Use of flash vacuum thermolysis in a stereocontrolled synthesis of optically active alkyl-substituted cyclopentenones with fragrant properties

Article abstract of DOI:10.1071/CH14093

The synthesis of four pairs of enantiopure antipodal substituted cyclopentenones is described. The synthetic sequences first comprise the preparation of a tricyclo[5.2.1.02,6]deca-4,8-dienone system, a subsequent kinetic enzymatic resolution of the appropriately functionalized tricyclic system, followed by a series of chemical transformations to install the desired substituents, and finally a retro Diels-Alder reaction using flash vacuum thermolysis to give the target products in high chemical and optical yields. The strategy makes effective use of the concept of transient chirality involving complete stereochemical control over reactions with the chiral tricyclic systems before thermal removal of the cyclopentadiene.

Full text of DOI:10.1071/CH14093

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2014, 67, 1234–1242
Full Paper
http://dx.doi.org/10.1071/CH14093
Use of Flash Vacuum Thermolysis in a Stereocontrolled
Synthesis of Optically Active Alkyl-substituted
Cyclopentenones with Fragrant Properties
A B
,
A
A
Binne Zwanenburg, Andries A. Volkers, and Antonius J. H. Klunder
A
Radboud University Nijmegen, Institute for Molecules and Materials, Department
of Organic Chemistry, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
B
Corresponding author. Email: B.Zwanenburg@science.ru.nl
The synthesis of four pairs of enantiopure antipodal substituted cyclopentenones is described. The synthetic sequences
first comprise the preparation of a tricyclo[5.2.1.02,6]deca-4,8-dienone system, a subsequent kinetic enzymatic resolution
of the appropriately functionalized tricyclic system, followed by a series of chemical transformations to install the desired
substituents, and finally a retro Diels–Alder reaction using flash vacuum thermolysis to give the target products in high
chemical and optical yields. The strategy makes effective use of the concept of transient chirality involving complete
stereochemical control over reactions with the chiral tricyclic systems before thermal removal of the cyclopentadiene.
Manuscript received: 25 February 2014.
Manuscript accepted: 6 April 2014.
Published online: 26 May 2014.
molecular weights of less than 300 g molꢀ1. They are usually
hydrophobic organic compounds containing a limited number
of functional groups. Olfactory research has long been chal-
lenged to investigate the structure–odour relationship,[2] and
these studies often examine the molecular properties that
determine the smell of a compound. Similar odours may be
caused by compounds with completely different structures;
conversely, compounds with similar structures may have very
different odours.
The effect of chirality on odour is not always clear. The
reported odour differences for enantiomers are sometimes so
small that they are often associated with the presence of trace
impurities, e.g. phosphine and sulfur-containing compounds.
The most dramatic differences usually occur in rigid mole-
cules[3] such as carvone.[4] Enantiomer S-(þ)-carvone has a
caraway-like odour whereas enantiomer R-(ꢀ)-carvone smells
like spearmint. For the determination of relationships between
odour and molecular structure, a collection of good, precise, and
reproducible odour data are important.[5]
Introduction
The introduction of synthetic fragrance ingredients caused a
revolution in the use of perfumes. Not until 100 years ago,
perfumes were made entirely from natural products and as a
consequence their use was restricted to wealthy people.
Nowadays, fragrances are used in many consumer goods vary-
ing from personal products, such as soaps, shampoos, and
deodorants, to household products such as detergents, cleaners,
and bleaches. In 1996, the estimated world consumption of
fragrance composites was valued at 2800 million dollars and
that of synthetic fragrances was valued at 1400 million dol-
lars.[1] The most significant turning point in the history of
this industry was the introduction of the famous perfume
Chanel No 5 in 1921. This was the first fine fragrance using
synthetic organic compounds to produce unique fragrance
aspects, and its immediate success led to growing interests in
synthetic perfumes. The advantages of synthetic ingredients are
low cost, availability, consistency, stability, originality, and
additional functionality.
For the scent of a compound to be detected by humans, the
compound needs to be volatile at ambient temperature. As
a consequence, odorants are non-ionic compounds with
In recent years, it has been shown that the endo-tricyclo
[5.2.1.02,6]decadienone system 1 is a useful synthon for
the synthesis of a great variety of naturally occurring
R
R
R
Lewis acid-mediated
chemical
RЈ
transformations
or thermal cycloreversion
RЈ
O
O
O
1
2
3
Scheme 1. Strategy for the synthesis of cyclopentenoids.
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

Synthesis of Cyclopentenoids Using FVT
1235
cyclopentenoids.[6,7] The synthetic strategy of cyclopentenones
3 using system 1 is outlined in Scheme 1. It usually involves
stereoselective addition to the enone moiety of 1, followed
by further chemical transformations to introduce appropriate
functionalities and then by thermal cycloreversion of the
functionalized tricyclodecenones 2 using flash vacuum thermo-
lysis (FVT). The availability of both antipodes of 1 in enantio-
pure form[6] completes this sequence for the enantioselective
synthesis of a variety of cyclopentenoids. The concept of
transient chirality has been extensively used,[6] whereby the
stereocontrol of reactions with the bicyclic compounds 1 is of
crucial importance.
Alkyl-substituted cyclopentenones are interesting com-
pounds as many of them have a pleasant smell that makes
them attractive targets for the perfume industry.[8] Notable
examples are cyclopentenones 4–7 (Fig. 1). Racemic mixtures
of these compounds are commercially used as fragrances. To
gain further insight in the fundamentals of structure–odour
relationship, it is desirable to study the fragrant properties of
cyclopentenones and preferably those of its optical antipodes as
well. These optically active alkyl-substituted cyclopentenoids
are therefore ideal substrates for structure–odour relationship
studies. All compounds contain similar substituents, but are
quite different in molecular shape. Stereocontrolled synthesis of
alkyl-substituted cyclopentenones is very difficult, but the
combined use of the endo-tricyclo[5.2.1.02,6]decadienone sys-
tem 1 with FVT is an attractive methodology for their synthesis
(Scheme 1). Earlier, we reported the synthesis of a variety of
substituted tricyclodecadienones 1 in a stereocontrolled and
enantioselective manner that are suitable starting substrates in
the approach depicted in Scheme 1. In this paper, the enantio-
selective synthesis of all possible stereoisomers of cyclopente-
nones 4–7 is reported.
cyclopentadiene and p-benzoquinone (Scheme 2), followed by a
Favourskii ring contraction of the resulting tricyclic epoxide 9.
Kinetic resolution of racemic tricyclic ester (þ/ꢀ)-10 with
pig liver esterase (PLE) at room temperature in a 0.1 M phos-
phate buffer (pH 8) containing acetonitrile as co-solvent resulted
in a slow hydrolysis reaction to give carboxylic acid (ꢀ)-11 in
excellent chemical yield and
a
high enantiopurity[10]
(Scheme 3). The enantiopurity could be further improved by
crystallization. The remaining ester (þ)-10 was obtained enan-
tiopure after a repeated enzyme treatment. Alkaline hydrolysis
of (þ)-10 resulted in the enantiopure antipode (þ)-11.
The second synthetic route to preparing enantiopure tricy-
clodecadienone 1 starts from 12 (dimer of cyclopentadiene).
Tricyclodecadienone 14 (1: R ¼ H) was synthesized via two
oxidation steps as depicted in Scheme 4. This sequence is in
principle easier than that shown in Schemes 2 and 3, but product
14 lacks the functionality at the C6 bridgehead position that is
present in compound 10. Enzymatic resolution was possible at
the stage of exo-alcohol 13[11], but was rather inefficient. The
enzymatic resolution of the endo-alcohol 15 appeared to be a
better choice[12] because purification could be carried out fast
and the ultimate yields were higher despite the additional
oxidation–reduction steps.
As shown in Scheme 5, treatment of racemic endo-alcohol
(þ/ꢀ)-15 with Lipase PS (Amano) and vinyl acetate in tert-
butyl methyl ether led to the enantioselective transesterification
of (ꢀ)-15 to acetate (ꢀ)-16 in high optical yield. Acetate (ꢀ)-16
could be easily separated from the remaining enantiopure
alcohol (þ)-15. Subsequent alkaline hydrolysis of (ꢀ)-16 gave
enantiopure alcohol (ꢀ)-15. Oxidation of antipodes (þ)-15 and
(ꢀ)-15 with manganese(IV) oxide in dichloromethane at room
temperature yielded the enantiopure tricyclodecadienones
(ꢀ)-14 and (þ)-14, respectively.
The carboxylic acid (þ)-11 is a convenient precursor for the
modified Barton decarboxylation[13] en route to preparing
6-bromo-endo-tricyclo[5.2.1.02,6]decadienone (þ)-(18).[14] This
Results and Discussion
Preparation of the Optically Active
Tricyclodecadienone Precursors
The tricyclodecadienone system 1 is readily obtained in enan-
tiopure form by two complimentary routes, both giving access to
either antipode. The first route starts from the Herz ester (10)[9]
that can be readily prepared by selective epoxidation of
the enone moiety in Diels–Alder adduct 8 derived from
COOEt PLE, buffer pH 8
0.2 M MeCN, rt
COOEt
HOOC
O
O
O
(ϩ/Ϫ)-10
(ϩ)-10
(Ϫ)-11
NaOH
MeOH
CH3
C5H11
CH3
CH3
C5H11
COOH
C5H11
C5H11
O
O
O
O
O
(ϩ)-11
4
5
6
7
Scheme 3. Kinetic enzymatic resolution of the Herz ester.
Fig. 1. Examples of cyclopentenones with fragrant properties.
O
O
O
COOEt
EtOH/OHϪ
H2O2/OHϪ
O
c.y.: 50–70 %
c.y.: Ͼ95 %
Ͼ95 %
O
O
O
O
8
9
10
Herz ester
Scheme 2. Synthesis of the Herz ester.

1236
B. Zwanenburg, A. A. Volkers, and A. J. H. Klunder
bromide can be either converted into the 6-methyl compound
(ꢀ)-20 or the parent ketone (ꢀ)-14. Treatment of enantiopure
(þ)-6-bromo-endo-tricyclo[5.2.1.02,6]decadienone (18) with
lithium dimethylcuprate in THF led to bromine/metal exchange
and formation of carbanion 19. Quenching of 19 with methyl
iodide afforded the methyl-substituted product 20. The
replacement of bromine in 18 was successfully observed for
both antipodes, thus giving (þ)- and (ꢀ)-20. Quenching of
anion 19 with water gave tricyclodecadienone (ꢀ)-14
(Scheme 6), which had the same optical rotation as (ꢀ)-14
obtained via the route depicted in Scheme 5. The latter reaction
connects both sets of synthetic routes (Schemes 2 and 3, and
Schemes 4 and 5), thereby ensuring the correctness of the
structures involved.
SeO2
dioxane/H2O
reflux
PCC
CH2Cl2
5ЊC
DIBAL
toluene
Ϫ78ЊC
c.y.: 63 %
c.y.: 76 %
c.y.: 91 %
HO
O
OH
12
13
14
15
Scheme 4. Preparation of the endo-alcohol 15.
Lipase PS
MnO2, CH2Cl2
rt, c.y.: 89 %
OAc
HO
OAc
HO
t-BuOMe
(ϩ/Ϫ)-15
(Ϫ)-16
c.y.: 49 %
(ϩ)-15
c.y.: 50 %
ee: Ͼ99 %
ee: Ͼ99 %
O
(Ϫ)-14
K2CO3/MeOH/rt
ee: Ͼ99 %
MnO2, CH2Cl2
rt
c.y.: 91 %
OH
(Ϫ)-15
O
(ϩ)-14
c.y.: 87 %
ee: Ͼ99 %
ee: Ͼ99 %
Scheme 5. Kinetic resolution of the endo-alcohol (þ/ꢀ)-15.
COOH
Barton’s
Br
Me
Me2CuLi
THF, 0ЊC
Ϫ
CCl3Br
MeI
procedure
O
O
O
O
O
(ϩ)-11
17
(ϩ)-18
19
(Ϫ)-20
c.y.: 75 %
Br
H
Me2CuLi
THF, 0ЊC
Ϫ
H2O
O
O
O
(ϩ)-18
19
(Ϫ)-14
c.y.: 95 %
[α]D21ϩ239.8Њ
[α]D22Ϫ136.1Њ
(c 0.80 in MeOH)
ee: 98 %
(c 1.06 in MeOH)
Scheme 6. Use of the Barton decarboxylation for the modification of the substituent at C6.

Synthesis of Cyclopentenoids Using FVT
1237
The two antipodes of each respective compound 11, 14, and
20 are suitable starting materials for the preparation of the FVT
precursor required for the synthesis of the cyclopentenones
targets.
endo-alkylation is also feasible. Moreover, the use of a strong
base to accomplish initial enolization at C4 in 22 may lead to
considerable epimerization at this position in cis-23 on quen-
ching with water during workup because cis-23 is thermo-
dynamically less stable than its epimer trans-dialkylated 24.
Fortunately, treatment of 22 with lithium dimethyl amide
(LDA), followed by addition of n-pentyl iodide resulted in cis-
4-n-pentyl-5-methyltricyclodecenone (23) in 55 % yield toge-
ther with some dialkylated product and starting material
(Scheme 8). No trans product was obtained at all. This finding
shows that cis-alkylation of 5-exo-substituted tricyclodece-
nones, such as 22, is quite possible despite enhanced steric
hindrance from the exo-face of the cyclopentanone moiety.
Also, the epimerization process is apparently too slow to disturb
isolation of the cis-compound under normal workup conditions.
Epimerization of cis-substituted (ꢀ)-23 to (ꢀ)-24 was readily
accomplished by treatment with sodium methoxide in methanol
at room temperature. The structures of both (ꢀ)-23 and (ꢀ)-24
were unambiguously established by 2D NMR analysis. Cis-
disubstituted cyclopentenone (ꢀ)-5a was obtained by FVT of
(ꢀ)-23. Both (ꢀ)-23 and (ꢀ)-5a are sensitive to epimerization
that would have occurred under acid-catalyzed retro Diels–
Alder reactions, but is completely absent under FVT conditions.
Thermolysis of (ꢀ)-24 led to the trans compound (ꢀ)-5b as
expected (Scheme 8).
Synthesis of the Two Antipodes of Enantiopure
Cyclopentenones 4–7
Retrosynthetically, the synthesis of g-n-pentylcyclopentenone
(4) requires 5-n-pentyltricyclodecadienone (21) as precursor
(Scheme 7). The 5-alkylated tricyclic ketone was obtained,
featuring complete exo-stereoselectivity by 1,4-addition of
freshly prepared lithium di-n-pentylcuprate in diethyl ether to
14. The observed exo-stereoselectivity of this addition reaction
is entirely consistent with that observed for other lithium dialkyl
cuprate additions to 14.[15]
Thermal cycloreversion of 21 was carried out using FVT.
Complete conversion was achieved at 5008C, giving the desired
cyclopentenone 4 in quantitative yield (Scheme 7). The two
antipodes of 4 were obtained in this way from enantiopure
tricyclodecenones (ꢀ) and (þ)-21, respectively. The level of
stereochemical purity was maintained. Both antipodes of 4 had a
penetrating but pleasant smell.
The synthetic sequence to preparing two of the four possible
stereoisomers of cyclopentenone 5 is depicted in Scheme 8.
Efforts to synthesize (ꢀ)-23 from (ꢀ)-14 in a three-component
coupling process were unsuccessful in contrast to our expecta-
tions.[16] The sequence involving independent reaction steps is
superior to the one-pot three-component version.
The required exo-5-methyltricyclodecenone (22) was
readily prepared by addition of lithium dimethylcuprate to
enone 14. The precursor required for preparing cis-4-methyl-
5-n-pentylcyclopentenone (5a) is cis-5-methyl-4-n-pentyltri-
cyclodecenone (23). Its synthesis is not trivial as a-alkylation
at the C4 position from the exo-face in 22 may be sterically
hampered by the adjacent 5-methyl group to such an extent that
In contrast to the exo-face lithium dipentylcuprate addition
to (ꢀ)-14 (see Scheme 8), pentyl addition to 20 occurred
exclusively at the endo-face (Scheme 9). In a different
study,[17]we observed an exo/endo ratio of 1 : 1 for the addition
reaction of dimethylcuprate to 20. Thus, the complete endo-
stereoselectivity observed in the present case is mainly caused
by increased steric interactions between the larger di-n-pentyl-
cuprate reagent and the 6-methyl substituent. Pyrolysis of
(ꢀ)-25 using FVT gave cyclopentenone (þ)-6 in quantitative
yield (Scheme 9).
H3C
C5H11
C5H11
CH3
CH3
(C5H11)2CuLi
Et2O, rt
(C5H11)2CuLi
FVT
FVT
500ЊC
Et2O, 0ЊC
C5H11
500ЊC
c.y.: 90 %
quantitative
yield
c.y.: 90 %
quantitative
yield
C5H11
O
O
O
O
O
O
(Ϫ)-20
(Ϫ)-25
(ϩ)-6
(Ϫ)-14
(Ϫ)-21
(Ϫ)-4
Scheme 9. Synthesis of 3,4-disubstituted cyclopentenone 6.
Scheme 7. Synthesis of g-n-pentylcyclopentenone 4.
CH3
Me2CuLi
Et2O, Ϫ78ЊC
LDA, I-C5H11
THF/HMPA
FVT
500ЊC
CH3
CH3
C5H11
c.y.: 55 %
c.y.: 95 %
4
quantitative yield
4
C5H11
O
O
O
O
(Ϫ)-14
(Ϫ)-22
(Ϫ)-23
(Ϫ)-5a
NaOMe/MeOH, rt
epimerization
quantitative yield
FVT
CH3
CH3
500ЊC
quantitative yield
4
C5H11
O
O
C5H11
(Ϫ)-24
(Ϫ)-5b
Scheme 8. Stepwise synthesis of 4,5-disustituted cyclopentenones 5.

1238
B. Zwanenburg, A. A. Volkers, and A. J. H. Klunder
To accomplish the synthesis of cyclopentenone 7, selec-
minꢀ1 followed by 10 min at 2508C (isothermal). Analytical
HPLC was performed with a Chiralcel OD (10 mm) cellulose
carbamate column (Baker, 250 ꢁ 4.6 mm) using either iso-
propanol (iPrOH) or ethanol and hexane mixtures as eluent.
Column chromatography was carried out at ambient pressure on
a Merck Kieselgel 60. Thin layer chromatography (TLC) was
carried out on a Merck pre-coated silica gel 60 F254 plates
(0.25 mm) using appropriate eluents. Spots were visualized
under UV following reaction with I2 or molybdate spray. Sol-
vents were dried using the following methods: dichloromethane
and hexane were distilled from calcium hydride, diethyl ether
was distilled from sodium hydride, ethyl acetate was distilled
from potassium carbonate, and toluene was distilled from
sodium. THF was first distilled from calcium hydride and then
from sodium with benzophenone as indicator under argon,
directly before use. All other solvents were of analytical grade.
All experiments were routinely conducted in conjunction
with GC and chiral HPLC to ensure chemical and optical purity
of the compounds, respectively. In all cases the optical purity
was $98 %.
tive 1,4-reduction of 5-methyltricyclodecadienone (20) was
required. However, this reduction proved to be impossible using
standard procedures.[6,17–20] Attempted reduction of (ꢀ)-20
with zinc in acetic acid under a variety of conditions did not
result in the desired ketone (ꢀ)-26 in contrast[19] to the fast zinc
reduction of parent tricyclodecadienone 14. Instead, similar
issues to those of the 1,4-reduction with ester 10 were encoun-
tered. It seems that for the zinc/acetic acid 1,4-reduction, no
functionality is allowed at the C6 position in the tricyclodeca-
dienone system. The reason for this is not clear. Treatment of
(ꢀ)-20 at low temperatures with LiAlH4 gave only the 1,2-
reduced product in contrast to the LiAlH4 reduction of the Herz
ester 10 that mainly led to the 1,4-reduction.[18] Improved results
were obtained when calcium in ammonia was used. Consequ-
ently, the desired ketone (ꢀ)-26 was isolated in good yields
(Scheme 10).
Treatment of (ꢀ)-26 with LDA, followed by quenching with
n-pentyl iodide exclusively led to exo-substituted tricyclodece-
none (ꢀ)-27. Cyclopentenone (ꢀ)-7 was obtained in quantita-
tive yields after FVT of (ꢀ)-27 (Scheme 10).
(1R,2R,6R,7S)-5-Oxotricyclo[5.2.1.02,6
]
deca-3,8-diene-2-carboxylic acid (1)-(11)
Conclusion
Compound (þ)-11 (8 g) was synthesized according to literature
procedures[10] and its spectral data were in agreement with those
reported. [a]D21 þ83.68 (c 1.03 in methanol (MeOH)); lit[10] [a]2D5
þ858, ee 98 %.
Effective, stereocontrolled, and enantioselective syntheses of
all possible stereoisomers and enantiomers of four cyclo-
pentenones 4–7 were successfully performed. The fragrance
properties of these optically pure cyclopentenones are very
interesting and will be further explored in structure–odour
relationship studies.
(1S,2S,6S,7R)-5-Oxotricyclo[5.2.1.02,6
]
deca-3,8-diene-2-carboxylic acid (2)-(11)
Experimental
Compound (ꢀ)-11 (8 g) was synthesized according to literature
procedures[10] and its spectral data were in agreement with
those reported. [a]D21 ꢀ82.58 (c 1.55 in MeOH); lit[10] [a]D25 ꢀ838,
ee 99 %.
General
Fourier transform infrared (FTIR) spectra were recorded on a
Biorad WIN-IR FTS-25 spectrophotometer. 1H- and 13C-NMR
spectra were recorded on a Bruker AM-400, a Bruker AC-300,
and a Bruker AC-100 at 298 K unless stated otherwise. Chem-
ical shifts are reported relative to TMS. Mass spectrometry (MS)
analyses were performed on a double focussing VG Analytical
7070E mass spectrometer. Gas chromatography mass spec-
trometry (GC–MS) analyses were performed using a Varian
Saturn II GC-MS ion trap system, equipped with a Varian 8100
autosampler. Separation was carried out on a fused silica HP-1
capillary column (DB-5, 30 m ꢁ 0.25 mm). Helium was used as
a carrier gas and electron impact (EI) was used as ionization
mode. Optical rotations were measured on a Perkin–Elmer 241
polarimetre. Melting points were determined with a Reichert
Thermopan microscope and are uncorrected. GC analyses were
performed on a Hewlett Packard HP5890A or a Hewlett Packard
HP5890II gas chromatograph (flame ionization detector, FID)
using a capillary column (HP-1, 25 m ꢁ 0.32 mm ꢁ 0.17 mm)
and nitrogen at 2 mL minꢀ1 (0.5 atm) as the carrier gas. The GC
temperature programs employed involved heating at either from
508C (5 min isothermal) to 2508C at 158C minꢀ1 followed by
2 min at 2508C (isothermal) or from 1008C to 2508C at 158C
(1S,2R,6S,7R)-Tricyclo[5.2.1.02,6
]
deca-4,8-dien-3-one (2)-(14)
Compound (ꢀ)-14 (10 g) was synthesized according to litera-
ture procedures[12] and its spectral data were in agreement with
those reported. [a]2D1 ꢀ138.98 (c 1.86 in MeOH); lit[14] [a]D25
ꢀ138.48, ee .99 %.
(1R,2S,6R,7S)-Tricyclo[5.2.1.02,6
]
deca-4,8-dien-3-one (1)-(14)
Compound (þ)-14 (10 g) was synthesized according to litera-
ture procedures[12] and its spectral data were in agreement with
those reported. [a]2D1 þ138.68 (c 0.99 in MeOH); lit[19] [a]D25
þ138.48, ee .99 %.
(1S,2S,6R,7R)-6-Bromotricyclo[5.2.1.02,6
]
deca-4,8-dien-3-one (1)-(18)
Compound (þ)-18 (7 g) was synthesized according to literature
procedures[15] and its spectral data were in agreement with those
reported. mp .808C (dec.). [a]2D1 þ239.88 (c 1.06 in MeOH).
H3C
CH3
CH3
CH3
LDA, I-C5H11
THF/HMPA
FVT
500ЊC
Ca/NH3(l)
c.y.: 75 %
c.y.: 60 %
quantitative
C5H11
yield
C5H11
O
O
O
O
(Ϫ)-20
(Ϫ)-26
(Ϫ)-27
(Ϫ)-7
Scheme 10. Synthesis of 3,5-disubstituted cyclopentenones 7.

Synthesis of Cyclopentenoids Using FVT
1239
(1R,2R,6S,7S)-6-Bromotricyclo[5.2.1.02,6
deca-4,8-dien-3-one (2)-(18)
]
30 min. A solution of 6-methyltricyclo[5.2.1.02,6]deca-4,8-dien-
3-one (ꢀ)-(20) (0.200 g, 1.25 mmol) in diethyl ether (1 mL)
was slowly added to the reaction mixture. After 45 min, the
reaction was complete and carefully quenched with satura-
ted NH4Cl(aq) (5 mL). Then, diethyl ether (10 mL) was added
and the reaction mixture was allowed to reach room tempera-
ture while NH3 evaporated. After aqueous workup using
standard procedures the crude product was purified by column
chromatography (EtOAc/hexane ¼ 1 : 6). Methyltricyclodece-
none (ꢀ)-26 (0.152 g, 0.94 mmol) was obtained as a colourless
oil (75 % yield). [a]2D3 ꢀ170.98 (c 0.94 in CDCl3). nmax
(CCl4)/cmꢀ1 2963 (C–H), 2927 (C–H), 2876 (C–H), 1735
(C¼O). dH (CDCl3, 400 MHz) 6.32 (1H, dd, 3J8,9 5.7, 3J8,7 3.1,
Compound (ꢀ)-18 was synthesized according to literature
procedures[15] and its spectral data were in agreement with those
reported. mp .808C (dec.). [a]2D1 ꢀ232.48 (c 1.00 in MeOH);
lit[15] [a]2D5 ꢀ222.48 (c 0.69 in MeOH).
(1S,2R,6S,7R)-Tricyclo[5.2.1.02,6
]
deca-4,8-dien-3-one (2)-(14)
The following experiment was carried out in dry THF under
inert atmosphere. Lithium dimethylcuprate was prepared at 08C
by adding 1.6 M MeLi (1.5 mL, 2.4 mmol) to a suspension of
CuI (0.230 g, 1.2 mmol) in THF (10 mL). After stirring for
3
H8), 6.12 (1H, dd, 3J9,8 5.7, J9,1 2.9, H9), 3.16 (1H, br s, H1),
15 min,
(1S,2S,6R,7R)-6-bromotricyclo[5.2.1.02,6]deca-4,8-
2.64 (1H, br s, H7), 2.40 (1H, d, 3J2,1 4.1, H2), 2.27 (2H, m, H4),
2.04 (2H, m, H5), 1.72 (1H, d, 2J10a,10s 8.6, H10a), 1.60 (1H, d,
2J10s,10a 8.6, H10s), 1.39 (3H, s, CH3). dC (H-dec, CDCl3,
100 MHz) 222.0 (quat.), 137.4, 135.5, 62.5, 53.7 (tert.), 50.8
(sec.), 47.7 (quat.), 47.4 (tert.), 41.5 (sec.), 31.6 (sec.), 29.7
(prim.). m/z (EI) 162 (,1 %, Mþ), 97 (100 %, Mþ–C5H5), 66
(82 %, C5Hþ6 ). m/z 162.10445. HRMS Anal. Calc. for C11H14O
(Mþ) 162.10447.
dien-3-one (þ)-(18) {([a]D21 þ239.88 (c 1.06 in MeOH); 0.225 g,
1.0 mmol)} in THF (1 mL) was added slowly and the reaction
mixture was then quenched with water (0.5 mL). After aqueous
workup using standard procedures, the crude product was
purified by column chromatography (ethyl acetate (EtOAc)/
hexane 1 : 6). Finally, tricyclo[5.2.1.02,6]deca-4,8-dien-3-one
(ꢀ)-(14) (0.139 g, 0.95 mmol) was obtained as a white solid in
95 % yield and its spectral data were in agreement with those
reported.[19] [a]D22 ꢀ136.18 (c 0.80 in MeOH); lit[19] [a]2D5
ꢀ138.48, ee 98 %.
(1S,2R,6S,7R)-6-Methyltricyclo[5.2.1.02,6
]
(1S,2R,6S,7R)-6-Methyltricyclo[5.2.1.02,6
]
dec-8-en-3-one (1)-(26)
deca-4,8-dien-3-one (2)-(20)
The same procedure as that used for the synthesis of enantiomer
(ꢀ)-26 was used. Starting from methyltricyclodecadienone
(þ)-20, methyltricyclodecenone (þ)-26 (0.155 g, 0.96 mmol)
was obtained as a colourless oil (75 % yield). [a]2D1 þ170.88
(c 0.86 in CDCl3). Other physical data are identical to those of its
antipode (ꢀ)-26.
Lithium dimethylcuprate was prepared at 08C by adding 1.6 M
MeLi (4.5 mL, 7.2 mmol) to a suspension of CuI (0.685 g,
3.6 mmol) in dry THF (30 mL) in an inert atmosphere. After
stirring for 15 min, bromotricyclodecadienone (þ)-18 (0.675 g,
3.6 mmol) in THF (1 mL) was added slowly and the reaction
mixture was then quenched with methyl iodide (2.1 mL,
30 mmol). After aqueous workup, using standard procedures,
the crude product was purified by column chromatography
(EtOAc/hexane ¼ 1 : 6). Methyltricyclodecadienone (ꢀ)-20
(0.365 g, 2.3 mmol) was obtained as a colourless oil (75 %
yield). [a]D20 ꢀ26.28 (c 0.98 in CDCl3). nmax (CCl4)/cmꢀ1 2967
(C–H), 2930 (C–H), 2870 (C–H), 1708 (C¼O). dH (CDCl3,
400 MHz) 7.24 (1H, d, 3J5,4 5.6, H5), 5.95 (1H, br s, H8), 5.90
(1H, br s, H9), 5.84 (1H, d, 3J4,5 5.6, H4), 3.22 (1H, br s, H1), 2.57
(1H, brs, H7), 2.44 (1H, d, 3J2,1 4.4, H2), 1.92 (1H, d, 2J10a,10s 8.8,
(1R,2S,5S,6R,7S)-5-n-Pentyltricyclo[5.2.1.02,6
dec-8-en-3-one (þ)-(21)
]
n-Pentyllithium (1.0 M) was prepared by dropwise addition of
n-pentyl bromide (6.2 mL, 50 mmol) to diethyl ether (50 mL)
containing Li metal (0.385 g, 55 mat) at room temperature
under an inert atmosphere. Lithium di-n-pentylcuprate was
prepared at 08C by adding pentyllithium (3.6 mL, 3.6 mmol) to a
suspension of CuI (0.342 g, 1.8 mmol) in diethyl ether (15 mL).
After stirring for 15 min, the temperature was lowered to ꢀ788C
and tricyclodecadienone (þ)-14 (0.220 g, 1.5 mmol) in diethyl
ether (1 mL) was added slowly. The reaction mixture was
stirred for 30 min followed by quenching with water. After
aqueous workup using standard procedures the crude product
was purified by column chromatography (EtOAc/hexane 1 : 10).
n-Pentyltricyclodecenone (þ)-21 (0.295 g, 1.35 mmol) was
obtained as a colourless oil (90 % yield). [a]2D1 þ125.18 (c 0.96
in CDCl3). nmax (CCl4)/cmꢀ1 2963 (C–H), 2927 (C–H),
2860 (C–H), 1734 (C¼O). dH (CDCl3, 400 MHz) 6.14 (2H, br s,
H8 þ H9), 3.16 (1H, br s, H1), 3.02 (1H, br s, H7), 2.92 (1H, m,
H2), 2.61 (1H, m, H6), 2.21 (1H, dd, 2J4n,4x 18.5, 3J4n,5n 9.0, H4n),
1.93 (1H, ddd, 2J4x,4n 18.5, 3J4x,5n 7.0, J 1.9, H4x), 1.68 (1H, br s,
H5n), 1.55 (1H, d, 2J10s,10a 8.2, H10s), 1.42 (1H, d, 2J10a,10s 8.2,
H10a), 1.28 (8H, br s, C4H8CH3), 0.89 (3H, t, 3J 7.0, C4H8CH3).
dC (H-dec, CDCl3, 100 MHz) 221.0 (quat.), 136.1, 135.3, 54.8
(tert.), 52.3 (sec.), 48.8 (tert.), 48.3 (sec.), 47.1, 46.1 (tert.),
37.9 (sec.), 36.7 (tert.), 31.9, 27.2, 22.6 (sec.), 14.0 (prim.). m/z
(EI) 218 (,1 %, Mþ), 153 (100 %, Mþ–C5H5), 66 (55 %,
C5Hþ6 ). m/z 218.1673. HRMS Anal. Calc. for C15H22O
(Mþ) 218.1671.
2
H10a), 1.75 (1H, d, J10s,10a 8.8, H10s), 1.45 (3H, s, CH3). dC
(H-dec, CDCl3, 100 MHz) 210.7 (quat.), 169.1, 135.3, 134.4,
132.2, 58.0 (tert.), 53.8 (quat.), 51.0 (sec.), 50.0, 46.6 (tert.), 23.6
(prim.). m/z (EI) 160 (14 %, Mþ), 145 (13 %, Mþ–CH3), 132
(37 %, Mþ–CO), 117 (63 %, C9H9þ), 66 (100 %, C5Hþ6 ). m/z
160.08878. HRMS Anal. Calc. for C11H12O (Mþ) 160.08882.
m/z 117.07028. HRMS Anal. Calc. for C9Hþ9 117.07043.
(1R,2S,6R,7S)-6-Methyltricyclo[5.2.1.02,6
deca-4,8-dien-3-one (1)-(20)
]
The same procedure as that employed for the synthesis of (ꢀ)-20
was used. Starting from bromotricyclodecadienone (ꢀ)-18,
methyltricyclodecadienone (þ)-20 (0.370 g, 2.3 mmol) was
obtained as a colourless oil (75 % yield). [a]2D1 þ25.88 (c 1.00
in CDCl3). Other physical data are identical to those of its
antipode (ꢀ)-20.
(1R,2S,6R,7S)-6-Methyltricyclo[5.2.1.02,6
dec-8-en-3-one (2)-(26)
]
Calcium (0.500 g, 12.5 mat) was added to condensed NH3
(25 mL) under an inert atmosphere at ꢀ508C and stirred for

1240
B. Zwanenburg, A. A. Volkers, and A. J. H. Klunder
(1S,2R,5R,6S,7R)-5-n-Pentyltricyclo[5.2.1.02,6
dec-8-en-3-one (ꢀ)-(21)
]
0.75 mmol), and resulting mixture was stirred overnight at room
temperature. After aqueous workup using standard procedures
epimerized product (þ)-24 (0.171 g, 0.74 mmol) was obtained
as a colourless oil in quantitative yield. [a]2D2 þ77.08 (c 0.79 in
CDCl3). nmax (CCl4)/cmꢀ1 2959 (C–H), 2930 (C–H), 2867
(C–H), 1734 (C¼O). dH (CDCl3, 400 MHz) 6.14 (1H, dd, 3J9,8
5.7, 3J9,1 3.0, H9), 6.02 (1H, dd, 3J8,9 5.7, 3J8,7 3.0, H8), 3.13 (1H,
br s, H1), 3.03 (1H, br s, H7), 3.03 (1H, br s, H2), 2.49 (1H, m,
H6), 1.90 (1H, m, H4x), 1.60 (1H, d, 2J10s,10a 8.3, H10s), 1.45 (1H,
The same procedure as that applied for the synthesis of enan-
tiomer (þ)-21 was used. Starting from tricyclodecadienone
(ꢀ)-14, n-pentyltricyclodecenone (ꢀ)-21 (0.290 g, 1.33 mmol)
was obtained as a colourless oil (90 % yield). [a]2D2 ꢀ126.08
(c 0.95 in CDCl3). Other physical data were identical to those of
its antipode (þ)-21.
2
d, J10a,10s 8.3, H10a), 1.35 (1H, br s, H5n), 1.30 (8H, br s,
(1S,2R,4R,5S,6R,7R)-5-Methyl-4-n-pentyltricyclo
[5.2.1.02,6]dec-8-en-3-one (ꢀ)-(23)
C4H8CH3), 1.18 (3H, d, 3J 6.6, CH3), 0.86 (3H, t, 3J 7.2,
C4H8CH3). dC (H-dec, CDCl3, 100 MHz) 219.5 (quat.), 137.0,
135.6, 60.1, 55.2 (tert.), 52.5 (sec.), 48.2, 45.3, 44.4, 38.5 (tert.),
32.1, 27.1, 26.8, 22.5 (sec.), 21.4, 14.0 (prim.). m/z (EI) 232
(,1 %, Mþ), 167 (99 %, Mþ–C5H5), 97 (28 %, C6H9Oþ), 96
(22 %, C6H8Oþ), 66 (100 %, C5Hþ6 ). m/z 232.18260. HRMS
Anal. Calc. for C16H24O (Mþ) 232.18272.
Lithium dimethylcuprate was prepared by adding 1.6 M MeLi
(4.5 mL, 7.2 mmol) to a suspension of CuI (0.690 g, 3.6 mmol) in
diethyl ether (30 mL) at 08C under an inert atmosphere. After
stirring for 15 min, tricyclodecadienone (ꢀ)-14 (0.435 g,
3.0 mmoL) in diethyl ether (2 mL) was added slowly and the
reaction mixture was stirred for 30 min followed by quenching
with water. After aqueous workup using standard procedures,
the crude product was purified by column chromatography
(EtOAc/hexane ¼ 1 : 10). Methyltricyclodecenone (ꢀ)-22
(0.450 g, 2.8 mmol) was obtained as a colourless oil (95 %
yield). [a]2D1 ꢀ71.48 (c 1.26 in CDCl3). Then, (ꢀ)-22 (0.450 g,
2.8 mmol) was added to freshly prepared LDA (3 mmol) in THF
(30 mL) with hexamethylphosphoramide (HMPA; 4 mL) as
co-solvent at 08C. After 30 min, excess n-pentyl iodide
(3.65mL, 28 mmol) was added and the reaction mixture was
allowed to reach room temperature and stirred for 1 h. After
aqueousworkup using standardprocedures, the crudeproductwas
purified by column chromatography (EtOAc/hexane¼ 1 : 10).
Methyl-n-pentyltricyclodecenone (ꢀ)-23 (0.360 g, 1.55 mmol)
was obtained as a colourless oil (55 % yield). Methyl-
tricyclodecenone (ꢀ)-22 (35 %) and dialkylated product (10 %)
were recovered. [a]D21 ꢀ193.48 (c 1.28 in CDCl3). nmax (CCl4)/
cmꢀ1 2962 (C–H), 2934 (C–H), 2871 (C–H), 1729 (C¼O). dH
(1S,2R,4S,5S,6R,7R)-5-Methyl-4-n-pentyltricyclo
[5.2.1.02,6]dec-8-en-3-one (ꢀ)-(24)
The same procedure as that applied for the synthesis of enan-
tiomer (þ)-24 was used. Starting from methyl-n-pentyl-
tricyclodecenone (ꢀ)-23, the epimerized product (ꢀ)-24
(0.170 g, 0.73 mmol) was obtained as a colourless oil in quan-
titative yield. [a]2D1 ꢀ76.58 (c 1.09 in CDCl3). Other physical
data were identical to those of its antipode (þ)-24.
(1R,2S,5S,6R,7S)-6-Methyl-5-n-pentyltricyclo[5.2.1.02,6
dec-8-en-3-one (þ)-(25)
]
The same procedure as that applied for the synthesis of (þ)-21
was used. Starting from methyltricyclodecadienone (þ)-20
(0.240 g, 1.5 mmol),) (þ)-25 (0.315 g, 1.36 mmol) was obtained
as a colourless oil (90 % yield). [a]2D1 þ218.48 (c 0.80 in CDCl3).
n
max (CCl4)/cmꢀ1 2964 (C–H), 2930 (C–H), 2860 (C–H), 1734
3
3
(CDCl3, 400 MHz) 6.21 (1H, dd, J8,9 5.7, J8,7 3.1, H8), 6.14
(1H, dd, 3J9,8 5.7, 3J9,1 3.0, H9), 3.18 (1H, br s, H1), 3.04 (1H, br
s, H7), 2.91 (1H, dd, J 9.3, J 4.7, H2), 2.45 (1H, dt, 3J6,5 9.3, 4J6,
CH3 2.7, H6), 2.02 (1H, m, H4n), 1.98 (1H, m, H5n), 1.52 (1H, d,
2J10s,10a 8.1, H10s), 1.38 (1H, d, 2J10a,10s 8.1, H10a), 1.23 (8H, br s,
C4H8CH3), 0.92 (3H, d, 3J 7.0, CH3), 0.87 (3H, t, 3J 7.1,
C4H8CH3). dC (H-dec, CDCl3, 100 MHz) 221.5 (quat.), 136.2,
135.1, 55.7, 53.1 (tert.), 52.6 (sec.), 48.4, 47.1, 46.7, 33.5 (tert.),
31.9, 27.4, 25.0, 22.5 (sec.), 18.1, 14.0 (prim.). m/z (EI) 232
(,1 %, Mþ), 167 (100 %, Mþ–C5H5), 97 (36 %, C6H9Oþ), 96
(86 %, C6H8Oþ), 66 (98 %, C5Hþ6 ). m/z 232.18283. HRMS
Anal. Calc. for C16H24O (Mþ) 232.18272.
(C¼O). dH (CDCl3, 400 MHz) 6.35 (1H, dd, 3J8,9 5.7, 3J8,7 3.0,
H8), 6.03 (1H, dd, J9,8 5.7, 3J9,1 3.0, H9), 3.12 (1H, br s, H1),
3
3
2.64 (1H, br s, H7), 2.47 (1H, d, J2,1 4.9, H2), 2.23 (1H, dd,
2J4n,4x 18.0, J4n,5x 8.7, H4n), 1.90 (1H, m, J4x,4n 18.0, J4x,5x
3
2
3
8.9, J 3.5, H4x), 1.72 (1H, d, 2J10a,10s 8.5, H10a), 1.63 (1H, br s,
2
H5x), 1.53 (1H, d, J10s,10a 8.5, H10s), 1.36 (3H, s, CH3), 1.30
(8H, br s, C4H8CH3), 0.89 (3H, t, 3J 6.8, C4H8CH3). dC (H-dec,
CDCl3, 100 MHz) 221.3 (quat.), 137.6, 135.6, 63.0, 51.7 (tert.),
51.1 (sec.), 50.6 (quat.), 47.8 (sec.), 47.4, 45.3 (tert.), 32.1, 30.7
(sec.), 29.7 (prim.), 29.1, 22.6 (sec.), 14.0 (prim.). m/z (EI) 232
(,1 %, Mþ), 167 (100 %, Mþ–C5H5), 96 (10 %, C6H8Oþ), 95
(10 %, C6H7Oþ), 66 (37 %, C5Hþ6 ). m/z 232.1828. HRMS Anal.
Calc. for C16H24O (Mþ) 232.1827.
(1R,2S,4S,5R,6S,7S)-5-Methyl-4-n-pentyltricyclo
[5.2.1.02,6]dec-8-en-3-one (þ)-(23)
(1S,2R,5R,6S,7R)-6-Methyl-5-n-pentyltricyclo[5.2.1.02,6
dec-8-en-3-one (ꢀ)-(25)
]
The same procedure as that applied for the synthesis of enan-
tiomer (ꢀ)-23 was used. Starting from tricyclodecadienone
(þ)-14, methyl-n-pentyltricyclodecenone (þ)-23 (0.360 g,
1.55 mmol) was obtained as a colourless oil (55 % yield).
Methyltricyclodecenone (þ)-22 (35 %, [a]2D1 þ171.08 (c 1.24 in
CDCl3)) and dialkylated product (10 %) were also recovered.
(þ)-23: [a]2D2 þ197.48 (c 0.99 in CDCl3). Other physical data
were identical to those of its antipode (ꢀ)-23.
The same procedure as that applied for the synthesis of
enantiomer (þ)-25 was used. Starting from methyl-
tricyclodecadienone (ꢀ)-20, (ꢀ)-25 (0.313 g, 1.35 mmol) was
obtained as a colourless oil (90 % yield). [a]2D1 ꢀ224.08 (c 1.04 in
CDCl3). Other physical data were identical to those of its
antipode (þ)-25.
(1R,2S,4S,6R,7S)-6-Methyl-4-n-pentyltricyclo[5.2.1.02,6
dec-8-en-3-one (þ)-(27)
]
(1R,2S,4R,5R,6S,7S)-5-Methyl-4-n-pentyltricyclo
[5.2.1.02,6]dec-8-en-3-one (þ)-(24)
To a solution of sodium (0.50 g, 22 mat) in methanol (25 mL)
was added methyl-n-pentyltricyclodecenone (þ)-23 (0.175 g,
To a freshly prepared reaction mixture of LDA (1 mmol) in THF
(10 mL) and HMPA (1 mL) as co-solvent was added methyl-
tricyclodecenone (þ)-26 (0.150 g, 0.93 mmol) at 08C. After

Synthesis of Cyclopentenoids Using FVT
1241
30 min, excess n-pentyl iodide (1.3 ml, 10 mmol) was added,
the reaction mixture was allowed to reach room temperature
and stirred for 30 min. After aqueous workup using standard
procedures, the crude product was purified by column chro-
matography (EtOAc/hexane ¼ 1 : 10). Methyl-n-pentyltri-
cyclodecenone (þ)-27 (0.130 g, 0.56 mmol) was obtained as a
colourless oil in 60 % yield. Starting material (þ)-26 (10 %) and
dialkylated product (30 %) were obtained as well. [a]2D1 þ143.38
(c 0.55 in CDCl3). nmax (CCl4)/cmꢀ1 2960 (C–H), 2930 (C–H),
2859 (C–H), 1730 (C¼O). dH (CDCl3, 400 MHz) 6.35 (1H, dd,
3J8,9 5.7, 3J8,7 3.2, H8), 6.07 (1H, dd, 3J9,8 5.7, 3J9,1 2.9, H9), 3.16
(1H, br s, H1), 2.61 (1H, br s, H7), 2.42 (1H, d, 3J2,1 4.6, H2), 2.02
(1H, m, H5n), 1.96 (1H, m, H5x), 1.68 (1H, d, 2J10a,10s 8.5, H10a),
1.64 (1H, m, H4n), 1.54 (1H, d, 2J10s,10a 8.5, H10s), 1.33 (3H, s,
CH3), 1.21 (8H, br s, C4H8CH3), 0.86 (3H, t, 3J 7.2, C4H8CH3).
dC (H-dec, CDCl3, 100 MHz) 223.3 (quat.), 137.2, 135.7, 63.0,
53.9, 52.1 (tert.), 50.6 (sec.), 48.3 (tert.), 45.1 (quat.), 39.4, 31.8,
31.1 (sec.), 30.5 (prim.), 27.1, 22.5 (sec.), 14.0 (prim.). m/z (EI)
232 (,1 %, Mþ), 167 (100 %, Mþ–C5H5), 96 (22 %, C6H8Oþ),
66 (55 %, C5Hþ6 ). m/z 232.18283. HRMS Anal. Calc. for
C16H24O (Mþ) 232.18272.
[a]2D2 ꢀ147.88 (c 1.50 in CDCl3). nmax (CCl4)/cmꢀ1 2961 (C–H),
2933 (C–H), 2873 (C–H), 2860 (C–H), 1699 (C¼O). dH (CDCl3,
3
3
400 MHz) 7.60 (1H, dd, J3,2 5.7, J3,4 2.8, H3), 6.11 (1H, dd,
3J2,3 5.7, 4J2,4 1.7, H2), 3.10 (1H, m, H4), 2.31 (1H, m, H5), 1.75
(1H, br s, C4H8CH3), 1.33 (7H, br s, C4H8CH3), 1.08 (3H, d, 3J
3
7.3, CH3), 0.90 (3H, t, J 6.8, C4H8CH3). dC (H-dec, CDCl3,
100 MHz) 211.9 (quat.), 168.5, 131.8, 49.5, 39.0 (tert.), 32.0,
28.1, 25.6, 22.5 (sec.), 15.8, 14.0 (prim.). m/z (EI) 167 (100 %,
MþþH), 166 (8 %, Mþ), 109 (8 %, Mþ–C4H9), 96 (10 %, Mþ–
C5H10), 95 (8, Mþ–C5H11). m/z 166.135790. HRMS Anal. Calc.
for C11H18O (Mþ) 166.135764.
(4S,5S)-4-Methyl-5-n-pentyl-2-cyclopenten-
1-one (þ)-(5a)
Cyclopentenoid (þ)-5a was prepared in quantitative yield, using
the same procedure as that described for (ꢀ)-5a. [a]2D2 þ149.68
(c 1.15 in CDCl3). Other physical data were identical to those of
its antipode (ꢀ)-5a.
(4R,5S)-4-Methyl-5-n-pentyl-2-cyclopenten-
1-one (ꢀ)-(5b)
FVT (sublimation oven: 1208C, FVT oven: 5008C) of
(1S,2R,4R,6S,7R)-6-Methyl-4-n-pentyltricyclo[5.2.1.02,6
dec-8-en-3-one (ꢀ)-(27)
]
(1S,2R,4S,5S,6R,7R)-5-methyl-4-n-pentyltricyclo[5.2.1.02,6
]
dec-8-en-3-one (ꢀ)-(24) (0.162 g, 0.70 mmol) gave pure
The same procedure as that applied for the synthesis of
enantiomer (þ)-27 was employed. Starting from methyl-
tricyclodecadienone (ꢀ)-26, (ꢀ)-27 (0.125 g, 0.54 mmol) was
obtained as a colourless oil in 60 % yield. Starting material
(ꢀ)-26 (10 %) and dialkylated product (30 %) were obtained as
well. [a]2D1 ꢀ145.18 (c 0.43 in CDCl3). Other physical data were
identical to those of its antipode (þ)-27.
(4R,5S)-4-methyl-5-n-pentyl-2-cyclopenten-1-one
(ꢀ)-(5b)
(0.115 g, 0.69 mmol) as a colourless oil in quantitative yield.
[a]2D2 ꢀ86.98 (c 1.50 in CDCl3). nmax (CCl4)/cmꢀ1 2961 (C–H),
2931 (C–H), 2873 (C–H), 2859 (C–H), 1698 (C¼O). dH (CDCl3,
3
3
400 MHz) 7.52 (1H, dd, J3,2 5.7, J3,4 2.4, H3), 6.09 (1H, dd,
3J2,3 5.7, 4J2,4 1.9, H2), 2,66 (1H, m, H4), 1,86 (1H, m, H5), 1.78
(1H, br s, C4H8CH3), 1.33 (7H, br s, C4H8CH3), 1.23 (3H, d, 3J
3
7.3, CH3), 0.89 (3H, t, J 5.4, C4H8CH3). dC (H-dec, CDCl3,
(4S)-4-n-Pentyl-2-cyclopenten-1-one (ꢀ)-(4)
100 MHz) 212.3 (quat.), 168.3, 132.5, 53.6, 42.8 (tert.), 31.9,
30.6, 27.0, 22.5 (sec.), 19.7, 14.0 (prim.). m/z (EI) 167 (100 %,
MþþH), 166 (14 %, Mþ), 109 (2 %, Mþ–C4H9), 95 (1 %, Mþ–
C5H11). m/z 166.135790. HRMS Anal. Calc. for C11H18O (Mþ)
166.135764.
FVT of (1S,2R,5R,6S,7R)-5n-pentyltricyclo[5.2.1.02,6]dec-8-
en-3-one (ꢀ)-(21) (0.220 g, 1.01 mmol) was carried out using
the conventional methodology[16] (sublimation oven: 1208C,
FVT oven: 5008C). Pure (4S)-4-n-pentyl-2-cyclopenten-1-one
(ꢀ)-(4) (0.151 g, 0.99 mmol) was obtained as a colourless oil in
quantitative yield. [a]2D1 ꢀ162.08 (c 2.33 in CDCl3). nmax (CCl4)/
cmꢀ1 2960 (C–H), 2929 (C–H), 2858 (C–H), 1707 (C¼O). dH
(4S,5R)-4-Methyl-5-n-pentyl-2-cyclopenten-
1-one (þ)-(5b)
3
3
(CDCl3, 400 MHz) 7.64 (1H, dd, J3,2 5.6, J3,4 2.4, H3), 6.14
(1H, dd, 3J2,3 5.6, 4J2,4 2.0, H2), 2,92 (1H, br s, H4), 2,52 (1H, dd,
2J5,5 18.8, 3J5,4 6.3, H5), 2.10 (1H, dd, 2J5,5 18.8, 3J5,4 2.1, H5),
1.57 (1H, br s, C4H8CH3), 1.35 (7H, br s, C4H8CH3), 0.90 (3H, t,
3J 6.8, C4H8CH3). dC (H-dec, CDCl3, 100 MHz) 210.1 (quat.),
168.6, 133.6, 41.5 (tert.), 41.1, 34.7, 31.8, 27.3, 22.5 (sec.), 14.0
(prim.). m/z (EI) 153 (100 %, MþþH), 152 (11 %, Mþ), 81 (4 %,
Mþ–C5H11). m/z 152.120114. HRMS Anal. Calc. for C10H16O
(Mþ) 152.120130.
Cyclopentenoid (þ)-5b was prepared in quantitative yield,
using the same procedure as that described for (ꢀ)-5b. [a]D22
þ89.88 (c 0.88 in CDCl3). Other physical data were identical to
those of its antipode (ꢀ)-5b.
(4S)-3-Methyl-4-n-pentyl-2-cyclopenten-1-one (ꢀ)-(6)
FVT (sublimation oven: 1208C, FVT oven: 5008C) of
(1R,2S,5S,6R,7S)-6-methyl-5-n-pentyltricyclo[5.2.1.02,6]dec-8-
en-3-one (þ)-25 (0.230 g, 0.99 mmol) afforded pure (ꢀ)-6
(0.163 g, 0.98 mmol) as a colourless oil in quantitative yield.
[a]2D1 ꢀ32.58 (c 1.72 in CDCl3). nmax (CCl4)/cmꢀ1 2959 (C–H),
2931 (C–H), 2860 (C–H), 1684 (C¼O). dH (CDCl3, 400 MHz)
5.90 (1H, s, H2), 2,75 (1H, br s, H5), 2,53 (1H, dd, 2J4,4 18.6, 3J4,5
6.5, H4), 2.10 (1H, d, 2J4,4 18.6, H4), 2.08 (3H, s, CH3), 1.75 (1H,
br s, C4H8CH3), 1.22 (7H, br s, C4H8CH3), 0.89 (3H, t, 3J 6.4,
C4H8CH3). dC (H-dec, CDCl3, 100 MHz) 209.1, 181.7 (quat.),
130.7, 44.3 (tert.), 41.7, 32.5, 31.8, 26.7, 22.5 (sec.), 17.3, 14.0
(prim.). m/z (EI) 167 (100 %, MþþH), 166 (4 %, Mþ), 109
(13 %, Mþ–C4H9), 96 (6 %, Mþ–C5H10), 95 (9 %, Mþ–C5H11).
m/z 166.135790. HRMS Anal. Calc. for C11H18O (Mþ)
166.135764.
(4R)-4-n-Pentyl-2-cyclopenten-1-one (þ)-(4)
Cyclopentenoid (þ)-4 was prepared in quantitative yield, using
the same procedure as that described for (ꢀ)-4. [a]2D1 þ158.78
(c 1.34 in CDCl3). Other physical data were identical to those of
its antipode (ꢀ)-4.
(4R,5R)-4-Methyl-5-n-pentyl-2-cyclopenten-1-one (ꢀ)-(5a)
FVT (sublimation oven: 1208C, FVT oven: 5008C) of
(1S,2R,4R,5S,6R,7R)-5-methyl-4-n-pentyltricyclo[5.2.1.02,6
]
dec-8-en-3-one (ꢀ)-(23) (0.162 g, 0.70 mmol) gave pure (ꢀ)-5a
(0.115 g, 0.69 mmol) as a colourless oil in quantitative yield.

1242
B. Zwanenburg, A. A. Volkers, and A. J. H. Klunder
(4R)-3-Methyl-4-n-pentyl-2-cyclopenten-1-one (þ)-(6)
(d) J. P. Eddolls, M. Iqbal, S. M. Roberts, M. G. Santoro, Tetrahedron
2004, 60, 2539. doi:10.1016/J.TET.2004.01.047
(e) J. Christoffers, T. Werner, W. Frey, A. Baro, Chem. Eur. J. 2004,
10, 1042. doi:10.1002/CHEM.200305486
(f) M. Iqbal, P. Evans, Tetrahedron Lett. 2003, 44, 5741. doi:10.1016/
S0040-4039(03)01297-8
(g) T. J. Brocksom, J. Nakamura, M. L. Ferreira, U. Brocksom,
J. Braz. Chem. Soc. 2001, 12, 597. doi:10.1590/S0103-
50532001000500004
Cyclopentenoid (þ)-6 was prepared in quantitative yield, using
the same procedure as that described for (ꢀ)-6. [a]2D1 þ33.88
(c 2.50 in CDCl3). Other physical data were identical to those of
its antipode (ꢀ)-6.
(5S)-3-Methyl-5-n-pentyl-2-cyclopenten-1-one (þ)-(7)
FVT (sublimation oven: 1208C, FVT oven: 5008C) of
(1R,2S,4S,6R,7S)-6-methyl-4-n-pentyltricyclo[5.2.1.02,6]dec-8-
en-3-one (þ)-(27) (0.114 m, 0.49 mmol) afforded pure (þ)-7
(0.079 g, 0.48 mmol) as a colourless oil in quantitative yield.
[a]2D0 þ32.28 (c 0.45 in CDCl3). nmax (CCl4)/cmꢀ1 2959 (C–H),
2931 (C–H), 2858 (C–H), 1689 (C¼O). dH (CDCl3, 400 MHz)
5.90 (1H, s, H2), 2,73 (1H, dd, 2J4,4 18.6, 3J4,5 6.6, H4), 2,39 (1H,
br s, H5), 2.25 (1H, d, 2J4,4 18.6, H4), 2.12 (3H, s, CH3), 1.78 (1H,
br s, C4H8CH3), 1.31 (7H, br s, C4H8CH3), 0.88 (3H, t, 3J 6.5,
C4H8CH3). dC (H-dec, CDCl3, 100 MHz) 212.3, 177.2 (quat.),
130.0, 46.8 (tert.), 39.9, 31.8, 31.4, 27.0, 22.5 (sec.), 19.4, 14.0
(prim.). m/z (EI) 167 (23 %, MþþH), 166 (4 %, Mþ), 109 (30 %,
Mþ–C4H9), 96 (100 %, Mþ–C5H10), 95 (21 %, Mþ–C5H11). m/z
166.135790. HRMS Anal. Calc. for C11H18O (Mþ) 166.135764.
(h) G. Mehta, D. S. Reddy, J. Chem. Soc., Perkin Trans. 1 2001, 1153.
doi:10.1039/B009307F
[8] (a) For some examples see: A. T. Levorse, R. A. Weiss, B. D. Newirth,
(International Flavors & Fragrances Inc., USA), U.S. Pat. Appl. Publ.
Cont.-in-part of U.S. Ser. No. 173,539, CODEN: USXXCO US
2007004608 A1 20070104 2007.
(b) A. T. Levorse, Jr, R. A. Weiss, B. D. Newirth, (International
Flavors & Fragrances Inc., USA), U.S. Pat. Appl. Publ. CODEN:
USXXAM US 7141699 B1 20061128 2006.
(c) K. Shimizu, (Asahi Kasei Chemicals Corporation, Japan),
Jpn. Kokai Tokkyo Koho CODEN: JKXXAF JP 2006160690 A
20060622 2006.
(d) M. G. Monteleone, M. J. Clements, L. Croce, Jr, R. P. Belco,
M. Pawla, (International Flavors & Fragrances Inc., USA), Eur. Pat.
Appl. CODEN: EPXXDW EP 1609846 A1 20051228 2005.
(e) H. C. Hailes, in Special Publication–Royal Society of Chemistry,
Advances in Flavours and Fragrances 2002, Vol. 277, pp. 127–137
(RSC: London).
(5R)-3-Methyl-5-n-pentyl-2-cyclopenten-1-one (ꢀ)-(7)
Cyclopentenoid (ꢀ)-7 was prepared in quantitative yield, using
the same procedure as that described for (þ)-7. [a]2D0 ꢀ33.18
(c 0.73 in CDCl3). Other physical data were identical to those of
its antipode (þ)-7.
(f) C. S. Letizia, J. Cocchiara, G. A. Wellington, C. Funk, A. M. Api,
Food Chem. Toxicol. 2000, 38(Suppl. 3), S227. doi:10.1016/S0278-
6915(00)80068-X
[9] A. J. H. Klunder, W. C. G. M. de Valk, J. M. J. Verlaak,
J. W. M. Schellekens, J. H. Noordik, V. Parthasarathi, B. Zwanenburg,
Tetrahedron 1985, 41, 963. doi:10.1016/S0040-4020(01)96416-6
[10] A. J. H. Klunder, W. B. Huizinga, A. J. M. Hulshof, B. Zwanenburg,
Tetrahedron Lett. 1986, 27, 2543. doi:10.1016/S0040-4039(00)
84580-3
Acknowledgements
We are greatly indebted to Professor Roger F. C. Brown for his continuous
interest in our research and his warm friendship for many years.
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