Enantio- and diastereoselective hydrogenation of farnesol and O-protected derivatives: Stereocontrol by changing the C=C bond configuration

Article abstract of DOI:10.1002/anie.200705521

(Chemical Presented) Four isomers-one catalyst: The four stereoisomers of hexahydrofarnesol can be prepared with high enantio- and diastereoselectivity by using the same chiral iridium catalyst 1 with different cis/trans isomers of farnesol (see scheme; B

Full text of DOI:10.1002/anie.200705521

Communications
DOI: 10.1002/anie.200705521
Asymmetric Catalysis
Enantio- and Diastereoselective Hydrogenation of Farnesol and
=
O-Protected Derivatives: Stereocontrol by Changing the C C Bond
Configuration**
Aie Wang, Bettina Wüstenberg, and Andreas Pfaltz*
=
We recently reported a class of chiral iridium catalysts derived
from pyridylphosphine ligands 1, which for the first time have
allowed highly selective asymmetric hydrogenation of
tivity of the two trialkyl-substituted C C bonds with the
allylic alcohol unit in its free and protected form. Further-
more, hexahydrofarnesol, which can be readily prepared by
this route in any of the four possible stereoisomeric forms,[6] is
an important building block for the syntheses of vitamins E
and K[7] or related antioxidants,[8] and insect pheromones.[9] It
also has an important function as a constituent of ether lipids
in archea[10] and was identified as a precursor of many
terpenoid compounds in plants[11] and geological sediments.[12]
Initial screening of a series of chiral N,P ligands was
performed with (2E,6E)-farnesol by using 1 mol% of catalyst
in dichloromethane at room temperature in the presence of
=
hydrogen (50 bar)(Table 1). Because the two prochiral C C
units are E-configured, the sense of chiral induction at the two
reaction sites was expected to be the same, leading either to
the 3R,7R or 3S,7S isomer depending on the absolute config-
uration of the ligand. The best enantio- and diastereoselec-
tivities were obtained with iridium complexes derived from
ligands which carried a methyl or phenyl substituent at the
position next to the pyridine N atom. Among the six-
membered ring derivatives 1a–e, ligand 1c, which has a
[1,2]
=
unfunctionalized trialkyl-substituted C C bonds.
Unlike
rhodium or ruthenium diphosphine complexes, these catalysts
do not require any special coordinating group next to the C C
=
bond. Enantiofacial selection by the catalysts in this case
results from discrimination between the H atom and a
sterically more demanding alkyl group at the monosubsti-
tuted olefinic C atom. Consequently, cis and trans olefins are
converted into products of opposite configuration.[1] Thus, the
sense of asymmetric induction can be controlled by proper
choice of the double bond geometry. In this way, two or more
stereogenic centers can be introduced with the desired
relative and absolute configuration by hydrogenation of a
di- or polyene.[3]
Table 1: Ir-catalyzed hydrogenation of (2E,6E)-farnesol.[a]
Herein we report the asymmetric hydrogenation of
farnesol and O-protected derivatives to demonstrate the
potential of this strategy. This class of substrates was chosen
because efficient routes to all four cis/trans isomers were
available,[5] and we were interested in comparing the reac-
L
3S,7R
3R,7R
3R,7S
3S,7S
ee [%] of (R,R)-3
[*] Dr. A. Wang, Dr. B. Wüstenberg,[+] Prof. Dr. A. Pfaltz
Department of Chemistry
[%][b]
[%][b]
[%][b]
[%][b]
University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
Fax: (+41)61-267-1103
1a S
1b R
1c S
1d R
1e S
1 f R
1g R
1h S
4
37.8
5.5
6.4
18.6
33.2
5.7
8.2
16.0
23
31.0
2.1
92.2
12.9
26.8
0.3
2.2
80.3
1
14.9
25.7
1.3
34.9
19.4
7.0
19.1
3.1
4
16.2
66.5
0.3
33.3
20.6
86.9
70.4
0.8
31
À94
99.3
À44
13
À99.3
À94
98
E-mail: andreas.pfaltz@unibas.ch
[+] Current address: Research Center Chemical Process Technology
DSM Nutritional Products
P.O. Box 3255, 4002 Basel (Switzerland)
[**] Financial support from the Swiss National Science Foundation, the
Federal Commission for Technology and Innovation (KTI), and
NovartisPharma (Fellowship Award to A.W.) isgratefully acknowl-
edged. We thank Dr. Thomas Netscher (DSM Nutritional Products)
for helpful discussions and a gift of farnesol.
72
79
À97
5
13.5
0.5
7
À99
[a] For detailed reaction conditionsese the Supporting Information;
cod=cycloocta-1,5-diene, BArF =tetrakis[bis-3,5-(trifluoromethyl)phen-
yl]borate. [b] Determined by GC methods. See the Supporting
Information.
Supporting information for thisarticle isavailable on the WWW
under http://www.angewandte.org or from the author.
2298
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Angewandte
Chemie
phenyl substituent on the pyridine ring and two ortho-tolyl
groups on the P atom, proved to be most effective. The
3R,7R product was formed in 92% yield and 99% ee, imply-
Electron-withdrawing protecting groups such as acetoxy
=
or trifluoroacetoxy groups reduced the reactivity of the C C
bond next to the oxygen atom. Acetate 8 required 0.2 mol%
of the catalyst for full conversion to the product, but the
stereoselectivity was essentially the same as for the free and
silyl-protected farnesol. Hydrogention of trifluoroacetate 10
was significantly slower and gave only 49% conversion after
2 hours with 1 mol% of catalyst. However, the stereoselec-
tivity was somewhat higher than in the reactions of the
corresponding alcohol, silyl ether, and acetate substrates. The
=
ing that the C C bond next to the hydroxy group was
hydrogenated with a facial selectivity of 93:7 and the central
=
C C bond reacted with an even higher selectivity of 98:2. The
corresponding five-membered ring derivative (1 f) gave a
similarly high stereoselectivity. Interestingly, in the five-
membered ring series of ligands, 1g and 1h, which have
cyclohexyl and tert-butyl groups, respectively, on the P atom,
also induced high stereoselectivities, whereas the analogous
six-membered ring derivatives 1d and 1e gave very poor
results. Most of the oxazoline- and imidazoline-based N,P li-
gands examined gave only low selectivities, the exception
being the selectivity of ligands 4 and 5.[13]
=
electron-poor C C bond next to the trifluoroacetoxy group
was less reactive (only 50% reduction after full consumption
=
of the substrate) than the two trialkyl-substituted C C bonds
(100% reduction). The difference in reactivity between these
=
two types of C C bonds was even larger in toluene: 66% of
6,7,10,11-tetrahydrofarnesyl trifluoroacetate was obtained, in
addition to 2% of 10,11-dihydrofarnesyl trifluoroacetate and
32% of the fully hydrogenated product. Although this
difference in reactivity is not sufficiently large for a com-
pletely selective hydrogenation of the two trialkyl-substituted
=
C C bonds (without affecting the allylic trifluoroacetate
unit), the option to lower the reactivity of allylic alcohols by
protection with electron-withdrawing groups may prove
useful in other cases.
Hydrogenation of (2E,6E)-farnesol under optimized con-
ditions with 0.1 mol% [Ir{(S)-1c}(cod)]BArF yielded hexahy-
drofarnesol with 99% conversion to a product mixture
containing 91% of the 3R,7R isomer in 99% ee (Scheme 1).
Virtually the same result was obtained in a preparative-scale
reaction (10 mmol; see the Experimental Section). The
corresponding triisopropylsilyl protected farnesol (6)
showed very similar reactivity and was converted into the
saturated silyl ether 7 with essentially the same enantio- and
diastereoselectivity.
Next we studied the hydrogenation of all four stereoiso-
mers of farnesol (Scheme 2). The required isomerically pure
substrates were prepared according to the procedures
reported by Wiemer and co-workers.[5c] By using catalyst
[Ir{(S)-1c}(cod)]BArF under standard conditions, the four
isomers were converted into the fully saturated products in
=
essentially quantitative yield. As expected, E-configured C C
bonds gave rise to the R configuration in the product with the
catalyst derived from (S)-1c, whereas stereogenic centers
=
with the S configuration were formed from Z-configured C C
bonds. Consequently, hydrogenation of each of the four
geometrical isomers of farnesol with the same catalyst led to a
different stereoisomer. In all cases, the major diastereoisomer
Scheme 1. Ir-catalyzed hydrogenation of (2E,6E)-farnesol derivatives.
TIPS=triisopropylsilyl; TFA=trifluoroacetoxy.
Scheme 2. Ir-catalyzed hydrogenation of farnesol stereoisomers.
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Communications
every 2 h to maintain the pressure). Hydrogen was carefully released
and the reaction mixture was concentrated under reduced pressure.
The residue was loaded onto a short plug of silica gel (3.5 ” 7 cm) and
washed with of diethyl ether (250 mL; freshly distilled, peroxide-
free). Concentration of the ether solution provided hexahydrofarne-
sol 3 as a colorless oil (2.22 g, 97%). Analytical data and determi-
nation of stereoselectivity: see the Supporting Information.
was formed with greater than 90% selectivity in very high
enantiomeric purity (greater than 99% ee). The Z-configured
=
C C bond of the allylic alcohol unit reacted with a somewhat
higher facial selectivity (96–97%) than the corresponding E-
=
configured C C bond (93–95%), whereas the facial selectiv-
=
ity of the central trisubstituted C C bond was virtually
independent of the E or Z geometry (98%).
The stereoselective syntheses of the four hexahydrofar-
nesol stereoisomers is also possible by stepwise hydrogena-
tion using Ru and Ir catalysts (Scheme 3). As shown by the
Received: December 3, 2007
Published online: February 12, 2008
Keywords: homogeneouscatalysis· hydrogenation · iridium ·
.
N,P ligands· terpenoids
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=
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Scheme 3. Consecutive Ru- and Ir-catalyzed hydrogenation of (2E,6E)-
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genated by Ru–diphosphine catalysts with high enantioselec-
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[Ru{(R)-tol-binap}](OAc)2. Subsequent hydrogenation of the
=
=
remaining two C C bonds with the Ir catalyst derived from
ligand (S)-1c produced (3S,7R)-hexahydrofarnesol with
greater than 99% ee in 93% diastereomeric purity. Since
the Ru and Ir catalysts are available in both enantiomeric
forms, all four stereoisomers of hexahydrofarnesol are
accessible from the same farnesol isomer by proper choice
of the configuration of the two catalysts.
In summary, we have shown two efficient and flexible
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catalyst with different geometrical isomers of the substrate, all
possible stereoisomeric products can be prepared in high
enantiomeric purity. Alternatively, if the substrate contains
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=
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Experimental Section
Iridium-catalyzed hydrogenation of farnesol: Under a nitrogen
atmosphere, (2E,6E)-farnesol (2) (2.22 g, 10 mmol) and [Ir{(S)-1c}-
(cod)]BArF (16 mg, 0.01 mmol) were dissolved in dichloromethane
(25 mL) in an autoclave (120 mL) equipped with an overhead stirrer.
The autoclave was pressurized with H2 (50 bar) and the solution was
stirred at 700 rpm for 12 h at room temperature (H2 was supplied
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