Musk or violet? Design, synthesis and odor of seco-derivates of a musky carotol lead

Article abstract of DOI:10.1016/j.tet.2006.10.020

By a six-step synthetic route consisting of a Li₂MnCl₄-catalyzed coupling of branched alkyl magnesium chlorides with isovaleryl and 3,3-dimethylbutanoyl chloride, Grignard reaction of the product with ethynyl magnesium bromide, dehydration and transformation into a Grignard reagent, subsequent reaction with acetaldehyde, (E)-selective hydrogenation of the alkynol triple bond with lithium aluminum hydride, and finally pyridinium chlorochromate oxidation, four sterically highly demanding target structures were synthesized diastereoselectively. These four molecular targets were designed as seco-structures to a musky carotol lead, and their olfactory profiles that merge violet like with musky notes to different extents, provide interesting insight into structure-odor correlation.

Full text of DOI:10.1016/j.tet.2006.10.020

Tetrahedron 62 (2006) 12211–12219
Musk or violet? Design, synthesis and odor of
seco-derivates of a musky carotol lead
*
Philip Kraft and Kasim Popaj
€
Givaudan Schweiz AG, Fragrance Research, Uberlandstrasse 138, 8600 Du€bendorf, Switzerland
Received 14 August 2006; revised 8 October 2006; accepted 10 October 2006
Available online 3 November 2006
ꢀ
Dedicated with best wishes to Professor Georg Frater on the occasion of his 65th birthday
Abstract—By a six-step synthetic route consisting of a Li2MnCl4-catalyzed coupling of branched alkyl magnesium chlorides with isovaleryl
and 3,3-dimethylbutanoyl chloride, Grignard reaction of the product with ethynyl magnesium bromide, dehydration and transformation into
a Grignard reagent, subsequent reaction with acetaldehyde, (E)-selective hydrogenation of the alkynol triple bond with lithium aluminum
hydride, and finally pyridinium chlorochromate oxidation, four sterically highly demanding target structures were synthesized diastereo-
selectively. These four molecular targets were designed as seco-structures to a musky carotol lead, and their olfactory profiles that merge violet
like with musky notes to different extents, provide interesting insight into structure–odor correlation.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
odor characteristics of b-ionone. He reported two synthetic
routes to 3, the first one of which commenced with a Refor-
matsky reaction of ethyl 2-bromo-3-methylbutanoate with
triethyl ortho-formiate, followed by Grignard reaction with
methyl magnesium iodide, hydrolysis, and aldol condensa-
tion of the intermediate aldehyde with acetone.4 The second
approach started from 3-isopropyl-4-methylpent-1-yn-3-ol
that was transformed into its acetate by reaction with ketene,
which was then rearranged by silver-catalyzed Saucy–
Marbet reaction6 to the corresponding aldehyde. Grignard
reaction with acetylene magnesium bromide and Rupe
rearrangement of the resulting 5-isopropyl-6-methylhept-
4-en-1-yn-3-ol at 50 ꢀC in formic acid concluded his second
synthesis of 3.
In the course of work for his master thesis on carotol deriv-
atives in the late 1960s in the laboratory of Professor Janusz
ꢀ
Kulesza in Lodz, Jozef Kula discovered an interesting
new musk odorant. Ozonolysis of carotol with subsequent
intramolecular aldol condensation and dehydration of the
resulting intermediate dihydroxy ketone afforded a product
mixture imparting a pleasant musky scent.1,2 They believed
this scent to originate from its main compound to which they
assigned structure 1 and named ‘mageritone’ (Fig. 1).1 Over
ꢀ
30 years later however, Jozef Kula, having become a profes-
sor at the University of Lodz, revisited this chemistry with
his group and found mageritone 1 to have only a weak and
uncharacteristic smell.2,3 The actual cause of the musk odor
of that mageritone-containing product mixture was the iso-
meric dienone 2, which was present at a concentration of less
than 5%. The odor and structure of this tetrahydroindene 2
was proven by a directed partial synthesis with isomerization
of the double bond catalyzed by Pd/C in refluxing cyclohex-
ene.3 It was characterized as emanating a dry musky odor
with a threshold of around 1 ng/L air.2
Already in the early 1960s, Kazimir Sestanj4 discovered that
the seco-structure 3, in which the two carbon atoms C-2 and
C-3 were cut out of the b-ionone ring,5 retained all important
Keywords: Alkynols; Carotol; Chemoselective hydrogenation; Ionone odor-
ants; Odor–structure correlation; seco-Derivatives.
* Corresponding author. Tel.: +41 44 8242520; fax: +41 44 8242926;
e-mail: philip.kraft@givaudan.com
Figure 1. Mageritone (1), the seco-b-ionone of Sestanj (3), and the first
target structure 4, devised as a seco-structure to the musk odorant 2.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.020

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P. Kraft, K. Popaj / Tetrahedron 62 (2006) 12211–12219
With the structural features and the odor characteristics of
Sestanj’s seco-b-ionone 3 in mind, the question arises as to
what would be the odor of a seco-structure of the carotol
derivative 2, in which C-2 and C-6 were cut out from the
2,6,7,7a-tetrahydro-1H-inden-5-yl system. This target com-
pound 4 (Fig. 1) should sterically mimic the musk odorant 2,
but would at the same time structurally resemble the trun-
cated ionone 3: Would the target molecule 4 thus smell
musky or violet like? Or better still, can one construct in
this way an odorant that would combine aspects of both pri-
mary odor notes? And finally, how would the exchange of a
tert-butyl by an isopropyl group and vice versa or, in other
words, how would the bulkiness of the substituents affect
the odor character and intensity? In the following, these
questions are addressed with the synthesis of 4 as well as
of three additional derivatives 27–29 (Scheme 1), in which
tert-butyl and isopropyl groups are permuted.
methyl-3-oxopentanoate with methyl lithium were to no
avail. Thus, we finally decided to employ acetylene chemis-
try, just as Sestanj4 had with his symmetric system. We
decided, however, against a Rupe rearrangement in the final
step, as yields are often low and Sestanj4 did not report one
for this step. Most importantly, however, we wanted to con-
trol the geometry of both double bonds of the target structure
4 and its derivatives 27–29 throughout the entire synthetic
sequence.
To ensure the (3E)-configuration of the double bond in con-
jugation with the carbonyl group in the target structures 4
and 27–29, the partial reduction of 2-alkynols8 with lithium
aluminum hydride was envisaged, followed by subsequent
oxidation of the resulting allylic alcohols. This partial hydro-
genation was discovered by Chanley and Sobotka in 1949,8a
and it proceeds in a completely trans-selective manner as
was rationalized by mechanistic studies.9 More recently, this
method had also been employed in a muscone synthesis of
Thies and Daruwala10 by siloxy-Cope ring expansion. The
oct-5-en-3-yn-2-ols required as substrates for the partial hy-
drogenation with lithium aluminum hydride were projected
to be prepared following the route recently reported by us in
the synthesis of seco-theaspiranes.11 The entire synthetic se-
quence is delineated in Scheme 1, and starts from isovaleryl
(5) and tert-butylacetyl chloride (6), respectively, which are
both commercially available.
In the synthesis of our first and principal target molecule 4,
isovaleryl chloride (5) was coupled with tert-butyl magne-
sium chloride applying the manganese-catalyzed acylation
reaction developed by Cahiez and Laboue.12 In the presence
of the soluble ate complex Li2MnCl4, prepared by mixing
manganese(II) chloride with 2 equiv of lithium chloride at
room temperature,13 2,2,5-trimethylhexan-3-one (7) was ob-
tained in 53% yield after 4.5 h of reaction at 0 ꢀC and room
temperature, standard workup, and purification by distilla-
tion in vacuo.
The construction of the but-3-yn-2-ol side chain was next on
the agenda, and to avoid protecting groups to selectively
eliminate one hydroxy group only, it was decided to carry
this out stepwise by a procedure developed by us in the syn-
thesis of seco-theaspiranes:11 Instead of employing the
Grignard reagent prepared from but-3-yn-2-ol and 2 equiv
of ethyl magnesium bromide, ketone 7 was to be reacted
with acetylene magnesium bromide, then transformed to a
Grignard reagent itself and reacted with acetaldehyde. The
intermediary tertiary carbinol 11 could then be dehydrated
without any selectivity issue. In addition, we had observed11
that the reaction with acetylene magnesium bromide was far
less prone to sterical hindrance than the analogous one with
the Grignard reagent of but-3-yn-2-ol. Thus, we were rather
astonished to find that the sterically crowded ketone 7 did not
react with acetylene magnesium bromide at room tempera-
ture or in refluxing THF. However, in the presence of stoi-
chiometric amounts of cerium chloride as introduced for
sterically hindered ketones by Imamoto et al.,14 the Grignard
reaction with ethynyl magnesium bromide went smoothly,
even at room temperature albeit not exothermic. After
quenching with aqueous ammonium chloride, extraction and
chromatographic purification furnished the desired tert-
butyl ethynyl carbinol 11 in excellent 68% yield.
Scheme 1. Synthesis of the target structures 4 and 27–29 from isovaleryl and
tert-butylacetyl chloride.
2. Results and discussion
Due to the severe steric hindrance of the tert-butyl and
isopropyl groups, the synthesis of target compound 4 turned
out to be far more difficult than anticipated. Attempts to
introduce the tert-butyl group by reacting the Wittig–Horner
reagent of Lee and Wiemer7 with isopropyl methyl ketone
failed utterly, and the aldol condensation of the lithium eno-
late of ethyl 3,3-dimethylbutanoate with isopropyl methyl
ketone also proved unsuccessful. Even all attempts to prepare
aldol adducts by treatment of ethyl 2-acetyl-3,3-dimethyl-
butanoate with isopropyl lithium, and ethyl 2-tert-butyl-4-

P. Kraft, K. Popaj / Tetrahedron 62 (2006) 12211–12219
12213
Tertiary alcohols could dehydrate following an E1 or E2
mechanism, and only the latter leads to a well-defined dou-
ble-bond geometry. As the bulky tert-butyl and the isopropyl
groups tend to adopt anti-periplanar conformations with
respect to one another, an anti-selective E2 dehydration
should provide the desired Z-configured enyne product 15,
and these reactive conformations should also favor an E2
mechanism over the E1 alternative. A quick conformational
search (MMFF/PM3) indicated the first conformer of 11 to
lead to E-geometry by anti-selective E2 elimination to be
disfavored by 2.47 kcal/mol, so we were confident of a
good selectivity. Heating the tert-butyl ethynyl carbinol 11
in a Kugelrohr apparatus to 110 ꢀC/240 mbar in the presence
of potassium hydrogen sulfate with trapping of the evaporat-
ing product in a cold trap at ꢁ78 ꢀC indeed provided
exclusively the desired Z-configured product 15 as was
established by a NOESY experiment on the first target
structure 4 (vide infra). Therefore, no special anti-selective
dehydration reagents, such as Martin’s sulfurane,15 were
required.
characteristics of violet and musk odorants, two independent
families of primary odorants with no known olfactory over-
lap. The intense woody-musky odor of the first target struc-
ture 4 was reminiscent of the violet-woody odor of b-ionone
as much as of the woody-musky odor of CashmeranÒ [6,7-
dihydro-1,1,2,3,3-pentamethyl-4(5H)-indanone],2,18 with
fruity facets in the direction of raspberries. Impressive was
also the odor threshold of 0.66 ng/L air that was measured
by us for the new odorant 4. Hence, it is only slightly weaker
than the best benchmarks of both the musk,2 ionone,19 and
irone20 family, and better than many commercial odorants.
Incited by the interesting olfactory properties of the ketodi-
enone 4 as well as by the short synthetic route to these steri-
cally crowded structures, it was desired to study the scope of
the synthetic sequence and the importance of the bulky
groups on the odor characteristics. The tert-butyl and isopro-
pyl groups should therefore be systematically permuted,
which amounted to the synthesis of the three additional
structures 27–29.
The isomerically pure (Z)-3-tert-butyl-5-methylhex-3-en-
1-yne (15) thus obtained in 54% yield after flash chroma-
tography was then transformed into the corresponding
Grignard reagent by reaction with methyl magnesium chlo-
ride. Addition of acetaldehyde, refluxing the resulting reac-
tion mixture overnight, quenching with aqueous ammonium
chloride, and the usual workup with chromatographic purifi-
cation furnished the first alk-5-en-3-yn-2-ol intermediate 19
in 85% yield. The stage was thus set for the crucial (E)-selec-
tive partial reduction of the triple bond according to the
method of Chanley and Sobotka.8 Carrying out this reaction
proved as easy as analogous hydride reductions of ketones,
and (Z)-5-tert-butyl-7-methyloct-5-en-3-yn-2-ol (19) was
simply added dropwise into a stirred suspension of 1 equiv
of lithium aluminum hydride in THF. After heating to reflux
for 3 h, the reaction was quenched with water and aqueous
sodium hydroxide. The standard workup procedure then
afforded alka-3,5-dien-2-ol 23 in an excellent 80% yield as
one single diastereoisomer, which was deduced from the
assignment of the target structure 4 to be also (3E,5E)-
configured.
Employing the manganese-catalyzed acylation detailed
above, isovaleryl (5) and 3,3-dimethylbutanoyl chloride (6)
were coupled with isopropyl (for 8 and 10, respectively) and
tert-butyl magnesium chloride (in case of 9), and the corre-
sponding methylhexan-3-ones 8–10 were obtained in 51–
52% yield. These were all submitted in the next step to the
cerium chloride-mediated Grignard reaction with ethynyl
magnesium bromide at room temperature, which yielded
after workup and chromatographic purification the acetylene
alcohols 12–14 in 71–76% yield. Dehydration of these
alcohols 12–14 with potassium hydrogen sulfate at 110 ꢀC/
240 mbar followed in all cases an anti-selective E2 mecha-
nism as was proven by NOESY experiments on the final
products 27–29, and the hex-3-en-1-ynes 16–18 were iso-
lated in 37–52% yield after chromatography. Transfer
Grignard reaction with methyl magnesium chloride, fol-
lowed by reaction of the resulting Grignard reagent with
acetaldehyde, then provided in 76–83% yield the sterically
demanding alkynols 20–22. The subsequent partial reduc-
tion of these oct-5-en-3-yn-2-ols 20–22 with lithium
aluminum hydride went smoothly, and the exclusively
(3E)-configured products 24–26 were isolated in excellent
80–83% yield. The synthesis of the three additional target
structures was completed with the pyridinium chlorochro-
momate oxidation of the allylic alcohols 24–26 that pro-
vided the highly methyl-substituted octa-3,5-dien-2-ones
27–29 in 70–75% yield as colorless odoriferous liquids. In
all cases, the geometry of both double bonds was unambig-
uously determined by distinct NOE crosspeaks between
the hydrogen atoms of the methyl groups and 4-H and 6-H,
respectively (see Section 4 for details).
All that was missing for the completion of the first target
molecule 4 was the oxidation of the allylic hydroxy function
to a carbonyl group, for which a full panoply of oxidation re-
agents is available, including activated manganese dioxide,
first employed by Ball et al.16 for the oxidation of vitamin
A, also a polyunsaturated allylic alcohol. Yet manganese
dioxide oxidations are generally slow, and we decided to
employ pyridinium chlorochromate on CeliteÒ,17 instead,
which we found most versatile and convenient to use.11,17b
And once more this reagent system worked very well, and
the corresponding ketone 4 was obtained as a colorless odor-
iferous liquid in 73% yield after simply filtering off the in-
soluble materials and chromatography of the resulting
residue on silica gel. Strong and distinct crosspeaks between
6-H and the protons of the tert-butyl group, as well as be-
tween 4-H and all seven protons of the isopropyl moiety in
the 1H–1H NOESYexperiment unequivocally proved the in-
tended (3E,5E)-configuration of our first target structure 4.
Most gratifyingly, however, the scent of ketodienone 4
also met our high expectations in that it combined
3. Olfactory evaluation and conclusions
Interestingly, the odor of the octa-3,5-dien-2-one target
structures 4 and 27–29 critically depends on the steric bulk
of the substituents. The smallest representative 27 with a
diisopropyl substituted D5 double bond was the weakest
odorant of the series, with an odor threshold as high as
251 ng/L air (Fig. 2). Its odor does not resemble musks or
ionones; instead it emanates a vague woody-fruity odor

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P. Kraft, K. Popaj / Tetrahedron 62 (2006) 12211–12219
4. Experimental
4.1. General methods
All reactions were performed under nitrogen atmosphere,
unless otherwise stated. Starting materials, reagents, and
solvents were purchased from SAFC, Acros or Alfa Aesar,
and used without further purification. Anhyd cerium(III)
chloride was prepared by heating the heptahydrate for 3 h
at 140 ꢀC/0.2 mbar. Merck silica gel 60 (particle size
0.040–0.063 mm) was used for flash chromatography. Ana-
lytical TLC was performed on precoated Merck silica gel 60
F254 plates on glass, and the products were visualized with
phosphomolybdic acid. Attenuated-total-reflection IR spec-
tra were recorded on a Bruker VECTOR 22 with Harrick
Figure 2. Comparison of the target structures 4 and 27–29 concerning the
odor character and threshold.
1
SplitPea micro ATR unit. H and 13C NMR spectra were
measured either with a Bruker AVANCE DPX-400 or an
AVANCE 500 TCI spectrometer. 13C multiplicities were
determined using DEPT pulse sequences. Mass spectra
were recorded with a Finnigan MAT 95 or on a HP Chemsta-
tion 6890 GC/5973 with mass sensitive detector. The Mikro-
analytisches Laboratorium Ilse Beetz in 96301 Kronach,
Germany, performed the elemental analyses. The odor
thresholds are geometrical means of individual thresholds
that were determined by GC-olfactometry injecting different
dilutions of sample substance into a gas chromatograph in
descending order of concentration until the panelists failed
to detect an odor at the correct retention time.
with earthy and rooty nuances. Replacement of the 5-isopro-
pyl group by a tert-butyl substituent gives the original target
structure 4, with its well-balanced woody-musky Cash-
meranÒ and typical violet-raspberry b-ionone characters.
And this striking shift in the odor character from 27/4
coincides with an almost 400-fold intensity gain in odor
threshold. Upon replacement of the second isopropyl group
of compound 4 by a tert-butyl moiety the good odor thresh-
old of 0.66 ng/L air even improved further slightly to
0.54 ng/L air, measured for the di-tert-butyl derivative 28.
Both the musk and the violet notes of the original target
structure 4 were retained in odorant 28. In comparison, the
violet note of 28 was described as sweeter but less fruity
as that of 4, devoid of a pronounced raspberry tonality, while
the musky side of 28 had also a woody character as in Cash-
meranÒ, but different from 4 exhibited also slightly campho-
raceous and agrestic facets. If the 5-tert-butyl moiety of this
musk odorant 28 is replaced by an isopropyl group, the musk
character disappears completely, while the fruity, raspberry
side reappears. So, target structure 29 can be considered en-
tirely an ionone odorant. Its floral-fruity odor of violets and
raspberries resembles those of a-irone and b-ionone; yet,
with 12.5 ng/L air, the seco-structure 29 is about 100 times
weaker than b-ionone (0.12 ng/L air)19 in terms of odor
threshold.
4.2. Preparation of compounds 4 and 7–29
4.2.1. 2,2,5-Trimethylhexan-3-one (7). Between 0 and
2 ꢀC, a tert-butyl magnesium chloride soln in Et2O (2 M,
500 mL, 1.00 mol) was added within 3 h to a stirred mixture
of isovaleryl chloride (5, 121 g, 1.00 mol) and Li2MnCl4
soln in THF (0.5 M, 60 mL, prepared according to Ref. 13)
in THF (1 L). The resulting reaction mixture was stirred
for additional 30 min at 0 ꢀC, and then for 1 h at room tem-
perature. Water (700 mL) was added dropwise with stirring,
and the aqueous layer was extracted with Et2O (2ꢂ500 mL).
The combined organic extracts were dried (Na2SO4) and
concentrated on a rotary evaporator at 42 ꢀC/100 mbar.
The resulting residue was purified by distillation in a 10-
cm Vigreux assembly to afford the title compound 7 at
46–48 ꢀC/6 mbar. Yield 53% (75.4 g); colorless liquid; IR
(neat, cmꢁ1) 1704 (n C]O), 1467 (das CH3), 1365 (ds
These data impressively demonstrate the importance of
hydrophobic volumes on both odor character and intensity,
and show how one can fine-tune olfactory properties with
only slight structural changes. With perhaps the exception
of 27, our design concept of new seco-structures devised
from the carotol musk odorant 2 and the truncated b-ionone
structure 3 worked out well. In terms of overall olfactory
performance, the original target structure 4, however,
remained the best, which highlights once again the signi-
ficance of the shape similarity in odorant design.
1
CH3); H NMR (CDCl3, ppm) d 0.89 (d, J¼7.0 Hz, 6H, 5-
Me2), 1.12 (s, 9H, 2-Me3), 2.16 (sept, J¼7.0 Hz, 1H, 5-H),
2.35 (d, J¼7.0 Hz, 2H, 4-H2); 13C NMR (CDCl3, ppm)
d 22.5 (q, 5-Me2), 23.9 (d, C-5), 26.2 (q, 2-Me3), 44.0 (s,
C-2), 45.4 (t, C-4), 215.3 (s, C-3); MS (EI, %) m/z 142 (6)
[M+], 85 (38) [M+ꢁC4H9], 57 (100) [C4H+9], 43 (8) [C3H+7].
4.2.2. 3-tert-Butyl-5-methylhex-1-yn-3-ol (11). In one dash,
a soln of 7 (48.4 g, 340 mmol) in THF (400 mL) was added
at 0 ꢀC to anhyd cerium(III) chloride (83.3 g, 340 mmol),
and the suspension was stirred at room temperature for
5 h. The resulting viscous slurry was added at ambient tem-
perature dropwise with stirring over a period of 30 min to
a soln of ethynyl magnesium bromide in THF (0.5 M,
1020 mL, 510 mmol), upon which no temperature rise was
observed. The reaction mixture was stirred at room temper-
ature overnight, quenched with satd aq NH4Cl (800 mL) and
The synthetic hurdle in the preparation of these highly
branched systems was tackled by simple and industrially ap-
plicable Grignard reactions from the ketones 7–10, which
are themselves easily accessible by Li2MnCl4-catalyzed
Grignard reactions on the acid chlorides 5 and 6. The chemo-
selective hydrogenation of 19–22 employing lithium alumi-
num hydride was however crucial for the success of this
efficient strategy, which opens up a general and stereode-
fined access to numerous polyene systems.

P. Kraft, K. Popaj / Tetrahedron 62 (2006) 12211–12219
12215
extracted with Et2O (3ꢂ400 mL). The combined organic ex-
tracts were dried (Na2SO4) and evaporated. Purification of
the residue by flash chromatography on silica gel furnished
the title compound 11. Yield 68% (38.9 g); yellowish oil; Rf
0.30 (pentane/Et2O 98:2); IR (neat, cmꢁ1) 3489 (n O–H),
3308 (n C^C–H), 1467 (das CH3), 1366 (ds CH3); 1H
NMR (CDCl3, ppm) d 1.02 (s, 9H, 10-Me3), 1.02–1.04 (2d,
J¼7.0 Hz, 6H, 5-Me2), 1.42 (dd, J¼14.0 and 7.5 Hz, 1H,
4-Ha), 1.58 (dd, J¼14.0 and 5.0 Hz, 1H, 4-Hb), 1.83 (br s,
1H, OH), 2.07 (dseptd, J¼7.5, 7.0 and 5.0 Hz, 1H, 5-H),
2.45 (s, 1H, 1-H); 13C NMR (CDCl3, ppm) d 24.1/24.7
(2q, 5-Me2), 24.9 (q, 10-Me3), 25.5 (d, C-5), 38.8 (s, C-10),
43.4 (t, C-4), 73.6 (d, C-1), 77.1 (s, C-3), 85.9 (s, C-2);
MS (EI, %) m/z 153 (4) [M+ꢁCH3], 111 (70) [M+ꢁC4H9],
70 (49) [C5H+10], 57 (93) [C4H+9], 43 (100) [C3H+7].
(139 mg, 3.65 mmol) in THF (2.0 mL), a soln of 19
(716 mg, 3.68 mmol) in THF (15 mL) was added dropwise
at room temperature, and the reaction mixture was refluxed
for 3 h. At 2–4 ꢀC water (0.15 mL) was added dropwise,
followed by 15% aq NaOH (0.15 mL) and again water
(0.45 mL). After stirring for a further 30 min at room temper-
ature, the formed precipitate was filtered off by suction with
the aid of a sintered funnel and washed with Et2O (20 mL).
The combined filtrates were evaporated under reduced pres-
sure and the resulting residue was purified by flash chroma-
tography on silica gel to provide the title compound 23. Yield
80% (579 mg); colorless oil; Rf 0.11 (pentane/Et2O 95:5); IR
(neat, cmꢁ1) 3331 (n O–H), 1461 (das CH3), 1360 (ds CH3),
1
1060 (n C–O), 969 (d C]C–H); H NMR (CDCl3, ppm)
d 0.92 (d, J¼6.5 Hz, 6H, 7-Me2), 1.02 (s, 9H, 10-Me3), 1.31
(d, J¼6.5 Hz, 3H, 1-H3), 1.58 (d, J¼1.0 Hz, 1H, OH), 2.58
(dsept, J¼9.5 and 6.5 Hz, 1H, 7-H), 4.37 (quintd, J¼6.5
and 1.0 Hz, 1H, 2-H), 5.09 (d, J¼9.5 Hz, 1H, 6-H), 5.53
(dd, J¼16.0 and 6.5 Hz, 1H, 3-H), 6.06 (d, J¼16.0 Hz, 1H,
4-H); 13C NMR (CDCl3, ppm) d 23.5 (q, C-1), 23.6/23.7
(2q, 7-Me2), 27.7 (d, C-7), 29.6 (q, 10-Me3), 35.1 (s, C-10),
69.2 (d, C-2), 128.6 (d, C-6), 131.2 (d, C-3), 136.9 (s, C-4),
143.5 (s, C-5); MS (EI, %) m/z 196 (5) [M+], 181 (3)
[M+ꢁCH3], 139 (16) [M+ꢁC4H9], 123 (24) [M+ꢁC4H9O],
57 (100) [C4H+9], 43 (88) [C3H+7].
4.2.3. (Z)-3-tert-Butyl-5-methylhex-3-en-1-yne (15). In
a Kugelrohr apparatus, the alkynol 11 (34.2 g, 203 mmol)
was heated to 110 ꢀC/240 mbar in the presence of KHSO4
(5.53 g, 40.6 mmol) for 3 h, with the evaporating product
mixture being trapped in a bulb cooled to ꢁ78 ꢀC. This
crude product was purified by flash chromatography on
silica gel to provide the title compound 15. Yield 54%
(16.5 g); colorless liquid; Rf 0.57 (pentane/Et2O 99:1); IR
(neat, cmꢁ1) 3312 (n C^C–H), 1461 (das CH3), 1362 (ds
1
CH3), 955 (d C]C–H); H NMR (CDCl3, ppm) d 0.98
(d, J¼7.0 Hz, 6H, 5-Me2), 1.08 (s, 9H, 10-Me3), 2.87 (dsept,
J¼9.5 and 7.0 Hz, 1H, 5-H), 3.11 (s, 1H, 1-H), 5.57 (d,
J¼9.5 Hz, 1H, 4-H); 13C NMR (CDCl3, ppm) d 22.4 (q,
5-Me2), 29.1 (q, 10-Me3), 29.8 (d, C-5), 34.9 (s, C-10), 81.4
(s, C-2), 81.8 (d, C-1), 129.7 (s, C-3), 142.3 (d, C-4); MS
(EI, %) m/z 150 (20) [M+], 107 (36) [M+ꢁCH3], 93 (42)
[M+ꢁC4H9], 57 (100) [C4H9+], 43 (16) [C3H+7].
4.2.6. (3E,5E)-5-tert-Butyl-7-methylocta-3,5-dien-2-one
(4). At room temperature, pyridinium chlorochromate
(795 mg, 3.68 mmol) was added portionwise to a suspension
of dienol 23 (481 mg, 2.45 mmol) and CeliteÒ (5.00 g) in
CH2Cl2 (25 mL). After stirring for 5 h at ambient tempera-
ture, the reaction mixture was diluted with Et2O (15 mL),
the insoluble materials filtered off over a pad of CeliteÒ
and washed with Et2O (10 mL). The combined filtrates
were evaporated on a rotary evaporator, and the resulting
residue was purified by chromatography on silica gel to fur-
nish the target compound 4. Yield 73% (348 mg); colorless
odoriferous liquid; odor description: very pleasant woody-
musky odor reminiscent of b-ionone and CashmeranÒ with
fruity facets in the direction of raspberries; odor threshold:
4.2.4. (Z)-5-tert-Butyl-7-methyloct-5-en-3-yn-2-ol (19). At
room temperature, a soln of 15 (790 mg, 5.26 mmol) in THF
(15 mL) was added dropwise to a stirred methyl magnesium
chloride soln in THF (3 M, 2.10 mL, 6.30 mmol), and the
resulting reaction mixture was refluxed for 2 h. A soln of
acetaldehyde (278 mg, 6.31 mmol) in THF (6 mL) was
then added within 5 min, and the reaction mixture was again
heated to reflux overnight. The reaction mixture was allowed
to cool to room temperature, quenched with satd aq NH4Cl
(100 mL), and extracted with Et2O (3ꢂ150 mL). The com-
bined organic extracts were dried (Na2SO4), and the solvent
was evaporated on a rotary evaporator. The resulting residue
was purified by flash chromatography on silica gel to furnish
the title compound 19. Yield 85% (868 mg); colorless oil; Rf
0.13 (pentane/Et2O 95:5); IR (neat, cmꢁ1) 3354 (n O–H),
1460 (das CH3), 1361 (ds CH3), 1073 (n C–O), 861 (d
0.66 ng/L air; Rf 0.10 (pentane/Et2O 98:2); IR (neat, cmꢁ1
)
1696 (n C]O conj), 1463 (das CH3), 1360 (ds CH3), 1247
(nas C]C–C]O), 980 (d C]C–H); 1H NMR (CDCl3,
ppm) d 0.95 (d, J¼6.5 Hz, 6H, 7-Me2), 1.08 (s, 9H,
10-Me3), 2.31 (s, 3H, 1-H3), 2.59 (dsept, J¼10.0 and
6.5 Hz, 1H, 7-H), 5.33 (d, J¼10.0 Hz, 1H, 6-H), 6.11 (d,
J¼16.5 Hz, 1H, 3-H), 7.22 (d, J¼16.5 Hz, 1H, 4-H);
1H–1H NOESY (CDCl3) 10-Me3ꢂ6-H, 7-Me2ꢂ4-H,
7-Hꢂ4-H; 13C NMR (CDCl3, ppm) d 23.4 (q, 7-Me2), 27.2
(q, C-1), 27.9 (d, C-7), 29.7 (q, 10-Me3), 35.4 (s, C-10),
131.8 (d, C-6), 135.5 (d, C-3), 142.2 (s, C-5), 142.7 (d,
C-4), 198.5 (s, C-2); MS (EI, %) m/z 194 (3) [M+], 151
(100) [MꢁC2H3O+], 123 (26) [MꢁC4H7O+], 57 (74)
[C4H+9], 43 (100) [C3H7+]. Anal. Calcd for C13H22O: C,
80.35; H, 11.41. Found: C, 80.38; H, 11.46.
1
C]C–H); H NMR (CDCl3, ppm) d 0.97 (d, J¼6.5 Hz,
6H, 7-Me2), 1.08 (s, 9H, 10-Me3), 1.51 (d, J¼6.5 Hz, 3H,
1-H3), 2.07 (br s, 1H, OH), 2.80 (dsept, J¼9.5 and 6.5 Hz,
1H, 7-H), 4.71 (q, J¼6.5 Hz, 1H, 2-H), 5.49 (d, J¼9.5 Hz,
1H, 6-H); 13C NMR (CDCl3, ppm) d 22.5 (q, 7-Me2), 24.6
(q, C-1), 29.2 (q, 10-Me3), 29.8 (d, C-7), 35.0 (s, C-10),
59.8 (d, C-2), 81.7 (s, C-3), 95.9 (s, C-4), 129.9 (s, C-5),
140.9 (d, C-6); MS (EI, %) m/z 194 (14) [M+], 179 (3)
[M+ꢁCH3], 123 (36) [M+ꢁC4H7O], 93 (42) [C7H+9], 57
(100) [C4H+9], 43 (100) [C3H+7].
4.2.7. 2,5-Dimethylhexan-3-one (8). As described for the
preparation of 7, from isopropyl magnesium chloride soln
in Et2O (2 M, 500 mL, 1.00 mol), isovaleryl chloride (5,
121 g, 1.00 mol) and Li2MnCl4 soln in THF (0.5 M,
60 mL), the title compound 8 was obtained after standard
workup and purification by distillation in a 10-cm Vigreux
assembly at 45–47 ꢀC/8 mbar. Yield 52% (66.7 g); colorless
4.2.5. (3E,5E)-5-tert-Butyl-7-methylocta-3,5-dien-2-ol
(23). To a stirred suspension of lithium aluminum hydride

12216
P. Kraft, K. Popaj / Tetrahedron 62 (2006) 12211–12219
liquid; IR (neat, cmꢁ1) 1708 (n C]O), 1466 (das CH3), 1365
(ds CH3); 1H NMR (CDCl3, ppm) d 0.90 (d, J¼7.0 Hz, 6H, 5-
Me2), 1.08 (d, J¼7.0 Hz, 6H, 2-Me2), 2.16 (sept, J¼7.0 Hz,
1H, 5-H), 2.32 (d, J¼7.0 Hz, 2H, 4-H2), 2.57 (sept,
J¼7.0 Hz, 1H, 2-H); 13C NMR (CDCl3, ppm) d 18.1 (q, 2-
Me2), 22.5 (q, 5-Me2), 24.2 (d, C-5), 41.0 (d, C-2), 49.4 (t,
C-4), 215.1 (s, C-3); MS (EI, %) m/z 128 (12) [M+], 85
(41) [M+ꢁC3H7], 57 (100) [M+ꢁC4H7O], 43 (39) [C3H+7].
C-6); MS (EI, %) m/z 180 (13) [M+], 165 (4) [M+ꢁCH3],
137 (26) [M+ꢁC3H7], 95 (24) [M+ꢁC6H12], 43 (100)
[C3H+7].
4.2.11. (3E,5Z)-5-Isopropyl-7-methylocta-3,5-dien-2-ol
(24). As described for the preparation of 23, from 20
(1.38 g, 7.66 mmol) and lithium aluminum hydride
(291 mg, 7.66 mmol) in THF (25 mL), the title compound
24 was obtained after standard workup and purification by
chromatography on silica gel. Yield 81% (1.13 g); colorless
oil; Rf 0.13 (pentane/Et2O 95:5); IR (neat, cmꢁ1) 3328
(n O–H), 1461 (das CH3), 1361 (ds CH3), 1055 (n C–O),
963 (d C]C–H); 1H NMR (CDCl3, ppm) d 0.97 (d,
J¼6.5 Hz, 6H, 7-Me2), 1.04 (d, J¼7.0 Hz, 6H, 10-Me2),
1.31 (d, J¼6.5 Hz, 3H, 1-H3), 1.73 (d, J¼1.0 Hz, 1H,
OH), 2.56 (sept, J¼7.0 Hz, 1H, 10-H), 2.73 (dsept, J¼9.5
and 6.5 Hz, 1H, 7-H), 4.38 (quintd, J¼6.5 and 1.0 Hz,
1H, 2-H), 5.16 (d, J¼9.5 Hz, 1H, 6-H), 5.72 (dd, J¼16.0
and 6.5 Hz, 1H, 3-H), 6.47 (d, J¼16.0 Hz, 1H, 4-H); 13C
NMR (CDCl3, ppm) d 22.4 (q, 10-Me2), 23.3 (q, 7-Me2),
23.5 (q, C-1), 26.3 (d, C-7), 29.4 (d, C-10), 69.6 (d, C-2),
126.0 (d, C-6), 132.2 (d, C-3), 134.6 (d, C-4), 139.2 (s,
C-5); MS (EI, %) m/z 182 (3) [M+], 164 (6) [M+ꢁH2O],
137 (18) [M+ꢁC2H5O], 109 (41) [M+ꢁC4H9O], 43 (100)
[C3H+7].
4.2.8. 3-Isopropyl-5-methylhex-1-yn-3-ol (12). As de-
scribed for the preparation of 11, from 8 (19.2 g, 150 mmol)
and anhyd cerium(III) chloride (37.0 g, 150 mmol) in THF
(200 mL), and a soln of ethynyl magnesium bromide in
THF (0.5 M, 450 mL, 225 mmol), the title compound 12
was obtained after standard workup and purification by chro-
matography on silica gel. Yield 71% (16.5 g); colorless oil;
Rf 0.31 (pentane/Et2O 98:2); IR (neat, cmꢁ1) 3467 (n O–H),
3309 (n C^C–H), 1468 (das CH3), 1368 (ds CH3); 1H NMR
(CDCl3, ppm) d 1.00 (d, J¼7.0 Hz, 6H, 10-Me2), 1.02 (d,
J¼6.5 Hz, 6H, 5-Me2), 1.48 (dd, J¼14.0 and 6.5 Hz, 1H,
4-Ha), 1.62 (dd, J¼14.0 and 6.0 Hz, 1H, 4-Hb), 1.81 (sept,
J¼7.0 Hz, 2H, 10-H, 1-H), 1.89 (br s, 1H, OH), 2.02 (sept,
J¼6.5 Hz, 1H, 5-H), 2.44 (s, 1H, 1-H); 13C NMR (CDCl3,
ppm) d 16.8–17.7 (2q, 10-Me2), 24.2–24.3 (2q, 5-Me2),
24.8 (d, C-5), 38.3 (d, C-10), 47.1 (t, C-4), 73.1 (d, C-1),
74.4 (s, C-3), 86.0 (s, C-2); MS (EI, %) m/z 139 (2)
[M+ꢁCH3], 111 (62) [M+ꢁC3H7], 97 (32) [M+ꢁC4H9], 43
(100) [C3H+7].
4.2.12. (3E,5Z)-5-Isopropyl-7-methylocta-3,5-dien-2-one
(27). As described for the preparation of 4, from 24
(910 mg, 5.00 mmol), pyridinium chlorochromate (1.62 g,
7.51 mmol) and CeliteÒ (10.0 g) in CH2Cl2 (50 mL), the
title compound 27 was obtained after standard workup and
purification by chromatography on silica gel. Yield 70%
(631 mg); colorless odoriferous liquid; odor description:
vague woody-fruity odor with earthy and rooty undertones;
odor threshold: 251 ng/L air; Rf 0.13 (pentane/Et2O 98:2);
IR (neat, cmꢁ1) 1669 (n C]O), 1463 (das CH3), 1358 (ds
4.2.9. (Z)-3-Isopropyl-5-methylhex-3-en-1-yne (16). As
described for the preparation of 15, from 12 (6.63 g,
43.0 mol) and KHSO4 (1.17 g, 8.60 mmol), the title com-
pound 16 was obtained after standard workup and purifica-
tion by chromatography on silica gel. Yield 52% (3.05 g);
colorless liquid; Rf 0.58 (pentane/Et2O 99:1); IR (neat,
cmꢁ1) 3312 (n C^C–H), 1465 (das CH3), 1362 (ds CH3),
923 (d C]C–H); 1H NMR (CDCl3, ppm) d 0.98 (d,
J¼6.5 Hz, 6H, 5-Me2), 1.07 (d, J¼7.0 Hz, 6H, 10-Me2),
2.32 (sept, J¼7.0 Hz, 1H, 10-H), 2.83 (dsept, J¼9.5 and
6.5 Hz, 1H, 5-H), 3.07 (s, 1H, 1-H), 5.56 (d, J¼9.5 Hz,
1H, 4-H); 13C NMR (CDCl3, ppm) d 21.6 (q, 10-Me2), 22.3
(q, 5-Me2), 29.6 (d, C-5), 34.8 (d, C-10), 81.0 (s, C-2), 81.4
(d, C-1), 126.3 (s, C-3), 144.0 (d, C-4); MS (EI, %) m/z
136 (25) [M+], 121 (29) [M+ꢁCH3], 93 (100) [M+ꢁC3H7],
79 (100) [C6H+8], 43 (17) [C3H+7].
1
CH3), 1253 (nas C]C–C]O), 971 (d C]C–H); H NMR
(CDCl3, ppm) d 1.00 (d, J¼6.5 Hz, 6H, 7-Me2), 1.07 (d,
J¼7.0 Hz, 6H, 10-Me2), 2.31 (s, 3H, 1-H3), 2.62 (sept,
J¼7.0 Hz, 1H, 10-H), 2.92 (dsept, J¼9.5 and 6.5 Hz, 1H,
7-H), 5.60 (d, J¼9.5 Hz, 1H, 6-H), 6.22 (d, J¼16.0 Hz,
1
1H, 3-H), 7.56 (d, J¼16.0 Hz, 1H, 4-H); H–1H NOESY
(C6D6) 7-Me2ꢂ6-H, 10-Me2ꢂ6-H, 7-Me2ꢂ4-H, 7-Hꢂ4-H;
13C NMR (CDCl3, ppm) d 22.3 (q, 10-Me2), 23.2 (q,
7-Me2), 26.9 (q, C-1), 27.5 (d, C-10), 28.9 (d, C-7), 126.2
(d, C-6), 139.0 (s, C-5), 139.6 (d, C-3), 143.4 (d, C-4),
198.9 (s, C-2); MS (EI, %) m/z 180 (2) [M+], 165 (3)
[M+ꢁCH3], 137 (100) [M+ꢁC3H7], 109 (50)
[M+ꢁC4H7O], 43 (76) [C3H7+]. Anal. Calcd for C12H20O:
C, 79.94; H, 11.18. Found: C, 80.00; H, 11.10.
4.2.10. (Z)-5-Isopropyl-7-methyloct-5-en-3-yn-2-ol (20).
As described for the preparation of 19, from 16 (1.50 g,
11.0 mol), methyl magnesium chloride soln in THF (3 M,
4.40 mL, 13.2 mmol) and acetaldehyde (582 mg,
13.2 mmol) in THF (30 mL), the title compound 20 was ob-
tained after standard workup and purification by chromato-
graphy on silica gel. Yield 83% (1.65 g); colorless oil; Rf
0.14 (pentane/Et2O 95:5); IR (neat, cmꢁ1) 3317 (n O–H),
1464 (das CH3), 1361 (ds CH3), 1070 (n C–O), 854 (d
4.2.13. 2,2,5,5-Tetramethylhexan-3-one (9). As described
for the preparation of 7, from tert-butyl magnesium chloride
soln in Et2O (2 M, 500 mL, 1.00 mol), 3,3-dimethylbutanoyl
chloride (6, 135 g, 1.00 mol) and Li2MnCl4 soln in THF
(0.5 M, 60 mL), the title compound 9 was obtained after
standard workup and purification by distillation in a 10-cm
Vigreux assembly at 47–49 ꢀC/3 mbar. Yield 52% (81.3 g);
colorless liquid; IR (neat, cmꢁ1) 1707 (n C]O), 1464 (das
1
C]C–H); H NMR (CDCl3, ppm) d 0.97 (d, J¼6.5 Hz,
6H, 5-Me2), 1.05 (d, J¼7.0 Hz, 6H, 10-Me2), 1.50 (d,
J¼6.5 Hz, 3H, 1-H3), 2.00 (br s, 1H, OH), 2.30 (sept,
J¼7.0 Hz, 1H, 10-H), 2.77 (dsept, J¼9.5 and 6.5 Hz, 1H,
5-H), 4.70 (q, J¼6.5 Hz, 1H, 2-H), 5.48 (d, J¼9.5 Hz, 1H,
1
CH3), 1364 (ds CH3); H NMR (CDCl3, ppm) d 1.02 (s,
13
6-H); C NMR (CDCl3, ppm) d 21.7 (q, 10-Me2), 22.4 (q,
9H, 5-Me3), 1.11 (s, 9H, 2-Me3), 2.37 (s, 2H, 4-H2); 13C
NMR (CDCl3, ppm) d 26.2 (q, 2-Me3), 29.6 (q, 5-Me3),
30.4 (s, C-5), 44.6 (s, C-2), 47.8 (t, C-4), 215.4 (s, C-3);
5-Me2), 24.6 (q, C-1), 29.5 (d, C-7), 34.9 (s, C-10), 58.9 (d,
C-2), 81.3 (s, C-3), 95.6 (s, C-4), 126.6 (s, C-5), 142.7 (d,

P. Kraft, K. Popaj / Tetrahedron 62 (2006) 12211–12219
12217
MS (EI, %) m/z 156 (4) [M+], 99 (22) [M+ꢁC4H9], 57 (100)
973 (d C]C–H); 1H NMR (CDCl3, ppm) d 1.00 (s,
9H, 10-Me3), 1.04 (s, 9H, 7-Me3), 1.31 (d, J¼6.5 Hz, 3H,
1-H3), 1.63 (d, J¼1.5 Hz, 1H, OH), 4.37 (quintd, J¼6.5
and 1.5 Hz, 1H, 2-H), 5.27 (d, J¼1.5 Hz, 1H, 6-H), 5.38
(dd, J¼16.0 and 6.5 Hz, 1H, 3-H), 6.12 (dd, J¼16.0 and
1.5 Hz, 1H, 4-H); 13C NMR (CDCl3, ppm) d 23.0 (q, C-1),
29.6 (q, 10-Me3), 31.7 (q, 7-Me3), 32.6 (s, C-7), 36.2 (s,
C-10), 69.2 (d, C-2), 128.2 (d, C-6), 133.1 (d, C-3), 136.7
(d, C-4), 144.0 (s, C-5); MS (EI, %) m/z 210 (2) [M+], 153
(6) [M+ꢁC4H9], 109 (58) [M+ꢁC6H13O], 57 (100) [C4H+9].
[C4H+9].
4.2.14. 3-tert-Butyl-5,5-dimethylhex-1-yn-3-ol (13). As
described for the preparation of 11, from 9 (18.8 g,
120 mmol) and anhyd cerium(III) chloride (29.6 g,
120 mmol) in THF (200 mL), and a soln of ethynyl magne-
sium bromide in THF (0.5 M, 360 mL, 180 mmol), the title
compound 13 was obtained after standard workup and puri-
fication by chromatography on silica gel. Yield 74%
(16.2 g); colorless oil; Rf 0.28 (pentane/Et2O 98:2); IR
(neat, cmꢁ1) 3486 (n O–H), 3308 (n C^C–H), 1466 (das
4.2.18. (3E,5E)-5-tert-Butyl-7,7-dimethylocta-3,5-dien-2-
one (28). As described for the preparation of 4, from 25
(762 mg, 3.62 mmol), pyridinium chlorochromate (1.17 g,
5.43 mmol) and CeliteÒ (5.0 g) in CH2Cl2 (40 mL), the
title compound 28 was obtained after standard workup and
purification by chromatography on silica gel. Yield 75%
(567 mg); colorless odoriferous liquid; odor description:
floral, sweet, violet, musky, with woody, slightly camphora-
ceous and agrestic facets; odor threshold: 0.54 ng/L air;
Rf 0.10 (pentane/Et2O 98:2); IR (neat, cmꢁ1) 1675 (n
C]O conj), 1462 (das CH3), 1359 (ds CH3), 1249 (nas
1
CH3), 1365 (ds CH3); H NMR (CDCl3, ppm) d 1.02 (s,
9H, 10-Me3), 1.12 (s, 9H, 5-Me3), 1.58 (d, J¼14.5 Hz, 1H,
4-Ha), 1.62 (d, J¼14.5 Hz, 1H, 4-Hb), 1.84 (br s, 1H, OH),
2.49 (s, 1H, 1-H); 13C NMR (CDCl3, ppm) d 24.9 (q,
10-Me3), 29.5 (s, C-5), 31.0 (q, 5-Me3), 39.7 (s, C-10), 46.7
(t, C-4), 74.7 (d, C-1), 75.6 (s, C-3), 86.8 (s, C-2); MS (EI,
%) m/z 167 (2) [M+ꢁCH3], 125 (6) [M+ꢁC4H9], 111 (26)
[M+ꢁC5H11], 57 (100) [C4H+9].
4.2.15. (Z)-3-tert-Butyl-5,5-dimethylhex-3-en-1-yne (17).
As described for the preparation of 15, from 13 (5.02 g,
2.75 mmol) and KHSO4 (749 mg, 5.50 mmol), the title com-
pound 17 was obtained after standard workup and purifica-
tion by chromatography on silica gel. Yield 37% (1.68 g);
colorless liquid; Rf 0.56 (pentane/Et2O 99:1); IR (neat,
cmꢁ1) 3311 (n C^C–H), 1462 (das CH3), 1361 (ds CH3),
1
C]C–C]O), 983 (d C]C–H); H NMR (CDCl3, ppm) d
1.05 (s, 9H, 10-Me3), 1.06 (s, 9H, 7-Me3), 2.30 (s, 3H,
1-H3), 5.42 (d, J¼1.5 Hz, 1H, 6-H), 6.02 (d, J¼16.5 Hz,
1
1H, 3-H), 7.37 (dd, J¼16.5 and 1.5 Hz, 1H, 4-H); H–1H
NOESY (C6D6) 10-Me3ꢂ6-H, 7-Me3ꢂ6-H, 7-Me3ꢂ4-H;
13C NMR (CDCl3, ppm) d 27.1 (q, C-1), 29.7 (q, 10-Me3),
31.6 (q, 7-Me3), 32.8 (s, C-7), 36.4 (s, C-10), 132.6 (d, C-
6), 135.8 (d, C-3), 142.5 (s, C-5), 145.2 (d, C-4), 197.9 (s,
C-2); MS (EI, %) m/z 193 (5) [M+ꢁCH3], 165 (73)
[M+ꢁC2H3O], 151 (38) [M+ꢁC4H9], 57 (100) [C4H+9].
Anal. Calcd for C14H24O: C, 80.71; H, 11.61. Found: C,
80.75; H, 11.63.
1
936 (d C]C–H); H NMR (CDCl3, ppm) d 1.10 (s, 9H,
10-Me3), 1.19 (s, 9H, 5-Me3), 3.24 (s, 1H, 1-H), 5.76 (s,
1H, 4-H); 13C NMR (CDCl3, ppm) d 29.2 (q, 10-Me3), 29.9
(q, 5-Me3), 32.4 (s, C-5), 35.9 (s, C-10), 81.9 (s, C-2), 85.0
(d, C-1), 129.5 (s, C-3), 144.7 (d, C-4); MS (EI, %) m/z
164 (26) [M+], 149 (58) [M+ꢁCH3], 107 (80) [M+ꢁC4H9],
57 (100) [C4H+9].
4.2.19. 2,5-Dimethylhexan-3-one (10). As described for the
preparation of 7, from isopropyl magnesium chloride soln in
Et2O (2 M, 500 mL, 1.00 mol), 3,3-dimethylbutanoyl chlo-
ride (6, 135 g, 1.00 mol) and Li2MnCl4 soln in THF
(0.5 M, 60 mL), the title compound 10 was obtained after
standard workup and purification by distillation in a 10-cm
Vigreux assembly at 46–48 ꢀC/6 mbar. Yield 51% (72.6 g);
colorless liquid; IR (neat, cmꢁ1) 1709 (n C]O), 1465 (das
4.2.16. (Z)-5-tert-Butyl-7,7-dimethyloct-5-en-3-yn-2-ol
(21). As described for the preparation of 19, from 17
(1.43 g, 8.70 mol), methyl magnesium chloride soln in
THF (3 M, 3.50 mL, 10.5 mmol) and acetaldehyde
(463 mg, 10.5 mmol) in THF (25 mL), the title compound
21 was obtained after standard workup and purification by
chromatography on silica gel. Yield 76% (1.38 g); colorless
oil; Rf 0.12 (pentane/Et2O 95:5); IR (neat, cmꢁ1) 3320 (n O–
H), 1460 (das CH3), 1360 (ds CH3), 1087 (n C–O), 931 (d
1
CH3), 1364 (ds CH3); H NMR (CDCl3, ppm) d 1.01 (s,
9H, 5-Me3), 1.05 (d, J¼7.0 Hz, 6H, 2-Me2), 2.34 (s, 2H,
4-H2), 2.56 (sept, J¼7.0 Hz, 1H, 2-H); 13C NMR (CDCl3,
ppm) d 17.9 (q, 2-Me2), 29.6 (q, 5-Me3), 30.8 (s, C-5),
42.0 (d, C-2), 52.6 (t, C-4), 214.4 (s, C-3); MS (EI, %) m/z
142 (10) [M+], 99 (26) [M+ꢁC3H7], 71 (34) [M+ꢁC4H7O],
57 (100) [C4H+9], 43 (39) [C3H+7].
1
C]C–H); H NMR (CDCl3, ppm) d 1.08 (s, 9H, 10-Me3),
1.17 (s, 9H, 7-Me3), 1.50 (d, J¼6.5 Hz, 3H, 1-H3), 1.95
(br s, 1H, OH), 4.72 (q, J¼6.5 Hz, 1H, 2-H), 5.69 (s, 1H,
13
6-H); C NMR (CDCl3, ppm) d 24.2 (q, C-1), 29.3 (q, 10-
Me3), 30.1 (q, 7-Me3), 32.5 (s, C-7), 36.0 (s, C-10), 59.0
(d, C-2), 82.6 (s, C-3), 98.3 (s, C-4), 129.7 (s, C-5), 143.3
(d, C-6); MS (EI, %) m/z 208 (16) [M+], 193 (6)
[M+ꢁCH3], 165 (17) [M+ꢁC2H5O], 151 (18) [M+ꢁC4H9],
57 (78) [C4H+9].
4.2.20. 3-Isopropyl-5,5-dimethylhex-1-yn-3-ol (14). As
described for the preparation of 11, from 10 (17.1 g,
120 mmol) and anhyd cerium(III) chloride (29.6 g,
120 mmol) in THF (180 mL), and a soln of ethynyl magne-
sium bromide in THF (0.5 M, 360 mL, 180 mmol), the title
compound 14 was obtained after standard workup and puri-
fication by chromatography on silica gel. Yield 76%
(15.4 g); colorless oil; Rf 0.30 (pentane/Et2O 98:2); IR
(neat, cmꢁ1) 3486 (n O–H), 3308 (n C^C–H), 1468 (das
4.2.17. (3E,5E)-5-tert-Butyl-7,7-dimethylocta-3,5-dien-2-
ol (25). As described for the preparation of 23, from 21
(1.17 g, 5.62 mmol) and lithium aluminum hydride
(213 mg, 5.62 mmol) in THF (25 mL), the title compound
25 was obtained after standard workup and purification by
chromatography on silica gel. Yield 80% (947 mg); color-
less oil; Rf 0.10 (pentane/Et2O 95:5); IR (neat, cmꢁ1) 3335
(n O–H), 1460 (das CH3), 1359 (ds CH3), 1057 (n C–O),
1
CH3), 1365 (ds CH3); H NMR (CDCl3, ppm) d 0.96–1.01
(2d, J¼7.0 Hz, 6H, 10-Me2), 1.11 (s, 9H, 5-Me3), 1.52 (d,
J¼14.5 Hz, 1H, 4-Hb), 1.68 (d, J¼14.5 Hz, 1H, 4-Ha),

12218
P. Kraft, K. Popaj / Tetrahedron 62 (2006) 12211–12219
1.78 (sept, J¼7.0 Hz, 1H, 10-H), 1.89 (br s, 1H, OH), 2.48 (s,
1H, 1-H); 13C NMR (CDCl3, ppm) d 16.7/17.7 (2q, 10-Me2),
31.1 (q, 5-Me3), 31.2 (s, C-5), 40.1 (d, C-10), 50.0 (t, C-4),
73.7 (s, C-3), 74.3 (d, C-1), 86.3 (s, C-2); MS (EI, %) m/z
153 (2) [M+ꢁCH3], 125 (14) [M+ꢁC3H7], 97 (18)
[M+ꢁC5H11], 57 (100) [C4H+9], 43 (33) [C3H+7].
4.2.24. (3E,5Z)-5-Isopropyl-7,7-dimethylocta-3,5-dien-2-
one (29). As described for the preparation of 4, from 26
(1.32 g, 6.72 mmol), pyridinium chlorochromate (2.17 g,
10.0 mmol) and CeliteÒ (10.0 g) in CH2Cl2 (70 mL), the
title compound 29 was obtained after standard workup and
purification by chromatography on silica gel. Yield 71%
(928 mg); colorless odoriferous liquid; odor description:
floral-fruity, violet, raspberries, reminiscent to a-irone and
b-ionone; odor threshold: 12.5 ng/L air; Rf 0.11 (pentane/
Et2O 98:2); IR (neat, cmꢁ1) 1669 (n C]O conj), 1460 (das
CH3), 1360 (ds CH3), 1254 (nas C]C–C]O), 976 (d
4.2.21. (Z)-3-Isopropyl-5,5-dimethylhex-3-en-1-yne (18).
As described for the preparation of 15, from 14 (8.75 g,
52.0 mol) and KHSO4 (1.42 g, 10.4 mmol), the title com-
pound 18 was obtained after standard workup and purifica-
tion by chromatography on silica gel. Yield 50% (3.91 g);
colorless liquid; Rf 0.59 (pentane/Et2O 99:1); IR (neat,
cmꢁ1) 3311 (n C^C–H), 1461 (das CH3), 1362 (ds CH3),
927 (d C]C–H); 1H NMR (CDCl3, ppm) d 1.06 (d,
J¼7.0 Hz, 6H, 10-Me2), 1.18 (s, 9H, 5-Me3), 2.31 (sept,
J¼7.0 Hz, 1H, 10-H), 3.19 (s, 1H, 1-H), 5.74 (s, 1H, 4-H);
13C NMR (CDCl3, ppm) d 21.7 (q, 10-Me2), 30.0 (q,
5-Me3), 32.7 (s, C-5), 36.9 (d, C-10), 81.3 (s, C-2), 84.2 (d,
C-1), 126.0 (s, C-3), 146.6 (d, C-4); MS (EI, %) m/z 150
(30) [M+], 135 (24) [M+ꢁCH3], 107 (100) [M+ꢁC3H7], 33
(42) [M+ꢁC4H9], 57 (7) [C4H+9], 43 (23) [C3H+7].
1
C]C–H); H NMR (CDCl3, ppm) d 1.05 (d, J¼7.0 Hz,
6H, 10-Me2), 1.22 (s, 9H, 7-Me3), 2.31 (s, 3H, 1-H3), 2.60
(sept, J¼7.0 Hz, 1H, 10-H), 5.77 (s, 1H, 6-H), 6.16 (d,
J¼16.5 Hz, 1H, 3-H), 7.82 (d, J¼16.5 Hz, 1H, 4-H);
1H–1H NOESY (CDCl3) 7-Me3ꢂ4-H, 10-Me2ꢂ6-H; 13C
NMR (CDCl3, ppm) d 22.6 (d, 10-Me2), 27.2 (q, C-1), 30.0
(d, C-10), 32.0 (q, 7-Me3), 33.1 (s, C-7), 126.1 (d, C-6),
140.2 (s, C-5), 141.0 (d, C-3), 145.3 (d, C-4), 198.9 (s,
C-2); MS (EI, %) m/z 194 (2) [M+], 179 (4) [M+ꢁCH3],
151 (100) [M+ꢁC2H3O], 137 (19) [M+ꢁC4H9], 57 (12)
[C4H+9], 43 (74) [C3H7+]. Anal. Calcd for C13H22O: C,
80.35; H, 11.41. Found: C, 80.34; H, 11.41.
4.2.22. (Z)-5-Isopropyl-7,7-dimethyloct-5-en-3-yn-2-ol
(22). As described for the preparation of 19, from 18
(2.11 g, 14.0 mol), methyl magnesium chloride soln in
THF (3 M, 5.60 mL, 16.8 mmol) and acetaldehyde
(741 mg, 16.8 mmol) in THF (40 mL), the title compound
22 was obtained after standard workup and purification by
chromatography on silica gel. Yield 80% (2.18 g); colorless
oil; Rf 0.13 (pentane/Et2O 95:5); IR (neat, cmꢁ1) 3317 (n O–
H), 1460 (das CH3), 1361 (ds CH3), 1070 (n C–O), 875 (d
Acknowledgements
Thanks are due to Dr. Gerhard Brunner for the NMR exper-
iments, to Dr. Fabian Kuhn for the mass spectrometry data,
to Katarina Grman for the determination of odor thresh-
olds, and to Alain E. Alchenberger and Anne-Sylvie Selez-
neff for the olfactory evaluations presented here. Careful
proofreading of the manuscript by Dr. Markus Gautschi,
Dr. Samuel Derrer, and Tony McStea is also acknowledged
with gratitude.
1
C]C–H); H NMR (CDCl3, ppm) d 1.04 (d, J¼7.0 Hz,
6H, 10-Me2), 1.16 (s, 9H, 7-Me3), 1.50 (d, J¼6.5 Hz, 3H,
1-H3), 1.97 (br s, 1H, OH), 2.29 (sept, J¼7.0 Hz, 1H,
10-H), 4.70 (q, J¼6.5 Hz, 1H, 2-H), 5.66 (s, 1H, 6-H);
13C NMR (CDCl3, ppm) d 21.8 (q, 10-Me2), 24.2 (q, C-1),
30.1 (q, 5-Me3), 32.8 (s, C-7), 36.8 (d, C-10), 59.0 (d, C-2),
81.8 (s, C-3), 97.7 (s, C-4), 126.1 (s, C-5), 145.2 (d, C-6);
MS (EI, %) m/z 194 (25) [M+], 179 (4) [M+ꢁCH3], 151
(43) [M+ꢁC3H7], 137 (17) [M+ꢁC4H9], 57 (15) [C4H+9],
43 (100) [C3H+7].
References and notes
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(1.91 g, 9.83 mmol) and lithium aluminum hydride
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26 was obtained after standard workup and purification by
chromatography on silica gel. Yield 83% (1.61 g); colorless
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1
C]C–H); H NMR (CDCl3, ppm) d 1.03 (d, J¼7.0 Hz,
6H, 10-Me2), 1.13 (s, 9H, 7-Me3), 1.51 (d, J¼6.5 Hz, 3H,
1-H3), 1.71 (d, J¼1.0 Hz, 1H, OH), 2.55 (sept, J¼7.0 Hz,
1H, 10-H), 4.38 (quintd, J¼6.5 and 1.0 Hz, 1H, 2-H), 5.34
(s, 1H, 6-H); 5.66 (dd, J¼16.0 and 6.5 Hz, 1H, 3-H), 6.68
(d, J¼16.0 Hz, 1H, 4-H); 13C NMR (CDCl3, ppm) d 22.6/
22.7 (2q, 10-Me2), 23.4 (q, C-1), 31.0 (d, C-10), 31.8 (q,
7-Me3), 32.2 (s, C-7), 69.5 (d, C-2), 127.2 (d, C-6), 132.1
(d, C-3), 136.5 (d, C-4), 140.6 (s, C-5); MS (EI, %) m/z
196 (3) [M+], 178 (5) [M+ꢁH2O], 153 (6) [M+ꢁC3H7],
139 (3) [M+ꢁC4H9], 123 (21) [M+ꢁC4H9O], 57 (46)
[C4H+9], 43 (100) [C3H+7].

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