A new enantioselective catalytic route to Florhydral

Article abstract of DOI:10.1055/s-2008-1067167

The valuable fragrance Florhydral [3-(3-isopropylphenyl)butanal] has been synthesized in almost enantiomerically pure form by a new catalytic route. The key step of the process is the enantioselective hydrogenation of (E)-3-(3-isopropylphenyl)but-2-en-1-ol, which is carried out with asymmetric inductions of up to 97% using an iridium-phosphinooxazoline chiral catalyst. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067167

PAPER
2547
A New Enantioselective Catalytic Route to Florhydral®
®
E
nantioselecti
a
r
s
of Floh
a
ydra
l
Bovo, Alberto Scrivanti, Matteo Bertoldini, Valentina Beghetto, Ugo Matteoli*
Dipartimento di Chimica, Università di Venezia, Calle Larga S. Marta 2137, 30123 Venezia, Italy
Fax +39(041)2348967; E-mail: matteoli@unive.it
Received 15 April 2008; revised 29 April 2008
tem,8 so that in the future also environmental concerns
will prompt to use stereochemically enriched fragrances.9
Manufacture and use of only the most olfactorily active
stereoisomer of a perfumery raw material, instead of the
Abstract: The valuable fragrance Florhydral® [3-(3-isopropylphe-
nyl)butanal] has been synthesized in almost enantiomerically pure
form by a new catalytic route. The key step of the process is the
enantioselective hydrogenation of (E)-3-(3-isopropylphenyl)but-2-
en-1-ol, which is carried out with asymmetric inductions of up to racemate, could lead to a lower consumption and disper-
97% using an iridium-phosphinooxazoline chiral catalyst.
sion of these compounds in the environment.
Florhydral® [3-(3-isopropylphenyl)butanal, 4] marketed
Key words: enantioselective hydrogenation, asymmetric catalysis,
iridium, fragrance asymmetric synthesis, chiral fragrances
by Givaudan, is a floral odorant widely used to convey at
once fresh and marine long lasting notes. Fuganti and co-
workers have been successful in synthesizing a single
enantiomer of Florhydral® by an enzymatic approach.
Evaluation of the odor profiles of the two enantiomers
showed that, even if they have similar olfactory notes, the
S-enantiomer is much more powerful as its odor threshold
is 25 times lower than that of the opposite enantiomer.10
Spurred by our interest in developing practical synthetic
routes to enantiomerically enriched fragrances,11,12 we
were interested to develop an enantioselective catalytic
route to this valuable fragrance.
Nowadays flavors and fragrances are increasingly synthe-
sized as enantiomerically pure compounds.1,2 Different
motivations stimulate chemists to devise stereoselective
syntheses for fragrances. Most importantly, the use of a
single stereoisomer of already known odorants until now
used as racemic or diastereomeric mixtures may be an an-
swer to the continuing quest of new odorants by perfur-
mers.3–7 Impetus to develop stereoselective syntheses of
odorants also comes from commercial considerations
since stereoselective processes may be protected by new
patents. Furthermore, many odorants are hardly biode-
graded and have been found to accumulate in the ecosys-
The three different routes outlined in Scheme 1 were rec-
ognized as the most promising. They all have the ketone 1
O
1
HWE
O
O
*
OEt
OH
cat.*
DIBAL
isomerization
2
3
4
Florhydral®
H2, cat.*
H2, cat.*
O
oxidation
DIBAL
*
OH
*
OEt
5
6
Scheme 1
SYNTHESIS 2008, No. 16, pp 2547–2550
x
x.
x
x
.
2
0
0
8
Advanced online publication: 08.07.2008
DOI: 10.1055/s-2008-1067167; Art ID: Z08908SS
© Georg Thieme Verlag Stuttgart · New York

2548
S. Bovo et al.
PAPER
as the common precursor,13 which can be converted into
the unsaturated ester 2 (E/Z ratio >12:1 by 1H NMR spec-
troscopy) using a Horner–Wadsworth–Emmons olefina-
tion.
F3C
F3C
O
X
B
Ph2P
N
Ir
The first devised synthetic pathway entails the reduction
of 2 with diisobutylaluminum hydride (DIBAL) followed
by the catalytic asymmetric isomerization of the allyl al-
cohol 3, which is the key step of the process. Asymmetric
isomerization of olefins has been widely studied;14 in par-
ticular, excellent results have been obtained with allyl-
amines so that the process is applied in the industrial
production of (–)-menthol.14 It seems more difficult to
achieve high asymmetric inductions in the isomerization
of allylic alcohols.15 As a matter of fact, high enantiose-
lectivities have been obtained only in few cases: very
good results (ee values up to 92%) were obtained by Fu16
using rhodium/phosphaferrocene catalysts, and interest-
ing results were obtained also by Crévisy17 with a rhodi-
um/phosphoramidite catalyst (ee values up to 64%) and
by Ikariya18 with ruthenium catalysts (62–74% ee).
4
BARF
[Ir-(S)-PHOX]-1 : X– = BARF–
–
[Ir-(S)-PHOX]-2 : X– = PF6
Figure 1 Chiral catalysts used in the asymmetric hydrogenation
The hydrogenation of 2 in the presence of [Ir-(S)-PHOX]-
1 under 10 atm of H2 at 23 °C in CH2Cl2 furnishes (R)-5
with 27% ee (Table 1, entry 1). This modest but promising
asymmetric induction is accompanied by an unsatisfacto-
ry reaction rate, thus, with the aim of increase both the rate
and the enantioselectivity, the hydrogen pressure was
raised to 50 atm. Favorably, the enantioselectivity in-
creases to 75%, but the reaction rate still remains unsatis-
factory; a further increase of the hydrogen pressure to 100
atm does not lead to better results since both the olefin
conversion and the asymmetric induction are practically
unaffected. Also an increase of the temperature does not
significantly improve the reaction rate and adversely af-
fects the asymmetric induction. Finally, it should be men-
tioned that at 0 °C the reaction rate becomes unacceptable
without significant variation of the asymmetric induction.
The most used catalysts for C=C isomerization are cation-
ic rhodium complexes containing chiral diphos-
phines;15,16,19 accordingly we carried out some exploratory
experiments on the isomerization of 3 in the presence of
[Rh(COD)(R)-BINAP]ClO4.20 At 70 °C in THF, an allyl
alcohol conversion of 35% is attained after 24 hours; un-
fortunately, the chemoselectivity of the reaction is poor
and the yield in the sought fragrance is only 13%, because
under these conditions the formed aldehyde further reacts
to give aldol condensation by-products. Chiral GC shows
that the asymmetric induction is also only quite modest,
(R)-Florhydral® (4) being formed only in 17% ee. Aiming
to improve both the chemo- and the enantioselectivity, a
second experiment was carried out at 50 °C using a longer
reaction time (72 h). Indeed, the lower reaction tempera-
ture favorably affects the asymmetric induction and (R)-
Florhydral® (4) is obtained in 37% ee; however, both the
reaction rate (substrate conversion: 22%) and the
chemoselectivity (24%) remain low, so that this elegant
and atom efficient synthetic scheme was not further ex-
plored.
Table 1 Asymmetric Hydrogenation of 2 in the Presence of [Ir-(S)-
PHOX]-1
Entry
Temp
(°C)
P (H2)
(atm)
Time
(h)
Conv
(%)
ee
(%)a,b
1
2
3
4
5
23
23
23
50
0
10
50
24
24
24
24
72
38
47
54
52
33
27 (R)
75 (R)
72 (R)
66 (R)
77 (R)
100
50
50
Reaction conditions: substrate: 0.30 mmol, cat.: 0.012 mmol, sub-
strate/cat. = 25:1, solvent: CH2Cl2 (10 mL).
As an alternative synthetic approach we investigated the
asymmetric hydrogenation of 2 followed by the transfor-
mation of the ester moiety of 5 into the aldehydic group in
two steps: i) reduction of the ester group to give 6, and ii)
oxidation to aldehyde of the methylol moiety. The key re-
action is the enantioselective hydrogenation of 2. The
asymmetric hydrogenation of b-substituted cinnamic ac-
ids and their derivatives has been relatively unex-
plored,21,22 nevertheless, very good results have been
obtained in the asymmetric hydrogenation of b-methyl-
cinnamates using iridium cationic catalysts containing
P–N ligands.23–25 To assess the practical feasibility of this
synthetic scheme, the asymmetric hydrogenation of 2 was
carried out in the presence of [Ir-(S)-PHOX]-123
(Figure 1), which is easily accessible owing to the com-
mercial availability of the chiral ligand.
a The ee values were determined by chiral HPLC.
b The configuration of the prevailing enantiomer was attributed by
transforming 5 into 6 whose chiroptical properties are known.10
These results prompted us to investigate a different syn-
thetic approach since, even if the enantioselectivity ob-
tained might be regarded as suitable for the production of
a chiral fragrance, the reaction rates are so poor that the
process does not appear to be of practical interest.
We focused our studies on the 2 → 3 → 6 → 4 alternative
route in which the stereogenic centre is formed by the
asymmetric hydrogenation of the allylic alcohol 3.
Among the catalysts which have been successfully used in
the asymmetric hydrogenation of substituted allylic alco-
hols, the iridium-phosphinooxazoline cationic complexes
Synthesis 2008, No. 16, 2547–2550 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of Florhydral®
2549
31 mmol) diluted with THF (12 mL). The resulting orange solution
was kept under stirring for 24 h, then treated with H2O (15 mL), and
extracted with Et2O (3 × 60 mL). The combined organic phases
were washed with brine (30 mL) and dried (MgSO4). The solvents
were removed in vacuo to give 2 as a pale yellow oil (E/Z = 12:1),
which was purified by chromatography (silica gel, eluent: hexane–
EtOAc, 9:1); yield: 5.0 g (70%); colorless oil.
1H NMR (300 MHz, CDCl3): d = 7.20–7.35 (m, 4 Harom), 6.13 (q,
J = 1.2 Hz, 1 H, HC=), 4.22 (q, J = 7.1 Hz, 2 H, CH2O), 2.93 (sept,
J = 6.8 Hz, 1 H, CH), 2.58 (d, J = 1.2 Hz, 3 H, CH3), 1.32 (t, J = 7.1
Hz, 3 H, CH3), 1.27 (d, J = 6.8 Hz, 6 H, CH3).
[Ir-(S)-PHOX]-1 and [Ir-(S)-PHOX]-2 (Figure 1) emerge
as particularly efficient being able to furnish high reaction
rates and enantiomeric excesses higher than 90%.23 Seren-
dipitously, at 23 °C under 50 atm of H2 the hydrogenation
of 3 in the presence of 1.0 mol% of [Ir-(S)-PHOX]-1 fur-
nished (R)-6 in quantitative yield and 97% ee (chiral GC,
see below) confirming the great efficiency of this Pfaltz’s
catalyst in asymmetric hydrogenation of allylic alcohols.
For the sake of comparison, the hydrogenation of 3 was
carried out under the same reaction conditions using
[Ir-(S)-PHOX]-2; with this catalyst the reaction rate (38%
substrate conversion after 20 h) and the enantioselectivity
(90%) turned out to be significantly lower.
13C NMR (75 MHz, CDCl3): d = 14.3, 18.0, 23.8, 34.2, 59.8, 116.9,
123.9, 124.4, 127.1, 128.4, 142.3, 149.1, 156.0, 166.9.
MS (EI): m/z (%) = 232 ([M]+, 50), 217 (11), 187 (22), 171 (40),
144 (100), 128 (41), 115 (35), 91 (16).
The strong influence of the nature of the counter ion when
using iridium hydrogenation catalysts has been investigat-
ed by Pfaltz and co-workers.23 The higher reaction rates
and the higher asymmetric inductions are attributed to the
Anal. Calcd for C15H20O2: C, 77.55; H, 8.68. Found: C, 77.38; H,
8.84.
(E)-3-(3-Isopropylphenyl)-2-but-2-enol (3)
–
fact that BARF– is a weaker coordinating ion than PF6 ,
To a chilled (0 °C) solution of 2 (960 mg, 4.14 mmol) in Et2O (30
mL) was slowly added diisobutylaluminum hydride (8.3 mL of a
1.0 M solution in hexanes, 8.3 mmol). The resulting yellow solution
was kept overnight under stirring, diluted with Et2O (50 mL), and
then cautiously treated with 4 N HCl (30 mL) at 0 °C. The organic
phase was separated and the aqueous phase extracted with Et2O
(3 × 10 mL). The combined organic phases were dried (MgSO4),
filtered, and taken to dryness. The resulting pale yellow oil was pu-
rified by chromatography (silica gel, eluent: hexane–EtOAc, 9:1);
yield: 630 mg (80%); colorless oil.
moreover BARF– also appears to be more stable under the
reaction conditions.
Oxidation of alcohol (R)-6 with pyridinium chlorochro-
mate affords in almost quantitative yield (R)-4. We used
this reaction also to evaluate the enantiomeric purity of 6;
in fact, while it was not possible to separate the enantio-
mers of 6 in GC on a Chiraldex G TA column, the same
column resolves very well the enantiomers of 4.
1H NMR (300 MHz, CDCl3): d = 7.14–7.35 (m, 4 Harom), 5.99 (tq,
J = 1.3, 6.6 Hz, 1 H, CH), 4.39 (d, J = 6.6 Hz, 2 H, CH2), 2.94 (sept,
J = 6.9 Hz, 1 H, CH), 2.11 (d, J = 1.3 Hz, 3 H, CH3), 1.50 (br s, 1
H, OH), 1.28 (d, J = 6.9 Hz, 6 H, CH3).
13C NMR (75 MHz, CDCl3): d = 16.1, 24.0, 34.2, 60.0, 123.7, 124.9,
125.4, 126.3, 128.2, 138.3, 142.9, 148.8.
In conclusion, we have developed a new strategy for the
synthesis of almost enantiomerically pure Florhydral® (4);
the process might be of practical feasibility provided that
a more economical and sustainable synthesis of 3 shall be
developed.
MS (EI): m/z (%) = 190 ([M]+, 27), 175 (10), 147 (100), 129 (48),
115 (47), 105 (42), 91 (34), 77 (18).
All compounds were characterized by 1H NMR and 13C NMR spec-
1
troscopy and mass spectrometry. H NMR and 13C NMR spectra
Anal. Calcd for C13H18O: C, 82.06; H, 9.53. Found: C, 82.21; H,
9.77.
were recorded on a Bruker Avance AC 300 spectrometer operating
at 300.213 and 75.44 MHz, respectively. GC-MS analyses were
performed on a Hewlett-Packard 5890 SERIES II gas chromato-
graph interfaced with an HP 5971 quadrupole mass detector. GC
analyses were performed on an Agilent 6850 gas chromatograph
with a FID detector. The enantiomeric excesses were determined ei-
ther by chiral GC using a Chiraldex G-TA column (50 m × 0.25 mm
i.d.) installed on an Agilent 6850 gas chromatograph with a FID de-
tector or by chiral HPLC using a CHIRALCEL OD-H column
(250 × 4.6 mm i.d.) installed on an Agilent 1100 chromatograph
equipped with an UV detector. Optical rotations were determined
using a PerkinElmer 241 polarimeter (Na lamp at 20 °C).
Asymmetric Isomerization of 3
In a typical experiment, under N2 in a Schlenk-flask were intro-
duced a THF solution (6 mL) of 3 (200 mg, 1.05 mmol) and
{Rh[(R)-BINAP](COD)}ClO4 (4.9 mg, 0.0052 mmol). The reactor
was heated at 70 °C with a thermostatic bath and the mixture stirred
for 24 h. After cooling to r.t., the mixture was evaporated, diluted
with Et2O (10 mL) and filtered on a short silica column (eluent:
Et2O). GC-MS and GC analyses showed that the substrate conver-
sion was 35% and that the crude reaction product was composed of
38% of 4, 12% of a dehydration product, and about 50% of aldol
condensation by-products. Chiral GC (Chiraldex GT-A column,
T = 100 °C, N2: 3.5 mL/min; S-enantiomer: tR = 61.35 min, R-enan-
tiomer: tR = 61.94 min) showed that (R)-4 was present in 17% ee;
the configuration of the prevailing isomer was determined by pola-
rimetry comparing the optical rotation data with the value reported
in the literature.10
(S)-2-(o-Diphenylphosphinophenyl)-3-tert-butyloxazoline was pur-
chased from Strem; all other reagents were available from commer-
cial sources and were used without further purification. 1-(3-
Isopropylphenyl)ethanone,13 {Ir[(S)-2-(o-diphenylphosphinophe-
nyl)-3-tert-butyloxazoline]COD}(BARF),23a {Ir[(S)-2-(o-diphe-
nylphosphinophenyl)-3-tert-butyloxazoline]COD}(PF6)23a
{Rh[(R)-BINAP](COD)}ClO4 were prepared as described in the
and
20
literature.
Asymmetric Hydrogenation of 2 in the Presence of [Ir-(S)-
PHOX]-1
In a typical experiment (Table 1, entry 2), a magnetically stirred 150
mL stainless steel autoclave was charged with a CH2Cl2 solution (10
mL) containing 2 (70 mg, 0.30 mmol) and [Ir-(S)-PHOX]-1 (18.7
mg, 0.012 mmol) under an inert atmosphere The reactor was then
pressurized with H2 (50 atm) and kept under stirring at 23 °C. After
(E)-3-(3-Isopropylphenyl)but-2-enoic Acid Ethyl Ester (2)
Under N2, to a chilled (0 °C) solution of BuLi in n-hexane (12.5 mL
of a 2.5 M solution in hexanes, 31 mmol) were sequentially added:
anhyd THF (10 mL), triethyl phosphonoacetate (6 mL, 30 mmol di-
luted in 10 mL of THF), anhyd LiBr (8.07 g, 93 mmol, dissolved in
20 mL of THF) and finally 1-(3-isopropylphenyl)ethanone (1; 5.0 g,
Synthesis 2008, No. 16, 2547–2550 © Thieme Stuttgart · New York

2550
S. Bovo et al.
PAPER
24 h, the crude product was concentrated and the residue filtered on
a short silica column (eluent: Et2O–hexane, 1:1). GC-MS and GC
analyses showed that the crude material was a mixture of unreacted
2 (53%) and (R)-5 (47%) (75% ee by chiral HPLC: CHIRALCEL
OD-H column (250 × 4.6 mm i.d.) with n-hexane as eluent (1.0 mL/
min), UV detector, l = 266 nm; S-enantiomer: tR = 11.17, R-enan-
tiomer: tR = 27.7 min). The configuration of the prevailing enan-
tiomer was inferred by polarimetry. The mixture of 2 and 5 obtained
in the asymmetric hydrogenation was treated with DIBAL to give a
mixture of 3 and 6, shown to be levorotatory. Since Fuganti10 has re-
MS (EI): m/z (%) = 190 ([M]+, 25), 175 (5), 147 (100), 133 (30),
105 (76), 91 (47), 77 (13).
Anal. Calcd for C13H18O: C, 82.06; H, 9.53. Found: C, 82.33; H,
9.70.
Acknowledgment
This work has been performed with the Financial Support from the
MIUR (Cofin 2004).
20
ported an [a]D +16.6 (c = 1.25, CHCl3) for (S)-6, we concluded
that the prevailing enantiomer formed by asymmetric hydrogena-
tion of 2 is (R)-5. A sample of racemic 5 for the chiral HPLC anal-
yses was obtained by hydrogenation of 2 in the presence of 5%
Pd/C.
1H NMR (300 MHz, CDCl3): d = 7.05–7.30 (m, 4 Harom), 4.10 (q,
J = 7.1 Hz, 2 H, CH2O), 3.28 (m, 1 H, CH), 2.89 (sept, J = 6.9 Hz,
1 H, CH), 2.59 (m, 2 H, CH2), 1.32 (d, J = 6.9 Hz, 3 H, CH3), 1.27
(d, J = 6.9 Hz, 6 H, CH3), 1.21 (t, J = 7.1 Hz, CH3).
References
(1) Abate, A.; Brenna, E.; Dei Negri, C.; Fuganti, C.; Gatti, F.
G.; Serra, S. J. Mol. Catal. B: Enzym. 2004, 32, 33.
(2) Blaser, H. U.; Spindler, F.; Studer, M. Appl. Catal., A. Gen.
2001, 221, 119.
(3) Bentley, R. Chem. Rev. 2006, 106, 4099.
(4) Sell, C. S. In Perspectives in Flavor and Fragrance
Research; Kraft, P.; Swift, K. A. D., Eds.; Verlag Helvetica
Chimica Acta: Zurich, 2005, 67.
(5) Chapuis, C.; Jacoby, D. Appl. Catal., A: Gen. 2001, 221, 93.
(6) Abate, A.; Brenna, E.; Fuganti, C.; Gatti, F. G.; Serra, S. In
Perspectives in Flavor and Fragrance Research; Kraft, P.;
Swift, K. A. D., Eds.; Verlag Helvetica Chimica Acta:
Zurich, 2005, 55.
(7) Brenna, E.; Fuganti, C.; Serra, S. Tetrahedron: Asymmetry
2003, 14, 1.
(8) Peck, A. M.; Hornbuckle, K. C. Atmos. Environ. 2006, 40,
6101.
(9) Niederer, M.; Bollhalder, R.; Hohl, C. J. Chromatogr., A
2006, 1132, 109.
(10) Abate, A.; Brenna, E.; Dei Negri, C.; Fuganti, C.; Serra, S.
Tetrahedron: Asymmetry 2002, 13, 899.
(11) Matteoli, U.; Ciappa, A.; Bovo, S.; Bertoldini, M.; Scrivanti,
A. Tetrahedron: Asymmetry 2007, 18, 797.
(12) Scrivanti, A.; Bovo, S.; Ciappa, A.; Matteoli, U.
Tetrahedron Lett. 2006, 47, 9261.
(13) Paganelli, S.; Ciappa, A.; Marchetti, M.; Scrivanti, A.;
Matteoli, U. J. Mol. Catal. A: Chem. 2006, 247, 138.
(14) (a) Akutagawa, S.; Tani, K. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; Wiley-VCH: Weinheim, 2000,
145. (b) Akutagawa, S. In Chirality in Industry; Collins, A.
N.; Sheldrake, G. N.; Crosby, J., Eds.; Wiley: New York,
1992, Chap. 16, 325.
MS (EI): m/z (%) = 234 ([M]+, 33), 160 (100), 147 (68), 131 (37),
117 (14), 105 (17), 91 (21).
Asymmetric Hydrogenation of 3 in the Presence of [Ir-(S)-
PHOX]-1
In a typical experiment, a magnetically-stirred 150 mL stainless
steel autoclave was charged, under an inert atmosphere, with a
CH2Cl2 solution of 3 (100 mg, 0.53 mmol) and [Ir-(S)-PHOX]-1
(9.8 mg, 0.0063 mmol). The reactor was pressurized with H2 (50
atm) and kept under stirring at 23 °C. After 20 h, the residual gas
was vented off, GC analysis of the crude mixture showed complete
conversion of the substrate. The mixture was concentrated and the
residue filtered on a short silica gel column (eluent: Et2O–hexane,
1:1) to afford (R)-6 (97% ee, as determined by chiral GC after oxi-
dation to 4: Chiraldex GT-A column, T = 100 °C, N2: 3.5 mL/min;
S-enantiomer: tR = 61.35 min, R-enantiomer: tR = 61.94 min);
yield: 90 mg (90%); colorless oil; [a]D20 –16.5 (c 1.20, CHCl3). The
spectroscopic data and the [a]D value agree with the literature.10
1H NMR (300 MHz, CDCl3): d = 7.01 – 7.25 (m, 4 Harom), 3.58 (td,
J = 3.0, 6.6 Hz, 2 H, CH2O), 2.81–2.296 (m, 2 H, CH + CH), 1.86
(q, J = 7.1 Hz, 2 H, CH2), 1.28 (d, J = 7.1 Hz, 3 H, CH3), 1.25 (d,
J = 7.1 Hz, 6 H, CH3).
13C NMR (75 MHz, CDCl3): d = 22.3, 24.0, 34.1, 36.5, 41.0, 61.3,
124.0, 124.3, 125.2, 128.4, 146.8, 149.0.
MS (EI): m/z (%) = 192 ([M]+, 40), 159 (16), 147 (70), 131 (53),
117 (26), 105 (100), 91 (42).
(15) van der Drift, R. C.; Bouwman, E.; Drent, E. J. Organomet.
Chem. 2002, 650, 1.
(16) Tanaka, K.; Fu, G. C. J. Org. Chem. 2001, 66, 8177.
(17) Boeda, F.; Mosset, P.; Crévisy, C. Tetrahedron Lett. 2006,
47, 5021.
Anal. Calcd for C13H20O: C, 81.20; H, 10.48. Found: C, 8.42; H,
10.36.
(18) Ito, M.; Kitahara, S.; Ikariya, T. J. Am. Chem. Soc. 2005,
127, 6172.
(19) Tani, K. Pure Appl. Chem. 1985, 57, 1845.
(20) Tani, K.; Yamagata, T.; Otsuka, S.; Kumobayashi, H.;
Akutagawa, S. Org. Synth. 1989, 67, 33.
(21) Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH:
Weinheim, 2000, 25.
(22) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029.
(23) (a) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem. Int.
Ed. 1998, 37, 2897. (b) Roseblade, S. J.; Pfaltz, A. Acc.
Chem. Res. 2007, 40, 1402. (c) Wuestenberg, B.; Pfaltz, A.
Adv. Synth. Catal. 2008, 350, 174.
(R)-3-(3-Isopropylphenyl)butanal (4)
To a solution of (R)-6 (168 mg, 0.88 mmol) in CH2Cl2 (3 mL) was
added pyridinium chlorochromate (750 mg, 3.5 mmol), the result-
ing suspension was stirred for 6 h, and then diluted with Et2O (10
mL). The mixture was filtered on a short silica gel column (eluent:
Et2O). Concentration of the filtrate afforded (R)-4 (97% ee as deter-
mined by chiral GC: Chiraldex GT-A column, T = 100 °C, N2: 3.5
mL/min; S-enantiomer: tR = 61.35 min, R-enantiomer: tR = 61.94
20
min); yield: 141 mg (85%); colorless oil; [a]D –27.5 (c 1.35,
CHCl3). The spectroscopic data and the [a]D value agree with the lit-
erature.10
1H NMR (300 MHz, CDCl3): d = 9.75 (t, J = 2.0 Hz, 1 H, CHO),
7.06–7.31 (m, 4 Harom), 3.38 (m, J = 6.8 Hz, 1 H, CH), 2.93 (sept,
J = 6.9 Hz, 1 H, CH), 2.64–2.83 (m, 2 H, CH2), 1.36 (d, J = 6.8 Hz,
3 H, CH3), 1.28 (d, J = 6.9 Hz, 6 H, CH3).
(24) Tang, W.; Wang, W.; Zhang, X. Angew. Chem. Int. Ed.
2003, 42, 943.
(25) Li, X.; Kong, L.; Gao, Y.; Wang, X. Tetrahedron Lett. 2007,
48, 3915.
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