Synthesis and odor of optically active 2-n-hexyl- and 2-n-heptylcyclopentanone and the corresponding δ-lactones

Article abstract of DOI:10.1016/S0040-4039(02)02312-2

Enantiomeric 2-n-hexyl- and 2-n-heptylcyclopentanones (3) and (4) have been synthesized by asymmetric hydrogenation of 2-n-hexylidene and 2-n-heptylidenecyclopentanones (1) and (2) with Ru₂Cl₄[p-tolyl-binap]₂NEt₃

Full text of DOI:10.1016/S0040-4039(02)02312-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9081–9084
Synthesis and odor of optically active 2-n-hexyl- and
-n-heptylcyclopentanone and the corresponding d-lactones
2
Takeshi Yamamoto,* Miharu Ogura, Akira Amano, Kenichiro Adachi, Toshimitsu Hagiwara and
Tsuneyoshi Kanisawa
Takasago International Corporation, Central Research Laboratory, Nishi-Yawata 1-4-11, Hiratsuka, Kanagawa 254-0074, Japan
Received 26 August 2002; revised 7 October 2002; accepted 11 October 2002
Abstract—Enantiomeric 2-n-hexyl- and 2-n-heptylcyclopentanones (3) and (4) have been synthesized by asymmetric hydrogena-
tion of 2-n-hexylidene and 2-n-heptylidenecyclopentanones (1) and (2) with Ru Cl [p-tolyl-binap] NEt complexes. The differences
2
4
2
3
in odor qualities between enantiomeric pairs of the ketones 3 and 4 have been found to be small, and the same odor threshold
values have been observed between the enantiomeric pairs, although the corresponding d-undeca- and d-dodecalactones (6) and
(
7), synthesized by Baeyer–Villiger oxidation of the chiral ketones 3 and 4, showed a fairly large difference in the threshold values
between the enantiomeric pairs. © 2002 Published by Elsevier Science Ltd.
Recently, many kinds of olfactory studies on optically
active aroma chemicals have been reported. Some of
these optically active aroma chemicals show very differ-
ent odor properties between the enantiomers and the
diastereomers. For example, it had been revealed that
ever, the optically active forms have not been synthe-
sized yet, and the odor properties of the enantiomers
are unknown.
1
As for the synthesis of optically active 2-alkylcyclopen-
tanones, Gadkari et al. have reported the synthesis of
(R)-undecylcyclopentanone by an asymmetric Grignard
reaction using (R)-2-amino-n-butanol. The optical
purity of this compound was not described. However,
the Baeyer–Villiger oxidation of (R)-undecylcyclopen-
tanone yielded (R)-5-hexadecanolide in an enantiomeric
(
+)-methyl epijasmonate, which is a key odorous com-
ponent of the jasmine flower, showed a different odor
and a much lower threshold value than the other three
stereoisomers. As related compounds with jasmine
2
odor, racemic 2-n-hexyl- and 2-n-heptylcyclohexanone
are well-known and used for perfume materials. How-
Scheme 1.
Keywords: asymmetric hydrogenation; BINAP–Ru(II); Baeyer–Villiger oxidation; 2-n-heptyl- and 2-n-hexylcyclopentanone; d-undeca- and
d-dodecalactone; enantiomer; optically active; odor.
*
Corresponding author. Tel.: +81-463-25-2218; fax: +81-463-25-2081; e-mail: takeshi yamamoto@takasago.com
–
0
040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02312-2

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T. Yamamoto et al. / Tetrahedron Letters 43 (2002) 9081–9084
3
excess of 50%. In another important study, Takaya et
al. had reported the highly enantioselective hydrogena-
tions of 2- or 4-alkylidene-g-butyrolactone and 2-alkyli-
denecyclopentanone catalyzed by BINAP–Ru(II)
complexes. That is, 2-n-pentylidenecyclopentanone in
CH Cl was hydrogenated at 100 atom to afford (S)-2-
As for the asymmetric hydrogenation of 1 and 2, we
have been interested in studying the catalytic activity
and the enantioselectivity of the products catalyzed by
7
Ru Cl [p-tolyl-binap] NEt complexes (5). As a result,
2
4
2
3
we successfully obtained the chiral ketones 3 and 4 in
over 95% ee and with a relative high catalytic activity
(S/C=1000) using the catalytic system of the chiral
complexes 5 and MeOH under the mild pressure (30
atm).
2
2
penthylcyclopentanone using
benzene)]Cl complex (S/C=100) in 94% ee and also
using a Ru(OCOCH ) {(R)-binap} complex (S/C=100)
in over 98% ee. These situations prompted us to
synthesize enantiomeric 2-n-hexyl and 2-n-heptylcy-
clopentanones (3) and (4) to study their odor
properties.
a
[RuCl{(R)-binap}-
(
3
2
4
A typical procedure is as follows; a degassed mixture of
1 (10 mmol) and the catalyst Ru Cl [(S)-p-tolyl-
2
4
binap] NEt (S)-5 (0.1 mmol) in methanol (12 ml) was
2
3
stirred under hydrogen pressure (70 atm) in an auto-
clave (100 ml) for 12 h, at 25°C. After evaporation of
the solvent, the mixture was distilled to remove the
catalyst. The distillate was purified by silica gel column
chromatography to give (R)-2-n-hexylcyclopentanone
(R)-3 (run 1; 89%, 96% ee). (S)-2-n-Hexylcyclopen-
tanone (S)-3 was also synthesized by using Ru Cl [(R)-
We wish to report here the synthesis and odor proper-
ties of chiral ketones 3 and 4 and the corresponding
5
d-lactones 6 and 7.
Synthetic routes to chiral ketones 3 and 4 and the
corresponding d-lactones 6 and 7 are shown in Scheme
2
4
1.
p-tolyl-binap] NEt (R)-5 in a similar manner. Some
2
3
representative results are shown in Table 1.
The starting materials (E)-2-n-hexylidene- and (E)-2-n-
heptylidenecyclopentanones (1) and (2) were obtained
in yields of 76 and 78% by the aldol condensation of
cyclopentanone with the corresponding aldehydes (n-
hexanal and n-heptanal) catalyzed by Ca(OH)2 and
dehydration with oxalic acid.
6
The hydrogenation proceeded under mild conditions; a
medium pressure (30–70 atm) and low temperature
(25°C). Enantioselectivity, chemoselectivity and cata-
lytic activity were fairly influenced by the solvent. The
highest catalytic activities were obtained in MeOH. The
Table 1. Asymmetric hydrogenation of 1 and 2 with chiral Ru Cl [p-tolyl-binap] NEt complexes
2
4
2
3
Run Substrate
mmol)
Cat. (S/C) Solv. (ml) Temp.
(°C)
Press.
(atm)
Time (h)
Conv.a
(%)
Select. (%)
Product
(
Config.b
(R)-3
(S)-3
(R)-4
(R)-4
(R)-4
(R)-4
(R)-4
(R)-4
(R)-4
(R)-4
(R)-4
(S)-4
c[h]
25
D
% eed
96
95
–e
1
2
3
4
5
6
7
8
9
1
1
1
1 (10)
1 (10)
2 (10)
2 (10)
2 (10)
2 (10)
2 (10)
2 (10)
2 (10)
2 (10)
2 (10)
2 (10)
(S)-5
100)
(R)-5
100)
(S)-5
1000)
(S)-5
1000)
(S)-5
1000)
(S)-5
100)
(S)-5
100)
(S)-5
100)
(S)-5
2000)
(S)-5
5000)
(S)-5
10000)
(R)-5
100)
MeOH
(12)
MeOH
(12)
iso-PrOH 50
(12)
EtOH
(12)
MeOH
(12)
MeOH
(12)
Acetone
(12)
25
25
70
70
30
30
30
70
70
70
70
30
30
70
12
12
24
24
12
12
24
24
8
100
100
23
89
87
51
63
90
87
88
95
89
83
82
88
−112.5
(c 1.01)
+112.3
(c 1.08)
(
(
e
–
(
50
50
25
25
25
25
50
75
25
42
–e
–e
(
100
100
55
−101.7
(c 1.12)
−103.3
(c 1.00)
−81.4
(c 1.01)
−102.5
(c 0.98)
−102.4
(c 1.20)
−93.9
(c 1.15)
−94.0
(c 1.10)
+102.9
(c 1.04)
96
97
77
96
96
88
88
97
(
(
(
CH Cl
94
2
2
(
(12)
MeOH
(12)
MeOH
(12)
MeOH
(12)
96
(
0
1
2
24
24
12
72
(
70
(
MeOH
(12)
100
(
a
b
c
A conversion was determined by gas chromatography.
Configration was assigned based on that of the lactone synthesized by Baeyer–Villiger oxidation of 3 and 4.
Solvent; MeOH.
d
e
%
ee was determined by gas chromatography (Chiraldex G-TA; 0.25 mm I.D.×30 m).
The optical rotation and % ee were not estimated because of the low conversion and low selectivity.

T. Yamamoto et al. / Tetrahedron Letters 43 (2002) 9081–9084
9083
Table 2. Odor properties of the chiral ketones 3 and 4
% ee Odor propertiesa
Compounds
Threshold
b
(
ppb)
(R)-(−)-3
(S)-(+)-3
(R)-(−)-4
(S)-(+)-4
96
95
97
97
Powerful diffusive sweet fruity, fatty somewhat jasmone-like floral odor with slightly oily minty
citrus note
Powerful diffusive warm jasmine-like floral odor with coconut-like fruity and slightly herbaceous
note
Powerful diffusive warm jasmine-like floral odor with somewhat mandalin-like citrus side note and 10
more tenacious than (S)-4
Heavy, coconut-like oily fruity and jasmine-like floral odor with somewhat herbaceous side note
70
70
10
a
Odor was evaluated on blotters by three perfumers 30 min after neat samples were taken on blotters.
Odor threshold concentrations in aqueous solution were determined by a triangular method similar to that reported by Acree.
b
2
a
Table 3. Optical purity (% ee) and odor properties of the lactones 6 and 7 synthesized by Baeyer–Villiger oxidation of the
ketones 3 and 4
% eeb
[h] /° (MeOH)
25
Odor properties [threshold (ppb)]
c
Substrate
% ee
Product
D
(R)-3
(S)-3
(R)-4
(S)-4
96
95
97
97
(R)-6
(S)-6
(R)-7
(S)-7
89
89
93
92
+44.9 (c 1.02)
−44.8 (c 1.05)
+42.6 (c 1.10)
−42.4 (c 1.06)
Fruity, sweet, creamy [100]
Fruity, sweet, milky [30]
Fruity, sweet, apricot [500]
Fruity, sweet [50]
a
To the ketone (3 or 4; 1 mmol) in CH Cl (10 ml) was added m-CPBA acid (1.5 mmol) in CH Cl (10 ml) at 0°C, then the mixture was stirred
2
2
2
2
at rt for 48 h.
b
c
%
ee was determined by GC (Chiraldex G-TA; 0.25 mm ID×30 m).
The odor evaluation was done by the same method as for the ketones 3 and 4.
reaction was completed with S/C=1000 (run 5), though
the conversion was 70% in the case of S/C=10,000 (run
of the substrate {(R)- and (S)-3 and -4} under the
present experimental conditions.
1
1). Higher chemoselectivity and enantioselectivities
were obtained in MeOH or in CH Cl than in acetone,
in iso-PrOH and in EtOH. The best enantioselectivity
of 97% ee was achieved in MeOH with S/C=100 (run
d-Lactones are widely found in many different kinds of
fruits and play very important roles in flavors. A com-
parison of odor properties of the enantiomers of d-lac-
tones was reported by Mosandl using the samples
2
2
6).
11
prepared by HPLC separation. In the odor evaluation
of the present work, it has been identified that the
(S)-forms have lower threshold values than the corre-
sponding (R)-forms, although the corresponding their
substrates 3 and 4 show the same values between the
enantiomeric pairs (Table 3).
Table 2 shows odor profiles of the chiral alkylketones 3
and 4 obtained in runs 1, 2, 6 and 12. Odor differences
in these enantiomeric pairs were not so large, and they
were determined to show a fundamentally jasmine-like
floral odor. However, the (R)-(−)-forms {(R)-(−)-3 and
-
4} showed a cleaner and more diffusive top-note than
the (S)-(+)-forms {(S)-(+)-3 and -4}.
Acknowledgements
It is reported that several cyclic compounds show a
large difference in the threshold values between enan-
8
tiomeric pairs, for example, a-damascone shows a 70
We thank Dr. J. Tsuji (Professor Emeritus, Tokyo
Institute of Technology), Dr. H. Tsuruta (Takasago
International Corporation) and Dr. H. Kumobayashi
9
times difference in values and nootkatone shows a 750
times difference in values. However, in the present
work, the same odor threshold concentrations between
the enantiomeric pairs of 3 and 4 have been observed,
although five-membered simple cyclic alkylketones 3
and 4 are structurally similar to methyl jasmonate.
(
Takasago International Corporation) for their kind
advice.
Regarding the corresponding enantiomeric d-lactones,
the results of Baeyer–Villiger oxidation of the alkylke-
tones 3 and 4 obtained in runs 1, 2, 6 and 12 using
m-chloroperbenzoic (m-CPBA) acid are shown in Table
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0
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(
(
m, 2H), 1.93 (m, 2H), 2.14 (qt, 2H, J=7.5, 1.4 Hz), 2.33
t, 2H, J=7.8 Hz), 2.58 (dtt, 2H, J=2.6, 1.5, 7.4 Hz),
1
6.54 (tt, 1H, J=2.7, 7.6 Hz). For 2; H NMR: l 0.88 (t,
3H, J=6.9 Hz), 1.30 (m, 6H), 1.45 (m, 2H), 1.93 (m, 2H),
2.14 (qt, 2H, J=7.5, 1.4 Hz), 2.33 (t, 2H, J=7.8 Hz),
2.58 (dtt, 2H, J=2.6, 1.5, 7.5 Hz), 6.55 (tt, 1H, J=2.7,