Bio-catalysed synthesis of optically active Undecavertol enantiomers

Article abstract of DOI:10.1016/j.tetasy.2005.04.022

Two enantiomers of Undecavertol were prepared by enzymatic methods and their odour properties evaluated.

Full text of DOI:10.1016/j.tetasy.2005.04.022

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1997–1999
Bio-catalysed synthesis of optically active
Undecavertolꢀ enantiomers
Agnese Abate, Elisabetta Brenna* and Ginevra Fregosi
Dipartimento di Chimica, Materiali ed Ingegneria Chimica del Politecnico, Via Mancinelli 7, I-20131 Milano, Italy
Received 14 March 2005; accepted 25 April 2005
Available online 23 May 2005
Abstract—Two enantiomers of Undecavertolꢀ were prepared by enzymatic methods and their odour properties evaluated.
ꢁ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
perception point of view.2 Second, it is necessary to find
new odourants to replace the 26 allergenic fragrances.
New odour sensations can be developed by preparing
new synthetic odourous molecules or investigating the
odour response of enantiomers. Finally, if two enantio-
mers show very different odour thresholds, the most
potent one can be employed in commercial formulations
in a reduced amount, thus decreasing the quantity of
chemicals interacting with human beings.
Fragrance materials are employed in a wide range of
products ranging from perfumes to skin products such
as creams, lotions, detergents and several other personal
and household products. Allergic skin reactions to fra-
grances have been observed in the past by some users,
but recently this problem has become very topical and
the real size of the problem has yet to be established.
The European CommissionÕs Scientific Committee on
Cosmetics and other Non-Food Products (SCCNFP)
recognised that some perfume constituents elicit derma-
tological reactions. This committee listed 26 substances
as skin-sensitising ingredients.1 According to the pro-
posed Seventh Amendment of the European Cosmetic
Directive, which has become effective on March 11,
2005, the identity of these compounds in cosmetics
should be labelled if they exceed 10 ppm in products
intended to remain on the skin, or 100 ppm in products
intended to be rinsed off therefrom. Among these 26
allergens, there are very common natural compounds,
such as citronellol, limonene, eugenol and cinnamic
aldehyde.
The preparation of enantiomerically pure stereoisomers
of chiral odourants is a relevant research topic. We have
shown over the last few years that this goal can be sat-
isfactorily reached by using enzyme-mediated ap-
proaches, that is, lipase-catalysed kinetic resolutions
and stereoselective bakersÕ yeast reactions.3 Herein, we
report on the preparation of the two enantiomers of
the commercial odourant Undecavertolꢀ 1 (Givaudan)
by means of lipase-mediated acetylation.
2. Results and discussion
On the website of Givaudan,4 Undecavertolꢀ is de-
scribed to have a powerful green-floral character, some-
what related to lily-of-the-valley, with natural fresh
fruity violet leaf and linden blossom aspects. It can be
used successfully in rose and fruity-pear accords. It re-
quires careful dosage and blending due to its exceptional
strength. Undecavertolꢀ is also widely employed both in
fine and functional perfumery. The commercial product
is a 98.5:1.5 mixture (GC/MS) of trans- and cis-isomers.
In light of these observations, the investigation of the
properties of the single enantiomers of chiral odourants
is now of primary importance for three main reasons.
First of all, as the enantiomers of chiral drugs may have
different pharmacological activities and side effects, the
enantiomers of chiral fragrances may show different
interactions with human beings, not only from an odour
*
Aldolic condensation of propanal, to give (E)-2-methyl-
2-pentenal, followed by Grignard addition of pentyl
Corresponding author. Tel.: +39 02 23993077; fax: +39 02
23993080; e-mail: elisabetta.brenna@polimi.it
0957-4166/$ - see front matter ꢁ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.04.022

1998
A. Abate et al. / Tetrahedron: Asymmetry 16 (2005) 1997–1999
magnesium bromide5 allowed us to prepare racemic 1,
as a 97.3:2.6 mixture (GC/MS) of trans- and cis-isomers.
Lipase-mediated acetylation of racemic 1 was investi-
gated in the presence of three commercial enzymic prep-
arations (lipase PS, PPL, CCL) in t-butyl methyl ether
solution, using vinyl acetate as an acyl donor. In all
cases, the reaction was rather slow with the highest value
of enantioselectivity being observed with lipase PS (see
Table 1). Lipase PS-mediated acetylation of ( )-1
(6 days) gave acetate derivative (+)-2 as a 93.5:6.5 mix-
ture of trans- and cis-isomers (GC/MS) (Scheme 1). This
latter was hydrolysed by reaction with KOH in metha-
nol, with the corresponding alcohol (+)-1 being ob-
tained as a 96.5:3.5 mixture of trans- and cis-isomers
(GC/MS). The enantiomeric excess was evaluated to
be 93% by using lanthanide chiral shift reagents.
cucumber and Neofolione (methyl non-2-enoate).
Odour threshold: 0.31 ng/L air.
Compound (S)-(ꢀ)-1: Weaker enantiomer, fruity-green
pinefir balsam note with aspects of tea, not so typical
of Undecavertolꢀ. Odour threshold: 4.7 ng/L air.
3. Conclusion
The two Undecavertolꢀ enantiomers were found to
show different odour qualities and strengths. Compound
(R)-(+)-1 was the most potent, and showed the best
odour profile. It can be used in perfume compositions
in half dosage with respect to the racemate. In this
way the same odour sensation can be elicited by employ-
ing a minor quantity of chemicals in products that are
directly in contact with human body.
Table 1.
Enzyme
ee (%) of (R)-2
ee (%) of (S)-1
The use of enzyme-mediated approach allowed once
again to obtain rapidly both the enantiomers of the sec-
ondary allylic alcohol 1.
Lipase PS
CCL
PPL
93
35
37
75
Racemic
Racemic
4. Experimental
The unreacted alcohol was treated with lipase PS, in t-
butyl methyl ether solution, in the presence of vinyl ace-
tate for 10 days. At the end of this period, (ꢀ)-1 was
recovered from the reaction mixture by column chroma-
tography. Compound (ꢀ)-1 was found to contain 2% of
the cis-isomer by GC/MS. The enantiomeric excess was
evaluated to be 75% by using lanthanide chiral shift
reagents.
Lipase PS Burkholderia cepacia (Amano Pharmaceuti-
cals Co., Japan), Porcine pancreatic lipase (PPL type
II, Sigma), Candida rugosa lipase (CRL, Sigma) were
employed in this work. GC–MS analyses were per-
formed on a HP 6890 gas-chromatography equipped
with a 5973 mass detector, using a HP-5MS column
(30 m · 0.25 mm · 0.25 lm). The following temperature
programme was employed: 60 ꢂC (1 min)/6 ꢂC/min/
150 ꢂC (1 min)/12 ꢂC/min/280 ꢂC (5 min). 1H and 13C
NMR spectra were recorded on a Bruker AC-250 spec-
The absolute configuration was assigned by converting
(ꢀ)-1 into (S)-(+)-36 by ozonolysis followed by triphen-
ylphosphine quenching. The samples of (+)-1
(ee = 93%) and (ꢀ)-1 (ee = 75%) were evaluated by
Givaudan perfumers and the following results were
obtained.
1
trometer (250 MHz H). The chemical shift scale was
based on internal tetramethylsilane. Optical rotations
were measured on a Dr. Kernchen Propol digital auto-
matic polarimeter. Microanalyses were determined on
a Analyzer 1106 Carlo Erba. TLC analyses were per-
formed on Merck Kieselgel 60 F254 plates. All chro-
matographic separations were carried out on silica gel
columns. Chiral shift reagent NMR experiments were
Compound (R)-(+)-1: Typical Undecavertolꢀ odour,
floral, green, fresh, violet leaves, stronger and greener
than the racemic commercial material, with aspects of
Scheme 1. Reagents and conditions: (i) Lipase PS, vinyl acetate, t-butylmethyl ether; column chromatography; (ii) O3, CH2Cl2/MeOH, ꢀ78 ꢂC; then
PPh3.

A. Abate et al. / Tetrahedron: Asymmetry 16 (2005) 1997–1999
1999
performed on a Bruker 400, by using Eu(hfc)3 and mon-
itoring the signal of the methyl group linked to the dou-
ble bond [2.75 ppm for (S)-1 and 2.81 ppm for (R)-1].
J = 7.3 Hz, 3H, CH3CH2C@), 0.88 (3H, t, J = 6.6 Hz,
CH3).
Unreacted alcohol 1 (16.0 g, 0.094 mol) was treated
again with lipase PS, in the same conditions, to afford,
after 10 days, enantiomerically enriched (S)-(ꢀ)-1
(9.9 g, 62%): chemical purity = 93% (GC/MS),
de = 96% (GC/MS), ee (by chiral shift reagent experi-
4.1. (E)-2-Methyl-2-pentenal
Propanal (58 g, 1.0 mol) was added dropwise over
30 min to
a solution of sodium hydroxide 1 M
(40 mL). The reaction mixture was stirred at room tem-
perature for 1 h, and then poured into water, extracted
with diethyl ether, dried and concentrated. The crude
product was purified by distillation under reduced pres-
sure (bp 80–81 ꢂC/100 mmHg), to give the title product
(75.4 g, 77%). Chemical purity 90% by GC/MS;
tR = 3.25 min; m/z: 98 (M+, 100), 83 (33), 69 (55), 55
(48), 41 (100). 1H NMR (CDCl3): d 9.38 (s, 1H,
CHO), 6.47 (t, J = 7.3 Hz, 1H, H–C@C), 2.35 (m, 2H,
CH2C@), 1.71 (s, 3H, CH3C@), 1.09 (t, J = 7.5 Hz,
3H, CH3CH2).
ments
on
the
corresponding
alcohol) = 75%,
20
D
accordance with those of the racemate.
½aꢁ ¼ ꢀ4.9 (c 0.98, CHCl3). MS and NMR data in
4.4. (3E,5R)-4-Methyl-3-decen-5-ol
Saponification of (R)-(+)-2 (7.0 g, 0.033 mol) with KOH
(2.21 g, 0.039 mol) in MeOH (50 mL) at rt gave (R)-(+)-
1
de = 87% (GC/MS), ee = 93% (chiral shift reagents);
(4.99 g, 89%): chemical purity 98% (GC/MS),
20
D
accordance with those of the racemate.
½aꢁ ¼ þ6.5 (c 1.16, CHCl3). MS and NMR data in
4.2. (E)-4-Methyl-3-decen-5-ol 1
4.5. Determination of the absolute configuration of (ꢀ)-1
(E)-2-Methyl-2-pentenal (73.0 g, 0.745 mol) was added
dropwise to a solution of pentyl magnesium bromide
(prepared from 1.102 mol of pentyl bromide and
2.136 mol of magnesium in 800 mL of diethyl ether) at
10 ꢂC. The mixture was refluxed for 1 h, poured into
ice, quenched with satd NH4Cl solution, and extracted
with diethyl ether. The organic phase was dried, concen-
trated and purified by column chromatography (86.1 g,
68%). Chemical purity 96% by GC/MS; tR = 12.05 min;
A solution of (ꢀ)-1 (0.500 g, 0.0031 mol) in CH2Cl2–
MeOH 7:3 (50 mL) was treated with ozone at ꢀ78 ꢂC.
After 10 min the mixture was quenched with triphenyl-
phosphine, warmed at rt, poured into water, extracted
with CH2Cl2, dried and concentrated. The residue was
chromatographed eluting with hexane–AcOEt 95:5, to
give (S)-(+)-3 (0.299 g, 67%): chemical purity 98%
(GC/MS), tR = 8.10 min; m/z: 144 (M+, 1), 126 (1), 111
1
1
m/z: 170 (M+, 6), 152 (10), 141 (50), 99 (100). H NMR
(1), 101 (45), 83 (90), 55 (100). H NMR in accordance
20
D
(CDCl3): d 5.34 (t, J = 7.0 Hz, 1H, H–C@C), 3.95 (t,
J = 6.7 Hz, 1H, CHOH), 2.01 (m, 2H, CH2C@), 1.57
(s, 3H, CH3C@), 1.55–1.10 (m, 8H, 4CH2), 0.94 (t,
J = 7.3 Hz, 3H, CH3CH2C@), 0.86 (t, J = 6.6 Hz, 3H,
CH3).
with that described in the literature.6 ½aꢁ ¼ þ57.3 (c
20
1.1, CHCl3) {lit.6 for (S)-3 ½aꢁ ¼ þ92 (c 0.03, CHCl3)}.
D
Acknowledgements
The authors thank Dr. Philip Kraft and Mr. Jean Jac-
ques Rouge (Givaudan Schweiz AG, Fragrance Re-
search, Switzerland) for the odour descriptions.
COFIN—Murst is acknowledged for financial support.
4.3. (5R,3E)-4-Methyl-3-decen-5-yl acetate and (5S,3E)-
4-methyl-3-decen-5-ol
A mixture of racemic 1 (25 g, 0.147 mol), lipase PS (5 g)
and vinyl acetate (15 mL) in t-butylmethyl ether
(200 mL) was stirred at rt for 6 days. The residue ob-
tained upon evaporation of the filtered mixture was
chromatographed. Column chromatography (hexane–
AcOEt 95:5) allowed us to recover the acetyl derivative
(R)-(+)-2 (7.2 g, 23%) and unreacted alcohol 1 (16.2 g,
65%).
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de = 87% (GC/MS), tR = 14.14 min; m/z: 197 (M+ꢀ15,
1), 170 (65), 152 (50), 99 (100); ee (by chiral shift rea-
gent experiments on the corresponding alcohol) = 93%;
20
D
½aꢁ ¼ þ29.6 (c 1.06, CHCl3). 1H NMR (CDCl3): d
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1H, CHOAc), 2.04 (s + m, 5H, OAc + CH2C@C), 1.60
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