Asymmetric catalysis in fragrance chemistry: a new synthetic approach to enantiopure Phenoxanol, Citralis and Citralis Nitrile

Article abstract of DOI:10.1016/j.tetasy.2007.03.014

A new approach to the synthesis of the single stereomers of the fragrances Phenoxanol, Citralis and Citralis Nitrile is reported. The key step of the synthesis is the asymmetric hydrogenation of (Z)- or (E)-3-methyl-5-phen

Full text of DOI:10.1016/j.tetasy.2007.03.014

Tetrahedron: Asymmetry 18 (2007) 797–802
Asymmetric catalysis in fragrance chemistry: a new synthetic
approach to enantiopure Phenoxanolꢀ, Citralisꢀ and Citralis Nitrileꢀ
Ugo Matteoli,* Alessandra Ciappa, Sara Bovo, Matheo Bertoldini and Alberto Scrivanti
`
Dipartimento di Chimica, Universita di Venezia, Dorsoduro, 2137, 30123 Venice, Italy
Received 9 March 2007; accepted 13 March 2007
Abstract—A new approach to the synthesis of the single stereomers of the fragrances Phenoxanolꢀ, Citralisꢀ and Citralis Nitrileꢀ is
reported. The key step of the synthesis is the asymmetric hydrogenation of (Z)- or (E)-3-methyl-5-phenyl-pent-2-en-1-ol, which leads
to the single enantiomers of Phenoxanolꢀ from which both enantiomers of Citralisꢀ are obtained by oxidation. Treatment of these com-
pounds with hydroxylamine finally led to Citralis Nitrileꢀ without any loss of enantiopurity. The odour profiles of the single enantiomers
of these fragrances are reported as well.
ꢁ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Odorants displaying floral notes (rose, jasmine, lily-of-the
valley, etc.6) are of particular interest for the fragrance
industry, as they are very much appreciated and widely
used. 3-Methyl-5-phenyl-pentan-1-ol (Phenoxanolꢀ, IFF,
Fig. 1), 3-methyl-5-phenyl-pentanaldehyde (Citralisꢀ,
Innospec, Fig. 1) and 3-methyl-5-phenyl-pentanenitrile
(Citralis Nitrileꢀ, Innospec, Fig. 1) are three synthetic
fragrances, which belong to the floral odorants domain
being reminiscent, albeit with some differences, of rose,
lily-of-the-valley and citrus. All three of these molecules
have a stereogenic centre but the odour profiles of the sin-
gle enantiomers have not yet been reported.
An answer to the continuing quest for new odour profiles
by the fragrance industry can come not only from the cre-
ation of new olfactory active molecules, but also by the
synthesis of the single stereomers of already known odor-
ants which until now has been used as racemic or diastero-
meric mixtures.1–3 As a matter of fact, ‘our sense of smell is
enantioselective’ so that the opposite enantiomers of an
odorant may show odour profiles different both in quality
and in intensity.1–3 Accordingly, the synthesis of fragrances
in highly enantiomerically enriched form and the evalua-
tion of their odour properties is currently of great interest.
Further interest is due to environmental concerns regarding
the increasing use of these compounds in many formula-
tions, from fine fragrances to household products. Differ-
ent odorants have been found in the sediments of lakes,
and even in living creatures;4 accordingly, next year legal
restrictions will apply to some fragrance ingredients in
the European Union and Switzerland.5 The manufacture
and use of the most olfactory active stereomer of a fra-
grance, instead of its racemic mixture, might be enough
to achieve the desired scent of a formulation and could
contribute to lower the amount of these compounds finally
dispersed in the environment.
CHO
Ph
Phenoxanol
OH
*
Ph
Citralis
*
CN
Ph
*
Citralis Nitrile
Figure 1. Chemical structures of Phenoxanolꢀ, Citralisꢀ and Citralis
Nitrileꢀ.
Transition-metal asymmetric catalysis is among the most
powerful tools available for the synthesis of enantiomeri-
cally enriched substances on a practical scale,7 and our
group has been involved for years in the research of the
application of homogeneous asymmetric catalysis pro-
cesses to the synthesis of enantiomerically enriched
*
Corresponding author. Tel.: +39 0412348572; fax: +39 0412348967;
e-mail: matteoli@unive.it
0957-4166/$ - see front matter ꢁ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.03.014

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U. Matteoli et al. / Tetrahedron: Asymmetry 18 (2007) 797–802
fragrances.8 Herein we report
a
new approach to
of NaH to give the a,b-unsaturated ester 5 (50% yield),
which was then reduced with DIBAL15 (45% total yield,
Scheme 3).
the enantioselective synthesis of Phenoxanolꢀ, Citralisꢀ and
Citralis Nitrileꢀ based on the catalytic asymmetric hydro-
genation of 3-methyl-5-phenyl-pent-2-en-1-ol (see Scheme
1); the evaluation of the odour profiles of the single stereo-
mers is also reported. It is worth mentioning that the (R)-
isomer of Phenoxanolꢀ has been prepared in 82% ee by
Brenna et al.9 through an enzymatic approach, while previ-
ous syntheses of enantiomerically enriched Citralis Nitrileꢀ
have been described by Pfaltz10 (ee up to 70%, by a cobalt
catalyzed asymmetric reduction of (E)- or (Z)-3-methyl-5-
phenyl-pentenenitrile with NaBH4), and by our group8d
(ee up to 98% via asymmetric hydrogenation of 2-pheneth-
ylacrylic acid).
O
O
(EtO)2P(O)CH2CO2Et
Ph
Ph
OEt
OH
Ph
NaH / THF
5
4
DIBAL
6
Scheme 3. Preparation of (E)-3-methyl-5-phenyl-pent-2-en-1-ol.
H2
The stereogenic centre is then formed by the asymmetric
hydrogenation of allylic alcohols 3 and 6, which are both
tri-substituted weakly coordinating functionalized olefins.
For the enantioselective hydrogenation of this type of sub-
strate, the literature suggests the use of chiral catalysts
based on iridium,16 or ruthenium.11,17
Ph
OH
Ph
Ph
OH
Phenoxanol
*
Cat.*
Oxdn.
NH2OH
CN
Citralis Nitrile
Scheme 1. Synthetic approach.
CHO
Ph
*
*
Among the iridium species which have been successfully
used in the asymmetric hydrogenation of allylic alcohols,
the ones containing chiral phosphooxazolines developed
by Pfaltz16a appear particularly well suited at being able
to give ees up to 97%16b (see Fig. 2).
Citralis
2. Results and discussion
+
-
The devised synthesis has as the key step the asymmetric
hydrogenation of (Z)- or (E)-3-methyl-5-phenyl-pent-2-
en-1-ol to give enantiomerically enriched Phenoxanol,
which is, then, oxidized to Citralis which is in turn trans-
formed in Citralis Nitrile (Scheme 1).
CF3
O
Ph2P
N
Ir
F3C
B
4
Since asymmetric hydrogenation usually requires stereo-
chemically well defined substrates in order to be carried
out with high asymmetric inductions,8b,11 two different ap-
proaches were adopted in order to prepare diastereopure
(Z)- or (E)-3-methyl-5-phenyl-pent-2-en-1-ol. To obtain
the (Z)-isomer, commercial 2-butyn-1-ol 1 was treated with
Red-Alꢀ and then with I2 to give (Z)-3-iodo-2-buten-1-ol 2
(91% yield).12 Negishi coupling of 2 with (2-phenyl-
ethyl)lithium13 afforded pure (Z)-3-methyl-5-phenyl-pent-
2-en-1-ol 3 (55% yield, Scheme 2).
Figure 2. Structure of [Ir-(S)-PHOX].
The asymmetric hydrogenation of 3 in the presence of
[Ir((S)-2-(o-diphenylphosphinophenyl)-3-tert-butyl-oxazo-
line)COD](BARF) ([Ir-(S)-PHOX]) proceeded with com-
plete chemoselectivity; using 2% of catalyst, total substrate
hydrogenation was observed after 21 h in all the experi-
ments carried out (see Scheme 4 and Table 1).
Ph
A preliminary experiment carried out at room temperature
under 10 atm of hydrogen showed that [Ir-(S)-PHOX]
afforded (R)-Phenoxanol as the prevailing stereomer in
about 67% ee (entry 1 of Table 1).
1. ZnCl2
1. Red-Al
2. I2
I
2. PhCH2CH2Li, Pd
OH
While aiming at raising the enantioselectivity, two other
experiments were carried out at room temperature, increas-
ing the hydrogen pressure to 50 and then up to 100 atm
(entries 1–3 of Table 1). Unfortunately, the asymmetric
induction turned out to be almost insensitive to the hydro-
gen pressure so that these experiments did not lead to
OH
OH
3
1
Scheme 2. Preparation of (Z)-3-methyl-5-phenyl-pent-2-en-1-ol.
On the other hand, (E)-allyl alcohol 6 was prepared by a
Horner–Wadsworth–Emmons reaction14 by reacting benz-
ylacetone with triethyl phosphonoacetate in the presence
significant improvements, even though
a maximum
enantioselectivity is obtained working at 50 atm. The influ-

U. Matteoli et al. / Tetrahedron: Asymmetry 18 (2007) 797–802
799
these molecules, the results appear somewhat disappoint-
ing, in particular when compared with the very high
asymmetric inductions attained by Pfaltz when using [Ir-
PHOX] catalysts in the hydrogenation of prochiral allyl
alcohols.16a
[Ir-(S)-PHOX]
Ph
Ph
OH
H2
(R)-7
3
OH
[Ir-(S)-PHOX]
A possible explanation can be found by taking into account
the structural differences between Pfaltz’s and our sub-
strates. In fact, the allyl alcohols studied by Pfaltz have
as a common structural feature, a phenyl ring conjugated
with the C@C double bond: in our opinion, such a combi-
nation of moieties could contribute to enhance the selectiv-
ity of the interaction of the substrates with the catalytic
centre and hence the enantioselectivity of the process. In-
deed, the literature reveals that asymmetric inductions
not greater than 68% have been obtained by using [Ir-
(S)-PHOX] to hydrogenate olefinic diols in which the
C@C double bond is not conjugated with aromatic
moieties.18
Ph
OH
Ph
OH
H2
6
(S)-7
Scheme 4. Asymmetric hydrogenation of 3 and 6 catalyzed by [Ir-(S)-
PHOX].
Table 1. Asymmetric hydrogenation of 3 and 6 in the presence of [Ir-(S)-
PHOX]a
Entry
Substrate
T (ꢂC)
P(H2) (atm)
eeb
Config.
1
2
3
4
5
6
3
3
3
3
3
6
23
23
23
0
60
23
10
50
100
100
100
50
67.5
69.0
66.0
46.0
67.0
64.4
(R)
(R)
(R)
(R)
(R)
(S)
While attempting to obtain better enantioselectivities, we
turned our attention to ruthenium based catalysts. In fact,
ruthenium complexes in combination with atropisomeric
diphosphines are exceedingly good catalysts for the asym-
metric hydrogenation of allylic alcohols as confirmed by
many examples reported in the literature.17
a Reaction conditions: substrate: 0.57 mmol; cat.: 1.14 · 10ꢀ2 mmol; sub-
strate/cat. = 50:1; solvent: CH2Cl2 (10 mL); t = 21 h.
b Determined by chiral GLC on the corresponding aldehydes.
ence of the temperature is shown in entries 3–5, Table 1: on
increasing the temperature to 60 ꢂC an almost negligible in-
crease in the enantioselectivity is observed; conversely, the
enantioselectivity dramatically decreased when lowering
the temperature from 23 to 0 ꢂC. This is a quite unusual
behaviour; however, it should be noted that a similar trend
has previously been reported by Pfaltz16d and also by us8d
when using Ir-PHOX catalysts.
In order to verify the usefulness of ruthenium catalysts in
the asymmetric hydrogenation of 3 and 6, we used a cata-
lyst prepared in situ by reacting [Ru(C6H6)Cl2]2 with an
(R)- or (S)-BINAP (ligand/complex = 2:1 molar ratio).19
The relevant data are collected in Table 2.
In all the experiments, the asymmetric inductions were very
high (ee >96%) thus demonstrating the practical applica-
bility of the devised synthetic approach. Using the ruthe-
nium catalytic system, the reaction is slower than in the
presence of the iridium catalyst; however, by increasing
the reaction time it is possible to attain total conversion
of the olefin, maintaining complete chemoselectivity.
Attempting to obtain higher reaction rates, 95% aqueous
methanol was used as the solvent, as suggested in the liter-
ature;17c however, no increase in the reaction rate was no-
ticed and even worse the enantioselectivity decreased (entry
2 of Table 2).
No improvement was obtained when using (E)-allylic alco-
hol 6 instead of (Z)-isomer 3 (entry 6): starting from 6, (S)-
Phenoxanol is obtained as the prevailing stereomer (64.4%
ee).
The inversion of the configuration of the prevailing enan-
tiomer on changing the stereochemistry of the C@C double
bond is a well known phenomenon8b,11 in asymmetric
hydrogenation and it is one of the compelling reasons to
use stereochemically pure unsaturated substrates. Even
though the above enantioselectivities might be considered
interesting, owing to the peculiar type of application of
As shown in Scheme 5, using (S)-BINAP, the hydrogena-
tion of (Z)-allyl alcohol 3 led to (S)-7 as the prevailing
Table 2. Asymmetric hydrogenation of 3 and 6 in the presence of the Ru/BINAP systema
Entry
Substrate
Ligand
Solv.
t (h)
Conv.b (%)
eec (%)
Config.
1
2
3
4
5
6
3
3
3
3
6
6
(S)-BINAP
(S)-BINAP
(S)-BINAP
(R)-BINAP
(S)-BINAP
(R)-BINAP
MeOH
aq MeOHd
MeOH
MeOH
MeOH
MeOH
21
21
48
48
48
48
48
40
100
100
100
100
97
86
97
96
97
98
(S)
(S)
(S)
(R)
(R)
(S)
a Reaction conditions: substrate: 0.57 mmol; (R)- or (S)-BINAP: 1.14 · 10ꢀ2 mmol; [Ru(C6H6)Cl2]2: 0.57 · 10ꢀ2 mmol; substrate/ruthenium = 50:1;
solvent: 10 mL, T = 23 ꢂC, P(H2) = 100 atm.
b Determined by GLC.
c Determined by chiral GLC on the corresponding aldehydes.
d 95% aqueous methanol.

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U. Matteoli et al. / Tetrahedron: Asymmetry 18 (2007) 797–802
H2, Ru-(S)-BINAP
Ph
Ph
OH
(S)-7
3
OH
H2, Ru-(R)-BINAP
H2, Ru-(S)-BINAP
Ph
OH
Ph
OH
(R)-7
6
Scheme 5. Asymmetric hydrogenation of 3 and 6 in the presence of the [Ru(C6H6)Cl2]2/BINAP catalytic system.
stereomer, instead the hydrogenation of the (E)-isomer
gives (R)-7. Accordingly, it is possible to obtain in high
enantiomeric purity, both enantiomers of 7 by choosing
the configuration either of the substrate or of the ligand
(Scheme 5). It is worth noting that in order to determine
the ees by chiral GLC (Chiraldex G-TA capillary column)
it was necessary to oxidize (R)-7 or (S)-7 to the correspond-
ing aldehydes (R)-8 or (S)-8 (Scheme 6) thus demonstrating
the feasibility of this step of our synthetic approach.
tonality’ (odour threshold: 5.0 ng/L air); (R)-(+)-Citralis is
‘very close to racemic Citralis, and stronger than its anti-
pode; aldehydic, fresh, floral, citronellal-like odour, remi-
niscent of verbena and lemongrass; a somewhat slightly
latex and plastic connotation is present as well’ (odour
threshold: 2.5 ng/L air); (S)-(ꢀ)-Citralis is ‘citronellal-like,
floral-aldehydic, but less fresh, more fruity in the direction
of red fruits, and with a fatty-rosy undertone that some-
what even reminds of Phenoxanol’ (odour threshold:
7.9 ng/L air); (S)-(+)-Citralis Nitrile is ‘typical citrus, rem-
iniscent of lemon peel and geranyl nitrile, with fresh, fruity
and slightly green nuances’ (odour threshold: 12.5 ng/L
air); (R)-(ꢀ)-Citralis Nitrile is ‘similar in smell, but slightly
stronger, and with additional waxy aspects, and a more
pronounced green, leafy side’ (odour threshold: 6.8 ng/L
air).
PCC
CHO
*
Ph
OH
Ph
*
CH2Cl2
(R)- or (S)- Citralis
(R)- or (S)- Phenoxanol
Scheme 6.
Indeed, in the presence of pyridinium chlorochromate, the
oxidation of alcohol 720 proceeds on a preparative scale
affording the desired Citralis in 90% yield (Scheme 6).
The final transformation of Citralis into Citralis Nitrile
was accomplished by treating the aldehydes with NH2OHÆ
HCl in the presence of NaI and CH3CN (Scheme 7), as
described by Ballini et al.21 (43% yield).
4. Conclusion
In conclusion the devised synthetic scheme allowed us to
obtain the single enantiomers of three different floral fra-
grances: Phenoxanolꢀ, Citralisꢀ and Citralis Nitrileꢀ in
very high enantiopurity. The synthesis appears convenient
since with a single enantioselective transformation it is pos-
sible to obtain three different fragrances. The Ru/BINAP
system prepared in situ appears very versatile allowing us
to prepare the sought after enantiomer by choosing the
configuration of either the olefin or the ligand.
NH2OH
CN
(R)- or (S)-9
CHO
(R)- or (S)-8
Ph
*
Ph
*
NaI, CH3CN
Scheme 7.
It was thus possible to evaluate the odour profiles of the
single stereomers of the three fragrances: even if no partic-
ularly striking differences were perceived, it is worth to note
that whatever the fragrance, one of the enantiomers is al-
ways stronger. It is also interesting to note that the (S)-Phe-
noxanol presents an olfactory activity not only more
intense than its opposite but also more complex and inter-
esting olfactive notes.
3. Odour profiles evaluation
Enantiopure samples of 7, 8 and 9 were submitted to a
panel of skilled perfumers (Givaudan) for the evaluation
of the odour profiles. The following descriptions were ob-
tained: (R)-(+)-Phenoxanol is ‘reminiscent of racemic Phe-
noxanol, but weaker. Its rose character is harsher, fattier
and more metallic compared to the racemate and its anti-
pode’ (odour threshold: 12.5 ng/L air); (S)-(ꢀ)-Phenoxa-
nolꢀ is ‘also reminiscent of a typical Phenoxanol note,
but stronger; softer, with a more powdery rose character
of pronounced floralcy with fruity facets in the direction
of red fruits and rhubarb, and a fresh even slightly aquatic
5. Experimental
5.1. General methods
Commercial solvents (J. T. Baker) were dried according to
literature methods.22 (S)- and (R)-BINAP were kindly sup-

U. Matteoli et al. / Tetrahedron: Asymmetry 18 (2007) 797–802
801
plied by Rhodia Phosphines UK. Anhydrous ZnCl2 was
prepared by treating commercial ZnCl2 according to a
literature method.23 [Ir((S)-2-(o-diphenylphosphinophenyl)-
3-tert-butyl-oxazoline)COD](BARF)16a and [Ru(C6H6)-
anhydrous CH2Cl2 contained in a small Schlenk flask were
added 100 mg (0.57 mmol) of (Z)-3-methyl-5-phenyl-pent-
2-en-1-ol under an inert atmosphere. The resulting solution
was transferred via cannula into a 150 mL stainless steel
autoclave which was then pressurized with 50 atm of H2,
and heated at 60 ꢂC by means of a thermostatic bath.
The system was kept under stirring for 21 h, then the resid-
ual gas vented off. The solvent was evaporated off and the
solid residue dissolved in n-pentane/diethyl ether (50:50),
and the solution passed through a short silica plug to
remove the catalyst. After solvent elimination, 98.0 mg
(96.5% yield) of (R)-7 (69.0% ee) were obtained as a yellow
oil.
24
Cl2]2 were prepared as described in the literature. All
other reagents were available from commercial sources (Al-
drich) and used without further purification, unless other-
wise noted. Flash-chromatographies were performed on
MN Kieselgel 60, 70–230 mesh. Yields refer to isolated
compounds of greater than 95% purity, as estimated by
1
GLC, and H NMR. All compounds were characterized
by 1H NMR, 13C NMR and mass spectrometry. 1H
NMR and 13C NMR spectra were recorded on a Bruker
Avance AC300 spectrometer operating at 300.213 and
75.44 MHz, respectively. GLC analyses were performed
on an Agilent 6850 gas chromatograph with a FID detec-
tor. GC–MS analyses were performed on a Hewlett-Pack-
ard 5890 SERIES II gas chromatograph interfaced with
an HP 5971 quadrupole mass detector. Enantiomeric ex-
cesses (ee) were determined by chiral GLC using a Chiral-
dex G-TA column (50 m · 0.25 mm) installed on a Agilent
6850 gas chromatograph with a FID detector. Optical rota-
tions (a) were determined using a Perkin–Elmer 241 polari-
meter (Na lamp at 25 ꢂC).
5.3.2. In the presence of the [Ru(C6H6)Cl2]2–BINAP cata-
lyst. In a typical experiment (entry 6 of Table 2), 10 mL
of anhydrous methanol was introduced in a small Schlenk
flask, which was then evacuated and filled with nitrogen.
Under a nitrogen flow were then added 7.1 mg (11.4 ·
10ꢀ3 mmol) of (R)-BINAP, 2.9 mg (5.7 · 10ꢀ3 mmol) of
[Ru(C6H6)Cl2]2 and 100 mg (0.57 mmol) of (E)-3-methyl-
5-phenyl-pent-2-en-1-ol to give a pale yellow solution
which was transferred via cannula to a 150 mL stainless
steel autoclave. The reactor was pressurized with 100 atm
of H2, and kept at 23 ꢂC under stirring by means of a ther-
mostatic bath. After 48 h, the residual gas was vented off,
the solvent evaporated and the solid residue dissolved in
diethyl ether. The resulting solution was passed through a
short silica plug to remove the catalyst. After solvent elim-
ination, 100.6 mg (99.0% yield) of (S)-7 were obtained
5.2. Synthesis of the unsaturated alcohols 3 and 6
5.2.1. (Z)-3-Iodo-2-buten-1-ol. Compound 2 was obtained
as a pale yellow oil in 91% yield according to a literature
1
method.12 The GC–MS and H NMR data were identical
to those reported in the literature. 13C NMR (CDCl3): d
1
33.6, 67.3, 102.3, 134.1.
(98.0% ee) as a yellow oil. The GC–MS and H NMR
data20 of (R)- or (S)-7 were identical to those reported in
the literature. 13C NMR (CDCl3): d 19.5, 29.2, 33.3, 39.0,
39.7, 61.0, 125.6, 128.26, 128.28, 142.8. The enantiomeric
excesses of (R)- or (S)-7 were determined by chiral GC
5.2.2. (Z)-3-Methyl-5-phenylpent-2-en-1-ol. Compound 3
was prepared as described by Negishi13 by reaction of the
lithium derivative of (2-iodoethyl)benzene25 with the zinc
derivative of 2. Olefin 3 was isolated as a pale yellow oil
in 55% yield. The GC–MS and 1H NMR data26 were iden-
tical to those reported in the literature.13C NMR (CDCl3):
d 23.3, 33.9, 34.2, 58.9, 125.2, 126.1, 128.3, 128.6, 138.4,
141.7.
after their oxidation to the corresponding aldehydes
25
with pyridinium chlorochromate (see below). ½aꢁD ¼ ꢀ14:7
25
(c 5, CH2Cl2); (S)-(ꢀ)-3-methyl-5-phenyl-pentanol. ½aꢁ
¼
þ14:5, (c 5, CH2Cl2); (R)-(+)-3-methyl-5-phenyl-pentaDnol.
5.2.3.
(E)-Ethyl-3-methyl-5-phenylpent-2-enoate. Com-
5.4. Synthesis of fragrances 8 and 9
pound 5 was prepared in 50% yield as described by Buch-
wald.14 The spectral data were identical to those reported
in the literature.
5.4.1. (R)- and (S)-3-Methyl-5-phenyl-pentanaldehyde.
Compound (R)- or (S)-8, was obtained by treating a dichlo-
romethane solution of (R)- or (S)-7 with an excess of pyrid-
inium chlorochromate; after removal of the solvent, the
residue was diluted with diethyl ether and filtered through
a short plug of silica gel to afford a pale yellow oil (90%
yield). MS (m/z): 176 [M]+; 158, 143, 131, 117, 105,
5.2.4. (E)-3-Methyl-5-phenylpent-2-en-1-ol. Compound 6
was obtained by reduction of ester 5 in the presence of DI-
BAL as described for the synthesis of (E)-3-phenyl-2-bu-
ten-1-ol.15 Olefin 6 was isolated as a pale yellow oil (90%
1
1
yield). The GC–MS and H NMR data26 were identical
91. H NMR (CDCl3): d 1.04 (d, 3H, CH3, J = 6.8 Hz);
to those reported in the literature. 13C NMR (CDCl3): d
16.4, 34.3, 41.4, 59.3, 123.8, 125.8, 128.29, 128.34, 139.2,
141.9.
1.63 (m, 2H, CH2); 2.06–2.17 (m, 1H, CH), 2.24–2.33 (m,
1H, CH2); 2.41–2.49 (m, 1H, CH2); 2.55–2.73 (m, 2H,
CH2); 7.16–7.31 (m, 5H, arom.); 9.75 (t, 1H, CHO,
J = 2.1 Hz). 13C NMR (CDCl3): d 19.8, 27.8, 33.2, 38.6,
50.9, 61.0, 125.8, 128.3, 128.4, 142.0, 202.7. Chiral GC con-
ditions: Chiraldex G-TA column, T = 110 ꢂC (isotherm);
5.3. Enantioselective hydrogenations
5.3.1. In the presence of [Ir-(S)-PHOX]. In a typical
experiment (entry 1 of Table 1), to a solution of
[Ir((S)-2-(o-diphenylphosphinophenyl)-3-tert-butyl-oxazo-
line)(COD)]BARF (17.68 mg, 0.0114 mmol) in 10 mL of
nitrogen flow = 3.5 mL/min; tR = 47.03 min (S); tR =
25
47.61 min (R). ½aꢁD ¼ ꢀ23:2 (c 1, CH2Cl2); (S)-(ꢀ)-3-
25
methyl-5-phenyl-pentanaldehyde; ½aꢁD ¼ þ22:9 (c 1, CH2-
Cl2); (R)-(+)-3-methyl-5-phenyl-pentanaldehyde.

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U. Matteoli et al. / Tetrahedron: Asymmetry 18 (2007) 797–802
11. Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akuta-
gawa, S.; Inoue, S.; Kasahara, I.; Noyori, R. J. Am. Chem.
Soc. 1987, 109, 1596.
12. (a) Dakoji, S.; Li, D.; Agnihotri, G.; Zhou, H.; Liu, H. J. Am.
Chem. Soc. 2001, 123, 9749; (b) Blanchette, M. A.; Malamas,
M. S.; Nantz, M. H.; Roberts, J. C.; Somfai, P.; Whritenour,
D. C.; Masamune, S. J. Org. Chem. 1989, 54, 2817.
13. Negishi, E.; Ay, M.; Gulevich, Y. V.; Noda, Y. Tetrahedron
Lett. 1993, 34, 1437.
5.4.2. (R)- or (S)-3-Methyl-5-phenyl-pentanenitrile. Com-
pound (R)- or (S)-9, was obtained by treatment of (R)- or
(S)-8 with NH2OHÆHCl in the presence of a catalytic
amount of NaI according to the method developed by Bal-
1
lini et al.21 (90% yield). The GC–MS and H NMR data27
of (R)- or (S)-9 were identical to those reported in the liter-
ature. 13C NMR (CDCl3): d 19.3, 24.5, 29.9, 33.0, 37.5,
118.7, 126.0, 128.2, 128.5, 141.3. Chiral GC conditions:
Chiraldex GT-A column, T = 120 ꢂC (isotherm), nitrogen
14. Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473.
flow = 3.5 mL/min, tR = 63.79 min (S), tR = 64.96 min
25
´
`
15. Martın, R.; Islas, G.; Moyano, A.; Pericas, M. A.; Riera, A.
(R). ½aꢁD ¼ þ2:4 (c 2.2, EtOH); (S)-(+)-3-methyl-5-phen-
25
Tetrahedron 2001, 57, 6367.
yl-pentanenitrile; ½aꢁD ¼ ꢀ2:3 (c 2.2, EtOH); (R)-(ꢀ)-3-
16. (a) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int.
Ed. 1998, 37, 2897; (b) McIntyre, S.; Ho¨rmann, E.; Menges,
F.; Smidt, S. P.; Pfaltz, A. Adv. Synth. Catal. 2005, 347, 282;
(c) Hedberg, C.; Ka¨llstro¨m, K.; Brandt, P.; Hansen, L. K.;
Andersson, P. G. J. Am. Chem. Soc. 2006, 128, 2995; (d)
Pfaltz, A.; Blankenstein, J.; Hilgraf, R.; Ho¨rmann, E.;
McIntyre, S.; Menges, F.; Scho¨nleber, M.; Smidt, S. P.;
methyl-5-phenyl-pentanenitrile.
Acknowledgements
Rhodia UK Ltd—Phosphorus Specialties and Derivatives
is acknowledged for generously supplying the BINAP
ligands. Dr. P. Kraft, Mr. A. Alchenberger, Mr. A. Vink-
snaitis and Mr. K. Grman from Givaudan AG are kindly
acknowledged for all the olfactory evaluations. The work
has been performed with the Financial Support of the
MIUR (COFIN 2004).
Wustenberg, B.; Zimmermann, N. Adv. Synth. Catal. 2003,
¨
345, 33; (e) Ka¨llstro¨m, K.; Andersson, P. G. Tetrahedron
Lett. 2006, 47, 7477; (f) Bell, S.; Wustenberg, B.; Kaiser, S.;
¨
Menges, F.; Netscher, T.; Pfaltz, A. Science 2006, 311, 642;
(g) Fan, Y.; Cui, X.; Burgess, K.; Hall, M. B. J. Am. Chem.
Soc. 2004, 126, 16688; (h) Perry, M. C.; Cui, X.; Powell, M.
T.; Hou, D.-R.; Reibenspies, J. H.; Burgess, K. J. Am. Chem.
Soc. 2003, 125, 113.
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