Chirality and fragrance chemistry: Stereoisomers of the commercial chiral odorants muguesia and pamplefleur

Article abstract of DOI:10.1021/jo048445j

(Chemical Equation Presented) The work describes the enzyme-mediated preparation and the odor evaluation of the single stereoisomers of the commercial odorants Muguesia and Pamplefleur. The synthetic approach to Muguesia stereoisomers helped to clear the assignment of the relative configuration of intermediate diols 5. The odor response of Pamplefleur isomers was found to be rather unusual. No stereoisomer prevailed, but each one played a definite role in establishing the odor sensation of the final blend.

Full text of DOI:10.1021/jo048445j

Chirality and Fragrance Chemistry: Stereoisomers of the
Commercial Chiral Odorants Muguesia and Pamplefleur
Agnese Abate, Elisabetta Brenna,* Claudio Fuganti, Francesco G. Gatti,
Tommaso Giovenzana, Luciana Malpezzi, and Stefano Serra
Dipartimento di Chimica, Materiali ed Ingegneria Chimica del Politecnico, Istituto CNR per la Chimica
del Riconoscimento Molecolare, Via Mancinelli 7, I-20131 Milano, Italy
elisabetta.brenna@polimi.it
Received September 3, 2004
The work describes the enzyme-mediated preparation and the odor evaluation of the single
stereoisomers of the commercial odorants Muguesia and Pamplefleur. The synthetic approach to
Muguesia stereoisomers helped to clear the assignment of the relative configuration of intermediate
diols 5. The odor response of Pamplefleur isomers was found to be rather unusual. No stereoisomer
prevailed, but each one played a definite role in establishing the odor sensation of the final blend.
CHART 1
Introduction
A scented breath marks the way for a new Life: this
is the outcome of a study recently reported in Science.1
Olfactory receptors are known to reside in spermatozoa.
Hatt et al. have shown that the floral odorant bourgeonal
is capable of influencing human sperm chemotaxis and
of increasing the speed of sperm cells (Chart 1). If
bourgeonal and undecanal are simultaneously present,
the bourgeonal effect is completely suppressed. Undeca-
nal is a competitive antagonist at the binding site of
bourgeonal. Thus, the perception of odor, even at the
beginning of Life, is basically a molecular recognition
process.
According to a mechanism which is not clear yet, the
structural features of a molecule are recognized by our
brain as a definite and characteristic odor sensation. The
olfactory receptors of human nose are capable of detecting
and discriminating thousands of volatile organic com-
pounds with different structure, thus showing a great
capacity for molecular recognition.
The spatial distribution of substituents around stereo-
genic elements, such as stereogenic centers, is expected
to be crucial when a process of molecular recognition is
involved. Since the recognition is performed by proteins,
the enantiomers of chiral molecules can be perceived in
different ways by our nose.
So far, the investigation of the odor properties of single
stereoisomers has shown different situations.2 (R)- and
(S)-R-ionone have very similar odor character, “Floral-
woody note, with an additional honey aspect”, and nearly
the same odor threshold (3.2 and 2.7 ng/L, respectively).3
* Corresponding author. Phone: ++39 0223993077. Fax: ++39
0223993080.
(1) Spehr, M.; Gisselmann, G.; Poplawski, A.; Riffell, J. A.; Wetzel,
C. H.; Zimmer, R. K.; Hatt, H. Science 2003, 299, 2054.
(2) Brenna, E.; Fuganti, C.; Serra S. Tetrahedron: Asymmetry 2003,
14, 1.
10.1021/jo048445j CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/26/2005
J. Org. Chem. 2005, 70, 1281-1290
1281

Abate et al.
SCHEME 1a
(+)- and (-)-florhydral show similar odor tonalities and
different odor thresholds (odor threshold ) 0.035 and 0.88
ng/L, respectively.4 (+)-Androstenone is odorless, while
the (-)-enantiomer is sweaty, urine, strong, and musky.5
When more than one stereogenic carbon atom are
present in a molecule, it may happen that the odor
vectors are the enantiomers of the same or of different
diastereoisomers.
a Key: (i) Lipase PS, tert-butylmethyl ether, vinyl acetate.
The scent of commercial Florol (two racemic diastereo-
isomers) is mainly due to the (2R,4R) and (2S,4S)
stereoisomers (odor threshold 1.21 and 26 ng/L air,
respectively), while the (2R,4S) and (2S,4R) isomers are
nearly odorless (odor threshold 520 and >600 ng/L air,
respectively).6
control of the relative and absolute configuration of
vicinal stereogenic carbon atoms. Interesting findings in
the chemistry of substrates with stereocenters in position
1,2 and 1,3 will be reported.
Results and Discussion
When the odor properties of the four stereoisomers of
Galaxolide were evaluated the following results were
obtained.7 The two (4S) stereoisomers were found to be
responsible for the odor of the commercial product.
(4S,7R)-cis-Galaxolide was described to be the most
powerful (odor threshold ) 0.63 ng/L air) of the Galax-
olide isomers and to possess a very pleasant clean musk
note. Slightly less powerful was the trans-diastereoisomer
(4S,7S) (odor threshold ) 1.0 ng/L air), which showed a
similar musk odor that differed from that of the(4S,7R)
diastereoisomer by its dry character. The (4R)-isomers
were found to be much weaker and to give no contribute
to the odor profile of the commercial product ((4R,7S)-
cis isomer odor threshold ) 130 ng/L air; (4R,7R)-trans
isomer odor threshold ) 440 ng/L air)).
Muguesia (1) and Pamplefleur (2) are available com-
mercially by IFF as mixtures of two racemic diastereo-
isomers. In the IFF catalog online, Muguesia is described
as floral, muguet, rose, and minty. Its usage is suggested
when aldehydic muguet ingredients are not stable.
Pamplefleur is described as citrus, grapefruit, floral,
vetivert, green, and diffusive. It represents the animal
moiety for jasmin types.
We optimized two enzyme-mediated approaches to all
the steroisomers of odorants 1 and 2.
Muguesia. Aldolic condensation of propiophenone with
acetaldehyde gave hydroxyketone 3 as a 1:1 mixture of
two racemic diastereoisomers, (2RS,3RS)-3 and (2RS,3SR)-
3.
Thus, the outcome of the study of enantioselectivity
in odor perception is completely unpredictable, but it is
now of great relevance. As a matter of fact, in the field
of fragrance chemistry, an increasing concern for human
health, and also for environmental preservation, has
favored the trend to employ single-enantiomer chemicals
in those products that are to directly interact with human
beings. If only the odor-active isomers are employed in
commercial products, the toxicological risks connected
with the exposure to chemicals present in perfumed
articles can be reduced. The first stereoisomerically
enriched fragrances have been put on the market: Kharis-
mal, Hedione HC, and Super Cepionate are methyl
dihydrojasmonates with a high content of cis diastereo-
isomer; Paradisone is optically active (+)-cis-methyl
dihydrojasmonate; and Sandranol, Dartanol, Sanjinol,
and Levosandol are optically active (-)-2-ethyl-4-(2,2,3-
trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol.
We are going to report herein on the preparation and
on the odor evaluation of all the stereoisomers of the
commercial odorants Muguesia (1) and Pamplefleur (2).
The work is part of a project devoted to the investigation
of the odor properties of single stereoisomers of known
absolute configuration. The preparation of the single
stereoisomers of these two fragrances gave us the chance
to investigate the potentiality of enzyme chemistry in the
Lipase PS-mediated acetylation of this mixture in tert-
butylmethyl ether, in the presence of vinyl acetate, gave
after 24 h an acetate fraction which was found to be a
3.1:1 mixture of the two enantiopure (ee ) 99%, HPLC)
3R diastereoisomers of derivative 4 (Scheme 1).
The unreacted alcohol was submitted to prolonged
Lipase PS-catalyzed transesterification, by monitoring
the steric course of the reaction by chiral HPLC. At the
end of the procedure, an alcoholic fraction was recovered
which was found to be a 1:1 mixture of the two enan-
tiopure (chiral HPLC) 3S diastereoisomers of compound
3.
The mixture of (2RS,3S)-3 was reduced with sodium
boron hydride in CH2Cl2-MeOH (Scheme 2).
The 1H NMR spectrum of the crude reduction mixture
showed that the main products (84%) were the two (3S)
diastereoisomers of diol 5 showing a syn conformation
at C1-C2. The mixture was chromatographed on a silica
gel column to afford diols (1S,2R,3S)-5 (de ) 99%, GC/
MS) and (1R,2S,3S)-5 (de ) 99%, GC/MS). This latter
was obtained as a crystalline compound. The two diol
derivatives were submitted to hydrogenolysis to afford
(2S,3S)-1 and (2S,3R)-1.
The mixture of (2RS,3R)-4 was reduced with lithium
aluminum hydride in THF. The 1H NMR spectrum of the
crude reduction mixture showed that the main products
(77%) were the two (3R) diastereoisomers of diol 5
showing an anti conformation at C1-C2. The mixture was
chromatographed on a silica gel column to give diol
(1S,2S,3R)-5 (de ) 99%, GC/MS) and (1R,2R,3R)-5 (de
) 99%, GC/MS). This latter was obtained as a crystalline
compound. The two diol derivatives were submitted to
hydrogenolysis to afford (2R,3R)-1 and (2R,3S)-1.
(3) Brenna, E.; Fuganti, C.; Serra, S.; Kraft, P. Eur. J. Org. Chem.
2002, 967.
(4) Abate, A.; Brenna, E.; Dei Negri, C.; Fuganti, C.; Serra, S.
Tetrahedron: Asymmetry 2002, 13, 899.
(5) Prelog, V.; Ruzicka, L.; Wieland, P. Helv. Chim. Acta 1944, 27,
66; Ohloff, G.; Maurer, B.; Winter, B.; Giersch, W. Helv. Chim. Acta
1983, 66, 192.
(6) Abate. Brenna, E.; Fronza, G.; Fuganti, C.; Gatti, F. G.; Serra,
S.; Zardoni, E. Helv. Chim. Acta 2004, 87, 765.
(7) Frater, G.; Mu¨ller, U.; Kraft, P. Helv. Chim. Acta, 1999, 82, 1656.
1282 J. Org. Chem., Vol. 70, No. 4, 2005

Chirality and Fragrance Chemistry
SCHEME 2a
a Key: (i) NaBH4, CH2Cl2, MeOH; (ii) column chromatography; (iii) H2, Pd/C, HClO4, EtOH; (iv) LiAlH4, THF; (v) Jones’ reagent,
acetone, 0 °C; (vi) MnO2, ChCl3, rt.
TABLE 1. 1H NMR Data of syn- and anti-1
compd
ref
δ H-C(2)
syn-1
8
3.85-3.76, multiplet
our work
3.76, qd, J2,Me ) 6.3 Hz, J2,3 ) 3.7,
3.78-3.68, multiplet
anti-1
8
9
3.70, quintet, J2,3 ) J2,Me ) 6 Hz
3.70, quintet, J2,3 ) J2,Me ) 6.4 Hz
our work
The relative configuration of Muguesia stereoisomers
was assigned according to the following considerations.
Dinnocenzo et al.8 prepared (2RS,3RS)-1 (syn-1) and
(2RS,3SR)-1 (anti-1) by reaction of benzylmagnesium
bromide with trans- and cis-2,3-epoxybutane. The 1H
NMR signals of H-C(2), that is to say of CHOH, are
reported in Table 1. Kazlauskas et al.9 prepared racemic
(2RS,3SR)-1 by the same procedure, and the correspond-
ing NMR data are reported in Table 1. The analysis of
the 1H NMR spectra allowed us to establish the relative
configuration of our Muguesia samples.
Interestingly enough, the reduction of (2RS,3S)-3 and
that of (2RS,3R)-4 were characterized by different steric
courses; i.e., the two reactions afforded two different pairs
of diastereoisomers.
The relative configuration of diols 5 was assigned on
the basis of these considerations. The relative configu-
ration of the stereogenic carbon atoms C2 and C3 of our
diol samples was univocally established by the 1H NMR
spectra of the hydrogenolysis products. Hence, the rela-
tive configuration of C1 and C2 had to be assessed. For
this purpose, we submitted the two crystalline diol
samples to X-ray diffraction analysis. The molecular
structure of the one obtained by NaBH4 reduction of
hydroxy ketone 3 is shown in Figure 1. The benzylic OH
FIGURE 1. View of (1R,2S,3S)-syn-anti-5; the numbering
corresponds to that used in the X-ray analysis. Selected torsion
angles (deg): O1-C1-C2-C11, 52.0(5); O1-C1-C2-C3,
73.4(5); C5-C1-C2-C3, 162.8(4); C11-C2-C3-O2, 179.9(4);
C1-C2-C3-C4, 179.6(4).
group was found to be in a syn arrangement with respect
to the methyl group and in an anti arrangement with
respect to the other OH group, as can be deduced from
the molecular geometry shown in Figure 1. The relative
configurations of the three carbon atoms C1, C2 and C3
are completely described also by the torsion angles
reported in the caption of Figure 1. It is interesting to
note that the aliphatic chain C1-C4 is perfectly trans-
planar, while the C1-C5 bond is rotated 17.2° out of the
chain plane. This feature accounts for the deviation of
the O1-C1-C3-C4 and O1-C1-C2-C11 torsion angles
from the standard gauche value of 60°.
(8) Dinnocenzo, J. P.; Simpson, T. R.; Zuilhof, H.; Todd, W. P.;
Heinrich, T. J. Am. Chem. Soc. 1997, 119, 987.
(9) Weissfloch, A. N. E.; Kazlauskas, R. J. J. Org. Chem. 1995, 60,
6959.
The other diol, obtained together with this crystalline
one in the same reduction reaction, showed the same
coupling constant (J1,2 ) 3 Hz) between H-C(1) and
J. Org. Chem, Vol. 70, No. 4, 2005 1283

Abate et al.
ethers of acyclic 2-alkyl-3-hydroxyketones was character-
ized by high 1,2-anti diastereoselectivity.11 This result
was attributed to the fact that the bulky tert-butyldi-
methylsilyl protecting group prevented intramolecular
chelation, so that the reaction proceeded through the
open-chain model proposed by Felkin12 and Anh.13 The
same preferential steric course was observed in LiAlH4
reduction of acetoxy ketones (2RS,3R)-4.
NaBH4 reduction usually gives poor 1,2-syn diastereo-
selectivity:10b it is well established that the use of ZnBH4
provides higher values of 1,2-syn selectivity due to a
contribution of zinc chelation.14 In the case of hydroxy
ketone 3 a particularly high value of selectivity was
observed.
Our findings on the configuration of diols 5 were found
to be in contrast with some results described in the
literature. The 1H NMR signals of CHPhOH and of
CHOH of the four isomeric diols 5 described by various
authors15-20 are reported in Table 2, compared to our
values. The following conclusions can be drawn, taking
into account that in diols 5 the presence of an intramo-
lecular hydrogen bond may induce a certain conforma-
tional rigidity.
The vicinal coupling constant J1-2 between H-C(1) and
H-C(2) is smaller when the conformation at C1-C2 is syn
rather than anti. Some perplexity is arisen by the data
reported for anti,syn-5 in ref 19.
The vicinal coupling constant J2-3 is similar to the
coupling constant between H-C(3) and the methyl group,
when the conformation at C2-3 is anti. It shows a lower
value when the conformation is syn. Some perplexity
arises from the data reported for syn,anti-5 in ref 19 and
for syn,syn-5 in refs 15-17.
In Table 3, the 13C NMR spectra of diols 5 found in
the literature are compared with our data. Once again,
some perplexity is caused by the spectrum described for
syn,syn-5 in refs 15-17 and by those described for
anti,syn-5 and syn,anti-5 in ref 19.
FIGURE 2. View of (1R,2R,3R)-anti-anti-5; the numbering
corresponds to that used in the X-ray analysis. Selected torsion
angles (deg): O1-C1-C2-C11, 177.9(3); O1-C1-C2-C3,
55.3(3); C5-C1-C2-C3, 178.3(2); C11-C2-C3-O2, 61.8(3);
C1-C2-C3-O2, 171.6(2).
H-C(2). Thus, the same syn arrangement of C1-C2 could
be attributed to this stereoisomer.
The molecular structure of the crystalline diol, obtained
by LiAlH4 reduction of acetate 4, is shown in Figure 2.
The benzylic OH group was found to be in an anti
arrangement with respect to the methyl group and in a
syn arrangement with respect to the other OH group, as
can be deduced from the molecular geometry shown in
Figure 2. The relative configurations of the three carbon
atoms C1, C2, and C3 is completely described also by the
torsion angles reported in the caption of Figure 2. In this
molecule, the chain C5-C1-C2-C3-O2 is all trans-
planar and makes an angle of about 64° with the
aromatic ring plane.
The other stereoisomer, obtained together with this
crystalline one in the same reduction reaction, showed a
It had been already noticed by Bloch in 198811 that in
1,3-diol derivatives the chemical shift (13C) of the carbon
atom of the methyl group linked to C(2) was sensible to
the relative configuration of the three vicinal stereo-
centers. Typical values were described to be as follows:
δ ) ∼4 ppm for syn,syn diols, δ ) ∼10-11 ppm for
syn,anti diols, and δ ) ∼13 ppm for anti,anti diols. The
upfield shift of the chemical shift of CH3-C(2) is clearly
due to the γ-effect of the OH groups.21
coupling constant (J1,2 ) 8.1 Hz) similar to that (J1,2
6.2 Hz) of anti,anti-5. Thus, an anti conformation at C1-
C2 was assigned to both of them.
)
The conclusion was that sodium boron hydride reduc-
tion of hydroxy ketones (2RS,3S)-3 gave mainly the two
diol diastereoisomers showing a syn conformation at C1-
C2; lithium aluminum hydride reduction of acetoxy
ketones (2RS,3R)-4 gave the two diastereoisomers show-
ing an anti conformation at C1-C2. Thus, 1,2-induction
dominated over 1,3-induction: the stereogenic center at
C2 controlled the steric course of the reduction of the
adjacent carbonyl group.10 It was reported in the litera-
ture that LiAlH4 treatment of tert-butyldimethylsilyl
(11) Bloch, R.; Gilbert, L.; Girard, C. Tetrahedron Lett. 1988, 29,
1021.
(12) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199
(13) Anh, N. T. Top. Curr. Chem. 1980, 88, 145
(14) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338.
(15) Bodnar, P. M.; Palmer, W. S.; Shaw, J. T.; Smitrovich, J. H.;
Sonnenberg, J. D.; Presley, A. L.; Woerpel, K. A. J. Am. Chem. Soc.
1995, 117, 10575.
(16) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044.
(17) Bodnar, P. M.; Palmer, W. S.; Ridgway, B. H.; Shaw, J. T.;
Smitrovich, J. H.; Woerpel, K. A. J. Am. Chem. Soc. 1997, 62, 44737.
(18) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson,
P. E. J. J. Chem Soc., Perkin Trans. 1 1995, 319.
(19) Vicario, J. L.; Badia, D.; Dominguez, E.; Rodriguez, M.; Carrillo,
L. J. Org. Chem. 2000, 65, 3754.
(10) To obtain 1,3-induction two strategies have been optimized: (i)
the use of a reducing agent capable of binding the hydroxyl function
and of promoting intramolecular hydride transfer; (ii) the use of an
additive to preorganize the substrate prior to the addition of the
reducing agent which gives intermolecular hydride addition. Examples
of the first strategy: (a) Evans, D. A.; Chapman, K. T.; Carreira, E.
M. J. Am. Chem. Soc. 1988, 110, 3560. (b) Anwar, S.; Bradley, G.;
Davis, A. P. J. Chem. Soc. Perkin Trans. 1 1991, 1383. Examples of
the second strategy: (c) Narasaka, K.; Pai, F.-C. Tetrahedron 1984,
40, 2238. (d) Evans, D. E.; Hoveyda, A. H. J. Org. Chem. 1990, 55,
5190. (e) Sarko, C. R.; Collibee, S. E.; Knorr, A. L.; DiMare, M. J. Org.
Chem. 1996, 61, 868. (f) Bartoli, G.; Bellucci, M. C.; Bosco, M.; Dalpozzo,
R.; Marcantoni, E.; Sambri, L. Chem. Eur. J. 2000, 6, 2590. (g) Bartoli,
G.; Bosco, M.; Marcantoni, E.; Massaccesi, M. Rinaldi, S.; Sambri, L.
Eur. J. Org. Chem, 2001, 4679;
(20) Morihata, K.; Horiuchi, Y.; Tanigichi, M.; Oshima, K.; Utimoto,
K. Tetrahedron Lett. 1995, 36, 5555.
(21) Gu¨nther, H. NMR Spectroscopy; John Wiley & Sons: New York,
1987.
1284 J. Org. Chem., Vol. 70, No. 4, 2005

Chirality and Fragrance Chemistry
TABLE 2. 1H NMR Data of Diols 5
compd
ref
δ H-C(1)
δ H-C(3)
syn,anti-5
15-17
20
5.12, d, J1,2 ) 1.8 Hz
5.11, d, J1,2 ) 3 Hz
3.83, quintuplet, J2,3 ) J3,Me ) 6.3 Hz
3.84, m
19
5.00, d, J1,2 ) 2.8 Hz
5.08, d, J1,2 ) 3 Hz
4.23, qd, J3,Me ) 6.6 Hz, J2,3 ) 1.7 Hz,
3.80, quintuplet, J2,3 ) J3,Me ) 6.2 Hz
3.83, quintuplet, J2,3 ) J3,Me ) 6.3 Hz
4.24, qd, J3,Me ) 6.9 Hz, J2,3 ) 1.8 Hz
4.42, qd, J3,Me ) 6.4 Hz, J2,3 ) 1.9 Hz
4.22, qd, J3,Me ) 6.2 Hz, J2,3 ) 1.9 Hz,
3.90, m
3.92 ppm, dq, J2,3 ) 8.1 J3,Me ) 6.1 Hz
4.04 ppm, qd, J3,Me ) 6.5 Hz, J2,3 ) 2.5 Hz
4.04 ppm, m
our work
15-17
20
syn,syn-5
5.04, d, J1,2 ) 1.7 Hz
5.05, d, J1,2 ) 3.3 Hz
5.00, d, J1,2 ) 2.8 Hz
5.03, d, J1,2 ) 2.7 Hz
4.52, d, J1,2 ) 7.4 Hz
4.54 ppm, d, J1,2 ) 9 Hz
4.68 ppm, d, J1,2 ) 7 Hz
4.71 ppm, d, J1,2 ) 6.6 Hz
4.72 ppm, d, J1,2 ) 7.2 Hz
5.01 ppm, d, J1,2 ) 2.8 Hz
4.70 ppm, d, J1,2 ) 6.9 Hz
19
our work
15, 17
Our work
18
anti,anti-5
anti,syn-5
15, 17
20
19
4.05 ppm, qd, J3,Me ) 6.3 Hz, J2,3 ) 2.4 Hz,
4.21 ppm, qd, J3,Me ) 6.4 Hz, J2,3 ) 1.8 Hz
4.05 ppm, qd, J3,Me ) 6.5 Hz, J2,3 ) 1.9 Hz.
Our work
TABLE 3. 13C NMR Data of Diols 5
compd
ref
δ 13C NMR
syn,anti-5
15-17
19
our work
15-17
19
142.6, 128.0, 127.0, 126.1, 75.0, 70.9, 45.5, 21.9, 11.5
143.3, 127.7, 126.3, 125.2, 78.6, 71.5, 44.9, 21.6, 3.6
142.7, 128.0, 127.0, 126.1, 74.7, 70.9, 45.7, 21.9, 11.3
142.6, 128.0, 127.0, 126.1, 75.0, 70.9, 45.5, 21.9, 11.5
143.0, 127.8, 126.7, 125.3, 78.2, 71.8, 44.8, 21.4, 3.6
143.3, 128.1, 127.0, 125.6, 78.5, 72.0, 45.0, 21.5, 4.1
143.3, 128.5, 128.0, 127.1, 81.2, 73.3, 46.4, 21.8, 13.5
143.3, 128.3, 127.8, 127.1, 81.0, 73.3, 46.1, 21.7, 13.3
143.7, 128.4, 127.6, 126.4, 78.1, 69.2, 44.5, 19.4, 12.1
143.5,127.9, 126.8, 125.3, 78.2, 71.8, 44.8, 21.3, 3.7
143.7, 128.2, 127.6, 126.4, 77.7, 68.9, 44.4, 18.9, 12.0
syn,syn-5
our work
15, 17
our work
15, 17
19
anti,anti-5
anti,syn-5
our work
SCHEME 3a
These observations are in agreement with the 13C NMR
spectra of our samples.
In ref 15, 1,3-diols of structure 5 were prepared from
silirane by benzaldehyde insertion and oxidation. The
authors had assigned the relative configuration of the
four possible stereoisomers of diol 5 by NMR analysis of
the corresponding acetonides and by X-ray structural
determination of crystalline derivatives. In the Support-
ing Information of ref 15 and in the Experimental Section
of refs 16 and 17 the 13C NMR spectra of syn,syn-5 and
of syn,anti-5 are described to be perfectly identical, and
a Key: (i). BH3(Me2S); (ii) LiBH4.
“The 1,3-syn/1,3-anti product distribution and the abso-
lute configuration of the newly created chiral center were
1
the H NMR spectra of these two stereoisomers are the
1
assigned by H NMR spectroscopy by comparison of the
same, starting from the quintet at 3.83 ppm to the
doublet at 0.82 ppm. Our idea is that a mistake in the
transcription of these data had been done at the begin-
ning in ref 15 and then reiterated by the same authors
in the following papers.
In ref 19, the authors described an “easy and cheap
methodology to access to 1,3-dioxygenated chiral nonra-
cemic building blocks”. They employed (S,S)-(+)-pseu-
doephedrine to perform stereoselective aldol reactions.
The chiral nonracemic aldol products were used as
starting materials for the conversion into useful chiral
building blocks, such as R-hydroxy acids, esters, and
ketones and into 1,3-syn and 1,3-anti diols. The key step
for the preparation of 1,3 -diols was described to be the
reduction of hydroxy ketones with BH3(Me2S) to give diols
1,3-syn and with LiBH4 to afford diols 1,3-anti (Scheme
3).
coupling constants (J1,2 ) 2.8 Hz for the syn isomer and
J1,2 ) 6.8 Hz and J2,3 ) 2.4 Hz for the anti isomers, see
Experimental Section) and also from the fact that in this
particular case (the reduction product of 6) the 1,3-syn
diol is a meso compound in which both carbon atoms C1
and C3 are equivalent”. Syn and anti are referred by
these authors to the relative arrangement of the OH
groups. However, neither the 1H NMR spectra of diols 5,
obtained by reduction of hydroxy ketones 3 and 7, nor
those of the diols obtained by reduction of 6 seem to
support these statements. According to the H and 13C
NMR spectra reported for substrates 5 in this work, it
seems that both BH3 and LiBH4 reduction of hydroxy
ketones 3 and 7 gave syn,syn-5.
1
The absolute configuration of Muguesia samples was
established as follows. The two Muguesia samples (+)-
and (-)-anti-1 (Scheme 2) were oxidized with Jones’
reagent at 0 °C to give (R)-(-)- and (S)-(+)-8, respectively.
The absolute configuration of 3-methyl-4-phenyl-2-bu-
tanone had been established by correlation with 2-meth-
Hydroxy ketone 6 was employed as a model compound,
and the conclusions drawn on this substrate were then
extended to the reduction of other hydroxy ketones,
among which (2R,3S)-3. The following sybilline sentence
was used to explain the assignment of configuration:
J. Org. Chem, Vol. 70, No. 4, 2005 1285

Abate et al.
TABLE 4. [r]D Values of Diols 5
compd
reference
(1R,2S,3R)-syn,syn-5
19
[R]D ) -12.3 (c 0.2, CH2Cl2)
[R]D ) +35.5 (c 0.46, CHCl3
[R]D ) +12.4 (c 0.1, CH2Cl2)
[R]D ) -27.7 (c 0.7, CHCl3)
26
(1S,2R,3S)-syn,syn-5
(1R,2S,3S)-syn,anti-5
19
our value
19
our value
19
26
[R]D ) +15.6 (c 0.1, CH2Cl2) wrong NMR
[R]D ) +52.3 (c 1.12, CH2Cl2)
(1R,2R,3S)-anti,syn-5
(1S,2S,3R)-anti,syn-5
[R]D ) +15.8 (c 0.1, CH2Cl2) wrong NMR
[R]D ) -44.6 (c 0.40, CHCl3)
[R]D ) +25.2 (c 1.1, CHCl3)
[R]D ) +27.8 (c 1.0, CHCl3)
our value
our value
(1R,2R,3R)-anti,anti-5
SCHEME 4a
SCHEME 5a
a Key: (i) PPL, tert-butylmethyl ether, vinyl acetate.
dized according to the Swern procedure and treated with
methylmagnesium chloride in diethyl ether. A 1:1 a
mixture of the two enantiopure (3S)-1 stereoisomers was
thus obtained.
a Key: (i) Baker’s yeast, water, glucose; (ii) DMSO, (COCl)2; (iii)
MeMgCl, Et3O.
Pamplefleur. (R)- and (S)-2-phenyl-1-propanol (11)
are commercial products. The need for a large quantity
of enantiopure (R)- and (S)-11, to be used as starting
materials for the preparation of the four isomers of
Pamplefleur, induced us to investigate the lipase-medi-
ated kinetic resolution of racemic primary alcohol 11.
Only a few examples of the lipase-mediated kinetic
resolution of racemic 11 were reported in the literature.
PPL-catalyzed acetylation in water-saturated hexane, in
the presence of vinyl acetate, gave after 12 h at 30 °C an
acetate derivative and an unreacted alcohol with poor
enantiomeric excess (ee ) 65% and 69%, respectively).
A mistake in the assignment of the CIP descriptors did
not allow us to verify the real stereochemistry of the
acetate and of the unreacted alcohol.28 Naemura et al.
reported that when racemic 11 was treated with Lipase
YS at 30 °C in diisopropyl ether solution, with isopropen-
yl acetate as an acyl donor, after 7 h a (-)-acetate
derivative and a (+)-unreacted alcohol were obtained,
yl-4-phenylpropionic acid.22-24 A further confirmation was
given by the fact that (+)-syn,anti-5 was oxidized with
MnO2 in CH2Cl2, to give (2S,3S)-(+)-3.25
The specific optical rotations of some stereoisomers of
diol 5 were reported in the literature and are collected
in Table 4: we could not find total correspondence
between our values of [R]D and the known data.26 The
[R]D value we obtained for (1S,2R,3S)-syn,syn-5 was in
accordance with that described in ref 26 for the enanti-
omer (1R,2S,3R)-syn,syn-5. This latter was used by
Hatakeyama et al. as a precursor for the preparation of
(+)-conagenin. On the contrary, the [R]D value described
by the same authors for (1S,2S,3R)-anti,syn-5 is contrast
with the value we obtained for the same enantiomer. No
NMR spectra are reported in ref 26, and the absolute
configurations are determined by the MTPA ester tech-
nique. (1S,2S,3R)-anti,syn-5 is described as a byproduct
in the preparation of (1R,2S,3R)-syn,syn-5, and it is not
correlated to any natural compound.
No correspondence was found between our data of
specific rotation and those described in ref 19 for com-
pounds of correct relative configuration.
The evaluation of Muguesia samples by professional
perfumers (see Olfactory evaluation) showed that the two
3S stereoisomers had the most interesting odor proper-
ties. We, then, optimized a baker’s yeast approach to the
mixture of the two (3S) isomers of Muguesia (Scheme 4).
Baker’s yeast reduction of unsaturated aldehyde 927
gave enantiomerically pure (S)-10. This latter was oxi-
with very low optical purity ([R]D ) -0.08 and [R]D
)
+0.60, respectively).29 Better results were described for
Lipase PS-mediated transesterification of racemic 11
with vinyl 3-(para-substituted phenyl)propanoates in
cyclohexane: (S)-12 (ee ) 97-98%) and (R)-11 (ee ) 34-
56%) were obtained.30 Enantiomeric ratios not higher
than 2.7 were described when sol-gel encapsulated
lipases were employed.31
Short reaction times and the use of PPL allowed us to
recover acetate 12 with ee ) 92% (chiral GC of the
corresponding alcohol) (Scheme 5).
The unreacted alcohol was enriched with the (R)-
isomer (ee ) 91%, chiral GC) by prolonged PPL-mediated
(22) Kirmse, W.; Gu¨nther, B.-R. J. Am. Chem. Soc. 1978, 100, 3619.
(23) Kashiwagi, T.; Fujimori, K.; Kozuka, S.; Oae, S. Tetrahedron
1970, 26, 3647.
(24) Rangaishenvi, M. V.; Singaram, B.; Brown, H. C. J. Org. Chem.
1991, 56, 3286.
(28) Chen, C.-S.; Liu, Y.-C. J. Org, Chem. 1991, 56, 1966.
(29) Naemura, K.; Fukuda, R.; Murata, M.; Konishi, M.; Hirose, K.;
Yobe, Y. Tetrahedron: Asymmetry 1995, 6, 2385.
(25) Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc. 1988,
110, 5579.
(30) Kawasaki, M.; Goto, M.; Kawataba, S.; Kometani, T. Tetrahe-
drom: Aymmetry 2001, 12, 585.
(26) Hatakeyama, S.; Fukuyama, H.; Mukugi, Y.; Irie, H. Tetrahe-
dron Lett. 1996, 37, 4047.
(31) Reetz, M. T.; Tielmann, P.; Wiesenhoefer, W.; Koenen, W.;
Zonta, A. Adv. Synth. Catal. 2003, 345, 717.
(27) Fuganti. C.; Grasselli P. Chem. Ind. (London) 1977, 983.
1286 J. Org. Chem., Vol. 70, No. 4, 2005

Chirality and Fragrance Chemistry
SCHEME 6a
a Key: (i) methylmalonic acid, diethyl ester, NaH, DMF; (ii) KOH, H2O, EtOH, reflux; (iii) LiAlH4, THF; (iv) PPL, tert-butylmethylether,
vinyl acetate; (v) Jones’ reagent, acetone; (vi) CH2N2 in Et2O; (vii) KOH, MeOH.
transesterification, and the steric course of the reaction
was monitored by chiral GC. (R)- and (S)-11 were
converted into the corresponding bromo derivatives (R)-
and (S)-13 (Scheme 6), which were then submitted to
malonic reaction with methylmalonic acid diethyl ester.
Saponification and decarboxylation of the reaction mix-
ture allowed us to obtain (2RS,4S)-14 and (2RS,4R)-14.
The two mixtures of enantiomerically enriched acid
diastereoisomers were then reduced to alcohols (2RS,4S)-2
and (2RS,4R)-2, respectively. (2RS,4S)-2 was treated
with PPL in tert-butylmethyl ether in the presence of
vinyl acetate. Short reaction times allowed us to recover
(2R,4S)-15 with de ) 84% (1H NMR δ CH3COO). The
unreacted alcohol was enriched with the (2S,4S) diaste-
reoisomer by prolonged PPL treatment to reach de )
52%.
Olfactory Evaluation. (2R,3S)-1: top note: floral,
rosy, buttery, rich, slightly green; dry down: floral, sweet,
lily of the valley and linalool-like.
(2S,3S)-1: top note: floral, balsamic, sweet, floral,
slightly fruity; dry down: floral, cinnamic, balsamic,
sweet.
(2S,3R)-1: top note: weak, floral-hesperidic, tea-like;
dry down: empty.
(2R,3R)-1: top note: very weak, slightly acidic and
agrestic, dry down: empty
(2R,4S)-2: natural fruity odor in the direction of
grapefuit and rhubarb, close to gardenol (methyl phenyl
carbinyl acetate) and 2,5-dimethyloct-2-en-6-one, slightly
metallic.
(2S,4S)-2: floral-fruity odor in the direction of grape-
fruit and linalool with earthy, woody, and bitter nuances,
also reminiscent of 2,5-dimethyloct-2-en-6-one and of
some aspects of vetiver oil.
(2S,4R)-2: fruity-citric odor, with some harsh, animalic,
and slightly woody nuances, also is a bit rubbery.
(2R,4R)-2: floral-fruity odor in the direction of rhubarb
with a touch of grapefruit, reminiscent of gardenol
(methylphenyl carbinyl acetate).
The Pamplefleur isomers have a high tenacity on
blotter (>24 h), so they are all quite substantive. In the
IFF catalog Pamplefleur is described as “Citrus, Grape-
fruit, Floral, Vetivert”: the odor descriptions show that
each isomer contributes to a particular facet of the final
odorant, to produce an unique blend. All the isomers
share a hesperidic grapefruit tonality. With respect to
this grapefruit note (2R,4S)-2 is the most typical, but
Pamplefleur is a complex blend in which all compounds
play a definite role.
On the contrary, the configuration at the carbon atom
in position 3 seems to be important in establishing the
odor properties of Muguesia: the (3R) stereoisomers are
weak and completely devoid of odor in the dry down note.
The (3S) stereoisomers are the effective odor vectors of
commercial Muguesia.
When the same procedure was applied to (2RS,4R)-2,
(2R,4R)-15 (de ) 85%, 1H NMR δ CH3COO) and (2S,4R)-2
(de ) 87%) were obtained. We took advantage of the PPL-
catalyzed enantioselective acetylation of the primary
function of alcohol 2 to separate the two enantiopure
diastereoisomers.
As for the configuration assignment, the absolute
configuration of 2-phenyl-1-propanol was known. The
relative configuration of the two stereogenic carbon atoms
was established as follows. The alcohol recovered unre-
acted by the PPL-mediated transesterification of (2RS,4R)-
2 was oxidized by Jones’ reagent and esterified with
diazomethane to give the corresponding methyl esters 16.
The same procedure was applied to the alcohol obtained
by hydrolysis of the acetate produced by PPL-catalyzed
1
transesterification of (2RS,4R)-2. The H NMR spectra
of the two methyl esters 16 were recorded and compared
with those described by Fleming for the two racemic
diastereoisomers. The relative configuration of the cor-
responding Pamplefleur isomers was thus assigned.32 The
1H and 13C NMR spectra of the two enantiomers of anti-2
were found to be in agreement with those described by
Heathcock et al. for the racemic substrate.33
Conclusions
(32) Barbero, A.; Blakemore, D. C.; Fleming, I.; Wesley, R. N. J.
Chem. Soc., Perkin Trans. 1 1997, 1329.
(33) Mori, I.; Bartlett, P. A.; Heathcock, C. H. J. Org. Chem. 1990,
55, 5966.
The preparation of the single isomers of Muguesia and
Pamplefleur is part of an extensive investigation of the
J. Org. Chem, Vol. 70, No. 4, 2005 1287

Abate et al.
CH3 of (2R,3R)-4), 3.73 (quintet, J ) 6.9 Hz, CH-CH3 of
(2S,3R)-4), 1.98 (s, OCOCH3 of (2S,3R)-4), 1.94 (s, OCOCH3
of (2R,3R)-4), 1.15-1.30 (four overlapping d, CHCH3 of both
diast); GC/MS (2R,3R)-4 tR ) 19.32 min, m/z 177 (M+ - 43,
2), 165 (10), 134 (18), 105 (100), 77 (25), (2S,3R)-4 tR ) 19.39
m/z 177 (M+ - 43, 2), 165 (10), 134 (10), 105 (100), 77 (22).
Anal. Calcd for C13H16O3: C, 70.89; H, 7.32. Found: C, 70.67;
H, 7.58.
The alcohol fraction (10.4 g, 40%) was submitted to pro-
longed Lipase-PS transesterification in the same conditions.
The reaction was monitored by chiral HPLC until a 1:1 of the
(2RS,3S)-3 (ee ) 99%, ee ) 99%) was obtained (6.71 g, 65%).
1H NMR and MS spectra were in accordance with those of the
mixture of racemic diastereoisomers.
phenomenon of stereoselectivity in the process of odor
perception. It is impossible to predict the results of this
kind of study. Single stereoisomers have to be prepared
and evaluated separately.
The odor response of Pamplefleur isomers is rather
unusual in the realm of chiral fragrances. It represents
a yet undiscovered case, in which no stereoisomer pre-
vails, but each one plays a definite role in establishing
the odor sensation of the final blend. Stereoselectivity is
shown not in the preference of our olfaction for a certain
stereoisomer, as it happens with Muguesia, but in the
fact that we perceive distinctly each stereoisomer in the
whole fragrant mixture.
(1S,2R,3S)-1-Phenyl-2-methyl-1,3-butanediol ((1S,2R,3S)-
syn,syn-5) and (1R,2S,3S)-1-Phenyl-2-methyl-1,3-butane-
diol ((1R,2S,3S)-syn,anti-5). The 1:1 mixture of (2RS,3S)-3
(6.60 g, 0.037 mol) was treated with NaBH4 (1.41 g, 0.037 mol)
in CH2Cl2-MeOH 2:1 (100 mL). After the usual workup, the
crude product was chromatographed on a silica gel column
(hexane/ethyl acetate 7:3) to afford, in order of elution, first
(1S,2R,3S)-syn,syn-5 (2.53 g, 38%) and then (1R,2S,3S)-
syn,anti-5 (2.32 g, 35%).
Once again, we have the opportunity to discover how
much data is encoded in the absolute configuration of a
chiral odorant.
The enantioselective approach to the four stereoiso-
mers of 1 and 2 was rather challenging, because of the
presence of two stereocenters in position 1-2 and 1-3,
respectively. The work shows how efficiently biocatalyzed
routes can provide samples of single stereoisomers for
the evaluation of odor properties.
(1S,2R,3S)-syn,syn-5: [R]D ) -27.7 (c 0.7, CHCl3); de ) 99%
1
(GC/MS); H NMR (250 MHz, CDCl3) δ (ppm) 7.40-7.20 (m,
According to our experience, the lipase-mediated trans-
esterification of hydroxy ketones is a highly enantiose-
lective process. We took advantage of it in the case of
Muguesia, but also in recent works devoted to the
preparation of all the stereoisomers of the chiral odorants
Floropal,34 Florol, and Clarycet6. Simple and accurate
chemistry allowed us to control the relative stereochem-
istry of the two vicinal stereogenic centers of final
compound 1. The additional stereocenter, introduced
rather unexpectedly in a diastereoselective way by
conventional reductions of substrates 3 and 4, was
fundamental to assist the separation of the precursors
of Muguesia stereoisomers.
We tried also to bring clarity in the assignment of the
relative configuration of diols 5. A certain confusion was
present in the literature as for the 1H and 13C NMR data
of the four diastereoisomers. 1,3-Diols of this type are
described to be important synthons of modern organic
chemistry. Thus, the univocal determination of their
configuration by spectroscopic data is of great relevance.
As for Pamplefleur, we optimized the lipase-mediated
acetylation of a racemic primary alcohol. We also ex-
ploited the preference of the enzyme for the acetylation
of OH groups of a certain absolute configuration, to
separate the two mixtures of enantiomerically enriched
diastereoisomers (2RS,4R)-2 and (2RS,4S)-2.
5H, aromatic hydrogens), 5.03 (d, 1H, J ) 2.7 Hz, PhCHOH),
4.22 (qd, 1H, J ) 6.2, 1.9 Hz, CH3CHOH), 1.70 (m, 1H, CHC-
(2)), 1.22 (d, 3H, J ) 6.2 Hz, CH3CHOH), 0.82 (d, 3H, J ) 6.9
Hz, CH3C(2)); 13C NMR (62.90 MHz, CDCl3) δ (ppm) 143.3,
128.1, 127.0, 125.6, 78.5, 72.0, 45.0, 21.5, 4.1; GC/MS tR ) 18.37
min, m/z 162 (M+ - 18, 10), 117 (13), 107 (100). Anal. Calcd
for C11H16O2: C, 73.30; H, 8.95. Found: C, 73.09; H, 8.79.
(1R,2S,3S)-syn,anti-5: mp 83-85 °C; [R]D ) +52.3 (c 1.12,
CHCl3); de ) 99% (GC/MS). 1H NMR (250 MHz, CDCl3) δ
(ppm) 7.42-7.22 (m, 5H, aromatic hydrogens), 5.08 (d, 1H, J
) 3.0 Hz, PhCHOH), 3.80 (quintet, 1H, J ) 6.2 Hz, CH3CHOH),
1.82 (m, 1H, CHC(2)), 1.28 (d, 3H, J ) 6.2 Hz, CH3CHOH),
0.79 (d, 3H, J ) 7.2 Hz, CH3C(2)); 13C NMR (62.90 MHz,
CDCl3) δ 142.7, 128.0, 127.0, 126.1, 74.7, 70.9, 45.7, 21.9, 11.3;
GC/MS tR ) 18.55 min, m/z 162 (M+ - 18, 12), 117 (15), 107
(100). Anal. Calcd for C11H16O2: C, 73.30; H, 8.95. Found: C,
73.46; H, 8.67.
(1S,2S,3R)-1-Phenyl-2-methyl-1,3-butanediol ((1S,2S,3R)-
anti,syn-5) and (1R,2R,3R)-1-Phenyl-2-methyl-1,3-butane-
diol ((1R,2R,3R)-anti,anti-5). The 3.1:1 mixture of (2RS,3R)-4
(7.20 g, 0.032mol) was treated with LiAlH4 (5.58 g, 0.040mol)
in THF (150 mL). After the usual workup, the crude product
was chromatographed on a silica gel column (hexane/ethyl
acetate 7:3) to afford, in order of elution, first (1S,2S,3R)-
anti,syn-5 (1.04 g, 18%) and then (1R,2R,3R)-anti,anti-5 (3.34
g, 58%).
(1S,2S,3R)-anti,syn-5: [R]D ) +25.2 (c 1.1, CHCl3); de ) 99%
1
(GC/MS); H NMR (250 MHz, CDCl3) δ (ppm) 7.40-7.20 (m,
5H, aromatic hydrogens), 4.70 (d, 1H, J ) 6.9 Hz, PhCHOH),
4.05 (qd, 1H, J ) 6.5, 1.9 Hz, CH3CHOH), 1.95 (m, 1H, CHC-
(2)), 1.21 (d, 3H, J ) 6.5 Hz, CH3CHOH)), 0.82 (d, 3H, J ) 6.9
Hz, CH3C(2)); 13C NMR (62.90 MHz, CDCl3) δ (ppm) 143.7,
Experimental Section
Acetate of 3-Hydroxy-2-methyl-1-phenylbutan-1-one
(2RS,3R)-4 and 3-Hydroxy-2-methyl-1-phenylbutan-1-
one (2RS,3S)-3. The 1:1 mixture of (2RS,3RS)-3 and
(2RS,3SR)-3 (26.0 g, 0.l46 mol) was treated with Lipase PS
(20 g) in tert-butylmethyl ether solution (200 mL), in the
presence of vinyl acetate (50 mL). After 24 h, an acetate
fraction (7.38 g, 23%) was recovered which was found to be a
3.1:1 mixture of (2R,3R)-4 (ee ) 99%, HPLC) and (2S,3R)-4
(ee ) 99%, HPLC)): 1H NMR (250 MHz, CDCl3): δ (ppm) 8.07
(m, Hortho of (2R,3R)-4), 7.90 (m, Horthoof (2S,3R)-4), 7.54 (m,
aromatic hydrogens of both diastereoisomers), 5.26 (m, CH-
OAc of both diastereoisomers), 3.81 (quintet, J ) 6.9 Hz, CH-
128.2, 127.6, 126.4, 77.7, 68.9, 44.4, 18.9, 12.0; GC/MS tR
)
18.32 min, m/z 162 (M+ - 18, 2), 117 (15), 107 (100). Anal.
Calcd for C11H16O2: C, 73.30; H, 8.95. Found: C, 73.44; H,
9.09.
(1R,2R,3R)-anti,anti-5: mp 85-87 °C; [R]D ) +27.8 (c 1.0,
CHCl3); de ) 99% (GC/MS); 1H NMR (250 MHz, CDCl3) δ
7.40-7.20 (m, 5H, aromatic hydrogens), 4.54 (d, 1H, J ) 9.0
Hz, PhCHOH), 3.92 (dq, 1H, J ) 8.1, 6.1 Hz, CH3CHOH), 1.85
(m, 1H, CHC(2)), 1.26 (d, 3H, J ) 6.1 Hz, CH3CHOH), 0.79
(d, 3H, J ) 6.9 Hz, CH3C(2)); 13C NMR (62.90 MHz, CDCl3) δ
(ppm) 143.3, 128.3, 127.8, 127.1, 81.0, 73.3, 46.1, 21.7, 13.3;
GC/MS tR ) 18.48 min, m/z 162 (M+ - 18, 10), 117 (30), 107
(100). Anal. Calcd for C11H16O2: C, 73.30; H, 8.95. Found: C,
73.11; H, 9.18.
(34) Abate, A.; Brenna, E.; Fronza, G.; Fuganti, C.; Ronzani, S.;
Serra, S. Helv. Chim. Acta 2003, 86 592.
1288 J. Org. Chem., Vol. 70, No. 4, 2005

Chirality and Fragrance Chemistry
(2S,3S)-3-Methyl-4-phenyl-2-butanol ((2S,3S)-syn-1).
(1S,2R,3S)-syn,syn-5 (2.40 g, 0.013 mol) was treated with H2
at athmospheric pressure and room temperature, in ethanol
(50 mL) in the presence of HClO4 (1 mL), using Pd/C 5% (0.240
g) as a catalyst. After the usual workup, the crude product
was purified by column chromatography on a silica gel column
(hexane/AcOEt 9:1) and bulb-to-bulb distilled (1.51 g, 71%):
de ) 99% (GC/MS); ee ) 99% (chiral GC of the corresponding
acetate derivative); [R]D ) -8.2 (c 0.98, CHCl3); 1H NMR (250
MHz, CDCl3) δ (ppm) 7.39-7.14 (m, 5H, aromatic hydrogens),
3.76 (qd, 1H, J ) 6.2, 3.7 Hz, CH3CHOH), 2.82 (dd, 1H, J )
13.5, 5.9 Hz, H-C(4)), 2.40 (dd, 1H, J ) 13.5, 8.9 Hz, H-C(4)),
1.78 (m, 1H, CHC(3)), 1.20 (d, 3H, J ) 6.2 Hz, CH3CHOH),
0.86 (d, 3H, J ) 6.7 Hz, CH3C(3)); 13C NMR (62.90 MHz,
CDCl3) δ (ppm) 140.9, 129.1, 128.1, 125.6, 70.4, 41.8, 39.3, 20.6,
13.4; GC/MS tR ) 13.86 min, m/z 164 (M+, 5), 146 (37), 131
(45), 91 (100). Anal. Calcd for C11H16O: C, 80.44; H, 9.82.
Found: C, 80.13; H, 9.68.
(3S)-(+)-3-Methyl-4-phenyl-2-butanone ((S)-8). (-)-an-
ti-1 (0.050 g, 0.304 mmol) was treated with Jones’ reagent at
0 °C. The reaction mixture was filtered on a silica gel column
(AcOEt) to afford (S)-(+)-8 (0.033 g, 68%): [R]D ) +31.8 (c 1.0,
CHCl3); [R]D ) +40.8 (c 0.95, EtOH) [lit.24 [R]D ) +45.5 (c 2,
EtOH, ee ) 99%)]; 1H NMR (250 MHz, CDCl3) δ (ppm) 7.45-
7.00 (m, 5H, aromatic hydrogens), 3.00 (dd, 1H, J ) 13.7, 6.4
Hz, H-C(4)), 2.82 (m, 1H, H-C(3)), 2.56 (dd, 1H, J ) 13.7, 6.9
Hz, H-C(4)), 2.08 (s, 3H, CH3CO), 1.09 (d, 3H, J ) 6.4 Hz, CH3-
C(3)); GC/MS tR ) 12.80 min, m/z 162 (M+, 44), 147 (40), 91
(100). Anal. Calcd for C11H14O: C, 81.44; H, 8.70. Found: C,
81.65; H, 8.48.
(2S,3S)-3-Hydroxy-2-methyl-1-phenylbutan-1-one
((2S,3S)-3). (+)-syn,anti-5 (0.050 g, 0.304 mmol) was treated
with manganese(IV) oxide (0.025 g) in methylene chloride (10
mL) at room temperature. After 24 h, the reaction mixture
was filtered and concentrated under reduced pressure to give
(2S,3S)-(+)-3 (0.043 g, 88%): [R]D ) +61.2 (c 1.1, CHCl3) [lit.25
[R]D ) +62.3 (CHCl3)]; 1H NMR (250 MHz, CDCl3) δ (ppm)
7.94 (m, 2H, aromatic hydrogens,), 7.56 (m, 1H, aromatic
hydrogen), 7.46 (m, 2H, aromatic hydrogens), 4.11 (quintet,
1H, J ) 6.4 Hz, CH-OH), 3.48 (quintet, 1H, J ) 6.9 Hz, CH-
CH3), 1.26 (d, 3H, J ) 6.4 Hz, CH3CHOH), 1.20 (d, 3H, J )
6.9 Hz, CH3CHCO). Anal. Calcd for C11H14O2: C, 74.13; H,
7.92. Found: C, 74.38; H, 7.78.
(R)-2-Phenylpropanol ((R)-11) and (S)-Acetic Acid
2-Phenylpropyl Ester ((S)-12). Racemic 11 (50.0 g, 0.368
mol) was treated with PPL (20 g) in tert-butylmethyl ether
solution (200 mL), in the presence of vinyl acetate (50 mL).
After 30 min, the reaction mixture was filtered and separated
by column chromatography on silica gel (hexane/ethyl acetate
9/1) to give (R)-12 (9.81 g, 15%): ee ) 92% (chiral GC of the
corresponding alcohol); [R]D ) -3.37 (c 1.18, CHCl3) [lit.36 [R]D
) -2.8 (c 10.09, CHCl3) for (S)-12]; 1H NMR (250 MHz, CDCl3)
δ 7.13-7.38 (m, 5H, aromatic hydrogens), 4.20 (dd, 1H, J )
10.8, 6.9 Hz, H-CHOAc), 4.20 (dd, 1H, J ) 10.8, 7.2 Hz,
H-CHOAc), 3.09 (m, 1H, CHCH3), 2.01 (s, 3H, OAc), 1.30 (d,
3H, J ) 6.9 Hz, CHCH3); GC/MS tR ) 13.48 min m/z 135 (M+
- 43, 1), 118 (100), 105 (92).
room temperature, (R)-11 (13.0 g, 0.065 mol) was added, and
the mixture was stirred for 24 h at room temperature. The
reaction mixture was poured into water and extracted with
ethyl acetate. The organic phase was dried (Na2SO4), and the
residue was dissolved in a mixture of NaOH 20% (50 mL) and
ethanol (100 mL). The mixture was refluxed for 12 h and
poured into water. The aqueous phase was acidified (HCl 10%)
and extracted with ethyl acetate. The organic phase was dried
(Na2SO4) and concentrated under reduced pressure to give
(2RS,4S)-14 (7.61 g, 61%): 1H NMR (250 MHz, CDCl3) δ (ppm)
7.35-7.05 (m, 5H, aromatic hydrogens), 2.79 (m, 1H, H-C(4)
of both diastereoisomers), 2.33 (m, 1H, H-C(2) of both diaste-
reoisomers), 2.05 (m, 1H, H-C(3) of both diastereoisomers), 1.60
(m, 1H, H-C(3) of both diastereoisomers), 1.20-1.28 (2d, 3H,
J ) 7.0 Hz, CH3-C(4) of both diastereoisomers), 1.05-1.20 (2d,
3H, J ) 6.5 Hz, CH3-C(2) of both diastereoisomers); GC/MS:
I diastereoisomer tR ) 17.80 min, m/z 192 (M+, 4), 119 (100),
105 (77); II diastereoisomer tR ) 18.18 min, m/z 192 (M+, 6),
119 (100), 105 (77). Anal. Calcd for C12H16O2: C, 74.97; H, 8.39.
Found: C, 74.64; H, 8.49.
(2S,4S)-2-Methyl-4-phenylpentanol ((2S,4S)-2) and
(2R,4S)-Acetic Acid 2-Methyl-4-phenylpent-1-yl Ester
((2R,4S)-15). (2RS,4S)-2 (5.50 g, 0.031 mol) was treated with
PPL (5 g) in tert-butylmethyl ether solution (50 mL) in the
presence of vinyl acetate (10 mL) for 1 h. The reaction mixture
was filtered and concentrated under reduced pressure. The
residue was chromatographed on a silica gel column to give
(2R,4S)-15 (0.750 g, 11%): [R]D ) -3.9 (c 0.96, CHCl3), ee )
1
91% (from (R)-11), de ) 84% (1H NMR δ CH3COO); H NMR
(250 MHz, CDCl3) δ (ppm) 7.30-7.05 (m, 5H, aromatic
hydrogens), 3.84 (m, 2H, CH2-OAc), 2.80 (m, 1H, CHPh), 2.02
(s, 3H, CH3COO), 1.80-1.30 (m, 3H, H-C(2) + 2H-C(3)), 1.25
(d, 3H, J ) 6.1 Hz, CH3-C(4)), 0.92 (d, 3H, J ) 6.9 Hz, CH3-
C(2)). Anal. Calcd for C14H20O2: C, 76.33; H, 9.15. Found: C,
76.58; H, 9.49.
The unreacted alcohol was submitted to prolonged PPL
treatment to give (2S,4S)-2 (0.772 g, 14%): [R]D ) +2.2 (c 0.90,
CHCl3), ee ) 91% (from (R)-11), de ) 52% (1H NMR of the
corresponding acetate, δ CH3COO); 1H NMR (250 MHz,
CDCl3)33 δ (ppm) 7.40-7.20 (m, 5H, aromatic hydrogens), 3.52
(dd, 1H, J ) 10.8, 5.2 Hz, CH-OH), 3.43 (dd, 1H, J ) 10.8, 6.1
Hz, CH-OH), 2.81 (m, 1H, CHPh), 1.62 (m, 2H), 1.40 (2H, m),
1.23 (d, 3H, J ) 6.5 Hz, CH3-C(4)), 0.90 (d, 3H, J ) 6.5 Hz,
CH3-C(2)); 13C NMR33 (62.90 MHz, CDCl3) δ (ppm) 147.8,
128.4, 126.9, 125.6, 68.1, 41.9, 37.0, 33.5, 22.2, 16.8. Anal.
Calcd for C12H18O: C, 80.85; H 10.18. Found: C, 80.61; H,
10.32.
(2R,4S)-2-Methyl-4-phenylpentanol ((2R,4S)-2). Saponi-
fication of (2R,4S)-15 (0.700 g, 3.18 mmol) with KOH (0.213
g, 3.82 mmol) in methanol (10 mL) gave after the usual workup
(2R,4S)-2 (0.470 g, 83%): [R]D ) -27.4 (c 0.95, CHCl3), ee )
91% (from (R)-11), de ) 84% (1H NMR δ CH3COO of the
corresponding acetate). NMR data were in agreement with
those of the enantiomer. Anal. Calcd for C12H18O: C, 80.85; H
10.18. Found: C, 81.05; H, 10.01.
(2S,4R)-2-Methyl-4-phenylpentanoic Acid Methyl Es-
ter ((2S,4R)-syn-16). A sample of the alcohol recovered
unreacted from the PPL transesterification of (2RS,4R)-2 was
treated with Jones’ reagent and then with diazomethane in
diethyl ether. The methyl ester obtained resulted to be (2S,4R)-
16 by comparison of its 1H NMR spectrum with the one
described for the racemic syn diastereoisomer in the literature:
The unreacted alcohol was enriched in the (R)-enantiomer
by prolonged PPL-mediated acetylation. The reaction was
monitored by chiral GC: (R)-11 (12.3 g, 25%), ee ) 91% (chiral
GC); [R]D ) +13.1 (c 1.09, CHCl3) [lit.37 [R]D ) +16.53 (c 1.471,
1
CHCl3)]. The HNMR spectrum was in accordance with that
reported in the literature.37
32
1H NMR (250 MHz, CDCl3) δ (ppm) 7.35-7.05 (m, 5H,
(2RS,4S)-2-Methyl-4-phenylpentanoic Acid ((2RS,4S)-
14). Diethyl methylmalonate (23.0 g, 0.132 mmol) was added
dropwise at 0 °C into a suspension of NaH (55% dispersion in
mineral oil, 3.40 g, 0.078 mol) in DMF (150 mL). After 1 h at
aromatic hydrogens), 3.58 (s, 3H, COOMe), 2.73 (m, 1H,
H-C(4)), 2.33 (m, 1H, H-C(2)), 2.05 (ddd, 1H, J ) 13.7, 8.8, 6.5
Hz, H-C(3)), 1.61 (m, 1H, H-C(3)), 1.26 (d, 3H, J ) 7.0 Hz,
CH3-C(4)), 1.14 (d, 3H, J ) 6.1 Hz, CH3-C(2)); GC/MS tR
)
16.50 min m/z 206 (M+, 4), 175 (14), 119 (91), 105 (82), 88 (100).
(35) Orsini, F. J. Org. Chem. 1997, 62, 1159.
(36) Matsumoto, T.; Ishida, T.; Yoshida, T.; Terao, H.; Takeda, Y.;
Asakawa, Y. Chem. Pharm. Bull. 1992, 40, 1721.
(37) Toda, A.; Aoyama, H.; Mimura, N.; Ohno, H.; Fujii, N.; Ibuka,
T. J. Org. Chem. 1998, 63, 7053-7061.
Acknowledgment. We thank Dr. Philip Kraft and
Mr. Jean Jacques Rouge (Givaudan Schweiz AG, Fra-
J. Org. Chem, Vol. 70, No. 4, 2005 1289

Abate et al.
Preparation and spectral data of (2RS,3RS)- and (2RS,3SR)-
3, (2R,3R)-syn-1, (2S,3R)-anti-1, (2R,3S)-anti-1, (R)-8, (S)-11,
(R)- and (S)-13, (2RS,4R)-14, (2RS,4S)-2, (2RS,4R)-2, (2S,4R)-
2, (2R,4R)-15, (2R,4R)-2), and (2R,4R)-anti-16. This material
is available free of charge via the Internet at http://pubs.acs.org.
grance Research, Switzerland) for the odor descriptions.
COFIN-Murst is acknowledged for financial support.
Supporting Information Available: General experimen-
tal methods and X-ray crystallographic crystallographic data.
CIF files of (1R,2S,3S)-syn-anti-5 and (1R,2R,3R)-anti-anti-5.
JO048445J
1290 J. Org. Chem., Vol. 70, No. 4, 2005