
The influence of temperature was examined at 5 bar of
hydrogen pressure with 1 mol% of [Ir((S)-1e)
(BArF =tetrakis[bis-3,5-(trifluoromethyl)phenyl]borate) as
catalyst in dichloromethane (Table 2). For both E and Z iso-
ACHTUNGTRNEN(UNG cod)]BArF
10
98 (ꢀ)
ACHTUNGTRENNUNG
[a] Reaction conditions: [Ir((S)-1e)ACHTUNGTRNEUNG(cod)]BArF, H2, 2 h, CH2Cl2, >99%
conversion.
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Chem. Asian J. 2011, 6, 599 – 606

Iridium-Catalyzed Asymmetric Hydrogenation
order to obtain full conversion. At low catalyst loadings, the
best results were obtained at high pressure and room tem-
perature, whereas at ꢀ208C the enantioselectivities were
somewhat lower and much longer reaction times were
needed.
nation of alkenes (E)- and (Z)-8, which are commercially
available in high purity (Scheme 1).
Complex [Ir((S)-1b)ACHTUNTGRENUNG(cod)]BArF, which proved to be the
most effective catalyst in the hydrogenation of cyclohexylbu-
Cyclohexyl alkene 3 is a more demanding substrate than
alkenes (E)- and (Z)-2, and only two ligands (S)-1b and (S)-
1 f have been identified so far that can induce enantioselec-
tivities above 90% ee ((S)-1b, 97% ee; (S)-1 f, 97% ee). Fur-
ther studies showed that the five-membered ring derivative
(S)-1b is superior to the corresponding six-membered ring
analogue (S)-1 f, as no decrease in enantisoselectivity was
observed with (S)-1b when the pressure was lowered from
50 bar to 5 bar (Table 4). Even at 1 bar hydrogen pressure,
the reduction went to completion within the standard reac-
tion time of 2 h while the enantioselectivity decreased only
slightly to 95% ee. With ligand (S)-1 f, however, only
86% ee was obtained when the pressure was reduced to
10 bar.
Scheme 1. Hydrogenation of 3,4-dimethyl-2-pentene (8).
Table 4. Optimized hydrogenation of (E)-2-cyclohexyl-2-butene (3).
tene 3 was again the catalyst of choice. Under 50 bar of hy-
drogen pressure, the hydrogenation of both isomers went
smoothly with 0.5 mol% of catalyst, yielding 2,3-dimethyl-
pentane (9) with 99% conversion. Enantioselectivies of
94% ee and 93% ee were obtained with (E)- and (Z)-8, re-
spectively. Consistent with previous studies, the E and the Z
isomer gave products of opposite configuration.
Cat. loading [mol%]
P [bar]
T [8C]
t [h]
ee [%]
1
1
1
1
0.1
0.1
50
5
1
5
50
50
23
23
23
2
2
2
2
2
97
97
95
97
97
95
ꢀ20
23
Hydrogenation of Tocotrienyl Acetate
ꢀ20
10
We have previously reported the highly diastereoslective hy-
drogenation of g-tocotrienyl acetate 4.[8] The pyridine-phos-
phinite (S)-1e had emerged as an optimal ligand in this
case, inducing very high face selectivities in the hydrogena-
tion of the two prochiral C=C bond units. Using 1 mol% of
catalyst at 50 bar hydrogen pressure, the natural RRR
isomer of g-tocopheryl acetate was formed almost exclusive-
ly (Scheme 2).
We have studied this reaction in more detail and have
found that the catalyst loading can be reduced to 0.1 mol%
without affecting the stereoselectivity. Because the biologi-
cally most active component of vitamin E is a-tocopherol
with three methyl groups at the benzene ring, it was of inter-
est to examine the hydrogenation of the corresponding pre-
cursor, a-tocotrienyl acetate 10. As expected the two deriva-
tives 4 and 10 gave very similar results. Again the catalyst
derived from ligand (S)-1e gave the best results and led to
the RRR isomer of a-tocopheryl acetate with a stereoselec-
tivity of greater than 97%. The lower stereoselectivity
(94%) in the reaction with 0.1 mol% catalyst, compared to
the analogous reaction of g-tocotrienyl acetate 4, is probably
due to traces of impurities in the substrate, which had a
stronger effect at low catalyst loadings. The highly stereose-
lective hydrogenation of tocotrienol derivatives, which
makes it possible to introduce two stereogenic centers in
With ligand (S)-1b at 5 bar hydrogen pressure, no appar-
ent influence on the enantioselectivity was observed when
the temperature was decreased to ꢀ208C. Reducing the cat-
alyst loading from 1 mol% to 0.1 mol% had no significant
effect on the enantioselectivity. As observed for substrates
(E)- and (Z)-2, at low catalyst loadings and 50 bar hydrogen
pressure the ee value decreased when the temperature was
lowered to ꢀ208C. Thus, high pressure and ambient temper-
ature seem to be optimal for hydrogenations with low cata-
lyst loadings.
Hydrogenation of 3,4-Dimethyl-2-pentene (8)
Pure alkenes are difficult to study because standard methods
for measuring the ee value often fail. We were fortunate
that Prof. Schurig and co-workers at the University of Tꢁ-
bingen offered help with the analysis of chiral alkanes (see
the Experimental Section). They were able to find a suitable
chiral phase for determining the ee value of alkane 9 by GC,
using two or three linked capillary columns with a mixed
phase of chirasil-b-dex[11] and 6-tert-butyldimethylsilyl-2,3-O-
methyl-b-cyclodextrin. This allowed us to study the hydroge-
Chem. Asian J. 2011, 6, 599 – 606
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601

A. Pfaltz et al.
FULL PAPERS
Scheme 4. i) 1,1,1-triethoxypropane, propionic acid, 1388C, 3 h (75%).
Table 5. Hydrogenation of (E)-ethyl-4-methylhept-4-enoate (14).
Ligand
Conversion [%][a]
ee [%][b]
(R)-1a
(R)-1b
(R)-1c
(S)-1c
(S)-1d
(R)-1e
(S)-1e[c]
>99
>99
>99
>99
>99
>99
>99
95 (R)
91 (R)
90 (R)
91 (S)
90 (S)
95 (R)
93 (S)
Scheme 2. Hydrogenation of g- and a-tocotrienyl acetate.
one step with high efficiency, demonstrates the potential of
this class of catalysts for the synthesis of complex chiral mol-
ecules.
[a] Determined by GC on a chiral stationary phase. [b] Determined by
GC; configuration determined by hydrolysis of ester 16 to the corre-
sponding acid and comparison of the optical rotation with the reported
value.[15] [c] 0.2 mol% catalyst was used.
Synthesis of the Insect Pheromone 13
Table 6. Hydrogenation of (E)-ethyl-4-methylhept-4-enoate (14) with
[Ir((R)-1a)ACTHNUTRGNEUNG
(cod)]BArF—effect of catalyst loading.[a]
Alkyl chains with tertiary methyl-substituted asymmetric
carbon atoms are found in many insect pheromones. The
pheromone of the caddisfly Hesperophylax occidentalis 13 is
a typical example.[12,13] We thought that Ir-catalyzed hydro-
genation of an alkene precursor such as 14 or the analogous
ethyl ketone 15 would be ideally suited for the introduction
of the remote stereogenic center with high enantioselectivity
(Scheme 3). From previous work we knew that ester as well
as keto groups are not hydrogenated under standard condi-
tions and do not interfere with the catalysis.
Entry
Cat. loading [mol%]
Conversion [%][b]
ee [%][c]
1
2
3
1
>99
>99
>99
57
95 (R)
95 (R)
94 (R)
96 (R)
96 (R)
0.2
0.1
0.05
0.05
4
5[d]
57
[a] Reaction conditions: [Ir((R)-1a)ACHTUNGTRNEUNG(cod)]BArF, 50 bar H2, CH2Cl2, RT,
2h. [b] Determined by GC. [c] Determined by chiral GC. [d] Reaction
time was 3 h.
that the catalyst loading could be reduced to 0.1 mol% with-
out notable effect on the ee value and conversion. With
0.05 mol% catalyst, the ee value remained high but the reac-
tion stopped at 57% conversion.
The actual pheromone 13 can be synthesized by convert-
ing the saturated ester 16 to the corresponding ethyl ketone
or, alternatively, by enantioselective hydrogenation of the
unsaturated ketone 15 (Scheme 3). Ethyl ketone 15 was pre-
pared from the unsaturated ester 14 by hydrolysis and con-
version into the acid chloride, followed by reaction with eth-
ylmagnesium bromide and catalytic amounts of FeIII acetyla-
cetonate (Scheme 5).[16] The hydrogenation of this substrate
gave very similar results to those obtained with the corre-
sponding ester 14 (Table 7) and led to the pheromone 13
with full conversion. As expected, the keto group was not
reduced under these conditions.
This enantioselective hydrogenation of the trialkyl-substi-
tuted C=C bond of ketone 15 opens up a short, efficient
route to the caddisfly pheromone 13 in high enantiomeric
purity, which favorably compares with the previously report-
ed asymmetric synthesis of this natural product.[13]
Scheme 3. Proposed synthetic pathway for the pheromone of the caddis-
fly 13.
The g,d-unsaturated ester 14 was readily prepared from
the commercially available allylic alcohol 17 in one step by
a Johnson–Claisen rearrangement as reported by Evans
et al. (Scheme 4).[14] Initial experiments with Ir complexes
derived from ligands 1a–d gave encouraging results with
enantiomeric excesses of 90–95% (Table 5). For this sub-
strate pyridine-phosphinite 1a and 1e were identified as the
ligands of choice. Further experiments (Table 6) showed
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Iridium-Catalyzed Asymmetric Hydrogenation
Table 8. Hydrogenation of (E)-2-methylpent-2-en-1-ol (19).
Scheme 5. i) NaOH, MeOH, H2O (>95%); ii) (COCl)2, DMF followed
by [FeACHTUNGTRENNUNG(acac)3], EtMgBr, THF (64%).
Ligands
Conversion [%][a]
ee [%][b]
(R)-1a
(R)-1c
22a
22b
23a
>99
>99
>99
>99
>99
>99
91 (R)
74 (R)
8 (R)
64 (R)
76 (R)
91 (R)
Table 7. Hydrogenation of (E)-6-methylnon-6-en-3-one (15).
23b
[a] Determined by GC. [b] Determined by chiral GC; configuration de-
termined by comparison with reported value for optical rotation.[19]
Ligand
Conversion [%][a]
ee [%][b]
(R)-1a
(R)-1b
(R)-1c
(S)-1d
(R)-1e
>99
>99
>99
>99
>99
95 (R)
92 (R)
90 (R)
92 (S)
96 (R)
[a] Determined by GC. In preparative reactions the yield of analytically
pure product was>95%. [b] Determined by chiral GC on a chiral sta-
tionary phase; configuration determined by comparison with reported
value for the optical rotation.[27]
23b, which gave the same ee value as the pyridine-phosphin-
ite 1a. The good performance of this ligand contrasts the re-
sults of the hydrogenation of unfunctionalized trialkyl-sub-
stituted olefins, where oxazoline-derived ligands induce only
modest enantioselectivity.
Synthesis and Hydrogenation of Allylic Alcohol 19
For comparison with the hydrogenations of substrates 14
and 15, we also studied the hydrogenation of the allylic alco-
hol 19 with an analogous substitution pattern at the C=C
bond, in order to see how a coordinating hydroxy group in-
fluenced the performance of the catalyst. The resulting satu-
rated alcohol 20 is of industrial importance and BASF has
developed a technical synthesis for the production of this
compound in high enantiomeric purity.[17] The first step is a
ruthenium-catalyzed hydrogenation of 19 at 200 bar hydro-
gen pressure, which affords the saturated alcohol in 75% ee.
The ee value is then improved in a second step by kinetic
resolution with a lipase.
Substrate 19 was synthesized from propanal by aldol con-
densation and subsequent reduction with sodium borohy-
dride (Scheme 6).[18] Hydrogenation studies were carried out
under standard conditions using 0.2 mol% catalyst at 50 bar
hydrogen pressure (Table 8). All catalysts used in this
screening gave full conversion within the standard reaction
time of 2 h. Among the pyridine-phophinite ligands that
were tested, 1a, which had already proven to be one of the
two optimal ligands for substrate 14, gave the best results
(91% ee). In addition, several other ligands, including the
phox derivatives 22a,b and 23a,b were evaluated. The high-
est enantioselectivity in this series was obtained with ligand
The results obtained with this substrate show that the
presence of a coordinating hydroxy group next to the C=C
bond does not have a beneficial effect, as observed for Rh
and Ru catalysts. In fact, lower enantioselectivities (91% vs.
95% ee) were obtained than in the hydrogenation of the
ester 14. These findings are in line with the selectivities ob-
served in the hydrogenation of tocopherol derivatives and
farnesol, where the trialkyl-substituted C=C bonds were re-
duced with higher face selectivity than the allylic alcohol
units. The good performance of Ir catalysts derived from li-
gands 1a and 23b demonstrates that Ir complexes of this
type are useful catalysts for the hydrogenation of allylic al-
cohols which can outperform Ru or Rh catalysts.
Conclusions
Chiral iridium complexes with bicyclic pyridine-phosphinites
1 as ligands are highly efficient catalysts that give high enan-
tioselectivity in the hydrogenation of unfunctionalized, tri-
alkyl-substituted olefins. By variation of the hydrogen pres-
sure, solvent, temperature, and catalyst loading, optimized
conditions were found that gave 96–99% ee in the hydroge-
nation of alkenes (E)- and (Z)-2 and 3 with 0.1 mol% cata-
lyst.
Both a- and g-tocotrienyl acetate can be hydrogenated
with excellent diastereoselectivity under catalyst control
with 0.1 mol% Ir complex derived from ligand 1e, giving
Scheme 6. i) NaOH, H2O, 50 8C (quant.); ii) NaBH4, MeOH, room tem-
perature (65%).
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FULL PAPERS
H2), tR =13.5 min (minor), tR =13.9 min (major); for (R)-9: GC
(50 m+25 m+40 m chirasil-b-Dex TM8, 408C, 2.1 bar H2), tR =27.4 min
(major), tR =28.4 min (minor). GC analysis was carried out by Dr. Harri
Czesla and Prof. Volker Schurig (University of Tꢁbingen). The absolute
configuration of 9 was determined by comparison of the optical rotation
with that reported in the literature.[24]
the natural RRR form of the corresponding vitamin E deriv-
ative. This transformation stands out as the most straightfor-
ward and simplest method for the introduction of the two
stereogenic centers in the tocopherol side chain. The poten-
tial of our catalysts in natural product syntheses is illustrated
by the enantioselective synthesis of an insect pheromone 13.
Although a coordinating hydroxy group next to the C=C
bond has no beneficial effect as observed for Rh and Ru
catalysts, the results obtained with allylic alcohol 19 show
that Ir P,N complexes can outperform Rh and Ru catalysts
in the asymmetric hydrogenation of this substrate class.
Hydrogenation of a-(R)-tocotrienyl acetate 10: Following the procedures
reported, a-tocopheryl acetate was converted into the corresponding
methyl ether for determining the diastereoselectivity.[25]
a-Tocopheryl acetate (12): 1H NMR (400 MHz, CDCl3): d=2.59 (t, J=
6.8 Hz, 2H), 2.34 (s, 3H), 2.09 (s, 3H), 2.02 (s, 3H), 1.98 (s, 3H), 1.79 (m,
2H), 1.57–1.01 (m, 21H), 1.23 (s, 3H), 0.86 (d, J=6.6 Hz, 6H), 0.85 (d,
J=6.3 Hz, 3H), 0.84 ppm (d, J=6.6 Hz, 3H); 13C NMR (101 MHz,
CDCl3): d=170.2, 149.8, 140.9, 127.0, 125.3, 123.4, 117.8, 75.5, 39.8(2C),
37.9, 37.9, 37.8, 37.7, 33.2, 33.1, 31.4, 28.4, 25.2, 24.9, 23.1, 23.0, 21.4, 21.0,
21.0, 20.2, 20.1, 13.4, 12.5, 12.2 ppm.
Experimental Section
a-Tocopherol: A mixture of tocopheryl acetate (0.05 mmol) and LiAlH4
(13 mg, 0.35 mmol) in THF (1 mL) was stirred at room temperature for
1.5 h and then cooled with ice before water (2.5 mL) was added cautious-
ly. The mixture was stirred for 10 min and extracted with ether (3ꢂ5
mL). The organic portions were combined, dried (Na2SO4), and concen-
trated, giving an oil, which was subjected directly to etherfication without
General: Reactions and manipulations of air- and moisture-sensitive
compounds were performed in a nitrogen-filled glovebox or using stan-
dard Schlenk techniques, unless otherwise indicated. All chemicals were
purchased from Acros Organics, Aldrich, Fluka, Merck, and TCI Chemi-
cals, except for g- and a-tocotrienyl acetate, which were gifts from Dr.
Thomas Netscher, DSM Nutritional Products.
1
further purification. H NMR (400 MHz, CDCl3): d=4.17 (s, 1H), 2.60 (t,
J=6.8 Hz, 2H), 2.16 (s, 3H), 2.11 (s, 6H), 1.78 (m, 2H), 1.60–1.00 (m,
21H), 1.23 (s, 3H), 0.87 (d, J=6.8 Hz, 6H), 0.85 (d, J=6.6 Hz, 3H),
0.84 ppm (d, J=6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=145.9,
144.9, 123.0, 121.4, 118.8, 117.8, 74.9, 40.2, 39.8, 37.9, 37.9, 37.8, 37.7, 33.2,
33.1, 32.0, 28.4, 25.2, 24.9, 24.2, 23.1, 23.0, 21.4, 21.2, 20.2, 20.1, 12.6, 12.2,
11.7 ppm.
General procedure for iridium-catalyzed hydrogenation: Under nitrogen,
substrate (0.05 or 0.1 mmol), the appropriate catalyst (0.1–1ꢂ10ꢀ3 mmol,
0.1–1 mol%), and dichloromethane (0.5 mL), or substrate (0.05 mmol)
and 0.5 mL of a dichloromethane solution of catalyst (5ꢂ10 ꢀ5 mmol,
0.1 mol%) were added to a glass vial (2 mL) charged with a magnetic
stirrer. The vial was placed in an autoclave and sealed. The autoclave
was pressurized with H2 and the solution was stirred at 700 rpm for a cer-
tain time. Then hydrogen was carefully released and the reaction mixture
concentrated under reduced pressure. Hexane (1 mL) was added and the
mixture filtered through a 0.2 mm syringe filter or a plug of silica gel.
Concentration of the hexane solution gave an oil, which was analyzed by
GC or HPLC.
a-Tocopheryl methyl ether: An aqueous solution of KOH (50% w/w, 40
uL, 0.5 mmol) was added to a solution of tocopherol (0.05 mmol) in
DME (0.2 mL) and the mixture was stirred at room temperature for
10 min. Then dimethyl sulfate (24 uL, 0.25 mmol) was added and the re-
action was stirred for 1.5 h. The reaction mixture was concentrated under
reduced pressure and stirred in a mixture of water/hexane (2:1, 10 mL)
for 5 min. The organic phase was separated and the aqueous phase was
extracted with hexane (2ꢂ5 mL). The combined organic phases were
dried (Na2SO4), concentrated, yielding an oil which was analyzed by GC.
1H NMR (400 MHz, CDCl3): d=3.63 (s, 3H), 2.58 (t, J=6,8 Hz, 2H),
Hydrogenation of olefins 2, 3, and 4: Substrate syntheses and analytical
procedures are described in reference [8].
Determination of the absolute configuration of 2-cyclohexylbutane (7):
(E)-2-Phenyl-2-butene[20] (132 mg, 1.0 mmol) was hydrogenated under
50 bar of hydrogen at room temperature using [Ir((S)-1b)ACTHUNRGTNEUNG(cod)]BArF
2.18ACHTUNGERTN(NNUG s, 3H), 2.14ACHTUNREGTG(NNUN s, 3H), 2.08ACHTNUGTNER(NUGN s, 3H), 1.78 (m, 2H), 1.59–1.00 (m, 21H),
1.23 (s, 3H), 0.86 (d, J=6.6 Hz, 6H), 0.85 (d, J=5.3 Hz, 3H), 0.84 ppm
(d, J=6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=149.8, 148.2, 128.1,
126.1, 123.3, 117.9, 75.2, 60.8, 40.5, 39.8, 37.9, 37.9, 37.8, 37.7, 33.2, 33.1,
31.7, 28.4, 25.2, 24.8, 24.3, 23.1, 23.0, 21.4, 21.0, 20.2, 20.1, 13.0, 12.2,
12.1 ppm; MS (EI, m/z): 444 (M+, 100%), 179 (96%); elemental analysis
(%) calcd for C30H52O2 (444.74): C 81.02, H 11.78; found: C 81.06,
H 11.80; GC: CP-Sil-88, 90 kpa H2, 2808C (injection), 2508C (detector),
1708C (170 min), tR =142.75 min (RRS), 144.99 min (RRR), 147.06 min
(RSR), 148.95 min (RSS).
Synthesis of 14:[14] A mixture of 6.00 g (59.9 mmol) of 2-methyl-1-penten-
3-ol, 38.9 g (240 mmol) of ethyl orthoacetate, and 0.53 mL (7.03 mmol) of
propionic acid was heated to 1388C. The ethanol formed was removed by
distillation. After 8 mL of ethanol had been collected (3 h), the solution
was allowed to cool to ambient temperature and 5.6 mL of 3.5% aqueous
acetic acid was added. After stirring for 1 h the solution was concentrated
in vacuo (358C/70 mbar). The colorless residue was dissolved in pentane
(5 mL) and dried with MgSO4. The suspension was loaded on top of a
plug of silica gel (d=5 cm, h=3 cm, suspended in pentane) and eluted
with pentane (200 mL). After removal of the solvent in vacuo (358C/
150 mbar) 9.06 g of a mixture of product 14 and a side product was ob-
tained as a colorless liquid and used for the next step without further pu-
rification.
(16 mg, 0.01 mmol) as catalyst, giving (S)-(+)-2-phenylbutane (133 mg,
99%) in 98% ee (GC, G-TA, 70 KPa H2, 508C (40 min), tR =20.28 min
(major), tR =21.57 min (minor)), ½aꢁ2D0 =+25.0 (CHCl3, c=1.0). Lit.[21]
½aꢁ2D0 =+10.4 (CHCl3, c=0.5). (S)-(+)-2-Phenylbutane (133 mg, 1.0 mmol)
was then hydrogenated over Rh/C in water (1 mL) under 5 bar of hydro-
gen at 408C for 24 h. The catalyst was filtered and rinsed with diethyl
ether. The organic phase was separated and the aqueous phase was ex-
tracted with diethyl ether (2ꢂ5 mL). The organic phases were combined,
dried (MgSO4), filtered, and concentrated, giving (S)-(ꢀ)-2-cyclohexylbu-
tane, ½aꢁ2D0 =ꢀ1.4 (CHCl3, c=2.0). Lit.:[22] ½aꢁ2D5 =+1.95 (benzene) for the
R enantiomer. Product 7 from the asymmetric hydrogenation of 3 had
the same optical rotation (½aꢁ2D0 =ꢀ1.4 (CHCl3, c=2.0) as the above au-
thentic (S)-2-cyclohexylbutane.
Hydrogenation of (E)- and (Z)-3,4-dimethyl-2-pentene (8): Under nitro-
gen, 3,4-dimethyl-2-pentene (8) (196 mg, 2 mmol) and [Ir((S)-1b)-
ACHTUNGTRENNUNG(cod)]BArF (15 mg, 0.01 mmol) were dissolved in dichloromethane
(10 mL) in an autoclave (120 mL) equipped with an overhead stirrer. The
autoclave was pressurized to 50 bar with H2 and the solution was stirred
at 700 rpm for 4 h at room temperature. Then hydrogen was carefully re-
leased and the solvent was removed by Kugelrohr distillation. Pentane
(2 mL) was added to the residue and the mixture filtered through a
0.2 mm syringe filter. The solution was then submitted to GC analysis.
2,3-Dimethyl-pentane (9): 1H NMR (400 MHz, CDCl3): d=1.58–1.52 (m,
1H), 1.40–1.33 (m, 1H), 1.20–1.1 (m, 2H), 0.88–0.85 (m, 6H), 0.80 (d, J=
6.6 Hz, 3H), 0.79 ppm (d, J=6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3):
d=40.8, 32.1, 27.1, 20.7, 18.4, 15.3, 12.4 ppm, consistent with reported
values[23]; for (S)-9: GC (50 m+25 m chirasil-b-Dex TM8,[11] 458C, 1.8 bar
In another experiment the product was purified by distillation at 838C
and 11 mbar to yield 7.6 g (75%) of analytically pure product 14 (>97%
1
E), whose H NMR data were consistent with the reported values.[14]
Ethyl 4-methylheptanoate (16): Analytical data were consistent with re-
ported values[26]; GC (Brechbꢁhler b-cyclodextrin DetButSil SE54 25 mꢂ
604
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 599 – 606

Iridium-Catalyzed Asymmetric Hydrogenation
0.25 mm, 60 KPa H2, 408C (0 min), 0.48Cminꢀ1
,
758C (2 min),
2-Methylpentan-1-ol (20): Analytical data were consistent with the values
reported[28]
GC (Brechbꢁhler b-cyclodextrin DetButSil SE54 25 mꢂ
108Cminꢀ1, 1808C (5 min)), tR =76.5 min (S), 77.4 min (R), 86.0 min (14).
;
0.25 mm, 60 KPa H2, 408C (0 min), 0.38Cminꢀ1
,
618C (2 min),
Synthesis of 18: The mixture of product 14 and side product (9.06 g) was
dissolved in MeOH (40 mL) and H2O (20 mL). NaOH (8.52 g) was
added and the suspension was stirred vigorously whereupon it heated up
to boiling temperature. After stirring at 508C for 2 h the solvent and
EtOH formed in the reaction were removed in vacuo (408C/100 mbar).
The aqueous solution was washed with CH2Cl2 (3ꢂ50 mL), cooled to
08C, and acidified with a solution of 20% HCl (35 mL). The pH was ad-
justed to 2 with a solution of 2% HCl. The resulting cloudy solution was
extracted with CH2Cl2 (3ꢂ50 mL), and the combined organic phases
were dried (MgSO4) and concentrated in vacuo (408C/13 mbar) to yield
6.80 g (91%, calculated over two steps) of (E)-4-methylhept-4-enoic acid
(18) as a colorless liquid, whose 1H NMR data were consistent with the
reported values.[14]
108Cminꢀ1, 1608C (5 min)), tR =59.9 min (R), 64.8 min (S), 73.6 min (19).
Acknowledgements
Financial support from the Swiss National Science Foundation, the Feder-
al Commission for Technology and Innovation (KTI), and Novartis
Pharma (Fellowship Award to A.W.) is gratefully acknowledged. R.P.A.F.
is grateful to Fundażo para a CiÞncia e Tecnologia (FCT) for a postdoc-
toral scholarship. We thank Dr. Thomas Netscher (DSM Nutritional
Products) for helpful discussions and a gift of a- and g-(R)-tocotrienyl
acetate. Dr. Harri Czesla and Prof. Volker Schurig are specially acknowl-
edged for their help in the determination of the enantiomeric excess of
alkane 9.
Synthesis of 15: Compound 18 (1.00 g, 8.05 mmol) was dissolved in dry
CH2Cl2 (7 mL) and the solution cooled to 08C. Then 0.82 mL
(9.66 mmol) of (COCl)2 and one drop of DMF were added. The solution
was stirred for 15 min at 08C and 1.5 h at room temperature until gas
evolution stopped. The solvent was removed in vacuo and the residue
distilled (378C, 0.08 mbar) to yield 0.96 g (5.98 mmol) of acid chloride as
a colorless oil. The acid chloride was immediately dissolved in dry THF
[1] a) J. M. Brown in Comprehensive Asymmetric Catalysis, Vol. 1 (Eds.:
E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999,
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Angew. Chem. Int. Ed. 2002, 41, 2008–2022.
[2] W. S. Knowles, Angew. Chem. 2002, 114, 2096–2107; Angew. Chem.
Int. Ed. 2002, 41, 1998–2007.
(20 mL) and 63 mg (0.18 mmol, 3%) of [FeACHTNUTRGNEUNG(acac)3] was added. The solu-
tion was cooled to 08C and 6.0 mL of EtMgBr (6.0 mmol, 1m in THF)
was added slowly over 1 h causing a color change from red to yellow to
black. After stirring for an additional 15 min at 08C the reaction was
quenched by addition of 1m HCl (10 mL). The organic layer was separat-
ed and the aqueous phase washed with Et2O (3ꢂ20 mL). The combined
organic phases were washed with saturated aqueous NaHCO3 (30 mL),
dried (MgSO4), and concentrated in vacuo (408C/13 mbar). Purification
by flash column chromatography (silica gel, pentane/Et2O=20:1) gave
0.80 g (5.16 mmol, 64%) of product 15 as a colorless liquid.
(E)-6-Methylnon-6-en-3-one (15): 1H NMR (400 MHz, CDCl3): d=0.91
(t, J=7.3 Hz, 3H), 1.04 (t, J=7.3 Hz, 3H), 1.59 (s, 3H), 1.97 (dq, J1 ꢂJ2 ꢂ
7.3 Hz, 2H), 2.23 (t, J=7.8 Hz, 2H), 2.42 (q, J=7.3 Hz, 2H), 2.49 (t, J=
7.8 Hz, 2H), 5.12 ppm (broadened t, Jꢂ7.1 Hz, 1H); 13C NMR
(101 MHz, CDCl3): 7.8, 14.3, 15.9, 21.1, 33.6, 35.9, 41.1, 126.9, 133.0,
211.6 ppm; elemental analysis (%) calcd for C10H18O (154.25): C 77.87,
H 11.76; found: C 77.86, H 11.66.
[3] Asymmetric Catalysis on Industrial Scale (Eds.: H. U. Blaser, E.
Schmidt), Wiley-VCH, Weinheim, 2004.
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Menges, M. Schoenleber, S. P. Smidt, B. Wꢁstenberg, N. Zimmer-
mann, Adv. Synth. Catal. 2003, 345, 33–43; c) S. J. Roseblade, A.
Pfaltz, Acc. Chem. Res. 2007, 40, 1402–1411. For recent work, see:
d) D. H. Woodmansee, M.-A. Mꢁller, M. Neuburger, A. Pfaltz,
Chem. Sci. 2010, 1, 72–78; e) A. Baeza, A. Pfaltz, Chem. Eur. J.
2010, 16, 4003–4009; f) A. Baeza, A. Pfaltz, Chem. Eur. J. 2010, 16,
2036–2039; g) M. G. Schrems, A. Pfaltz, Chem. Commun. 2009,
6210–6212; h) A. Baeza, A. Pfaltz, Chem. Eur. J. 2009, 15, 2266–
2269.
Asymmetric hydrogenation of 15: Preparative reactions were carried out
according to the general procedure and Table 7, using 1–5 mmol of sub-
strate (3 mL CH2Cl2 per mmol 15). After releasing hydrogen, the reac-
tion solution was concentrated in vacuo at 308C. The resulting brown oil
was Kugelrohr distilled (0.1 bar, 758C) to give product 13 in 95–97%
yield as a colorless oil.
[5] For reviews see: X. Cui, K. Burgess, Chem. Rev. 2005, 105, 3272–
3297; T. L. Church, P. G. Andersson, Coord. Chem. Rev. 2008, 252,
513–531 and 4c.
[6] For recent publications of other groups, see: a) Y. Zhu, K. Burgess,
Adv. Synth. Catal. 2008, 350, 979–983; b) Y. Zhu, K. Burgess, J. Am.
Chem. Soc. 2008, 130, 8894–8895; c) P. Kaukoranta, M. Engman, C.
Hedberg, J. Bergquist, P. G. Andersson, Adv. Synth. Catal. 2008, 350,
1168–1176; d) P. Cheruku, J. Diesen, P. G. Andersson, J. Am. Chem.
Soc. 2008, 130, 5595–5599; e) M. Dieguez, J. Mazuela, O. Pamies,
J. J. Verendel, P. G. Andersson, J. Am. Chem. Soc. 2008, 130, 7208–
7209; f) S.-M. Lu, C. Bolm, Angew. Chem. 2008, 120, 9052–9055;
Angew. Chem. Int. Ed. 2008, 47, 8920–8923; g) W.-J. Lu, Y.-W.
Chen, X.-L. Hou, Angew. Chem. 2008, 120, 10287–10290; Angew.
Chem. Int. Ed. 2008, 47, 10133–10136; h) J. Mazuela, J. J. Verendel,
M. Coll, Schꢃffner, A. Bçrner, P. G. Andersson, O. Pꢄmies, M. Diꢅ-
guez, J. Am. Chem. Soc. 2009, 131, 12344–12353; i) J. Mazuela, A.
Paptchikhine, O. Pꢄmies, P. G. Andersson, M. Diꢅguez, Chem. Eur.
J. 2010, 16, 4567–4576.
[7] S. Kaiser, S. P. Smidt, A. Pfaltz, Angew. Chem. 2006, 118, 5318–
5321; Angew. Chem. Int. Ed. 2006, 45, 5194–5197.
[8] S. Bell, B. Wꢁstenberg, S. Kaiser, F. Menges, T. Netscher, A. Pfaltz,
Science 2006, 311, 642–644.
[9] A. Wang, B. Wꢁstenberg, A. Pfaltz, Angew. Chem. 2008, 120, 2330–
2332; Angew. Chem. Int. Ed. 2008, 47, 2298–2300.
[10] For other examples for the stereoselective introduction of two ste-
reocenters by hydrogenation of a substrate containing two trisubsti-
tuted trans C=C bonds, see a) J. Zhou, K. Burgess, Angew. Chem.
2007, 119, 1147–1149; Angew. Chem. Int. Ed. 2007, 46, 1129–1131;
6-Methylnonan-3-one (13): Analytical data consistent with reported
values;[13,27] GC (Macherey–Nagel Hydrodex b-3P 25 mꢂ0.25 mm,
100 KPa H2, 408C (5 min), 0.58Cminꢀ1, 708C (0 min), 108Cminꢀ1, 1808C
(10 min)), tR =58.5 min (R), 60.5 min (S), 65.5 min (15).
Synthesis of 21: Propanal (29.3 mL, 23.4 g, 0.4 mol) was added over a
period of 1 h to a 1m aqueous solution of sodium hydroxide at 508C. The
mixture was further stirred for 1 h at 508C and, after cooling to room
temperature, was extracted with diethyl ether (3ꢂ50 mL). The combined
organic phases were dried over magnesium sulfate and concentrated in
vacuo to yield 19.9 g (quant.) of analytically pure (E)-2-methylpent-2-
enal (21), which was used in the next step without further purification.
1
The H NMR data were consistent with the reported values.[18a]
Synthesis of 19: To a solution of aldehyde 21 (18.6 g, 0.19 mol) in 300 mL
of methanol, sodium borohydride (9.33 g, 0.25 mol) was slowly added
during 30 min. The solution was kept at ambient temperature by the use
of a water bath. After the addition was complete, the reaction was stirred
for an additional 2 h. Then water (200 mL) was added, and the mixture
extracted (3ꢂ100 mL) with diethyl ether. The combined organic phases
were dried over MgSO4, and the solvent was removed in vacuo to yield
analytically pure (E)-2-methylpent-2-en-1-ol (19) (12.4 g, 65%), whose
13
1H and C NMR data were consistent with the reported values.[18b]
Chem. Asian J. 2011, 6, 599 – 606
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
605

A. Pfaltz et al.
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Published online: October 21, 2010
606
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Chem. Asian J. 2011, 6, 599 – 606