The search for new odorants: Synthesis of animalic fragrant and musky/ambery compounds

Article abstract of DOI:10.1002/cbdv.201400038

An overview of the recent research which allowed us to discover novel animalic odorants is presented. The new derivatives were prepared from readily available starting materials via easy reaction steps in good yields. They possess very different structures, such as bicyclic pentanols, glycolates, or tricyclic ketones, and all show interesting notes in the animalic fragrant family: from costus, leathery to ambery and musky scents, making them all attractive for different purposes.

Full text of DOI:10.1002/cbdv.201400038

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1517
The Search for New Odorants: Synthesis of Animalic Fragrant and Musky/
Ambery Compounds
by Caroline Plessis
Mane S. A., Chemistry Research Centre, 620 Route de Grasse, F-06620 Le Bar-sur-Loup
(phone: þ33493097000; fax: þ33493425425; e-mail: caroline.plessis@mane.com)
An overview of the recent research which allowed us to discover novel animalic odorants is
presented. The new derivatives were prepared from readily available starting materials via easy reaction
steps in good yields. They possess very different structures, such as bicyclic pentanols, glycolates, or
tricyclic ketones, and all show interesting notes in the animalic fragrant family: from costus, leathery to
ambery and musky scents, making them all attractive for different purposes.
Introduction. – Natural animal raw materials can be described as rich and warm,
leathery, and with fecal aspects and unique undertones related to their origin
(castoreum, civet, musk deer, ambergris). Despite unclean aspects, animal odorants,
throughout centuries, have always played important roles in compositions, such as
texturing agents (warmness, leathery, powdery) and as fixatives (resulting in long-
lasting perfumes). They also give opulence/richness to some accords, notably white
flowers [1].
Natural animal raw materials were, therefore, studied in detail to unveil the active
principles. Fascinating essential molecules were prepared by highly challenging
syntheses mainly in two important olfactory families: Musk and Amber [2].
Found in leathery Chypre perfumes with Castoreum undertones late 1980s,
animalic notes regained interest recently, in luxury niche perfume houses, notably in
Arabian oud fragrances.
Ambery or musky proprietary molecules are important for our portfolio. Never-
theless, the molecules presented here, belonging to the broad animalic family, were
discovered rather by serendipity while working on ꢀnon-amberyꢁ-oriented projects,
demonstrating again how amazing and exciting fragrance chemistry can be. The first
part deals with new cyclopentanols obtained from both (þ)-(S)- and (ꢀ)-(R)-2-methyl-
5-(prop-1-en-2-yl)cyclohex-2-enone ((S)- and (R)-carvone), the second part describes
new glycolates, and the last part is about a new tricyclic ambery odorant.
Cyclopentanol Derivatives. – Hydroxy ester 1a was prepared by Ley and co-
workers [3] as a starting material for thapsigargins (Scheme 1). Leyꢁs group
emphasized the effectiveness of their first steps on large scale, using cheap reagents
and starting from easily available (S)-carvone (2). With its interesting structure,
obtained stereospecifically, this small molecule was appealing as a synthon.
ꢂ 2014 Verlag Helvetica Chimica Acta AG, Zꢃrich

1518
CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
Scheme 1
i) a) H2O2, NaOH, MeOH, 108; 88%. b) LiCl, CF3COOH, THF, r.t.; 95%. ii) a) Dihydropyran, cat.
pyridinium p-toluenesulfonate (PPTS), CH2Cl2, r.t.; 87%. b) MeONa, MeOH, 08; 95%; dr >95 :5. iii)
Cat. PPTS, MeOH, 408; 84%.
Its enantiomer 1a* (Scheme 2) was reported earlier by another group, starting from
also available (R)-carvone (2*), by similar chemistry in the synthesis of iridomyrme-
cins, also pointing out the good stereoselectivity of the sequence [4].
For clarity and easier understanding, in the following, the * indicates that the
molecule is the enantiomer of the correspondingly numbered compound. As outlined
above, therefore, this indicates that the 1a* is prepared via a sequence starting from 2*,
whereas 1a is synthesized from 2.
Actually, both enantiomers, 1a and 1a*, were since reported as starting material for
various natural products synthesis by other groups [5]. As chirality can be important in
olfaction, and since olfactory properties of these compounds and derivatives were not
described, we prepared both isomers following the procedure of Ley and co-workers.
The only modification we made was using EtOH instead of MeOH in the first step for
the synthesis of the carvone epoxide. We obtained alcohols 1a and 1a* in 48 and 38%
yields, respectively, over five steps (86% average yield per step, 82% resp.), via
their corresponding THP derivatives 3a and 3a* (cf. Scheme 1). Unfortunately, the
odors of compounds 1a and 1a* were only slightly floral.
However, given the easy preparation of the THP intermediates 3a and 3a* from
inexpensive carvones 2 and 2*, respectively, we focused on the preparation of 3, as a
Scheme 2

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1519
source of other new derivatives. For industrial purposes, it was important to replace
MeOH and CH2Cl2 for toxicity and environmental reasons, and THF for recovery
purposes.
Based on previous experience [6], the epoxidation was directly carried out in
EtOH, instead of MeOH, without influencing the overall yields. Thus epoxides 4 and 4*
(Scheme 3) were prepared in 83% yield from both carvones (average yield reported by
Ley and co-workers: 88.6%).
Scheme 3
i) H2O2, NaOH, EtOH, 108. ii) LiCl, CF3COOH, r.t. iii) Dihydropyran, cat. PPTS, r.t. iv) Na,
ROH, 08.
The opening of the epoxides to the chlorhydrins 5 and 5* was then performed in 2-
MeTHF with similar yield as in THF (Table 1).
The THP (tetrahydropyran-2-yl) protection step carried out in toluene instead of
CH2Cl2 proceeded with very good yields to afford compounds 6 and 6* (Table 2).
Table 1. Chlorhydrins 5 Obtained in 2-MeTHF vs. THF
Compound
Solvent
Crude yield [%]
THF
2-MeTHF
75
85
5
THF
2-MeTHF
80
100
5*

1520
CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
Table 2. Protected Chlorhydrins 6 Obtained in Toluene vs. CH2Cl2
Compound
Solvent
Crude yield [%]
CH2Cl2
Toluene
87
83
6
CH2Cl2
Toluene
84
quant.
6*
The Favorskii rearrangement was performed in EtOH and afforded the so far
unknown ethyl esters 3b and 3b* instead of the methyl derivatives 3a or 3a*, however,
in lower yields (Table 3).
Performing the reaction sequences in different solvent systems (Scheme 3, and
Table 4) led to 3 in quite similar overall yields.
From the ethyl esters 3b and 3b*, corresponding alcohols 1b and 1b* were prepared
to evaluate their olfactory properties. The deprotection was either performed in MeOH
as described, or in EtOH for safer use. The yields were almost quantitative. However,
again, these compounds showed no interesting odors.
The new structures that were further envisaged were obtained by simple trans-
formations (Scheme 4).
Table 3. Esters 3 Obtained via Favorskii Rearrangement in EtOH or MeOH
Compound
Solvent
Crude
Compound
Solvent
Crude
yield [%]
yield [%]
3a R¼Me
3b R¼Et
MeOH
EtOH
62
33
3a* R¼Me
3b* R¼Et
MeOH
EtOH
68
52
Table 4. Sequence Yields to Obtain 3 from 2 Using Different Solvents (Scheme 3)
Entry
Compound
Step ii
Step iii
Step iv
Yield [%]
1
2
3
4
5
3a
THF
THF
2-MeTHF
2-MeTHF
2-MeTHF
CH2Cl2
CH2Cl2
Toluene
Toluene
Toluene
MeOH
MeOH
MeOH
EtOH
EtOH
48
52
39
28
39
3a*
3a*
3b
3b*

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1521
Scheme 4
i) cat. PPTS, MeOH. ii) Ac2O, cat. 4-(dimethylamino)pyridine (DMAP). iii) AcCl, Et3N, cat. TsOH,
tBuOMe. iv) Pyridinium dichromate (PDC)/SiO2, CH2Cl2. v) LiAlH4, Et2O. vi) Cat. PPTS, MeOH,
then TfOH, toluene.
After deprotection of derivatives 3 to yield alcohols 1, the corresponding acetates 7
were prepared in good yields. From alcohols 1, also the corresponding cyclopentanones
8 were obtained. Then, the ester 3 was further transformed to the corresponding
alcohol 9a, which was then esterified and deprotected to afford compounds 10.
Alcohols 9a also underwent cyclization with the isopropenyl group, and the THP group
was removed to furnish the bicyclic compounds 11a. All the obtained compounds were
evaluated by a perfumer panel as compiled in Table 5.
The only rather interesting compounds were bicyclic derivatives 11a. So, we
prepared new, differently substituted bicycles. This could be easily performed by
condensing a Grignard reagent onto the ester 3 instead of hydride reduction. Thus, the
obtained alcohols 9b and 9c, with dimethyl and diethyl substituents, respectively, were
obtained. Compounds 9b and 9c were further cyclized to afford 11b and 11c,
respectively, in good yields (Scheme 5). To obtain bicyclic compound 11d*, a
Kulinkowich reaction was performed on 3*, leading to cyclopropyl alcohol 9d* [7],
reacting the ester with EtMgCl in the presence of (iPrO)4Ti. Enantiomer 11b* was
obtained in 59% yield from alcohol 9b*, by using EtOH to remove the THP group in
the one-pot cyclization/deprotection step.
Then, acetates 12 as well as the corresponding cyclopentanones 13 (Scheme 6) were
prepared from 11.
Acetates 12 were easily obtained by treating bicyclic alcohols 11 with Ac2O in good
yields (average yields 60–70%), whereas ketone 13a* was prepared from oxo-ester 8a*

1522
CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
Table 5. Odor Descriptions of the Carvone Derivatives
Compound
Odor
Compound
Odor
Slightly floral,
a bit smokey
Slightly floral
1a
1a*
1b*
Lactonic, powdery,
musky, weak
Weak
Spearmint, Carvone,
chlorophylle,
7a
8a
7a*
8a*
´
«cedrat confit»
Very weak
Very weak
Carnation, eugenol,
weak
10*
Fishy,
fish flesh
Leathery, animal,
phenolic, indolic,
smokey
11a
11a*
Scheme 5
i) a) R’MgX, THF, 0–108; or b) EtMgCl, (iPrO)4Ti, Et2O. ii) Cat. PPTS, 2 equiv. MeOH (a) or EtOH)
then TfOH, toluene.
by reducing the ester and performing the one-pot deprotection-cyclization sequence, in
overall good yield. However, some epimerization occurred at the a-C-atom.
All the new bicyclic derivatives were also evaluated by a perfumer panel (Table 6).
Despite interesting tonalities, compounds 12 and 13 were too weak, only the bicyclic
alcohols 11 showed attractive notes, 11a* being the outstanding molecule.

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1523
Scheme 6
The final steps of the preparation of compound 11a* had to be improved from an
industrial point of view. Some improvements were already performed along the
different syntheses of the compounds 11, notably the way the one-pot cyclization-
deprotection was carried out. Finally, we found that the yield was improved and the
process was cleaner, by performing the deprotection first at 608 in toluene in the
presence of TsOH and 2 equiv. of MeOH or EtOH, and only then adding
trifluoromethylsulfonic acid (triflic acid, TfOH) to perform the cyclization at 808. We
then tried to avoid the use of LiAlH4 industrially. Literature survey revealed that
NaBH4 by adding catalysts in different solvents is a convenient alternative [8]. The
conditions that were evaluated are compiled in Table 7 (Entries 1–4). Other
possibilities were aluminum hydrides such as Synhydridꢄ (Entry 5) or DIBAl-H
(Entry 6). Only the latter gave a good conversion.
Finally, we achieved a better overall yield of 11a* from ester 3a* (Scheme 7), by
performing the THP removal, followed by cyclization in the presence of TfOH in one
pot (Table 8, Entry 2). Using DIBAl-H instead of LiAlH4 also gave better results, and
the resulting toluene solution after hydrolysis can be directly used in the subsequent
cyclization step (Entry 3).
New cyclopentanol derivatives were prepared in good yields via simple steps,
starting from inexpensive and available carvones (2 and 2*). Among the different
structures, an interesting bicyclic compound 11a*, prepared in 27% yield over six steps
(average yield: 80.4%) from (þ)-(R)-enantiomer 2*, was found as a nice leathery and
animalic odorant.
Scheme 7

1524
CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
Table 6. Odor Descriptions of the Bicyclic Derivatives
Compound
Odor description
Fishy, fish flesh
Compound
Odor description
Leathery,
animal, phenolic,
indolic, smokey
11a
11b
11a*
Green, metallic,
raw vegetables,
earthy
Woody, leathery,
sligthly honey,
animal
11b*
11c*
Marine, oyster,
weak
Spicy, pepper,
a bit Carvone,
weak
11d*
12a*
12b*
13a*
Slightly plastic, weak
Woody, vetiver,
weak
12a
Marine, aqueous,
algae, weak
Musky, lactonic,
powdery, weak
Table 7. Reduction Conditions to Obtain Alcohol 9a*
Entry
Reducing agent
Catalyst
Solvent
Yield of 9a* [%]
Reaction time
1
2
3
4
5
6
NaBH4
NaBH4
MeOH
MeOH
Me2NPh
–
–
–
t-AmOHa)
THF
THF
THF
Toluene
Toluene
Only isomers
–
–
–
–
88
1 week
5 h
4 h
1 h
0.5 h
2.5 h
NaBH4 þZnCl2
Ca(BH4)2
NaAl(MeOC2H4O)2H2
DIBAl-H
a) tert-Amyl alcohol (2-methylbutan-2-ol).

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1525
Table 8. Sequence Yields to Obtain 11a* from 3a* Using Different Conditions (Scheme 7)
Entry
Reducing agent (Step 1)
Cyclization/Deprotection (Step 2)
Yield [%]
1
2
3
LiAlH4
LiAlH4
DIBAl-H
TfOH/Toluene then MeOH
34%
45%
53%
PPTS/MeOH/Toluene then TfOH
PPTS/MeOH/Toluenea) then TfOH
a) Toluene from the Step 1.
Glycolate Derivatives. – Finding a new great galbanum-type green note to be added
to our captives portfolio is not easy, the reference being the very powerful Dynasconeꢄ
(14; Fig.). On alkyl butenyl ketones and intensities, a tremendous work has been
accomplished by Bajgrowicz and co-workers [9] in association with structureꢀactivity
relationships (SARs) for a green/galbanum olfactophore model. The study also dealt
with some allyl glycolates, which are also well known in the galbanum family, such as
Cyclogalbanateꢄ (15), allyl amyl glycolate (16) or allyl phenoxyacetate (17; Fig.).
These compounds have a more fruity pineapple-type aspect than Dynasconeꢄ, but they
are an attractive class of compounds because of their potentially facile industrial
preparation.
We prepared new aryl derivatives of the Acetate PA type (allyl phenoxyacetate), as
well as new allyl alkoxyacetates [10]. Both syntheses are trivial. In the case of
alkoxyacetates 18 and 19, the chosen alkyl alcohol 20 was deprotonated with NaH and
the obtained alcoholate was condensed onto ClCH2COONa. The allyl derivatives 18 or
19 are then simply obtained by esterification of the acid with allylic alcohol or (Z)-hex-
3-enol, respectively (Scheme 8, Table 9).
Concerning the 2-(aryloxy)acetates 21 and 22, the synthesis is even simpler: the
corresponding phenol 23 was reacted with allyl chloroacetate or (Z)-hex-3-enyl
chloroacetate, respectively, in the presence of K2CO3 in refluxing acetone (Scheme 9
and Table 10).
All the target compounds were obtained in fair unoptimized yields (35–55%).
Among all the prepared derivatives, only compounds 18a and 19a belong to the green
family, which is not surprising due to the (Z)-hex-3-en-1-ol moiety. However, 18a and
Figure. Synthetic galbanum-type raw materials

1526
CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
Scheme 8
Table 9. Odor Descriptions of the Glycolate Derivatives 18 and 19 (Scheme 8)
Starting alcohol
Compound
Odor
18a
19a
20a R¼(Z)-Hex-3-en-1-yl
Green, cut grass,
watery, clean (Ironed
linen), powerful
20a
Clean (Ironed linen),
green
18b
18c
20b R¼3,3,5-Trimethylcyclohexyl
Leathery, burnt, green
Costus, musky
20c R¼4-(tert-Butyl)cyclohexyl
Scheme 9

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1527
Table 10. Odor Descriptions of the Glycolate Derivatives 21 and 22 (Scheme 9)
Starting Phenol
Product
Odor
23a R1 ¼R3 ¼H; R2 ¼R4 ¼Me
Musky, hot iron,
not powerful
21a
23b R1 ¼iPr; R2 ¼R3 ¼H;
R4 ¼Me
Costus
21b
22c
21d
21e
23c R1 ¼R2 ¼R4 ¼H;
R3 ¼Me
Animal, leathery
23d R1 ¼MeO; R2 ¼R4 ¼H;
R3 ¼allyl
Eugenol, carnation-type,
woody
23e R1 ¼MeO; R2 ¼R4 ¼H;
R3 ¼prop-2-enyl
Spicy (isoeugenol),
leathery, carnation,
saffron, fruity (plums,
dried plums), woody
(vetiver), sweet
23f R1 ¼MeO; R2 ¼R4 ¼H;
R3 ¼Me
Vanilla, spicy
(isoeugenol)
21f
22f
22g
23f
Vanilla, smokey
Vanilla, plastic
23g R1 ¼allyl; R2 ¼R3 ¼R4 ¼H
19a are far from galbanum-type odorants, but with a nice clean effect and an enhanced
substantivity; their green notes are very interesting as such, in regard to (Z)-hex-3-en-
1-ol. None of the (cyclohexyl)oxy or phenoxy derivatives exhibited the expected green
or fruity odor. Further, nice spicy notes, with carnation or vanilla aspects, were found

1528
CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
for alkoxy- and/or allyl-substituted phenoxy compounds, whereas interesting animal
notes, such as costus, leathery, and musky (the latter being, however, quite weak), were
observed for alkyl-substituted cyclohexyl or phenoxy derivatives.
In the easily accessible glycolate family, different new molecules were synthesized
in good yields, all showing interesting notes. The most interesting compound in the
animalic family was the thymol-derived glycolate 21b.
New Ambery Odorants. – Since we had an easy access to cyclopentanols 1 from a-
methylcyclohex-2-enones 2 (see above), we had a look at other starting materials. We
first prepared new compounds 2 from aldehydes and ethyl vinyl ketones (Scheme 10),
but ethyl vinyl ketone is neither inexpensive, nor easy to prepare and handle. Then,
we envisaged the reverse way and developed a method to prepare novel a-
methylcyclohex-2-enones 24 from pentan-3-one and different methylidene aldehydes
25 [11].
The chemistry of methylidene aldehydes is well-known and documented in the
perfumery [12]; they are mostly used in DielsꢀAlder reactions with isoprene (26) or
myrcene (27) to access to very interesting molecules such as Cassiffixꢄ (28i) [13], or
Melafleurꢄ (29a) [14] (Scheme 11). The DielsꢀAlder reactions with isoprene were
carried out with high-molecular-weight methylidene aldehydes (Reaction 1), whereas,
in the case of myrcene, the reactions were performed with the simplest ones: acrolein
(25a) or methacrolein (25b; Reaction 2). Among the different structures prepared from
pentanal, limonenal, Vandor Bꢄ, etc., bicyclic ethers 28d–28i were further obtained by
reduction of the DielsꢀAlder adduct, followed by cyclization. Cassiffixꢄ (28i), a
compound with a nice substantive camphoraceous cassis note, was thus prepared from
isoprene and methylidene-campholenaldehyde. The work on myrcene (27), leading to
bicyclic and further tricyclic structures by acidic rearrangements, was aimed at
molecules in the ambery family. However, even with a nice intense green fruity scent,
Melafleur (29a; from acrolein) is neither woody nor ambery. Of the further cyclized
compounds, neither Patchwood (30a) [14] nor Herbanone (30b) [14][15], obtained
from acrolein and methacrolein, respectively, showed the desired ambery character.
They are described as woody, camphoraceous.
We prepared several methylidene aldehydes 25 [11] and applied our tandem
Michaelꢀaldol reaction to the corresponding cyclohexenones 24 in good yields. The
Scheme 10

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1529
Scheme 11
compounds obtained had interesting odors with citrus-aldehydic or woody notes,
however, no real animalic ones. Only compound 24h, obtained from Vandor Bꢄ, could
be considered in that direction with sweaty, urinous aspects. As Aldronꢄ (31) is
concerned, it was controversial, some perfumers were really disgusted by the powerful
note, whereas others perceived it very light, dry, woody, and somehow ambery.
With many different methylidene aldehydes in hand, we were interested again in
the work of Sprecker and co-workers [14], since some derivatives were not examplified,
and the structures are still appealing as potential ambery notes, even if Patchwood and
Herbanone are not ambery. Contrary to the work we have performed with pentan-3-
one [11], we mainly focused on the smallest aldehydes 25a–25f (Scheme 12 and
Table 11) [16].
Scheme 12

1530
CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
Table 11. Preparation and Odor Description of Tricyclic Ketones 30 (Scheme 12)
Aldehyde R Compound Yield (two steps) [%]
Odor
25a
25b
25c
25d
25e
25f
H
30a
40 (one step from myrac aldehyde) Camphoraceous, aromatic
Me 30b
Et 30c
Pr 30d
iPr 30e
Bu 30f
16
12
35
38
13
Camphoraceous, aqueous, woody, fatty
Camphoraceous, slightly ambery, weak
Ambery, woody
Woody, dry, weak
Weak, fatty
We prepared derivatives 30 including Patchwood (30a) and Herbanone (30b) (for
comparison). Actually, being heavier, the new compounds exhibited less and less
camphoraceous aspects, and the Pr derivative 30d turned out to be a nice ambery
odorant. Obtained as a racemate in cis-decaline configuration (confirmed by X-ray
crystallography), we also prepared the trans-decaline racemate 30d’ by heating 30d in
MeOH in the presence of KOH (Scheme 13). Compound 30d’ exhibited, however, a
less powerful odor than the cis isomer.
Scheme 13
On the route to original cyclohexenones and their derivatives, we prepared new
bridged tricyclic compounds via a DielsꢀAlder reaction, followed by cyclization. A
novel ambery odorant 30d with subtle fruity undertones was thus discovered, easily
synthesized in good yields from inexpensive and available myrcene and 2-methyl-
idenepentanal (25d).
In conclusion, new interesting structures were found in the leathery-animal family
while working on completely different topics. It was all the more fascinating as some of
the structures were designed to be green, pineapple odorants. We discovered 11a*, a
bicyclic cyclopentanol, 21b, a thymol-derived glycolate, and 30d, a tricyclic ketone. All
the new derivatives were prepared in good yields via simple steps, from inexpensive and
readily available starting materials. Finally, it allowed us to add a fine ambery
compound, filling a gap in our captives portfolio.
Experimental Part
General. All the reagents and solvents were commercially available, and were used without any
further purification, unless otherwise mentioned. Spectral data of compounds 1a, 3a, 4–6, and 1a*, 3a*,
4*–6*, prepared from (þ)-(S)-carvone (2) and (ꢀ)-(R)-carvone (2*), resp., have already been reported
[3][4]. GC: HP 6890 with a polar DBWAX-FF column. Optical rotations: Bellinghamþ ADP 220. IR
Spectra: Nicolet iS5 ATR diamond spectrometer; ˜n in cmꢀ1. NMR Spectra: Bruker 200-MHz or Fourier

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1531
300 instrument; in CDCl3; d in ppm rel. to Me4Si as internal standard; J in Hz. MS: Agilent 5975 MSD
quadrupole EI spectrometer; in m/z.
Ethyl (1R,2S,3R,5R)-2-Methyl-5-(prop-1-en-2-yl)-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentanecar-
boxylate (3b*). To a freshly prepared 2.25m EtONa soln. (52 g, (2.26 mol) of Na in 1 l of abs. EtOH) was
added dropwise at 108 chlorhydrin 6* (637 g, 2.22 mol; prepared from 2*). After completion of the
reaction (monitored by GC), the mixture was poured onto 1 l H2O/tBuOMe 1:1 soln. The aq. phase was
extracted three times with tBuOMe (200 ml), and the combined org. layers were washed with a sat. aq.
NaHCO3 soln. (250 ml) and brine (250 ml), dried (MgSO4), filtered, and concentrated in vacuo. The
crude oil was purified by distillation to give THP derivative 3b* as a 53 :47 ratio of diastereoisomers
(482 g, 45% over the 4 steps). B.p. 1358/1.3 Torr. Major isomer: 1H-NMR (200 MHz): 1.05 (d, J¼7, 3 H ) ;
1.14 (t, J¼7.2, 3 H); 1.25–1.59 (m, 4 H); 1.67 (s, 3 H); 1.60–1.87 (m, 3 H); 1.93 (dd, J¼2.81, J¼8.81,
1 H); 2.37–2.63 (m, 1 H); 2.63–2.84 (m, 1 H); 2.94–3.28 (m, 1 H); 3.36–3.52 (m, 1 H); 3.73–3.89 (m,
1 H); 3.89–4.10 (m, 2 H); 4.10–4.21 (m, 1 H); 4.48–4.58 (m, 1 H); 4.64 (s, 1 H); 4.70 (s, 1 H). MS: 296
1
(<1, Mþ ), 195 (10), 194 (14), 149 (11), 121 (51), 85 (100), 67 (10), 41 (10). Minor isomer: H-NMR
(200 MHz, selected data): 0.94 (d, J¼7.0, 3 H); 3.89–4.10 (m, 1 H); 4.58–4.68 (m, 1 H). MS: 296 (<1,
Mþ ), 194 (20), 149 (12), 121 (64), 85 (100), 67 (12), 41 (12).
Ethyl (1S,2R,3S,5S)-2-Methyl-5-(prop-1-en-2-yl)-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentanecar-
boxylate (3b). Starting from 2, 3b was obtained in 33% yield over the 4 steps as a 58 :42 ratio of
diastereoisomers, as described for 3b*. Major isomer: 1H-NMR (200 MHz): 1.05 (d, J¼6.9, 3 H); 1.14 (t,
J¼7.2, 3 H); 1.30–1.60 (m, 4 H); 1.67 (s, 3 H); 1.61–1.89 (m, 3 H); 1.94 (dd, J¼3.0, 9.0, 1 H); 2.30–2.63
(m, 1 H); 2.63–2.90 (m, 1 H); 2.90–3.32 (m, 1 H); 3.36–3.52 (m, 1 H); 3.74–3.90 (m, 1 H); 3.90–4.12
(m, 2 H); 4.12–4.23 (m, 1 H); 4.50–4.59 (m, 1 H); 4.64 (s, 1 H); 4.70 (s, 1 H). MS: 296 (<1, Mþ ), 194
(18), 121 (52), 85 (100), 67 (12), 41 (12). Minor isomer: 1H-NMR (200 MHz; selected data): 0.95 (d, J¼
7.0, 3 H); 3.90–4.11 (m, 1 H); 4.58–4.70 (m, 1 H). MS: 296 (<1, Mþ ), 194 (17), 149 (11), 121 (64), 85
(100), 67 (12), 41 (14).
Ethyl (1R,2S,3R,5R)-3-Hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclopentanecarboxylate (1b*). A soln.
of 3b* (20 g, 67.5 mmol) in MeOH (35 ml) with cat. amount of PPTS (0.1 g, 0.5 wt-%) was heated under
reflux until completion of the reaction (monitored by GC). The mixture was poured into H2O/tBuOMe
1:1 (50 ml), and the aq. phase was extracted once with tBuOMe (15 ml). The combined org. layers were
washed with a sat. aq. NaHCO3 soln. (15 ml) and brine (15 ml), dried (MgSO4), filtered, and
concentrated in vacuo. The crude oil was purified by distillation to give 1b* (11.4 g, 73%). B.p. 978/1 Torr.
IR: 889m, 1014m, 1030m, 1138m, 1176s, 1375m, 1713m, 1728m, 2936w, 2967w, 3447w. 1H-NMR
(200 MHz): 1.03 (d, J¼7, 3 H); 1.18 (t, J¼7.2, 3 H); 1.70 (s, 3 H); 1.66–1.89 (m, 1 H); 2.01 (ddd, J¼4.2,
J¼11.0, 14.8, 1 H); 2.35–2.55 (m, 1 H); 2.77 (dd, J¼8.6, 10.2, 1 H); 3.20 (td, J¼7.2, 10.4, 1 H); 4.02 (qd,
J¼3.6, 7.2, 2 H); 4.16–4.28 (m, 1 H); 4.68 (s, 1 H); 4.75 (s, 1 H). 13C-NMR (50 MHz): 13.55; 14.12; 22.58;
39.32; 42.39; 46.57; 52.90; 60.05; 74.92; 111.39; 145.0; 174.49. MS: 212 (1, Mþ ), 122 (10), 121 (100), 120
(19), 115 (21), 105 (14), 95 (10), 93 (14), 87 (26), 79 (12), 69 (14), 41 (13). Odor description: Lactonic,
powdery, musky, weak.
Methyl (1S,2R,3S,5S)-3-Acetoxy-2-methyl-5-(prop-1-en-2-yl)cyclopentanecarboxylate (7a). Alcohol
1a (33.6 g, 171 mmol) was heated with Ac2O (100 g, 980 mmol) and cat. amount of DMAP. AcOH and
excess Ac2O were removed from the mixture. After cooling, the mixture was poured into H2O/tBuOMe
(1:1; 150 ml), and the org. phase was washed with a sat. aq. NaHCO3 soln. (4ꢁ50 ml) and brine (50 ml),
dried (MgSO4), filtered, and concentrated in vacuo. The crude oil was purified by distillation to give 7a
(27.3 g, 67%). B.p. 908/0.4 Torr. IR: 891m, 993m, 1018s, 1142m, 1171s, 1193s, 1237s, 1371m, 1435m, 1732s,
2950w, 2970w. 1H-NMR (300 MHz): 0.97 (d, J¼7.0, 3 H); 1.71 (m, 3 H); 1.81–1.90 (m, 1 H); 2.01–2.17
(m, 1 H); 2.03 (s, 3 H); 2.57–2.71 (m, 1 H); 2.82 (dd, J¼8.9, 9.2, 1 H); 3.05–3.17 (m, 1 H); 3.59 (s, 3 H);
4.66–4.69 (m, 1 H); 4.77–4.80 (m, 1 H); 5.30 (br. t, J¼4.9, 1 H). 13C-NMR (75 MHz): 13.78; 21.02;
22.36; 36.87; 41.01; 46.67; 51.29; 53.70; 77.58; 111.64; 144.49; 170.54; 174.29. MS: 180 (9), 122 (10), 121
(100), 120 (13), 105 (19), 93 (13), 91 (10), 79 (11), 43 (23). Odor description: Very weak.
Methyl (1R,2S,3R,5R)-3-Acetoxy-2-methyl-5-(prop-1-en-2-yl)cyclopentanecarboxylate (7a*). A
t
soln. of 1a* (19 g, 96 mmol) and Et3N (11.6 g, 115 mmol) in BuOMe (100 ml) was cooled to 58, and
AcCl (9 g, 115 mmol) in tBuOMe (20 ml) was added dropwise. The mixture was further stirred to r.t. for
14 h and then poured into a cold 10% aq. HCl soln. (100 ml). The separated org. phase was washed with

1532
CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
sat. aq. NaHCO3 (50 ml) and twice with brine (50 ml), dried (MgSO4), filtered, and the solvents were
evaporated. The crude product was purified by distillation to give 7a* (10.4 g, 45%). B.p. 808/0.15 Torr.
IR: 891m, 993m, 1017s, 1142m, 1171s, 1193s, 1237s, 1371m, 1435m, 1732s, 2950w, 2970w. 1H-NMR
(300 MHz): 0.97 (d, J¼7.0, 3 H); 1.71 (m, 3 H); 1.82–1.91 (m, 1 H); 2.01–2.18 (m, 1 H); 2.04 (s, 3 H);
2.58–2.71 (m, 1 H); 2.82 (dd, J¼8.3, 9.9, 1 H); 3.11 (td, J¼7.1, 10.2, 1 H); 3.59 (s, 3 H); 4.67–4.70 (m,
1 H); 4.77–4.81 (m, 1 H); 5.30 (br. t, J¼4.9, 1 H). 13C-NMR (75 MHz): 13.80; 21.04; 22.37; 36.89; 41.03;
46.68; 51.31; 53.71; 77.61; 111.65; 144.50; 170.57; 174.32. MS: 180 (9), 122 (11), 121 (100), 120 (14), 105
´
(17), 93 (12), 79 (10), 43 (24). Odor description: spearmint, carvone, chlorophylle, ꢀcedrat confitꢁ.
Methyl (1S,2R,5S)-2-Methyl-3-oxo-5-(prop-1-en-2-yl)cyclopentanecarboxylate (8a). Compound 3a
(80 g, 283 mmol) was deprotected as described for 1a* to give crude 1a quantitatively. To a suspension of
PDC (69 g, 182 mmol) and silica gel (60 g) in CH2Cl2 (200 ml) was added a soln. of 1a (30 g, 151 mmol) in
CH2Cl2 (50 ml). The mixture was further stirred overnight and filtered over a pad of Clarcelꢄ. The org.
soln. was washed with a 10% aq. Na2S2O3 soln. and with brine, and dried (MgSO4), filtered, and
evaporated in vacuo. The crude oil was purified by distillation to give 8a (14.4 g, 49%), which was
crystalline and could be crystallized from hexane. M.p. 658. B.p. 758/0.5 Torr. IR: 869m, 892s, 1043m,
1071m, 1156s, 1175s, 1238m, 1375m, 1443m, 1723s, 2875w, 2919w, 2952w, 2969w, 2981w. 1H-NMR
(200 MHz): 1.14 (d, J¼7.4, 3); 1.76 (s, 3 H); 2.36 (dd, J¼8.1, 18.3, 1 H); 2.64 (ddd, J¼1.6, 7.7, 18.3, 1 H);
2.65–2.83 (m, 1 H); 3.01 (dd, J¼6.1, 7.3, 1 H); 3.19 (q, J¼7.7, 1 H); 3.65 (s, 3 H); 4.71–4.74 (m, 1 H);
4.84–4.89 (m, 1 H). 13C-NMR (50 MHz): 15.16; 21.77; 41.18; 43.18; 45.20; 51.60; 52.68; 112.32; 143.48;
173.04; 218.31. MS: 196 (25, Mþ ), 137 (51), 136 (18), 128 (15), 127 (18), 12), 109 (24), 108 (14), 101 (21),
100 (14), 96 (43), 95 (54), 94 (12), 93 (37), 91 (14), 85 (17), 81 (12), 79 (24), 77 (18), 69 (83), 68 (100), 67
(76), 65 (12), 59 (13), 55 (15), 53 (27), 41 (38), 39 (31). Odor description: very weak.
Methyl (1R,2S,5R)-2-Methyl-3-oxo-5-(prop-1-en-2-yl)cyclopentanecarboxylate (8a*). Obtained
from 1a* (35 g, 176 mmol) as described for 8a. Recrystallization from hexane (40% yield). M.p. 658.
1H-NMR (200 MHz): 1.08 (d, J¼7.4, 3 H); 1.70 (s, 3 H); 2.30 (dd, J¼8.1, 18.3, 1 H); 2.57 (ddd, J¼1.6, 7.7,
18.3, 1 H); 2.62–2.76 (m, 1 H); 2.96 (dd, J¼6.1, 7.3, 1 H); 3.14 (q, J¼7.7, 1 H); 3.59 (s, 3 H); 4.64–4.69
(m, 1 H); 4.77–4.83 (m, 1 H). 13C-NMR (50 MHz): 14.99; 21.63; 41.03; 43.04; 45.04; 51.42; 52.50; 112.13;
143.40; 172.90; 218.05. Odor description: weak.
[(1R,2S,3R,5R)-2-Methyl-5-(prop-1-en-2-yl)-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]methanol
(9*). To a soln. of 3a* (100 g, 0.337 mol) [3] in toluene (150 ml) was added dropwise at r.t. a 1m soln. of
DIBAl-H in toluene (680 ml, 0.680 mol). After completion of the reaction (followed by GC), the
mixture was poured into ice/AcOH (800 g/120 g). The aq. phase (pH 5–6) was extracted three times
with toluene (150 ml), and the combined org. layers were washed with a sat. aq. NaHCO3 soln. (200 ml)
and then with brine (200 ml). The org. phase was dried (MgSO4), filtered, and evaporated in vacuo to
give crude 9* (96% purity) as a 50 :50 mixture of diastereoisomers (72.4 g, 81%).
[(1R,2S,3R,5R)-3-Hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclopentyl]methyl Acetate (10*). Alcohol
9* was converted to its acetate as described for 7a, and 10* was obtained after removal of the THP group
as described for 1b*. Yield: 30% over five steps from 5*. B.p. 858/0.04 Torr. IR: 555m, 606m, 888m, 970m,
1030s, 1085w, 1231s, 1367m, 1452w, 1646w, 1716m, 1738s, 2937w, 2961w, 3436w. 1H-NMR (300 MHz): 1.05
(d, J¼7.1, 3 H); 1.73 (s, 3 H); 1.79–1.88 (m, 2 H); 1.98 (s, 3 H); 2.04–2.15 (m, 2 H); 2.95–3.06 (m, 1 H);
3.78 (dd, J¼7.4, 11.0, 1 H); 3.92 (dd, J¼6.5, 11.1, 1 H); 4.15 (br. t, J¼4.1, 1 H); 4.63–4.66 (m, 1 H); 4.77–
4.81 (m, 1 H). 13C-NMR (75 MHz): 14.13; 20.81; 23.60; 38.68; 42.81; 44.11; 44.62; 65.85; 74.24; 110.80;
144.55; 171.21. MS: 152 (23), 137 (17), 134 (47), 123 (14), 121 (59), 120 (10), 119 (100), 114 (20), 109
(23), 107 (16), 106 (12), 105 (25), 99 (13), 95 (26), 94 (13), 93 (45), 92 (16), 91 (45), 83 (40), 82 (10), 81
(38), 79 (41), 77 (26), 72 (10), 71 (22), 70 (12), 69 (28), 68 (16), 67 (30), 65 (10), 55 (41), 53 (19), 43
(100), 41 (31), 39 (20). Odor description: carnation, eugenol, weak.
(3aS,4S,5R,6aR)-Hexahydro-1,1,4-trimethyl-1H-cyclopenta[c]furan-5-ol (11a*). A mixture of 9*
(72.4 g, 0.284 mol), PPTS (1.5 g, 2 wt-%) and MeOH (67 g, 2.1 mol) in toluene (150 ml) was heated to
608, and the conversion was monitored by GC. After 2 h, TfOH was added (0.38 g, 0.5% (w/w)), and the
mixture was further stirred at 808. After completion of the reaction (GC), the mixture was poured into a
sat. aq. NaHCO3 soln. (100 ml). The aq. phase was extracted twice with toluene (50 ml), and the
combined org. layers were washed with brine (50 ml), dried (MgSO4), filtered, and evaporated in vacuo.
The residue was purified by distillation to give 11a* (21 g, 43%). B.p. 1238/0.9 Torr. [a]D ¼ ꢀ67.6. IR:

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1533
1
1134m, 1180–1237m, 2870m, 2929m, 2967m, 3425w. H-NMR (200 MHz): 1.01 (d, J¼7, 3 H); 1.13 (s,
3 H); 1.19 (s, 3 H); 1.53–1.85 (m, 3 H); 2.40 (m, 1 H); 2.59 (td, J¼8.4, 9.2, 1 H); 3.51 (dd, J¼2.4, 9.15,
1 H); 3.88 (dd, J¼7.2, 9.1, 1 H); 4.08–4.17 (m, 1 H). 13C-NMR (50 MHz): 13.72; 23.78; 26.68; 36.52;
46.67; 50.13; 51.43; 70.64; 77.97; 81.43. MS: 170 (<1, Mþ ), 155 (100), 109 (17), 95 (29), 71 (21), 67 (16),
59 (31), 57 (17), 55 (22), 43 (48), 41 (20). Odor description: leathery, animal, phenolic, indolic, smokey.
(3aR,4R,5S,6aS)-1,1,4-Trimethylhexahydro-1H-cyclopenta[c]furan-5-ol (11a). Obtained in 24%
yield over six steps from 2 via 3, as described for 11a*. B.p. 708/0.06 Torr. [a]D ¼ þ61.9. IR: 917m,
964m, 998m, 1018m, 1035m, 1058m, 1134m, 1365m, 2870w, 2929m, 2966m, 3419w. 1H-NMR (200 MHz):
1.02 (d, J¼7, 3 H); 1.14 (s, 3 H); 1.20 (s, 3 H); 1.55–1.82 (m, 3 H); 2.42 (m, 1 H); 2.61 (td, J¼8.4, 9.2,
1 H); 3.53 (dd, J¼2.2, 9.2, 1 H); 3.90 (dd, J¼7.2, 9.1, 1 H); 4.13–4.20 (m, 1 H). 13C-NMR (50 MHz):
13.74; 23.84; 26.72; 36.60; 46.71; 50.20; 51.50; 70.69; 78.16; 81.43. MS: 170 (<1, Mþ ), 156 (10), 155 (100),
115 (10), 109 (16), 107 (19), 97 (13), 95 (31), 94 (13), 93 (12), 91 (12), 83 (12), 81 (10), 79 (30), 77 (12),
71 (21), 67 (20), 59 (33), 57 (16), 55 (21), 53 (11), 43 (47), 41 (18), 39 (13). Odor description: fishy, fish
flesh.
(3aR,4R,5S,6aS)-Hexahydro-1,1,3,3,4-pentamethyl-1H-cyclopenta[c]furan-5-ol (11b). To a soln. of
crude 3a (40 g, 0.142 mol) in THF (150 ml) was added dropwise at 108 a 3m soln. of MeMgCl in THF
(100ml). When the reaction was complete (GC), the mixture was poured into ice-cold tBuOMe/10% aq.
HCl 1:1. The aq. phase was extracted twice with tBuOMe (100 ml), and the combined org. layers were
washed with sat. aq. NaHCO3 soln. (100 ml), brine (100 ml) and dried (MgSO4). The solvents were
filtered and evaporated in vacuo. The residue was further cyclized as described for 11a* to give 11b
(14.7 g, 36% over two steps). B.p 808/0.05 Torr. IR: 830m, 890m, 978s, 1139m, 1262m, 1365m, 2931w,
2968m, 3420w. 1H-NMR (200 MHz): 1.02 (d, J¼6.8, 3 H); 1.18 (s, 3 H); 1.20 (s, 3 H); 1.27 (s, 3 H); 1.29 (s,
3 H); 1.60–1.85 (m, 2 H); 1.92–2.08 (m, 1 H); 2.30 (t, J¼9.2, 1 H); 2.90 (td, J¼8.7, 9.2, 1 H); 4.19–4.27
(m, 1 H). 13C-NMR (50 MHz): 14.45; 26.83; 27.20; 32.37; 33.08; 36.51; 40.84; 54.11; 60.51; 78.88; 80.51;
80.62. MS: 198 (<1, Mþ ), 184 (13), 183 (100), 123 (53), 122 (25), 121 (21), 111 (12), 107 (68), 97 (28), 95
(14), 91 (16), 83 (12), 81 (28), 79 (18), 69 (16), 67 (16), 59 (10), 55 (22), 53 (10), 43 (59), 41 (23), 39 (10).
Odor description: green, metallic, raw vegetables, earthy.
(3aS,4S,5R,6aR)-Hexahydro-1,1,3,3,4-pentamethyl-1H-cyclopenta[c]furan-5-ol (11b*). Obtained
from 3a* in 51% yield over the two steps, as described for 11b. B.p. 768/0.06 Torr. IR: 831m, 889m,
1
977m, 1139m, 1262w, 1365m, 2930w, 2968m, 3406w. H-NMR (200 MHz): 1.03 (d, J¼6.8, 3 H); 1.13 (s,
3 H); 1.21 (s, 3 H); 1.28 (s, 3 H); 1.30 (s, 3 H); 1.55–1.90 (m, 2 H); 1.94–2.11 (m, 1 H); 2.31 (t, J¼9.3,
1 H); 2.91 (td, J¼8.6, 9.2, 1 H); 4.21–4.28 (m, 1 H). 13C-NMR (50 MHz): 14.45; 26.86; 27.23; 32.40;
33.12; 36.54; 40.87; 54.16; 60.57; 78.99; 80.53; 80.64. MS: 198 (<1, Mþ ), 184 (13), 183 (100), 123 (48), 122
(24), 121 (20), 111 (10), 107 (68), 97 (26), 95 (13), 91 (16), 83 (11), 81 (26), 79 (17), 77 (10), 69 (14), 67
(16), 59 (10), 55 (18), 43 (51), 41 (21). Odor description: woody, leathery, sligthly honey, animal.
(3aS,4S,5R,6aR)-3,3-Diethylhexahydro-1,1,4-trimethyl-1H-cyclopenta[c]furan-5-ol (11c*). Obtained
from 3a* and EtMgCl as described for 11b. B.p. 908/0.02 Torr. IR: 982m, 1048w, 1142m, 1456w, 2878w,
1
2937m, 2965m, 3409w. H-NMR (200 MHz): 0.78 (t, J¼7.4, 3 H); 0.75 (t, J¼7.3, 3 H); 0.99 (d, J¼6.8,
3 H); 1.09 (s, 3 H); 1.21 (s, 3 H); 1.36–1.77 (m, 7 H); 2.35 (t, J¼9.9, 1 H); 2.83 (td, J¼8.6, 9.9, 1 H); 4.18–
4.27 (m, 1 H). 13C-NMR (50 MHz): 8.69; 8.71; 14.57; 27.08; 27.78; 32.21; 32.61; 36.24; 39.75; 54.06; 58.93;
79.45; 80.11; 85.36. MS: 226 (<1, Mþ ), 198 (12), 197 (100), 123 (67), 122 (22), 121 (32), 107 (42), 97
(16), 95 (13), 91 (15), 81 (27), 79 (16), 77 (11), 69 (15), 67 (11), 57 (84), 55 (17), 43 (19), 41 (18). Odor
description: marine, oyster, weak.
(3aR,5R,6S,6aS)-Hexahydro-3,3,6-trimethylspiro[cyclopenta[c]furan-1,1’-cyclopropan]-5-ol
(11d*). To a soln. of 3a* (103 g, 0.365 mol) in Et2O (300 ml) was added (iPrO)4Ti (10.3 g, 0.036 mol).
After stirring for 10 min, a 25 wt-% EtMgCl soln. in Et2O (270 ml, 0.767 mol) was added dropwise at 108.
After completion of the (GC), conc. H2SO4 (37 g, 0.377 mol) was added carefully. The org. phase was
washed with sat. aq. NaHCO3 soln. (100 ml) and brine (100 ml), and dried (MgSO4). The solvents were
filtered and evaporated in vacuo. The residue was further cyclized as described for 11a* to give 11d*
(10.3 g, 10%). B.p. 668/0.02 Torr. IR: 835m, 865m, 902m, 970s, 1002m, 1136m, 1170m, 1191m, 1266w,
1
1365w, 1455w, 2874w, 2929w, 2968w, 3426w. H-NMR (200 MHz): 0.46–0.90 (m, 4 H); 0.95 (d, J¼7.0,
3 H); 1.20 (s, 3 H); 1.32 (s, 3 H); 1.68–1.77 (m, 2 H); 1.90–2.09 (m, 1 H); 2.19 (dd, J¼7.4, 9.0, 1 H); 2.85
(q, J¼9.0, 1 H); 4.19 (br. q, J¼3.1, 1 H). 13C-NMR (50 MHz): 4.47; 14.54; 16.52; 23.77; 28.21; 36.39;

1534
CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
45.04; 53.71; 54.07; 65.56; 77.99; 81.54. MS: 196 (8, Mþ ), 181 (10), 167 (16), 163 (11), 153 (14), 152 (44),
139 (32), 137 (48), 128 (24), 127 (19), 126 (10), 125 (80), 124 (12), 123 (36), 122 (39), 121 (49), 111 (26),
110 (12), 109 (33), 108 (14), 107 (100), 105 (27), 99 (16), 98 (22), 97 (79), 96 (20), 95 (42), 93 (33), 91
(39), 83 (32), 82 (13), 81 (72), 80 (14), 79 (59), 77 (35), 71 (20), 70 (27), 69 (68), 67 (37), 65 (15), 59
(16), 57 (56), 56 (19), 55 (61), 53 (27), 43 (70), 41 (61), 39 (28). Odor description: spicy, pepper, a bit
carvone, weak.
(3aR,4R,5S,6aS)-Hexahydro-1,1,4-trimethyl-1H-cyclopenta[c]furan-5-yl Acetate (12a). Obtained in
71% yield from 11a as described for 7a. B.p. 608/0.04 Torr. IR: 843w, 961m, 969m, 996m, 1019s, 1043m,
1059m, 1138m, 1172m, 1237s, 1366m, 1734s, 2873w, 2933w, 2968w. 1H-NMR (300 MHz): 0.94 (d, J¼6.9,
3 H); 1.14 (s, 3 H); 1.19 (s, 3 H); 1.64–1.92 (m, 3 H); 2.01 (s, 3 H); 2.37–2.58 (m, 2 H); 3.53 (dd, J¼2.2,
9.2, 1 H); 3.88 (dd, J¼7.0, 9.2, 1 H); 5.14–5.20 (m, 1 H). 13C-NMR (75 MHz): 13.92; 21.07; 23.71; 26.56;
34.17; 45.22; 50.77; 51.33; 70.52; 81.0; 81.31. MS: 212 (<1, Mþ ), 198 (11), 197 (100), 155 (15), 154 (11),
137 (16), 109 (11), 107 (30), 95 (46), 94 (61), 93 (16), 91 (18), 79 (62), 77 (15), 67 (14), 55 (18), 43 (90),
41 (17), 39 (10). Odor description: slightly plastic, weak.
(3aS,4S,5R,6aR)-Hexahydro-1,1,4-trimethyl-1H-cyclopenta[c]furan-5-yl Acetate (12a*). Obtained
from 11a* as described for 7a in 24% yield over six steps from 5b. B.p. 608/0.04 Torr. IR: 843w, 961m,
1
969m, 996m, 1019s, 1043m, 1059m, 1138m, 1172m, 1237s, 1366m, 1734s, 2873w, 2933w, 2968w. H-NMR
(300 MHz): 0.96 (d, J¼6.9, 3 H); 1.15 (s, 3 H); 1.20 (s, 3 H); 1.65–1.93 (m, 3 H); 2.03 (s, 3 H); 2.38–2.60
(m, 2 H); 3.54 (dd, J¼2.2, 9.2, 1 H); 3.90 (dd, J¼7.2, 9.2, 1 H); 5.15–5.21 (m, 1 H). 13C-NMR (75 MHz):
13.94; 21.10; 23.73; 26.58; 34.19; 45.24; 50.79; 51.35; 70.54; 81.04; 81.34. MS: 212 (<1, Mþ ), 198 (12), 197
(100), 155 (15), 154 (10), 137 (17), 109 (11), 107 (33), 95 (47), 94 (64), 93 (17), 91 (19), 81 (10), 79 (65),
77 (16), 67 (13), 55 (19), 43 (93), 41 (17), 39 (10). Odor description: woody, vetiver, weak.
(3aS,4S,5R,6aR)-Hexahydro-1,1,3,3,4-pentamethyl-1H-cyclopenta[c]furan-5-yl Acetate (12b*). Ob-
tained in 59% yield from 11b* as described for 7a. B.p. 658/0.05 Torr. IR: 832w, 987s, 1017m, 1046m,
1142m, 1174m, 1186m, 1237ss, 1365m, 1735s, 2933w, 2970m. 1H-NMR (200 MHz): 0.95 (d, J¼6.7, 3 H);
1.13 (s, 3 H); 1.21 (s, 3 H); 1.28 (s, 3 H); 1.30 (s, 3 H); 1.65–1.97 (m, 3 H); 2.04 (s, 3 H); 2.31 (t, J¼9.1,
1 H); 2.84 (q, J¼8.7, 1 H); 5.28 (td, J¼1.7, 4.7, 1 H). 13C-NMR (50 MHz): 14.68; 21.10; 26.80; 27.15;
32.30; 32.97; 34.33; 39.58; 54.13; 61.34; 80.46; 80.59; 81.50. MS: 240 (<1, Mþ ), 225 (32), 165 (27), 123
(41), 122 (32), 121 (17), 107 (100), 91 (17), 81 (10), 79 (14), 43 (46), 41 (10). Odor description: marine,
aqueous, algae, weak.
(3aR,6aR)-Tetrahydro-1,1,4-trimethyl-1H-cyclopenta[c]furan-5(3H)-one (13a*). A soln. of 8a*
(10 g, 50 mmol), ethylene glycol (30 g, 483 mmol), HC(OEt)3 (14 g, 100 mmol) and a cat. amount of
TsOH (0.1 g) was stirred at r.t. After completion of the reaction, the mixture was poured into H2O/
tBuOMe 1:1 (100 ml). The org. layer was washed with a sat. aq. NaHCO3 soln. (50 ml) and then with
brine (50 ml). The org. phase was dried (MgSO4), filtered, and evaporated in vacuo. The crude oil was
further converted as described for 11a*, MeOH being replaced by acetone in the one-pot deprotection/
cyclization step. Crude compound was purified by column chromatography (CC; SiO2; AcOEt/hexane
10 :90) to give pure 13a* (3.7 g, 42%) as a 75 :25 mixture of diastereoisomers. IR: 826m, 1038m, 1065m,
1170m, 1366w, 1737s, 2872w, 2933w, 2970w. Major isomer: 1H-NMR (200 MHz): 1.07 (d, J¼7.3, 3 H); 1.16
(s, 3 H); 1.23 (s, 3 H); 2.14–2.24 (m, 1 H); 2.29–2.33 (m, 1 H); 2.35 (s, 1 H); 2.42–2.68 (m, 2 H); 3.63
(dd, J¼3.4, 9.2, 1 H); 4.03 (dd, J¼6.6, 9.3, 1 H). 13C-NMR (50 MHz): 15.01; 24.71; 27.82; 39.17; 46.41;
47.43; 49.54; 70.19; 81.74; 220.7. MS: 168 (1, Mþ ), 153 (93), 111 (27), 110 (38), 95 (16), 82 (65), 81 (15),
68 (12), 67 (100), 59 (15), 55 (24), 53 (15), 43 (53), 41 (34), 39 (18). Minor isomer: 1H-NMR (200 MHz):
1.01 (d, J¼7.2, 3 H); 1.20 (s, 3 H); 1.25 (s, 3 H); 1.96–2.01 (m, 1 H); 2.07–2.14 (m, 1 H); 2.42–2.68 (m,
2 H); 3.16–3.34 (m, 1 H); 3.49 (dd, J¼8.6, 9.3, 1 H); 3.91 (t, J¼9.1, 1 H). 13C-NMR (50 MHz): 10.61;
24.17; 27.74; 37.87; 45.50; 46.73; 46.80; 66.54; 82.03; 221.1. MS: 168 (<1, Mþ ), 154 (11), 153 (100), 111
(21), 110 (26), 95 (15), 82 (41), 81 (13), 67 (78), 59 (10), 55 (19), 53 (12), 43 (45), 41 (20), 39 (14). Odor
description: musky, lactonic, powdery, weak.
Representative Procedure for the Synthesis of Alkyl Glycolates 18 or 19: Prop-2-enyl (3Z)-(Hex-3-
enyloxy)-acetate (18a). Step 1. (Z)-Hex-3-enol (50 g, 0.5 mol) was added dropwise to a suspension of
NaH (21 g, 0.55 mol) in THF (500 ml), and the mixture was further stirred under reflux for 3 h. After
cooling to r.t., ClCH2COONa (58 g, 0.5 mol) was added portionwise, and the mixture was further reacted
under reflux overnight. It was then poured into H2O/tBuOMe 1:1 (500 ml), and the aq. phase was

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1535
acidified and extracted three times with tBuOMe (150 ml). The extracted layers were washed with H2O
and brine, and dried (MgSO4). The solvents were evaporated to give crude (3Z)-(hex-3-enyloxy)acetic
acid.
Step 2. A soln. of (3Z)-2-(hex-3-enyloxy)acetic acid in cyclohexane (300 ml) with a cat. amount of
TsOH (0.5 g) was heated at 808, and allyl alcohol (35 g, 0.6 mol) was added dropwise. After removal of
the formed H2O using a DeanꢀStark apparatus, the soln. was cooled, washed with a sat. aq. NaHCO3 soln.
and with brine, and dried (MgSO4). The solvents were evaporated, and the crude product was purified by
distillation to give 18a (48 g, 48%). B.p. 658/0.67 Torr. IR: 723w, 930w, 993w, 1136s, 1197s, 1274m, 1429w,
1460w, 1738m, 1758s, 2876m, 2936m, 2965m, 3012w. 1H-NMR (200 MHz): 0.95 (t, J¼7.5, 3 H); 1.94–2.13
(m, 2 H); 2.24–2.46 (m, 2 H); 3.53 (t, J¼7.1, 1 H); 4.06 (s, 2 H); 4.08–4.12 (m, 2 H); 4.14 (t, J¼7.0, 1 H);
5.15–5.37 (m, 3 H); 5.37–5.60 (m, 1 H); 5.79–6.02 (m, 1 H). 13C-NMR (50 MHz): 14.13; 20.53; 26.63;
64.23; 67.04; 72.29; 118.10; 123.29; 133.69; 134.73; 170.34. MS: 198 (<1, Mþ ), 82 (86), 71 (20), 67 (83), 55
(57), 41 (100), 39 (30). Odor description: green, cut grass, watery, clean (ironed linen), powerful.
(3Z)-Hex-3-enyl (3Z)-2-(Hex-3-enyloxy)acetate (19a). It was prepared as described for 18a using
(Z)-hex-3-enol in Steps 1 and 2. Yield: 36%. B.p. 1078/1.2 Torr. IR: 723w, 995w, 1045w, 1070w, 1137s,
1195s, 1283m, 1430w, 1461w, 1738m, 1758s, 2876m, 2935m, 2965s, 3012m. 1H-NMR (200 MHz): 0.95 (t, J¼
7.5, 6 H); 1.95–2.14 (m, 4 H); 2.26–2.46 (m, 4 H); 3.52 (t, J¼7.1, 2 H); 4.07 (s, 2 H); 4.14 (t, J¼7.0, 2 H);
5.20–5.60 (m, 4 H). 13C-NMR (50 MHz): 14.18; 14.26; 20.55; 20.59; 26.65; 27.62; 64.21; 68.24; 71.40;
123.33; 124.27; 133.94; 134.73; 170.47. MS: 240 (<1, Mþ ), 83 (44), 82 (90), 67 (74), 55 (100), 41 (46).
Odor description: clean (ironed linen), green.
Prop-2-enyl 2-(3,3,5-Trimethylcyclohexyloxy)acetate (18b). It was prepared was described for 18a
using 3,3,5-trimethylcyclohexanol in Step 1 (obtained from the reduction of isophorone) and allyl alcohol
in Step 2. It consisted of a 93 :7 cis/trans mixture. Yield: 53%. B.p. 938/1.2 Torr. IR: 931m, 987m, 1129s,
1183s, 1193s, 1275m, 1365w, 1388w, 1430w, 1457m, 1738m, 1761s, 2838w, 2870m, 2914m, 2951s, 2992w. cis-
Isomer: 1H-NMR (200 MHz): 0.71–1.14 (m, 3 H); 0.85 (d, J¼6.4, 3 H); 0.85 (s, 3 H); 1.39 (ddd, J¼2.2,
5.2, 12.9, 1 H); 1.72 (qd, J¼2.3, 14.4, 1 H); 1.80–2.07 (m, 2 H); 3.71 (quint, J¼2.8, 1 H); 4.06 (dd, J¼
16.4, 21.4, 2 H); 4.62 (td, J¼1.3, 5.7, 2 H); 5.18–5.38 (m, 2 H); 5.91 (tdd, J¼5.7, 10.3, 17.1, 1 H). 13C-NMR
(50 MHz): 22.99; 23.46; 27.67; 31.15; 34.47; 39.08; 40.72; 48.97; 65.64; 66.07; 76.63; 118.94; 132.25; 171.11.
MS: 240 (<1, Mþ ), 141 (81), 125 (18), 109 (35), 83 (91), 69 (86), 67 (26), 57 (23), 55 (55), 43 (23), 41
1
(100), 39 (26). trans-Isomer: H-NMR (200 MHz, selected data): 1.46–1.63 (m, 1 H); 3.48 (tt, J¼4.3,
11.4, 1 H); 4.12 (s, 2 H). 13C-NMR (50 MHz, selected data): 22.80; 26.13; 27.55; 33.54; 41.14; 44.92; 48.10;
65.73; 66.03; 76.98; 119.10. MS: 240 (<1, Mþ ), 141 (58), 125 (24), 109 (22), 83 (73), 69 (100), 67 (18), 57
(25), 55 (48), 43 (19), 41 (80), 39 (19). Odor description: Costus, musky.
Prop-2-enyl 2-(4-(tert-Butyl)cyclohexyloxy)acetate (18c). It was prepared as described for 18a using
4-(tert-butyl)cyclohexanol in Step 1 and allyl alcohol in Step 2. Yield: 35%. B.p. 1108/0.8 Torr. It consisted
of a 10 :90 cis/trans-mixture. IR: 929w, 987w, 1133s, 1190s, 1276w, 1366w, 1451w, 1737m, 1760s, 2865m,
1
2946s. trans-Isomer: H-NMR (200 MHz): 0.82 (s, 9 H); 0.88–1.10 (m, 3 H); 1.10–1.40 (m, 2 H); 1.70–
1.87 (m, 2 H); 2.10–2.16 (m, 2 H); 3.24 (tt, J¼4.3, 10.9, 1 H); 4.13 (s, 2 H); 4.63 (td, J¼1.3, 5.8, 2 H);
5.19–5.37 (m, 2 H); 5.91 (tdd, J¼5.8, 10.3, 17.1, 1 H). 13C-NMR (50 MHz): 25.47 (2 C); 27.55 (3 C); 32.23
(3 C); 47.23; 65.29; 65.49; 79.44; 118.63; 131.76; 170.65. MS: 254 (<1, Mþ ), 155 (49), 83 (31), 81 (36), 67
(26), 57 (100), 55 (24), 41 (63). cis-Isomer: 1H-NMR (200 MHz, selected data): 3.57–3.65 (m, 1 H); 4.08
(s, 2 H). 13C-NMR (50 MHz, selected data): 21.29 (2 C); 27.45 (3 C); 30.27 (2 C); 47.88; 65.20; 65.55;
74.26; 118.51; 131.80. MS: 254 (<1, Mþ ), 155 (48), 117 (21), 83 (29), 81 (44), 67 (44), 57 (100), 55 (28),
41 (71). Odor description: leathery, burnt, green.
Representative Procedure for the Synthesis of Phenoxyglycolates 21 or 22: Prop-2-enyl 2-(3,5-
dimethylphenoxy)acetate (21a). A soln. of 3,5-dimethylphenol (20 g, 163 mmol) in refluxing acetone
(150 ml) was treated overnight with prop-2-enyl 2-chloroacetate (22 g, 163 mmol) and K2CO3 (22.5 g,
163 mmol). The mixture was then poured into H2O/tBuOMe 1:1 (200 ml), and the aq. phase was
t
extracted twice with BuOMe (50 ml). The combined org. phases were washed with brine and dried
(MgSO4). The solvents were evaporated, and the crude product was purified by distillation to give 21a
(12.5 g, 35%). B.p. 938/0.02 Torr. IR: 687m, 830m, 929m, 987m, 1032w, 1096m, 1157s, 1171s, 1200s, 1277m,
1
1299m, 1324s, 1383w, 1442m, 1473m, 1596s, 1615m, 1739m, 1764s, 2922m, 3020w. H-NMR (200 MHz):
2.26 (s, 3 H); 2.29 (s, 3 H); 4.63 (s, 2 H); 4.71 (td, J¼1.2, 5.8, 2 H); 5.22–5.42 (m, 2 H); 5.94 (tdd, J¼5.8,

1536
CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
10.3, 17.0, 1 H); 6.55 (br. s, 2 H); 6.65 (br. s, 1 H). 13C-NMR (50 MHz): 21.35; 65.20; 65.67; 112.34; 118.89;
123.48; 131.45; 139.26; 157.75; 168.75. MS: 220 (99, Mþ ), 135 (69), 105 (100), 103 (17), 91 (16), 79 (29),
77 (36), 41 (25), 39 (19). Odor description: musky, hot iron, not powerful.
Prop-2-enyl 2-(2-Isopropyl-5-methylphenoxy)acetate (21b). It was prepared from thymol as
described for 21a. Yield: 43%. B.p. 908/0.03 Torr. IR: 813m, 932m, 986m, 1071m, 1102m, 1120m, 1167s,
1194s, 1279m, 1416m, 1445m, 1507m, 1614w, 1740m, 1765s, 2871w, 2962m. 1H-NMR (200 MHz): 1.25 (d,
J¼6.9, 6 H); 2.32 (s, 3 H); 3.40 (sept., J¼6.9, 1 H); 4.68 (s, 2 H); 4.73 (td, J¼1.3, 5.8, 2 H); 5.22–5.42 (m,
2 H); 5.95 (tdd, J¼5.7, 10.4, 17.1, 1 H); 6.57 (br. s, 1 H); 6.81 (br. d, J¼7.7, 1 H ) ; 7.14 ( br. d, J¼7.7, 1 H ) .
13C-NMR (50 MHz): 21.72; 23.22; 27.03; 66.07; 112.77; 119.21; 122.75; 126.71; 131.99; 135.02; 136.71;
155.39; 169.31. MS: 248 (100, Mþ ), 233 (68), 207 (18), 187 (12), 179 (23), 149 (59), 147 (22), 121 (53),
105 (50), 91 (42), 77 (21), 41 (62), 39 (30). Odor description: costus.
Hex-3-enyl 2-(4-Methylphenoxy)acetate (22c). It was prepared from p-cresol and (Z)-hex-3-enyl 2-
chloroacetate as described for 21a. Yield: 49%. B.p. 1168/0.2 Torr. IR: 724m, 818m, 996m, 1086s, 1191s,
1290s, 1391w, 1443m, 1458m, 1512s, 1589w, 1391m, 1737s, 1762s, 2874m, 2932m, 2964s, 3012m. 1H-NMR
(200 MHz): 0.97 (t, J¼7.5, 3 H); 2.05 (br. quint., J¼7.6, 2 H); 2.29 (s, 3 H); 2.41 (br. q, J¼7.0, 2 H); 4.20
(t, J¼6.9, 2 H); 4.59 (s, 2 H); 5.21–5.37 (m, 1 H); 5.44–5.60 (m, 1 H); 6.76–6.85 (m, 2 H); 7.04–7.13 (m,
2 H). 13C-NMR (50 MHz): 14.15; 20.42; 20.55; 26.61; 64.62; 65.52; 114.50 (2 C); 123.89; 129.92 (2 C);
130.96; 134.84; 155.71; 169.09. MS: 248 (38, Mþ ), 166 (100), 121 (35), 108 (14), 107 (12), 91 (54), 82 (22),
77 (14), 67 (36), 65 (21), 55 (35), 41 (28). Odor description: animal, leathery.
Prop-2-enyl 2-[4-(Prop-2-enyl)-2-methoxyphenoxy]acetate (21d). It was prepared from eugenol as
described for 21a. Yield: 39%. B.p. 1108/0.02 Torr. IR: 749w, 805m, 851w, 919m, 991m, 1036s, 1072m,
1148s, 1189s, 1262s, 1420m, 1464m, 1512s, 1593m, 1639w, 1738s, 1762s, 2836w, 2939m, 2977w, 3003w,
1
3079w. H-NMR (200 MHz): 3.32 (br. d, J¼6.7, 2 H); 3.85 (s, 3 H); 4.64–4.70 (m, 2 H); 4.68 (s, 2 H);
5.00–5.05 (m, 1 H); 5.05–5.13 (m, 1 H); 5.19–5.37 (m, 2 H); 5.80–6.03 (m, 2 H); 6.64–6.80 (m, 3 H).
13C-NMR (50 MHz): 39.69; 55.72; 65.55; 66.60; 112.47; 114.63; 115.65; 118.76; 120.28; 131.43; 134.43;
137.30; 145.46; 149.47; 168.72. MS: 262 (100, Mþ ), 163 (25), 115 (14), 109 (9), 103 (17), 91 (17), 77 (10),
41 (22). Odor description: eugenol, carnation-type, woody; not as powerful as eugenol, isoeugenol, or
methyl-Diantilisꢄ.
Prop-2-enyl 2-[2-Methoxy-4-(prop-2-enyl)phenoxy]acetate (21e). It was prepared from isoeugenol
as described for 21a. It consisted of a 30 :70 (Z)/(E) mixture. Yield: 41%. B.p. 1268/0.05 Torr. IR: 784w,
816w, 859w, 933w, 966m, 985m, 1036m, 1071m, 1144s, 1191s, 1259s, 1272s, 1259s, 1272s, 1298m, 1416m,
1463m, 1512s, 1585w, 1602w, 1738m, 1762s, 2916w, 2938w, 3019w. (Z)-Isomer: 1H-NMR (200 MHz): 1.89
(dd, J¼1.6, 7.3, 3 H); 3.87 (s, 3 H); 4.64–4.73 (m, 2 H); 4.69 (s, 2 H); 5.18–5.38 (m, 2 H); 5.72 (ddd, J¼
8.1, 12.5, 14.4, 1 H); 6.07 (q, J¼6.4, 1 H); 6.34–6.40 (m, 1 H); 6.72 (br. s, 1 H); 6.77–6.82 (m, 1 H); 6.82–
6.86 (m, 1 H). 13C-NMR (50 MHz): 14.55; 55.80; 65.64; 66.49; 112.84; 114.10; 118.36; 121.15; 125.87;
129.27; 131.44; 132.33; 145.77; 149.15; 168.65. MS: 262 (100, Mþ ), 163 (47), 162 (16), 115 (16), 107 (29),
103 (13), 91 (21), 77 (10), 41 (19), 39 (10). (E)-Isomer: 1H-NMR (200 MHz): 1.85 (dd, J¼1.4, 6.4, 3 H);
3.87 (s, 3 H); 4.64–4.73 (m, 2 H); 4.69 (s, 2 H); 5.18–5.38 (m, 2 H); 5.91 (tdd, J¼5.8, 10.4, 17.3, 1 H); 6.14
(q, J¼6.3, 1 H); 6.26–6.31 (m, 1 H); 6.77 (br. s, 1 H); 6.77–6.82 (m, 1 H); 6.88–6.91 (m, 1 H). 13C-NMR
(50 MHz): 18.29; 55.75; 65.64; 66.55; 109.26; 114.49; 118.36; 118.85; 124.46; 130.36; 131.44; 132.80;
146.22; 149.58; 168.65. MS: 262 (100, Mþ ), 163 (43), 162 (16), 115 (13), 107 (24), 103 (11), 91 (17), 77
(8), 41 (16), 39 (9). Odor description: spicy (isoeugenol), leathery, carnation, saffron, fruity (plums,
dried plums), woody (vetiver), sweet; not as powerful as eugenol, isoeugenol, or methyl-Diantilisꢄ.
Prop-2-enyl (2-Methoxy-4-methylphenoxy)acetate (21f). It was prepared from 2-methoxy-4-meth-
ylphenol as described for 21a. Yield: 53%. B.p. 1008/0.04 Torr. IR: 800w, 929w, 987w, 1037m, 1071w, 1148s,
1156s, 1191s, 1269s, 1465w, 1513s, 1593w, 1737m, 1762s, 2939w. 1H-NMR (200 MHz): 2.29 (s, 3 H); 3.85 (s,
3 H); 4.65–4.71 (m, 2 H); 4.66 (s, 2 H); 5.20–5.38 (m, 2 H); 5.91 (tdd, J¼5.8, 10.3, 17.1, 1 H); 6.62–6.79
(m, 3 H). 13C-NMR (50 MHz): 20.99; 55.73; 65.59; 66.76; 113.10; 114.81; 118.80; 120.73; 131.49; 132.34;
144.99; 149.38; 168.84. MS: 236 (100, Mþ ), 151 (11), 137 (46), 136 (39), 109 (20), 91 (40), 77 (16), 65
(15), 41 (21), 39 (17). Odor description: vanilla, spicy (isoeugenol).
Hex-3-enyl 2-(2-Methoxy-4-methylphenoxy)acetate (22f). It was prepared from 2-methoxy-4-
methylphenol and (Z)-hex-3-enyl 2-chloroacetate as described for 21a. Yield: 50%. B.p. 1148/0.02 Torr.
IR: 798w, 817w, 997w, 1038s, 1075m, 1148s, 1156s, 1191s, 1268s, 1414w, 1465m, 1513s, 1593w, 1735m, 1762s,

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1537
1
2874w, 2935m, 2963m, 3010w. H-NMR (200 MHz): 0.95 (t, J¼7.5, 3 H); 2.03 (br. quint., J¼7.6, 2 H);
2.29 (s, 3 H); 2.39 (br. q, J¼7.1, 2 H); 3.85 (s, 3 H); 4.18 (t, J¼7.0, 2 H); 4.64 (s, 2 H); 5.27 (m, 1 H); 5.49
(m, 1 H); 6.61–6.77 (m, 3 H). 13C-NMR (50 MHz): 14.13; 20.52; 21.0; 26.6; 55.75; 64.50; 66.74; 113.09;
114.71; 120.73; 123.22; 132.26; 134.74; 145.07; 149.38; 169.17. MS: 278 (100, Mþ ), 196 (55), 151 (11), 137
(44), 136 (27), 109 (15), 91 (26), 77 (12), 67 (17), 65 (11), 55 (28), 41 (22). Odor description: vanilla,
smokey.
Prop-2-enyl 2-[2-(Prop-2-enyl)-phenoxy]acetate (22g). It was prepared from 2-allylphenol as
described for 21a. Yield: 50%. B.p. 1008/0.02 Torr. IR: 754s, 919m, 989m, 1072m, 1092m, 1129m, 1194s,
1276m, 1296m, 1441m, 1455m, 1493s, 1589m, 1601w, 1639w, 1739s, 1764s, 2980w, 3079w. 1H-NMR
(200 MHz): 3.48 (br. d, J¼6.6, 2 H); 4.68 (s, 2 H); 4.71 (dt, J¼1.2, 5.9, 2 H); 5.02–5.07 (m, 1 H); 5.07–
5.15 (m, 1 H); 5.23–5.40 (m, 2 H); 6.04 (ddt, J¼5.8, 9.2, 15.1, 1 H); 5.94 (tdd, J¼5.7, 10.4, 17.1, 1 H); 6.7–
6.8 (m, 1 H); 6.91–7.01 (m, 1 H); 7.12–7.23 (m, 2 H). 13C-NMR (50 MHz): 34.23; 65.59; 65.67; 111.39;
115.50; 118.88; 121.66; 127.21; 129.26; 130.14; 131.42; 136.76; 155.51; 168.66. MS: 232 (95, Mþ ), 145
(100), 133 (22), 131 (27), 117 (20), 115 (75), 105 (17), 91 (62), 77 (20), 41 (53), 39 (37). Odor
description: vanilla, plastic.
4-(4,4-Dimethylpentan-2-yl)-2,6-dimethylcyclohex-2-enone (24h). A mixture of pentan-3-one
(64.5 g, 0.75 mol, 1.5 equiv.), 2-methylidene-3,5,5-trimethylhexanal (prepared from 71 g, 0.5 mol,
1 equiv. of. Vandor Bꢄ) and KOH (5.6 g, 0.1 mol, 0.2 equiv.) in H2O/EtOH (150 ml/100 ml) was heated
at 708 overnight. After completion of the reaction, the mixture was cooled, and AcOH (6 g, 0.1 mol,
t
0.2 equiv.) was added. The aq. layer was extracted three times with BuOMe, and the combined org.
layers were washed with brine, dried (MgSO4), and filtered. The solvents were evaporated, and the crude
product was purified by distillation to give 24h as a colourless oil in 56% yield over the two steps. It
consisted of a mixture of four detectable isomers in a 23 :17:30 :30 ratio. B.p. 88–928/0.4 Torr. IR: 1364m,
1453w, 1673s, 2868w, 2954m. 1H-NMR (200 MHz): 0.75–1.37 (m, 2 H); 0.87–0.95 (m, 12 H); 1.12 (d, J¼
7.2, 3 H); 1.37–2.0 (m, 3 H); 1.76 (m, 3 H); 2.20–2.62 (m, 2 H); 6.45–6.57 (m, 1 H). 13C-NMR (50 MHz,
selected data): 29.89 (3 C); 32.40/31.67/31.02 (Cq); 34.80/34.17 (CH2); 48.46/47.97/47.92/47.74 (CH2);
135.75/135.37/134.33 (Cq); 149.06/148.64/148.60/148.20 (CH); 196.52 (CO). MS: 222 (12, Mþ ), 124 (99),
123 (11), 109 (48), 95 (18), 81 (11), 79 (16), 77 (11), 67 (11), 57 (100), 55 (18), 43 (16), 41 (30). Odor
description: woody, ambery, hazelnut, a little bit sandalwood.
Representative Procedure for the Preparation of Compounds 30. (2S,4aS,8aR)- and (2R,4aR,8aS)-
Hexahydro-5,5-dimethyl-2-propyl-2,4a-methanonaphthalen-1-one (30d). Myrcene (136 g, 1 mol) in
toluene (350 ml) was reacted with 2-methylidenepentanal (120 g, 1.22 mol) at r.t. with a cat. amount
of AlCl3 (8 g, 0.06 mol) during 16 h. The solvent was removed, and the residue was flash-distilled (107 g;
b.p. 1008/1 Torr). The crude oil obtained was further reacted in toluene (600 ml) at 60 8 in the presence of
H2SO4 (4 g) during 24 h. The crude product was purified by distillation (b.p. 1048/0.8 Torr) to give 30d
(81 g, 35%). The compound was further crystallized from hexane at ꢀ288. M.p. 458. IR: 1465, 1730, 2870,
1
2934, 2960. H-NMR (200 MHz): 0.89 (t, J¼7, 3 H); 0.95 (s, 3 H); 0.99 (s, 3 H); 1.17–1.93 (m, 16 H);
2.00–2.06 (m, 1 H). 13C-NMR (50 MHz): 14.96; 19.47; 21.02; 21.96; 22.54; 23.56; 26.28; 31.55; 32.68;
33.61; 36.77; 41.05; 51.97; 53.84; 59.37; 220.72. MS: 234 (61, Mþ ), 205 (13), 191 (40), 177 (22), 165 (14),
164 (15), 163 (22), 151 (12), 150 (40), 149 (100), 135 (29), 126 (36), 122 (30), 121 (22), 109 (76), 108
(49), 107 (30), 105 (14), 95 (15), 93 (34), 91 (36), 81 (23), 79 (35), 77 (25), 69 (11), 67 (33), 55 (24), 41
(29). Odor description: nice, linear and longlasting (>2 weeks) ambery note.
(2S,4aS,8aS)- and (2R,4aR,8aR)-Hexahydro-5,5-dimethyl-2-propyl-2,4a-methano-1-one (30d’).
Compound 30d in MeOH was refluxed in the presence of KOH (10% (w/w)) until complete conversion
to 30d’ (24 h). IR: 1462, 1739, 2869, 2929, 2955. 1H-NMR (200 MHz): 0.89 (m, 9 H); 1.12–1.85 (m, 16 H);
1.89–2.00 (m, 1 H). 13C-NMR (50 MHz): 14.96; 19.37; 20.76; 23.93; 24.11; 25.94; 29.64; 30.90; 31.45;
32.05; 37.90; 38.43; 50.44; 52.21; 58.89; 220.59. MS: 234 (66, Mþ ), 205 (14), 191 (40), 177 (24), 165 (16),
164 (16), 163 (26), 151 (13), 150 (43), 149 (96), 135 (33), 126 (46), 125 (11), 123 (10), 122 (36), 121 (25),
110 (11), 109 (100), 108 (66), 107 (34), 105 (17), 95 (20), 93 (41), 91 (43), 81 (36), 80 (12), 79 (44), 77
(31), 69 (18), 67 (46), 65 (11), 55 (36), 53 (14), 43 (15), 41 (44), 39 (14).
2-Ethylhexahydro-5,5-dimethyl-2,4a-methanonaphthalen-1-one (30c). It was obtained from methyl-
idene butanal and myrcene as described for 30d. Yield: 12%. B.p. 868/0.7 Torr. IR: 1366w, 1378w, 1449w,
1460w, 1729s, 2873m, 2931m, 2962m. 1H-NMR (200 MHz): 0.87 (t, J¼7, 3 H); 0.97 (s, 3 H); 1.01 (s, 3 H);

1538
CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1.15–1.95 (m, 14 H); 2.0–2.10 (m, 1 H). 13C-NMR (50 MHz): 10.27; 20.92; 21.82; 22.56; 23.57; 26.29;
32.04; 33.51; 36.67; 40.44; 51.89; 53.99; 60.01; 220.75. MS: 220 (47, Mþ ), 191 (23), 177 (17), 163 (21), 151
(14), 150 (12), 149 (20), 137 (13), 136 (42), 135 (100), 126 (37), 121 (40), 109 (19), 108 (25), 107 (33), 105
(19), 95 (92), 94 (44), 93 (45), 91 (49), 81 (27), 79 (45), 77 (34), 69 (13), 67 (33), 65 (12), 55 (39), 53
(16), 43 (10), 41 (34), 39 (12).
Hexahydro-5,5-dimethyl-2-(propan-2-yl)-2,4a-methanonaphthalen-1-one (30e). It was obtained
from methylideneisovaleraldehyde and myrcene as described for 30d. Yield: 38%. B.p. 858/0.3 Torr.
IR: 1365w, 1384w, 1452w, 1463w, 1735s, 2870w, 2931m, 2954m. 1H-NMR (300 MHz): 0.9 (d, J¼6.8, 3 H);
0.9 (d, J¼6.9, 3 H); 0.96 (s, 3 H); 1.0 (s, 3 H); 1.1–1.8 (m, 10 H); 1.84–1.95 (m, 1 H); 1.95–2.15 (m, 2 H);
2.2–2.37 (m, 1 H). 13C-NMR (75 MHz): 18.09; 19.65; 20.78; 21.72; 22.41; 23.51; 26.19; 26.37; 29.62; 33.4;
36.60; 37.55; 51.38; 54.60; 63.39; 220.87. MS: 234 (46, Mþ ), 191 (30), 177 (13), 165 (11), 164 (11), 163
(17), 151 (10), 150 (38), 149 (100), 135 (31), 126 (24), 122 (20), 121 (22), 109 (85), 108 (57), 107 (40),
105 (20), 95 (18), 93 (42), 91 (46), 81 (28), 79 (36), 77 (28), 69 (22), 67 (35), 65 (11), 55 (32), 53 (13), 43
(19), 41 (38), 39 (11).
2-Butylhexahydro-5,5-dimethyl-2,4a-methanonaphthalen-1-one (30f). It was obtained from 2-
methylidenehexanal and myrcene as described for 30d. Yield: 13%. B.p. 968/0.45 Torr. IR: 1366w,
1384w, 1450m, 1467m, 1734s, 2861m, 2905m, 2932m, 2954m. 1H-NMR (300 MHz): 0.85 (t, J¼7, 3 H); 0.93
(s, 3 H); 0.97 (s, 3 H); 1.15–1.75 (m, 17 H); 1.82–1.92 (m, 1 H); 1.97–2.05 (m, 1 H). 13C-NMR (75 MHz):
13.97; 20.79; 21.73; 22.33; 23.32; 23.46; 26.18; 28.24; 28.76; 32.40; 33.38; 36.54; 40.80; 51.84; 53.74; 59.23;
220.61. MS: 248 (41, Mþ ), 206 (23), 205 (14), 191 (34), 179 (12), 178 (18), 177 (18), 165 (11), 164 (32),
163 (100), 149 (25), 136 (24), 135 (12), 126 (28), 123 (66), 122 (58), 121 (25), 119 (12), 109 (18), 107 (34),
105 (19), 95 (21), 93 (43), 91 (45), 81 (39), 80 (23), 79 (43), 69 (16), 67 (41), 55 (31), 43 (11), 41 (27).
I would like to thank Piotr Jaunky and his team for their contribution to this article through the
results on tricyclic ketones. I also would like to thank Yvan Klimkowicz for his helpful laboratory work,
´
concerning my own projects, as well as Cedric Gauvin who performed part of the work on bicyclic
cyclopentanols, as a trainee. Acknowledgements are also dedicated to the analytical team and to our
perfumers who have evaluated the different compounds. Finally, I would like to thank Jean-Jacques
Chanot and Jean Mane for giving me the opportunity to present this overview during the F&F conference
in Leipzig, last September.
REFERENCES
´
ˆ
[1] J.-P. Petitdidier, Parfums, Cosmetiques, Aromes 1990, 90, 79; D. P. Anonis, Perfum. Flavor. 1997, 22,
43.
[2] G. Ohloff, W. Pickenhagen, P. Kraft, in ꢀScent and Chemistry, the Molecular World of Odorsꢁ, Verlag
Helvetica Chimica Acta, Zꢃrich, and Wiley-VCH. Weinheim, 2012, p. 339.
[3] S. V. Ley, A. Antonello, E. P. Balskus, D. T. Booth, S. B. Christensen, E. Cleator, H. Gold, K.
Hçgenauer, U. Hꢃnger, R. M. Meyres, S. F. Oliver, O. Simic, M. D. Smith, H. Søhoel, A. J. A.
Woolford, Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12073; S. P. Andrews, M. Ball, F. Wiershem, E.
Cleator, S. F. Oliver, K. Hçgenauer, O. Simic, A. Antonello, U. Hꢃnger, M. D. Smith, S. V. Ley,
Chem. – Eur. J. 2007, 13, 5688.
[4] E. Lee, C. H. Yoon, J. Chem. Soc., Chem. Commun. 1994, 4, 479; E. Lee, J. W. Lim, C. H. Yoon, Y.-S.
Sung, Y. K. Kim, J. Am. Chem. Soc. 1997, 119, 8391.
[5] H. Yang, X. Qiao, F. Li, H. Ma, L. Xie, X. Xu, Tetrahedron Lett. 2009, 50, 1110; F. Zhang, Y. Jia,
Tetrahedron 2009, 65, 6840; T. G. Elford, D. G. Hall, J. Am. Chem. Soc. 2010, 132, 1488; L. Sun, F.
Shah, M. A. Helal, Y. Wu, Y. Pedduri, A. G. Chittiboyina, J. Gut, P. J. Rosenthal, M. A. Avery, J.
Med. Chem. 2010, 53, 7864; V. Navickas, D. Ushakov, M. E. Maier, M. Strçbele, H.-J. Meyer, Org.
Lett. 2010, 12, 3418; H. Yang, Y. Gao, X. Qiao, L. Xie, X. Xu, Org. Lett. 2011, 13, 3670.
[6] A. Muratore, PhD Thesis, University of Nice-Sophia-Antipolis, Nice, 2007; A. Muratore, J.-J.
Chanot, to V. Mane & Fils, WO 2011033479 (Chem. Abstr. 2011, 154, 361214).
[7] O. G. Kulinkowich, Russ. Chem. Bull., Int. Ed. 2004, 53, 1065.

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
1539
[8] S. D. Burke, R. L. Danheiser, ꢀ Handbook of reagents for Organic Synthesis – Oxidizing and
Reducing agentsꢁ, Eds. S. D. Burke, R. L. Danheiser, John Wiley & Sons, New-York, 1999; K. Soai,
H. Oyamada, M. Takase, A. Ookawa, Bull. Chem. Soc. Jpn. 1984, 57, 1948; A. Saeed, Z. Ashraf, J.
Chem. Sci. 2006, 118, 419; T. Yamakawa, M. Masaki, H. Nohira, Bull. Chem. Soc. Jpn. 1991, 64,
2730; H. C. Brown, S. Narasimhan, Y. Moon Choi, J. Org. Chem. 1982, 47, 4702; T. Okada, Y. Abe, to
Takeda Chemical Industries, Ltd., U.S. Pat. 4,842,775 (Chem. Abstr. 1989, 111, 57262).
[9] J. A. Bajgrowicz, K. Berg-Schultz, G. Brunner, Bioorg. Med. Chem. 2003, 11, 2931.
[10] C. Plessis, J. Mane, J.-J. Chanot, to V. Mane & Fils, EP 2,168,941 (Chem. Abstr. 2010, 152, 405317); C.
Plessis, J. Mane, J.-J. Chanot, to V. Mane & Fils, EP 2,138,479 (Chem. Abstr. 2009, 152, 104322).
[11] C. Plessis, J.-J. Chanot, to V. Mane & Fils, FR 1259524, filed October 5, 2012.
[12] A. P. S. Narula, Perfum. Flavor. 2003, 28, 62.
[13] A. P. S. Narula, J. J. De Virgilio, to International Flavors and Fragrances, Inc., EP 485,061 (Chem.
Abstr. 1992, 117, 111854).
[14] M. L. Hagedorn, P. Klemarczyk, T. J. OꢁRourke, J. M. Sanders, W. L. Schreiber, E. J. Shuster, M. A.
Sprecker, J. F. Vinals, H. Watkins, to International Flavors and Fragrances, Inc., U.S. Pat. 4,250,338
(Chem. Abstr. 1981, 95, 6643); M. A. Sprecker, J. M. Sanders, W. L. Schreiber, H. Watkins, J. F.
Vinals, E. J. Shuster, T. J. OꢁRourke, M. L. Hagedorn, P. Klemarczyk, to International Flavors and
Fragrances, Inc., U.S. Pat. 4,301,302 (Chem. Abstr. 1982, 96, 103735).
´
[15] W. Lenselink, G. Sipma, to PFw, EP 29 2559 (Chem. Abstr. 1981, 95, 204219); G. Frater, U. Mꢃller, P.
Kraft, Helv. Chim. Acta 1999, 82, 522.
[16] P. Jaunky, J.-J. Chanot, J. Mane, to V. Mane & Fils, FR 2,983,476 (Chem. Abstr. 2013, 159, 76037).
Received January 20, 2014