A practical, enantioselective synthesis of the fragrances canthoxal and silvial, and evaluation of their olfactory activity

Article abstract of DOI:10.1055/s-0034-1379254

The fragrances (S)-(+)- and (R)-(-)-canthoxal [(S)-(+)- and (R)-(-)-3-(4-methoxyphenyl)-2-methylpropanal] and (+)- and (-)-Silvial [(+)- and (-)-3-(4-isobutylphenyl)-2-methylpropanal] have been synthesized in high enantiopurity via a simple fou

Full text of DOI:10.1055/s-0034-1379254

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 272–278
paper
272
V. Beghetto et al.
Paper
Synthesis
A Practical, Enantioselective Synthesis of the Fragrances Canthoxal
and Silvial®, and Evaluation of Their Olfactory Activity
Enantioselective Synthesis of Canthoxal and Silvial®
Valentina Beghetto*a
CHO
Alberto Scrivantia
Matteo Bertoldinia
Manuela Aversab
Aurora Zancanaroa
Ugo Matteolia
O
*
MeO
(+)- and (–)-canthoxal
R
CHO
4 steps, including
catalytic asymmetric
hydrogenation
>96% ee
*
i-Bu
a Dipartimento di Scienze Molecolari e Nanosistemi, Università
Ca’ Foscari Venezia, Dorsoduro 2137, 30123 Venezia, Italy
b Consorzio Interuniversitario CIRCC, UdR di Venezia, Via C.
Ulpiani 27, 70126 Bari, Italy
(+)- and (–)-Silvial®
beghetto@unive.it
Received: 31.07.2014
Accepted after revision: 18.09.2014
Published online: 24.10.2014
para position of the aromatic ring. It is worth noting that
this substituent plays an important role in determining not
only the olfactory activity, but also the biological impact of
these molecules. Thus, allergenic and possible carcinogenic
activities have been demonstrated for lilial, but not for the
other three fragrances.5,6
DOI: 10.1055/s-0034-1379254; Art ID: ss-2014-z0478-op
Abstract The fragrances (S)-(+)- and (R)-(–)-canthoxal [(S)-(+)- and
(R)-(–)-3-(4-methoxyphenyl)-2-methylpropanal] and (+)- and (–)-Sil-
vial® [(+)- and (–)-3-(4-isobutylphenyl)-2-methylpropanal] have been
synthesized in high enantiopurity via a simple four-step strategy start-
ing from the commercially available 4-substituted benzaldehydes. The
key synthetic step is the catalytic asymmetric hydrogenation of the ap-
propriate 3-aryl-2-methylacrylic acid which has been carried out em-
ploying an in situ prepared ruthenium/axially chiral phosphine catalyst
(up to 98% ee). The olfactory activity of the single enantiomers has
been evaluated.
O
*
R
canthoxal (1a) R = OMe
Silvial® (1b) R = i-Bu
lilial (1c) R = t-Bu
Key words fragrance synthesis, asymmetric hydrogenation, rutheni-
um, canthoxal, Silvial®
cyclamal (1d) R = i-Pr
Figure 1 Arylpropanal fragrances
We have long been interested in the synthesis of enan-
tiomerically enriched fragrances and in the evaluation of
their olfactive notes, since the olfactory activities of two
enantiomeric fragrances can be different both in quality
and in intensity.1 Accordingly, the availability of the single
stereoisomers of a fragrance is of great interest, as they
could be employed as new perfumery materials.2 Environ-
mental concerns provide further impetus for the synthesis
of enantiopure fragrances. In fact, since fragrance ingredi-
ents are eventually dispersed in the biosphere, the use of
the most active stereoisomer instead of a racemate could
lead to a lower consumption of these chemicals and hence
reduce their impact on the environment.3 Further motiva-
tions derive from patentability opportunities,2 and the im-
portant role that the availability of single stereoisomers
plays in studying molecular structure–odour relationships.4
Canthoxal (1a), Silvial® (1b), lilial (1c) and cyclamal (1d)
are four fragrances characterized by a common aldehydic
structural motif (Figure 1), so that the differences in their
olfactive profiles can be ascribed to the group present in the
There are papers dealing with the preparation of the en-
antiomers of 1c,7,8 and the odour profiles of (+)-1c and (–)-
1c have been reported.9 Only recently, two different re-
search groups have reported the preparation of enantioen-
riched cyclamal;8,10 in particular, Kawasaki and co-workers
have developed an enzymatic enantioselective synthesis of
(R)-1d or (S)-1d and have described the olfactive profiles of
the enantiomers.10
In contrast, the olfactive notes of the enantiomers of 1a
and 1b have not yet been reported. Accordingly, we deemed
it interesting to synthesize enantiopure canthoxal (its par-
tial deracemization has been reported8) and Silvial in order
to evaluate their odour profiles.11
Asymmetric catalytic hydrogenation of a prochiral ole-
fin12 is one of the most efficient and practical approaches
used to form a chiral centre. Thus, in order to synthesize
nonracemic 1a and 1b, we devised the synthetic strategy
outlined in Scheme 1.
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V. Beghetto et al.
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Synthesis
O
This is a key issue, since the asymmetric hydrogenation of
the E- or Z-isomer of an olefin often leads to the formation
of opposite enantiomers.7b,14
O
P
O
EtO
OH
EtO
OH
O
The key step of the synthetic strategy is the asymmetric
catalytic hydrogenation of the α,β-unsaturated carboxylic
acids 3a and 3b. Nowadays, a large number of chiral phos-
phorus auxiliaries are available for transition-metal-cata-
lyzed asymmetric hydrogenation. According to our experi-
ence,14 the most convenient approach is to employ a cata-
lytic system allowing for a rapid screening of the candidate
ligands. A particularly handy system is that prepared by
combining, in situ, benzeneruthenium(II) chloride dimer
{[RuCl2(C6H6)]2} and a chiral bidentate phosphine ligand in
a 1:2 molar ratio.15
HWE
R
R
2a: R = OMe
2b: R = i-Bu
3a,b
H2
chiral catalyst
O
OH
*
R
4a,b
BMS
O
Keeping in mind the excellent results obtained in the
synthesis of other fragrances,16a in the first experiments the
ferrocenylphosphine ligand (S,R)-Mandyphos-416 (see Fig-
ure 2) was employed as the chiral auxiliary, and (E)-3a was
chosen as the model substrate (see Table 1).
OH
DMP
*
*
R
R
5a,b
1a,b
Scheme 1 The designed canthoxal (1a) and Silvial (1b) syntheses
In an exploratory experiment, carried out at 30 °C under
40 atm of hydrogen, a moderately good (50%) enantiomeric
excess (ee) was obtained (Table 1, entry 1). This result
prompted us to investigate whether the enantioselectivity
could be improved by some fine-tuning of the reaction con-
ditions. Thus, a second experiment was carried out in the
presence of triethylamine as promoter (amine/substrate
molar ratio = 1:1), since it is known that the hydrogenation
rate with ruthenium catalytic systems can often be im-
proved by the addition of tertiary amines as promoters,
even though their presence does not always have a favour-
able effect on the enantioselectivity.17
We chose as starting compounds the para-substituted
benzaldehydes 2a and 2b, which are commercially avail-
able. Horner–Wadsworth–Emmons (HWE) olefination em-
ploying 2-(diethoxyphosphoryl)propanoic acid13 stereose-
lectively transformed 2a and 2b into the corresponding α,β-
unsaturated acids (E)-3a and (E)-3b in >85% yield. HWE ole-
fination was the selected methodology because it usually
proceeds with high control of the C=C stereoisomerism.
OMe
OMe
N
N
H
P
Fe
P
H
P
Fe
P
H
N
H
N
MeO
(R,S)-Mandyphos-1
OMe
(S,R)-Mandyphos-4
t-Bu
OMe
t-Bu
PPh2
PPh2
MeO
MeO
PPh2
PPh2
MeO
MeO
PAr2
Ar =
PAr2
(R)-BINAP
(S)-MeOBIPHEP
(S)-3,5-t-Bu-4-MeO-MeOBIPHEP
Figure 2 Molecular structures of the employed chiral ligands
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V. Beghetto et al.
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Synthesis
With the aim of achieving higher enantioselectivities, a
different set of ligands was tested (Table 2). The experi-
ments were carried out at 0 °C in the presence of the amine
promoter and the hydrogen pressure was kept constant at
40 atm.
Table 1 Asymmetric Hydrogenation of (E)-3a and (E)-3b in the Pres-
ence of the [RuCl2(C6H6)]2/(S,R)-Mandyphos-4 Catalytic Systema
Entry Sub-
Temp H2
Time
Et3N/3 3a,b/R Convb eec (%)
strate (°C)
(atm) (h)
a,b
u
(%)
At first, we tested (R,S)-Mandyphos-1, a ferrocenyl li-
gand which differs from (S,R)-Mandyphos-4 in that it has
no hindered aryl substituents on the phosphorus atoms
(see Figure 2). Employing this ligand, we obtained complete
substrate hydrogenation (Table 2, entry 1), but the resulting
enantioselectivity was significantly lower than with (S,R)-
Mandyphos-4. As also suggested by the data in Table 1, this
indicates that steric hindrance, either on the substrate or on
the ligand, has a significant positive effect on the asymmet-
ric induction.
Ligands with axial chirality, such as (R)-BINAP and (S)-
MeOBIPHEP (Figure 2), gave significantly better enantiose-
lectivities than (R,S)-Mandyphos-1, although they were
somewhat less effective than (S,R)-Mandyphos-4 (Table 2,
entries 2 and 3).
1
2
3
4
5
6
3a
3a
3a
3a
3b
3b
30
30
0
40
3
0
100:1 91
100:1 100
100:1 100
100:1 100
50d
65d
71d
75d
84e
86e
40
3
1:1
40
18
18
24
24
1:1
1:1
1:1
1:1
0
100
40
0
50:1
50:1
100
100
0
100
a Reaction conditions: substrate (0.91 mmol), [RuCl2(C6H6)]2 (4.5 μmol);
Ru/ligand, 1:1 (mol/mol)], Et3N (0.9 mmol), MeOH (10 mL).
b Determined by GLC.
c All acids have a positive specific rotation (determined by polarimetry).
d Determined by HPLC analysis of the anilide using a Chiralcel OD-H col-
umn.
e Determined by chiral GLC (β-Dex 120 column).
The use of triethylamine led to an enhancement of the
asymmetric induction up to 65% ee and, when the tempera-
ture was lowered to 0 °C, the ee increased to 71%, although
a longer reaction time was necessary to reach total sub-
strate hydrogenation (Table 1, entries 2 and 3). A further,
modest improvement of the enantioselectivity (up to 75%
ee) was obtained by increasing the hydrogen pressure to
100 atm (Table 1, entry 4), in agreement with the frequent-
ly observed positive effect of hydrogen pressure on the en-
antioselectivity in ruthenium-catalyzed hydrogenations.
Entries 5 and 6 in Table 1 report the results of the asym-
metric hydrogenation of (E)-3b under the best reaction
conditions found for (E)-3a. According to these data, it ap-
pears that higher asymmetric inductions (up to 86% ee) can
be obtained with (E)-3b. This very good result can be tenta-
tively attributed to the higher steric hindrance of (E)-3b. In
this connection, it is worth noting that such a level of enan-
tioselectivity, albeit not completely satisfactory, could be
considered acceptable for an application in fragrance syn-
thesis.
Considering the observed steric hindrance effect, we
deemed it may be possible to obtain better results using
(S)-(6,6′-dimethoxybiphenyl-2,2′-diyl)bis[bis(3,5-di-tert-
butyl-4-methoxyphenyl)phosphine] [(S)-3,5-t-Bu-4-MeO-
MeOBIPHEP], a highly hindered homologue of (S)-MeO-
BIPHEP. In fact, when we employed this ligand, enantiose-
lectivity values close to 96% ee were obtained with both 3a
and 3b (Table 2, entries 4 and 5).
With the optimized asymmetric hydrogenation reaction
conditions in hand, we prepared the sought saturated acids
on a 1-gram scale. When (S)-3,5-t-Bu-4-MeO-MeOBIPHEP
was employed, enantiomerically enriched (+)-4a and (+)-4b
were obtained in 95% ee and 97% ee, respectively. Analo-
gously, when (R)-3,5-t-Bu-4-MeO-MeOBIPHEP was em-
ployed, enantiomerically enriched (–)-4a and (–)-4b were
obtained in 95% ee and 98% ee, respectively.
According to the synthetic plan depicted in Scheme 1,
the enantiomerically enriched acids 4 were reduced to the
corresponding primary alcohols 5 by reaction with borane–
Table 2 Asymmetric Hydrogenation of (E)-3a and (E)-3b in the Presence of [RuCl2(C6H6)]2/Chiral Ligand Catalytic Systemsa
Entry
Substrate
Ligand
Time (h)
3a,b/Ru
Convb (%)
eec (%)
1
2
3
4
5
3a
3a
3b
3a
3b
(R,S)-Mandyphos-1
18
18
24
18
24
100:1
100:1
50:1
100
100
100
100
100
45d (–)
62d (–)
67e (+)
96d (+)
96e (+)
(R)-BINAP
(S)-MeOBIPHEP
(S)-3,5-t-Bu-4-MeO-MeOBIPHEP
(S)-3,5-t-Bu-4-MeO-MeOBIPHEP
100:1
100:1
a Reaction conditions: substrate (0.91 mmol), [RuCl2(C6H6)]2 (4.5 μmol); Ru/ligand, 1:1 (mol/mol); substrate/Et3N, 1:1 (mol/mol)], MeOH (10 mL), H2 (40 atm),
0 °C.
b Determined by GLC.
c Specific rotation sign determined by polarimetry.
d Determined by HPLC analysis of the anilide using a Chiralcel OD-H column.
e Determined by chiral GLC (β-Dex 120 column).
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methyl sulfide complex (BMS), a reducing reagent which
assures complete configuration retention at the α-carbon18
and short reaction times. In fact, at room temperature, 1-
gram-scale reductions of (+)-4a and (–)-4a were complete
in 1 hour, giving (–)-5a and (+)-5a, respectively. The chiral
alcohols were obtained in about 90% isolated yield and with
complete retention of the enantiomeric purity. Analogous-
ly, reductions of (+)-4b and (–)-4b afforded (–)-5b and
(+)-5b in about 89% yield.
The last step of the canthoxal and Silvial syntheses re-
quired the partial oxidation of the 5a and 5b enantiomers
to the corresponding aldehydes (Scheme 1). The reaction
was conveniently carried out employing Dess–Martin per-
iodinane (DMP), and the single enantiomers of 1a and 1b
were obtained in about 70% isolated yield. As we were un-
able to directly determine the enantiomeric excesses of the
obtained aldehydes via chiral GLC or HPLC, samples (+)-1a,b
and (–)-1a,b were further oxidized with silver nitrate19 to
give the parent acids (+)-4a,b and (–)-4a,b whose enantio-
meric purities were found to be unchanged with respect to
the corresponding acids obtained by asymmetric hydroge-
nation.
(+)-1b: strong, floral, Silvial, fatty, creamy, green, alde-
hydic, typically lily of the valley, more powerful than Silvial
(ODT: 1.50 ng/L).
(–)-1b: weak, floral, muguet, lilial-like, aldehydic, green
(ODT: 7.45 ng/L).
Summing up, we have devised a new synthesis of the
single enantiomers of canthoxal and Silvial. The developed
approach entails a minimum number of simple and high-
yielding atom-economical steps. The chiral centre is formed
by catalytic asymmetric hydrogenation which can be car-
ried out with excellent enantioselectivity by using a conve-
nient in situ formed ruthenium catalyst derived from an ax-
ially chiral ligand of the MeOBIPHEP family. It was, thus,
possible to evaluate the odour profiles of the single stereo-
isomers of both fragrances: even if no particularly striking
differences were perceived, it is worth noting that whatever
the fragrance, the (+)-enantiomer is always stronger; in
particular, the odour detection threshold of (+)-Silvial is
about five times lower than the opposite enantiomer.
All manipulations were carried out under nitrogen using standard
Schlenk techniques. The starting aldehydes were purchased from TCI
Europe. All other reagents and solvents and were purchased from Al-
drich and purified according to literature procedures.21 (S)-MeOBI-
PHEP, (R)- and (S)-3,5-t-Bu-4-MeO-MeOBIPHEP, (R,S)-Mandyphos-1
and (S,R)-Mandyphos-4 were a generous gift from Solvias. (R)-BINAP
According to the literature,20 the absolute configuration
of (–)-5a is (S) and that of (+)-5a is (R); since reduction of
(+)-4a leads to (–)-5a, it can be inferred that the absolute
configuration of (+)-4a is (S) and that of (–)-4a is (R). Upon
oxidation, (–)-5a affords (+)-1a whose absolute configura-
tion is hence (S); thus, the configuration of (–)-1a is (R)
(Scheme 2).
22
was a generous gift from Rhodia UK Ltd. [RuCl2(C6H6)]2 and 2-
(diethoxyphosphoryl)propanoic acid were prepared as described in
the literature.23
1H and 13C NMR spectra were recorded on a Bruker Avance AC 300
spectrometer operating at 300.21 and 75.44 MHz, respectively. GC-
MS analyses were performed on a Hewlett-Packard 5890 Series II gas
chromatograph interfaced with an HP 5971 quadrupole mass detec-
tor. GLC analyses were performed on an Agilent 6850 gas chromato-
graph. Enantiomeric excesses were determined by chiral GLC using a
β-Dex 120 column (30 m × 0.25 mm) or by chiral HPLC using a Chiral-
cel OD-H column (250 mm × 4.6 mm) on an Agilent 1100 HPLC sys-
tem equipped with a UV detector at 254 nm. Specific rotations (α)
were determined using a Perkin-Elmer 241 polarimeter (Na lamp at
25 °C). High-resolution mass spectra were recorded on a Thermo Fin-
nigan MAT 95 XP mass spectrometer.
OH
O
DMP
MeO
MeO
(S)-(–)-5a
(S)-(+)-canthoxal (1a)
BMS
O
AgNO3
OH
MeO
(E)-3-(4-Methoxyphenyl)-2-methylacrylic Acid (3a)
(S)-(+)-4a
Under inert atmosphere, to chilled (–60 °C) anhydrous THF (120 mL)
were sequentially added a 2.5 M solution of n-BuLi in n-hexane (31
mL, 79 mmol) and 2-(diethoxyphosphoryl)propanoic acid (8.3 g, 39.5
mmol) in THF (40 mL); the mixture was stirred for 1 h at –60 °C, then
4-methoxybenzaldehyde (2a; 5.25 g, 39.6 mmol) in THF (20 mL) was
added. The yellow solution was stirred at –60 °C for 2 h, then was al-
lowed to warm to r.t. and kept under stirring overnight. The reaction
mixture was quenched with H2O (100 mL), leading to the precipita-
tion of a white solid which was removed by filtration. The filtrate was
then basified to pH 11 with a 10% aq solution of Na2CO3, concentrated
and then extracted with Et2O (3 × 40 mL). The combined aqueous
phases were acidified with 1 M HCl to give 3a as a white powder.
Spectroscopic and analytical data were in complete agreement with
the corresponding literature data24,25 (see Supporting Information).
Scheme 2 Specific rotation–absolute configuration relationship for
canthoxal
Samples of (+)-1a, (–)-1a, (+)-1b and (–)-1b were sub-
mitted to a panel of skilled perfumers (Givaudan) for the
evaluation of odour profiles and odour detection thresholds
(ODT). The following descriptions were obtained:
(S)-(+)-1a: floral, anisic, fruity-watery odour with a
sweet fennel-type character recalling anethol (ODT: 31.1
ng/L).
(R)-(–)-1a: floral, anisic, fruity-watery odour with green
accents and slightly rubbery aspects; weaker than (S)-(+)-
1a (ODT: 45.2 ng/L).
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Yield: 6.4 g (85%); white powder; mp 154–156 °C.
tion. The ee was determined to be 97% by chiral GLC [β-Dex 120 capil-
lary column, 30 m × 0.25 mm × 0.25 μm, carrier gas N2, 3.0 mL/min;
tR = 138.13 min (major), 143.07 min (minor)].
(E)-3-(4-Isobutylphenyl)-2-methylacrylic Acid (3b)
Yield: 171 mg (87%); colourless oil.
[α]D25 +19.8 (c 0.50, acetone).
Compound 3b was prepared from aldehyde 2b according to the pro-
cedure above for 3a.
Yield: 7.7 g (88%); white powder; mp 90–92 °C.
Rf = 0.43 (n-hexane–EtOAc, 7:3).
1H NMR (300 MHz, CDCl3): δ = 11.36 (s, 1 H), 7.81 (s, 1 H), 7.37 (d,
J = 8.1 Hz, 2 H), 7.19 (d, J = 8.1 Hz, 2 H), 2.51 (d, J = 7.2 Hz, 2 H), 2.18 (s,
3 H), 1.91 (m, 1 H), 0.93 (d, J = 7.2 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 174.8, 142.9, 141.3, 133.1, 130.0 (2 C),
129.4 (2 C), 126.7, 45.4, 30.3, 22.5 (2 C), 13.9.
GC-MS (EI): m/z = 218 [M]+, 175, 129, 115, 91, 77.
HRMS (EI): m/z [M]+ calcd for C14H18O2: 218.1307; found: 218.1295.
1H NMR (300 MHz, CDCl3): δ = 11.0 (br s, 1 H), 7.10–7.00 (m, 4 H),
3.10–3.03 (m, 1 H), 2.80–2.61 (m, 2 H), 2.44 (d, J = 7.1 Hz, 2 H), 1.85
(m, 1 H), 1.17 (d, J = 6.4 Hz, 3 H), 0.90 (d, J = 6.6 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 182.8, 139.9, 136.4, 129.3 (2 C), 128.8
(2 C), 45.2, 41.4, 39.0, 30.4, 22.5 (2 C), 16.6.
GC-MS (EI): m/z = 220 [M]+, 177, 147, 105, 91, 77, 51.
HRMS (EI): m/z [M]+ calcd for C14H20O2: 220.1463; found: 220.1453.
(S)-(+)-3-(4-Methoxyphenyl)-2-methylpropanoic Acid [(S)-(+)-4a];
Typical Procedure
(–)-3-(4-Isobutylphenyl)-2-methylpropanoic Acid [(–)-4b]
The asymmetric hydrogenation of 3b was carried out in the presence
of (R)-3,5-t-Bu-4-MeO-MeOBIPHEP, as described above for 3a, giving
(–)-4b as a colourless oil in 85% yield. The ee was determined to be
98% by chiral GLC [β-Dex 120 capillary column; tR = 138.13 min (mi-
nor), 143.07 min (major)].
The asymmetric hydrogenation experiments were carried out in a
150-mL stainless steel autoclave with magnetic stirring. In a typical
experiment (Table 2, entry 4), 3a (175 mg, 0.91 mmol) was intro-
duced into a Schlenk tube together with anhydrous MeOH (10 mL).
Under inert atmosphere, [RuCl2(C6H6)]2 (2.3 mg, 4.5 μmol), (S)-3,5-t-
Bu-4-MeO-MeOBIPHEP (10.4 mg, 9.0 μmol) and anhydrous Et3N (125
μL, 91.0 mg, 0.9 mmol) were added to the solution which was stirred
for about 30 min. The reaction mixture was then transferred via can-
nula into the autoclave which was pressurized to 40 atm with H2 and
thermostated at 0 °C under stirring. After 18 h, the autoclave was
warmed to r.t.; the residual gas was vented off and the reaction mix-
ture was analyzed by GLC. The crude reaction mixture was concen-
trated to dryness and then diluted with Et2O (50 mL). The organic
phase was extracted with a 10% aq solution of Na2CO3 (3 × 30 mL). The
combined aqueous layers were acidified to pH 1 with a 10% aq solu-
tion of HCl and extracted with CH2Cl2 (3 × 30 mL). The combined or-
ganic phases were dried over MgSO4 and, after chromatographic puri-
fication, the solvent was removed under reduced pressure to give (S)-
(+)-4a as a colourless oil in 85% yield. Spectroscopic and analytical
data were in complete agreement with the corresponding literature
data24 (see Supporting Information). To determine the ee, a sample of
(S)-(+)-4a was treated with aniline to give the corresponding ani-
lide;24 the ee was 95% [Chiralcel OD-H column; n-hexane–i-PrOH,
92:8, 0.8 mL/min; detection: UV at 254 nm; tR = 17.15 min (minor),
21.2 min (major)].
Yield: 167 mg (85%); colourless oil.
[α]D25 –19.8 (c 0.5, acetone).
(S)-(–)-3-(4-Methoxyphenyl)-2-methylpropan-1-ol [(S)-(–)-5a]
Under inert atmosphere, to cooled (0 °C) anhydrous Et2O (50 mL), (S)-
(+)-4a (1.09 g, 5.6 mmol) and a 2 M THF solution of BMS (3.7 mL, 7.3
mmol) were sequentially added. The mixture was allowed to warm to
r.t.; after 1 h, the mixture was cooled to 0 °C and a mixture of H2O and
glycerin (3:1, 8 mL) was slowly added. The mixture was then extract-
ed with Et2O (3 × 50 mL). The combined organic phases were dried
over MgSO4 and, after chromatographic purification, the solvent was
removed under reduced pressure to give (S)-(–)-5a as a pale yellow oil
in 92% yield. Spectroscopic and analytical data were in complete
agreement with the corresponding literature data20 (see Supporting
Information). The ee was 96% [Chiralcel OD-H column; n-hexane–
i-PrOH, 95:5, 1.0 mL/min; tR = 21.34 min (minor), 23.55 min (major)].
Yield: 928 mg (92%); pale yellow oil.
[α]D25 –11.0 (c 1, CHCl3) [Lit.20 [α]D25 –11.4 (c 1.02, CHCl3)].
Rf = 0.63 (n-hexane–EtOAc, 7:3).
Yield: 150 mg (85%); colourless oil.
(R)-(+)-3-(4-Methoxyphenyl)-2-methylpropan-1-ol [(R)-(+)-5a]
[α]D25 +31.0 (c 0.51, acetone) [Lit.24 [α]D25 +30.3 (c 0.50, acetone)].
The synthesis was carried out from (R)-(–)-4a, as described above for
(S)-(–)-5a, to give (R)-(+)-5a in 89% yield. The ee was 97% [Chiralcel
OD-H column; tR = 21.34 min (major), 23.55 min (minor)].
Rf = 0.47 (n-hexane–EtOAc, 7:3).
(R)-(–)-3-(4-Methoxyphenyl)-2-methylpropanoic Acid [(R)-(–)-4a]
Yield: 905 mg (89%); pale yellow oil.
[α]D25 +11.5 (c 1.02, CHCl3).
The asymmetric hydrogenation of 3a was carried out as described
above, but employing (R)-3,5-t-Bu-4-MeO-MeOBIPHEP as the ligand
to give (R)-(–)-4a in 83% yield. The ee was 95% [anilide analysis; Chi-
ralcel OD-H column; n-hexane–i-PrOH, 92:8, 0.8 mL/min; tR = 17.15
min (major), 21.2 min (minor)].
(–)-3-(4-Isobutylphenyl)-2-methylpropan-1-ol [(–)-5b]
The synthesis was carried out from (+)-4b, as described above for (S)-
(–)-5a, to give (–)-5b in 92% yield as a colourless oil after chromato-
graphic purification.
Yield: 146 mg (83%); colourless oil.
[α]D25 –30.0 (c 0.50, acetone).
Yield: 1.070 g (92%); colourless oil.
[α]D25 –14.6 (c 0.5, CHCl3).
(+)-3-(4-Isobutylphenyl)-2-methylpropanoic Acid [(+)-4b]
The asymmetric hydrogenation of 3b was carried out in the presence
of (S)-3,5-t-Bu-4-MeO-MeOBIPHEP, as described above for 3a, giving
(+)-4b as a colourless oil in 87% yield after chromatographic purifica-
Rf = 0.60 (n-hexane–EtOAc, 7:3).
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1H NMR (300 MHz, CDCl3): δ = 7.13–7.07 (m, 4 H), 3.54–3.48 (m, 2 H),
2.78–2.72 (m, 1 H), 2.48 (d, J = 7.2 Hz, 2 H), 2.47–2.35 (m, 1 H), 2.29 (s,
1 H), 1.98–1.88 (m, 2 H), 0.95–0.93 (m, 9 H).
Rf = 0.75 (n-hexane–Et2O, 1:1).
1H NMR (300 MHz, CDCl3): δ = 9.72 (s, 1 H), 7.09–7.06 (m, 4 H), 3.09–
3.03 (m, 1 H), 2.68–2.55 (m, 2 H), 2.44 (d, J = 7.2 Hz, 2 H), 1.85 (m, 1
H), 1.08 (d, J = 6.9 Hz, 3 H), 0.91 (d, J = 6.6 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 139.2, 137.9, 129.0 (2 C), 128.9 (2 C),
67.7, 45.1, 39.4, 37.9, 30.3, 22.5 (2 C), 16.6.
GC-MS (EI): m/z = 206 [M]+, 163, 147, 131, 105, 91, 77, 51.
13C NMR (75 MHz, CDCl3): δ = 204.7, 139.9, 136.0, 129.3 (2 C), 128.8
(2 C), 48.2, 45.1, 36.4, 30.3, 22.5 (2 C), 13.3.
HRMS (EI): m/z [M]+ calcd for C14H22O: 206.1671; found: 206.1663.
GC-MS (EI): m/z = 204 [M]+, 161, 147, 105, 91, 77.
HRMS (EI): m/z [M]+ calcd for C14H20O: 204.1514; found: 204.1506.
(+)-3-(4-Isobutylphenyl)-2-methylpropan-1-ol [(+)-5b]
The synthesis was carried out from (–)-4b as described above for (–)-
5b.
(–)-3-(4-Isobutylphenyl)-2-methylpropanal [(–)-Silvial, (–)-1b]
The synthesis was carried out from (+)-5b, as described above for (+)-
1b, to give (–)-1b in 75% yield as a colourless oil. According to the pro-
cedure described above for (+)-1a, the ee was found to be 98%.
Yield: 1.022 g (88%); colourless oil.
[α]D25 +14.5 (c 0.5, CHCl3).
Yield: 770 mg (75%); colourless oil.
[α]D25 –7.20 (c 0.55, acetone).
(S)-(+)-3-(4-Methoxyphenyl)-2-methylpropanal [(S)-(+)-Canthox-
al, (S)-(+)-1a]
To cooled (0 °C) CH2Cl2 (100 mL) were sequentially added (S)-(–)-5a
(910 mg, 5.0 mmol), NaHCO3 (1.89 g, 22.5 mmol) and a 3 M solution
of Dess–Martin periodinane (2.5 mL, 7.5 mmol). After 1 h, the solu-
tion was allowed to warm to r.t. and then was hydrolyzed with an aq
solution of Na2SO3 (50 mL) and a sat. aq solution of NaHCO3 (50 mL).
The mixture was extracted with EtOAc (4 × 70 mL) and the combined
organic phases were dried over MgSO4. After concentration to a small
volume and chromatographic purification, the solvent was removed
under reduced pressure to give (S)-(+)-1a as a colourless oil in 70%
yield. Spectroscopic and analytical data were in complete agreement
with the corresponding literature data26 (see Supporting Informa-
tion). To establish the ee of (S)-(+)-1a and the sign–configuration rela-
tionship, to a solution of (+)-1a (100 mg, 0.57 mmol) in EtOH (3 mL)
was added AgNO3 (100 mg, 0.58 mmol) in H2O (2 mL). Then, to the
resulting mixture, a solution of NaOH (96 mg) in H2O (2 mL) was
slowly added under stirring. After being stirred for 1 h at r.t., the mix-
ture was diluted with H2O (15 mL) and filtered. The filtrate was acidi-
fied to pH 1 with a 10% aq solution of HCl and extracted with CH2Cl2
(2 × 10 mL). Concentration of the extracts under reduced pressure af-
forded (+)-4a (85 mg) which was transformed into the corresponding
anilide and analyzed by chiral HPLC as reported above; the ee was
found to be 97%.
Acknowledgment
Dr. P. Kraft, Mrs. K. Grman, Mr. A. Alchenberger and Mrs. D. Lelievre
(Givaudan) are kindly acknowledged for the olfactory evaluations.
Solvias is acknowledged for the generous gift of a chiral ligands kit.
Rhodia UK Ltd is acknowledged for generously supplying (R)-BINAP.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379254.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 272–278