An alternative stereoselective synthesis of (R)- and (S)-Rosaphen via asymmetric catalytic hydrogenation

Article abstract of DOI:10.1002/chir.20989

We report an alternative synthesis of the two enantiomers of the floral fragrance Rosaphen. The key intermediate 2-methyl-5-phenylpentanoic acid 3 is synthesized via asymmetric hydrogenation (ee up to 99%) in the presence of an in situ prepared ruthenium

Full text of DOI:10.1002/chir.20989

CHIRALITY 23:779–783 (2011)
An Alternative Stereoselective Synthesis of (R)- and (S)-Rosaphen1
via Asymmetric Catalytic Hydrogenation
*
UGO MATTEOLI, VALENTINA BEGHETTO, ALBERTO SCRIVANTI, MANUELA AVERSA, MATTEO BERTOLDINI, AND SARA BOVO
Dipartimento di Scienze Molecolari e Nanosistemi, Universita` Ca` Foscari di Venezia, Dorsoduro 2137, 30123 Venezia, Italy
Contribution to the Carlo Rosini Special Issue
ABSTRACT
Rosaphen1. The key intermediate 2-methyl-5-phenylpentanoic acid 3 is synthesized via asymmetric
hydrogenation (ee up to 99%) in the presence of an in situ prepared ruthenium catalyst containing
We report an alternative synthesis of the two enantiomers of the floral fragrance
C
VV
the chiral ferrocenyl phosphine Mandyphos-4. Chirality 23:779–783, 2011.
2011 Wiley-Liss, Inc.
KEY WORDS: fragrances; ruthenium; Mandyphos-4; enantioselective hydrogenation;
MeOBIPHEP
INTRODUCTION
of the single stereomers is also reported together with
their odor thresholds.
It is now well recognized that human nose may perceive in
a different way the enantiomers of a chiral odorant; in other
words, the olfactory notes of two enantiomers may be differ-
ent both in quality and in intensity.1–6 This phenomenon is
not only of great scientific interest, but also of primary practi-
cal importance for at least three main reasons: (i) in perfum-
ery there is an increasing demand for odorants to create new
unique olfactive notes; (ii) there are environmental and
safety concerns arising from the increasing use of odorants
and their interaction with the ecosystem and human beings;
and (iii) the synthesis of single enantiomer is patentable.7
The odorants displaying floral notes (rose, jasmine, lily-of-
the-valley, etc.) are of particular interest in perfumery as they
are very much appreciated and widely used.8,9 Rosaphen1
[2-methyl-5-phenyl-1-pentanol], which belongs to this class of
fragrances, is at present merchandized as racemate by Sym-
rise.
Only very recently, while the present manuscript was in
preparation, an enzymatic synthesis of the two enantiomers
of Rosaphen has been published by Kawasaki et al., who also
reported the description of their olfactive notes, albeit the
relevant odor thresholds were not determined.10
Besides the work by Kawasaki et al. in the literature,
there are a few reports dealing with the asymmetric syn-
thesis of 2-methyl-5-phenyl-1-pentanol and all concern the
preparation of the (R)-isomer11–13 for which the absolute
configuration–optical rotation relationship is reported by
Santini et al.11 It is worth mentioning that the synthesis
reported by Owston and Fu13 is a rare example of an
asymmetric Suzuki reaction.
EXPERIMENTAL
General Information
All manipulations were carried out under nitrogen by using standard
Schlenk techniques. Solvents and NEt3 were purchased from Aldrich
and purified according to literature procedures.20 All other reagents
(Aldrich) were used without further purification. (R)-MeOBIPHEP,
(R,S)-Mandyphos-4, and (S,R)-Mandyphos-4 were kind gifts from Sol-
vias. [RuCl2(benzene)]2 and 2-(diethoxyphosphoryl)propanoic acid22
21
were prepared as described in the literature.
All products 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 300.21 and 75.44 MHz,
respectively. Gas Chromatography-Mass Spectrometry (GC-MS) analy-
ses were performed on a Hewlett-Packard 5890 SERIES II gas chromato-
graph interfaced with a HP 5971 quadrupole mass detector. Gas Liquid
Chromatography (GLC) analyses were performed on an Agilent 6850
gas chromatograph Flame Ionization Detector (FID). The enantiomeric
excesses (ees) were determined by chiral GLC using a Chiraldex G-TA
column (50 m 3 0.25 mm) installed on an Agilent 6850 gas chromato-
graph with a FID detector. Optical rotatory power values (a) were deter-
mined using a Perkin-Elmer 241 polarimeter (Na lamp at 258C).
Preparation of (E)-2-Methyl-5-phenylpent-2-enoic acid
((E)-2)
Under inert atmosphere, to 75 ml of chilled (2608C) anhydrous THF
were sequentially added 19 ml of a 2.7 M solution of n-BuLi in hexanes
(51.3 mmol), 2-(diethoxyphosphoryl)propanoic acid (5.3 g, 25.2 mmol in
10 ml of THF), and after 1 h of stirring at 2608C, hydrocinnamaldehyde
(3.19 g, 23.8 mmol in 10 ml of tetrahydrofuran (THF)). The resulting yel-
low solution was kept under stirring at 2608C for 3 h, then it was
allowed to reach room temperature and kept under stirring overnight.
The reaction mixture was then cooled to 08C, quenched with water (50
ml) and extracted with diethyl ether (33 50 ml). The combined organic
phases were extracted with a 1 M solution of NaHCO3 (33 20 ml); the
combined aqueous layers were then acidified with 50 ml of 1 M HCl and
extracted with CH2Cl2 (33 30 ml). The combined organic phases were
Transition metal asymmetric catalysis is among the most
powerful tools suitable for the synthesis of enantiomeri-
cally enriched substances on practical scale14 and our
research group has been for years involved in the applica-
tion of homogeneous asymmetric catalysis7 to the synthe-
sis of enantiomerically enriched fragrances such as Galaxo-
lide1,15 Florydral1,16,17 Citralis Nitrile1,18 and Phenoxa-
nol1.19 We wish to report here a new approach to the
enantioselective synthesis of (R)- and (S)-Rosaphen based
on the catalytic asymmetric hydrogenation of 2-methyl-5-
phenylpent-2-enoic acid. A description of the odor profiles
*Correspondence to: A. Scrivanti, Dipartimento di Scienze Molecolari
e Nanosistemi, Universita` Ca` Foscari di Venezia, Dorsoduro 2137, 30123
Venezia, Italy. E-mail: scrivanti@unive.it
Received for publication 16 February 2011; Accepted 24 May 2011
DOI: 10.1002/chir.20989
Published online 17 August 2011 in Wiley Online Library
(wileyonlinelibrary.com).
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2011 Wiley-Liss, Inc.

780
MATTEOLI ET AL.
TABLE 1. Asymmetric hydrogenation of (E)-2 to 3 in the presence of [RuCl2(benzene)]2/(R)-MeOBIPHEP
Entry
T (8C)
H2 (atm)
NEt3/2
t (h)
Conv. (%)a
ee (%)b
(Sign)-(Config.)c
1
2
3
4
5
6
7
50
25
0
50
25
0
50
50
50
50
50
50
20
0
0
0
1/1
1/1
1/1
1/1
24
24
24
6
24
24
6
100d
100
74
100
100
100
100
64
70
78
64
48
28
78
(2)-(R)
(2)-(R)
(2)-(R)
(2)-(R)
(2)-(R)
(2)-(R)
(2)-(R)
50
Reaction conditions: substrate: 0.53 mmol, [RuCl2(benzene)]2: 2.65 3 1023 mmol, substrate/Ru: 100:1 (mol/mol), Ligand/Ru: 1/1 (mol/mol), solvent: CH3OH (10
ml).aDetermined by GLC.
bDetermined on the methyl ester of 3 by chiral GLC (CHIRALDEX G-TA).
cThe sign–configuration relationship of 3 was determined by polarimetry and comparison with literature data.12
dIsolated yield: 70%.
finally dried over MgSO4 and, after filtration on a short silica gel column
(eluent: diethylether), the solvent was removed in vacuum to give 2 as a
pale yellow oil ((E)-2/(Z)-2 >99%) in 93% yield. The spectroscopic data
are in agreement with the literature.12
CH3OH))23 allowed us to assign its prevailing configuration as (R). A
sample of 3 (50 mg, 0.26 mmol) was derivatized to the corresponding
methyl ester and analyzed by chiral GLC (Chiraldex GT-A column, T 5
1108C, N2: 3.8 ml/min, tR 5 70.93 min, tS 5 71.81 min); the ee of the
methyl ester of (R)-3 was 64%.
1H NMR (300 MHz, CDCl3) d: 1.83 (s, 3H, CH3), 2.58 (m, 2H,
ArCH2CH2), 2.82 (t, 2H, J 5 7.34 Hz, ArCH2CH2), 7.02 (t, 1H, J 5 7.34 Hz,
CH¼C), 7.2127.39 (m, 5H, arom), 11.80212.40 (br s, 1H, OH). 13C NMR
(75 MHz, CDCl3) d: 11.8, 30.7, 34.5, 126.1, 127.7, 128.3, 128.4, 140.9, 143.8,
173.7. MS (EI): m/z (%) 5 190 ([M]1, 10), 175 (15), 91 (70), 77 (8), 65 (20).
Asymmetric Hydrogenations with (R,S)-Mandyphos-4
The asymmetric hydrogenation of (E)-2 for the synthesis of (R)-3 was
carried out as described in the previous section. In a typical experiment
(entry 4 of Table 2), 100 mg (0.53 mmol) of (E)-2 were introduced in a
Schlenk tube together with 20 ml of CH3OH, then, under inert atmos-
phere, 1.4 mg (2.65 3 1023 mmol) of [RuCl2(benzene)]2, 33.3 mg (5.3 3
1023 mmol) of (R,S)-Mandyphos-4, and 75 ll (54 mg, 0.53 mmol) of
NEt3 were added to the solution and kept under stirring for about 1 h.
The reaction mixture was then transferred via cannula into the autoclave
which was cooled to 08C and pressurized with 20 atm of H2. After 24 h,
the residual gas was vented off and the reaction mixture was analyzed
by GLC to determine the substrate conversion (100%). After the
described treatment, enantiopure (R)-3 was recovered in 75% yield.
Asymmetric Hydrogenations with (R)-MeOBIPHEP
The asymmetric hydrogenation experiments were carried out in a 150
ml magnetically stirred stainless steel autoclave. In a typical experiment
(entry 1 of Table 1), 100 mg (0.53 mmol) of (E)-2 were introduced in a
Schlenk tube together with 10 ml of CH3OH. Under inert atmosphere,
1.4 mg (2.65 3 1023 mmol) of [RuCl2(benzene)]2 and 16.7 mg (5.3 3
1023 mmol) of (R)-MeOBIPHEP were added to the solution and kept
under stirring for about 30 min. The reaction mixture was then trans-
ferred via cannula into the autoclave which was pressurized with 50 atm
of H2 and heated to 508C. After 24 h the autoclave was cooled to room
temperature, the residual gas vented off and the reaction mixture ana-
lyzed by GLC to determine the substrate conversion.
The raw reaction mixture was taken to dryness and then treated with
a 1 M solution of NaHCO3 (33 20 ml); the combined aqueous layers
were acidified to pH 1 with 1 M HCl and extracted with CH2Cl2 (33 30
ml). The combined organic phases were finally dried over MgSO4 and,
after filtration on a short silica gel column (eluent: diethylether), the sol-
vent was removed in vacuum to give 3 as pale yellow oil in 70% yield.
The spectroscopic data are in agreement with the literature.23
Synthesis of (S)-2-Methyl-5-phenylpentanoic acid ((S)-3)
The asymmetric hydrogenation of (E)-2 for the synthesis of (S)-3 was
carried out as described above for the synthesis of (R)-3 employing (S,R)-
Mandyphos-4 as ligand. Enantiopure (S)-3 was recovered in 78% yield.
Synthesis of (R)-2-Methyl-5-phenylpentanol ((R)-4)
Under inert atmosphere, a solution of (R)-3 (400 mg, 2.08 mmol in 15
ml of THF, [a]2D5 5 –6.5 (c 0.1, CH3OH)) was added dropwise under stir-
ring to a solution of NaBH4 (200 mg, 5.40 mmol in 15 ml of THF). Once
no more gas evolution was observed, a solution of I2 (538 mg, 2.10 mmol
in 15 ml of THF) was added dropwise and the reaction mixture kept
under stirring overnight at reflux temperature.
At room temperature, 50 ml of CH3OH were added to the mixture and
stirred for further 1 h, then the solvent was partially evaporated to pre-
cipitate a white solid which was dissolved in 50 ml of an aqueous solu-
tion of KOH (20%) and left under stirring for 4 h. Finally, the solution
was extracted with CH2Cl2 (43 30 ml); the combined organic phases
1H NMR (300 MHz, CDCl3) d: 1.25 (d, 3H, J 5 6.97 Hz, CH3),
1.4421.62 (m, 1H, CH2CH2CH), 1.6521.82 (m, 3H, CH2CH2CH and
ArCH2CH2), 2.50–2.61 (m, 1H, CH), 2.70 (t, 2H, J 5 7.53 Hz, ArCH2),
7.21–7.39 (m, 5H, arom), 11.10–11.70 (br s, 1H, OH). 13C NMR (75
MHz, CDCl3) d: 16.8, 28.9, 33.0, 35.7, 39.2, 125.7, 128.2, 128.3, 142.0,
183.1. MS (EI): m/z (%) 5 192 ([M]1, 7), 174 (7), 117 (20), 91 (70), 77
(10), 65 (20). Comparison of the optical rotatory power of 3 ([a]2D5 5 –
4.2 (c 0.1, CH3OH)) with the literature data ([a]2D5 5 –6.6 (c 0.1,
TABLE 2. Asymmetric hydrogenation of (E)-2 to 3 in the presence of [RuCl2(benzene)]2/(R,S)-Mandyphos-4
Entry
T (8C)
H2 (atm)
NEt3/2
t (h)
Conv. (%)a
ee (%)b
(Sign)-(Config.)c
1
2
3
4
5
25
0
25
0
20
20
20
20
100
0
0
1/1
1/1
1/1
24
24
24
24
1
97
50
100
100d
96
97
>99
97
>99
95
(2)-(R)
(2)-(R)
(2)-(R)
(2)-(R)
(2)-(R)
25
Reaction conditions: substrate: 0.53 mmol, [RuCl2(benzene)]2: 2.65 3 1023 mmol, substrate/cat. 5 100/1 (mol/mol), Ligand/Ru 5 1/1 (mol/mol), solvent:
CH3OH (10 ml).aDetermined by GLC.
bDetermined on the methyl ester of 3 by chiral GLC (CHIRALDEX G-TA).
cThe sign–configuration relationship of 3 was determined by polarimetry and comparison with literature data.12
dIsolated yield: 75%.
Chirality DOI 10.1002/chir

ASYMMETRIC CATALYTIC SYNTHESIS OF ROSAPHEN
were dried over MgSO4 and, after filtration on a short silica gel column
781
(eluent: diethyl ether/n-hexane 40/60), the solvent was removed in vac-
uum to give (R)-4 as pale yellow oil in 88% yield.
According to the optical rotatory power data ([a]2D5 5 110.2 (c 1.0,
CH2Cl2)), the optical purity (o.p.) of (R)-4 was 99% ([a]2D5;max 5 110.3 (c
1.0, CH2Cl2)).12 To determine the ee value of alcohol 4, it was oxidized
to acid 3 as follows: a solution of 4 in DMF was treated with a solution
of pyridinium dichromate in water and the resultant mixture was stirred
overnight at room temperature24; after standard work up the resulting
acid 3 was derivatized and analyzed by chiral GC as described above (ee
> 99%, Chiraldex GT-A column (0.25 mm 3 50 m); nitrogen flow 3.8 ml/
min; T5 1108C; tR5 70.93 min, tS5 71.81 min).
Fig. 1. Molecular structure of (R)-MeOBIPHEP, (R,S)-Mandyphos-4 and
(S,R)-Mandyphos-4.
The spectroscopic data are in agreement with the literature.12
towards (E)-2 is greater than 99% as shown by 1H NMR
spectroscopy.
1H NMR (300 MHz, CDCl3) d: 0.99 (d, 3H, J 5 6.59 Hz, CH3), 1.08–
1.24 (m, 1H, CH2CH2CH), 1.36–1.52 (m, 2H, CH2CH2CH and OH), 1.56–
1.76 (m, 3H, ArCH2CH2 and CH), 2.56–2.64 (m, 2H, ArCH2), 3.40–3.56
(m, 2H, CH2OH), 7.20–7.40 (m, 5H, arom). 13C NMR (75 MHz, CDCl3)
d: 16.4, 28.8, 32.7, 35.6, 36.1, 68.2, 125.6, 128.2, 128.3, 142.5. MS (EI): m/
z (%) 5 178 ([M]1, 54), 160 (95), 117 (87), 104 (69 ), 91 (43).
The asymmetric hydrogenation of the a,b-unsaturated car-
boxylic acid 2 is the key step of the designed synthetic strat-
egy.31–35 A very convenient approach for preliminary studies
consists in the use of a catalytic system generated in situ
from [RuCl2(benzene)]2 and a chiral bidentate phosphine
ligand in the 1/2 molar ratio.36–38 In fact, this simply
assembled catalytic system is readily tunable by changing
the nature of the ligand.
Synthesis of (S)-2-Methyl-5-phenylpentanol ((S)-4)
The reduction of (S)-3 was carried out as described above for (R)-3.
Enantiopure (S)-4 was recovered in 90% yield.
A substrate to ruthenium molar ratio of 100/1 was
employed in all the hydrogenation experiments.
The results of a first set of experiments obtained using the
atropisomeric diphosphine (R)-MeOBIPHEP (see Fig. 1) are
reported in Table 1. At 508C and 50 atm of hydrogen, the pro-
chiral olefin 2 is totally hydrogenated in 24 h to give (–)-(R)-
3 in fairly good ee (64%) (see Experimental section). By low-
ering the reaction temperature to 258C, the enantioselectivity
increases to 70% with complete conversion of the substrate.
Further improvement of the ee (78%) is obtained working at
08C, although the conversion is only 74%.
RESULTS AND DISCUSSION
In order to synthesize enantiomerically pure Rosaphen, we
devised the three steps synthetic strategy reported in
Scheme 1. The starting product is the commercially available
and inexpensive hydrocinnamaldehyde 1 which is first con-
verted into the prochiral 2-methyl-5-phenylpent-2-enoic acid
2 by means of a Horner–Wadsworth–Emmons (HWE) olefi-
nation.25 Then, 2 is hydrogenated in the presence of a chiral
transition metal catalyst to give (R)- or (S)-2-methyl-5-phenyl-
pentanoic acid, (R)- or (S)-3. In the last step, (R)- or (S)-3 is
reduced with NaBH4/I2 to give (R)- or (S)-2-methyl-5-phenyl-
pentan-1-ol (4) ((R)- or (S)-Rosaphen) with complete reten-
tion of the enantiopurity.26
The HWE olefination, a modification of the well known
Wittig reaction,27 is preferred because it offers a good control
of the E/Z diastereoselectivity in the product, E/Z isomer
ratios higher than 9/1 being usually obtained.28 Control of
the olefin diastereoselectivity is of primary importance
because it often occurs such that the asymmetric hydrogena-
tion of the E and the Z isomers leads to opposite enantiom-
ers.19,29,30
Thus, we were prompted to evaluate the effect of the addi-
tion of triethylamine as promoter on the reaction.
As a matter of fact, it is well known that the rate of the hy-
drogenation with ruthenium catalysts may be improved by
adding an amine as the co-catalyst; although it is worth not-
ing that a positive effect on the reaction rate is not always
accompanied by an enhancement in enantioselectivity.18,39,40
The data of the experiments with triethylamine (in 1/1
molar ratio with respect to the substrate) are reported in
entries 4–7 of Table 1. As expected, addition of amine leads
to faster hydrogenation rates (compare entries 3 and 6). By
comparing the asymmetric inductions, it appears that at 508C
the presence of the amine has no effect, while at 258C or 08C
the ees obtained with the amine are lower than those
obtained without this co-catalyst. It is noteworthy that, as far
as the dependence of enantioselectivity on the temperature
is concerned, two different trends are found: without amine
the selectivity increases on decreasing the temperature,
while the opposite behavior is observed using the co-catalyst.
In this connection, it should be noted that the enantioselec-
tivity in the presence of the amine does not depend on the
reaction time. In fact, an experiment carried out under the
same conditions of entry 4 of Table 1 in 24 h gives the same
enantioselection (64% ee).
2-(Diethoxyphosphoryl)propanoic acid, prepared by a liter-
ature method,22 is a co-reactant particularly activated in
HWE owing to the presence of the electron-withdrawing
COOH moiety, so that the sought 2-methyl-5-phenylpent-2-
enoic acid 2 is obtained in about 93% isolated yield. In keep-
ing with the adopted strategy, the diastereoselectivity
Last row of Table 1 shows the effect of the hydrogen pres-
sure on the reaction: a decrease from 50 to 20 atm (compare
entries 4 and 7) leads to a significant increase in the asym-
metric induction (ee 64% and 78%, respectively), as in other
ruthenium catalyzed hydrogenations.41
Although under these conditions, we are able to obtain ees
up to about 80%, this result was not considered completely
Scheme 1. The designed synthesis of Rosaphen1
.
Chirality DOI 10.1002/chir

782
MATTEOLI ET AL.
satisfactory. Therefore, deeming that substantial improve-
ments in enantioselectivity could not be achieved by a fur-
ther fine tuning of the reaction conditions, we decided to test
(R,S)-Mandyphos-4 [(aR,aR)-2,20-bis(a-N,N-dimethylamino-
phenylmethyl)-(S,S)-1,10-bis[di(3,5-dimethyl-4-ethoxyphenyl)-
phosphino]ferrocene (see Fig. 1)], a completely different
ligand belonging to the class of ferrocenyl diphosphines.42
The results are summarized in Table 2.
In entries 1 and 2 are reported the experiments carried out
using [RuCl2(benzene)]2/(R,S)-Mandyphos-4 in the absence
of co-catalyst. At once, this new system appears much more
stereoselective than the one based on (R)-MeOBIPHEP
since at room temperature under 20 atm of hydrogen the
reaction proceeds with complete substrate conversion giving
(R)-3 in 97% ee. When the temperature is lowered to 08C
almost complete enantioselectivity is obtained (>99%);
unfortunately, under these conditions the reaction rate is
depressed and only 50% of the substrate is hydrogenated in
24 h (entries 1 and 2 of Table 2).
In order to turn the process into a practically feasible one,
a more sustainable reduction of acid 3 to alcohol 4 should
be developed. Indeed, a straight 3 to 4 transformation could
be accomplished by catalytic hydrogenation of the carboxylic
moiety; either homogeneous43,44 or heterogeneous45 cata-
lysts might be employed.
In the devised synthesis, a further weakness is the HWE
olefination which does not meet the concept of atom effi-
ciency and has to be carried out at low temperatures. As sug-
gested by an anonymous reviewer, alternative precursors of
3 or 4 such as a,b-unsaturated acids, aldehydes, or allyl
alkohols could be synthesized by Mannich or aldol reactions
which are more atom efficient than HWE olefination and fea-
sible at ordinary temperatures. A variety of asymmetric
hydrogenations of such intermediates either enzymatic46–51
or catalytic18,52 are available and have been the subject of a
recent review by Saudan.53
ACKNOWLEDGMENTS
The data reported in entries 3–5 are obtained using trie-
thylamine as co-catalyst. In entries 3 and 4, carried out under
20 atm of hydrogen, the enantioselectivity remains unaf-
fected while a strong enhancement in the reaction rate is
observed. When the hydrogen pressure is increased to 100
atm (entry 5), very high reaction rates are obtained, but,
adversely, this is accompanied by a small decrease in the
enantioselectivity.
Solvias is acknowledged for generously supplying the (R)-
MeOBIPHEP and the two enantiomers of the Mandyphos-4
ligand. Dr. P. Kraft, Mr. A. Alchenberger, Mrs. D. Lelievre,
Mrs. K. Grman and panelist team from Givaudan are kindly
acknowledged for the olfactory evaluations.
LITERATURE CITED
By comparing the data in Table 2, it appears that the most
suitable conditions for the asymmetric hydrogenation are
those of entry 4. Therefore, these conditions were adopted to
prepare about 0.5 g of practically enantiopure (R)-3. Analo-
gously, enantiopure (S)-3 was synthesized employing (S,R)-
Mandyphos-4.
1. Bentley R. The nose as a stereochemist. Enantiomers and odor. Chem
Rev 2006;106:4099–4112.
2. Abate A, Brenna E, Fuganti C, Gatti FG, Serra S. Odor and (bio)diversity:
single enantiomers of chiral fragrant substances. Chem Biodivers
2004;1:1888–1898.
3. Sell CS. Scent through the looking glass. Chem Biodivers 2004;1:1899–
1920.
According to the last step of the planned synthesis
(Scheme 1), pure samples of (R)- or (S)-3 were reduced with
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ants. Tetrahedron: Asymmetry 2003;14:1–42.
26
NaBH4/I2 with complete retention of enantioselectivity to
5. Kraft P, Fra´ter G. Enantioselectivity of the musk odor sensation. Chirality
2001;13:388–394.
give (R)- or (S)-4, in about 90% isolated yield.
Samples of (R)- and (S)-Rosaphen were submitted to a
panel of skilled perfumers (Givaudan) for the evaluation of
the odor profiles. The following description was obtained for
(2)-(S)-Rosaphen: floral rosy odor in the direction of phenyl-
ethyl esters, with green, powdery, honey-like, and slightly
animalic aspects (odor threshold: 3.45 ng/l); while for (1)-
(R)-Rosaphen the description is: transparent floral rosy and
watery odor in the direction of citronellol and mefrosol (3-
methyl-5-phenylpentan-1-ol) (odour threshold: 9.95 ng/l).
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opments in the chemistry of odorants. Angew Chem Int Ed
2000;39:2980–3010.
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Lipase-mediated preparation of optically active isomers of Rosaphen1. J
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CONCLUSIONS
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synthase inhibitor zaragozic acid C. J Org Chem 1994;59:2261–2266.
In conclusion, we have developed a new three-step synthe-
sis of the single enantiomers of Rosaphen which allowed us
to evaluate the odor profiles of the single stereomers and
determine their odor thresholds. Even if no particular strik-
ing differences were perceived in the odor profiles or in their
intensities, it is worth to mention that (R)-Rosaphen presents
the more complex and interesting olfactive notes.
In the devised synthetic approach, the critical step is repre-
sented by the asymmetric hydrogenation of the (E)-2-methyl-
5-phenylpent-2-enoic acid 2. The enantiomeric excesses
obtained with the catalyst prepared by mixing [RuCl2(ben-
zene)]2 and (R,S)-Mandyphos-4 or (R,S)-Mandyphos-4 are
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