Synthesis of a spirocyclic seco structure of the principal vetiver odorant Khusimone

Article abstract of DOI:10.1002/ejoc.201201318

The three-dimensional structure of tricyclic compounds with a zero-bridge to one bridgehead atom is determined by the underlying spirocyclic framework. (-)-Khusimone (1), the principal odorant of vetiver oil (content up to 2 %), is such a tricyclic norsesquiterpene, and dissection of the 7,8-bond between the methylene and the gem-dimethyl unit of 1 results in a spirocycle extending over an almost identical molecular volume and shape. Given that the vetiver rule postulates that one α-branched carbonyl osmophore in a certain spatial distance to a bulky moiety is responsible for the odor of vetiver, a 7,8-seco structure of 1 could prove or disprove these structural requirements. Therefore, (4R*,5R*)-7-isopropyl-4-vinylspiro[4.4]nonan-1-one [(4R*,5R*)-2] was synthesized in a 10-step synthetic sequence commencing with Steglich esterification of allyl alcohol (15) and isovaleric acid (14). Ireland-Claisen rearrangement of the formed allyl isovalerate (16) with subsequent lithium aluminum hydride reduction of resulting γ,δ-unsaturated acid 18, Appel bromination of corresponding alcohol 19, and ozonolysis provided 4-bromo-3-isopropylbutanal (23) in 19 % overall yield as a building block for the projected spiroannulation reactions. Although attempts on cyclopentanone (7) failed, cyclopent-2-en-1-one, via its TMS-trapped lithium 3-vinylcyclopent-1-enolate 12, turned out to be a successful starting material. Evans' variant of the Mukaiyama aldol reaction with 1-trimethylsiloxy-3-vinylcyclopent-1-ene (12) in the presence of BF ₃·OEt₂, followed by palladium-catalyzed conjugate tin hydride reduction of resulting enone 28 provided 2-(4′-bromo-3′- isopropylbutyl)-3-vinylcyclopentanone (29) in 50 % overall yield as the anlation precursor. LDA-mediated 5-exo-tet cyclization of 29 concluded the synthesis of the racemic 7,8-seco-/6-epi-7,8-secokhusimone mixture (4R*,5R*)-2, which possessed a floral, rosy, green, geranium-like odor with a threshold of 42.0 ng L^-1 air, which is 10 times less intense than that of (-)-khusimone (1). Most importantly, seco structure (4R*,5R*)-2 did not display any woody nor any vetiver character, which proves the postulated vetiver rule wrong. Dissecting the bond between the methylene and the gem-dimethyl unit of khusimone leads to a spirocycle of almost identical shape, which was synthesized by 1,4-conjugate addition of a vinyl Gilman reagent, Mukaiyama aldol condensation of a bromo aldehyde prepared by Ireland-Claisen rearrangement of allyl isovalerate, and subsequent cyclization. Copyright

Full text of DOI:10.1002/ejoc.201201318

FULL PAPER
DOI: 10.1002/ejoc.201201318
Synthesis of a Spirocyclic Seco Structure of the
Principal Vetiver Odorant Khusimone
Philip Kraft*[a] and Natacha Denizot[a][‡]
Dedicated to Professor Scott E. Denmark on the occasion of his 60th birthday
Keywords: Fragrances / Natural products / Spiro compounds / Structure–activity relationships
The three-dimensional structure of tricyclic compounds with
a zero-bridge to one bridgehead atom is determined by the
underlying spirocyclic framework. (–)-Khusimone (1), the
principal odorant of vetiver oil (content up to 2%), is such
a tricyclic norsesquiterpene, and dissection of the 7,8-bond
between the methylene and the gem-dimethyl unit of 1 re-
sults in a spirocycle extending over an almost identical mo-
lecular volume and shape. Given that the “vetiver rule” pos-
tulates that one α-branched carbonyl osmophore in a certain
spatial distance to a bulky moiety is responsible for the odor
of vetiver, a 7,8-seco structure of 1 could prove or disprove
these structural requirements. Therefore, (4R*,5R*)-7-iso-
propyl-4-vinylspiro[4.4]nonan-1-one [(4R*,5R*)-2] was syn-
thesized in a 10-step synthetic sequence commencing with
Steglich esterification of allyl alcohol (15) and isovaleric acid
(14). Ireland–Claisen rearrangement of the formed allyl iso-
4-bromo-3-isopropylbutanal (23) in 19% overall yield as a
building block for the projected spiroannulation reactions.
Although attempts on cyclopentanone (7) failed, cyclopent-
2-en-1-one, via its TMS-trapped lithium 3-vinylcyclopent-1-
enolate 12, turned out to be a successful starting material.
Evans’ variant of the Mukaiyama aldol reaction with 1-tri-
methylsiloxy-3-vinylcyclopent-1-ene (12) in the presence of
BF3·OEt2, followed by palladium-catalyzed conjugate tin hy-
dride reduction of resulting enone 28 provided 2-(4Ј-bromo-
3Ј-isopropylbutyl)-3-vinylcyclopentanone (29) in 50% overall
yield as the anlation precursor. LDA-mediated 5-exo-tet cy-
clization of 29 concluded the synthesis of the racemic 7,8-
seco-/6-epi-7,8-secokhusimone mixture (4R*,5R*)-2, which
possessed a floral, rosy, green, geranium-like odor with a
threshold of 42.0 ngL–1 air, which is 10 times less intense
than that of (–)-khusimone (1). Most importantly, seco struc-
valerate (16) with subsequent lithium aluminum hydride re- ture (4R*,5R*)-2 did not display any woody nor any vetiver
duction of resulting γ,δ-unsaturated acid 18, Appel bromin-
ation of corresponding alcohol 19, and ozonolysis provided
character, which proves the postulated vetiver rule wrong.
“Me, my thoughts are flower strewn
Ocean storm, bayberry moon
I have got to leave to find my way [...]
I have got to find the river,
prises perfumes such as ‘Aromatics Elixir’ (Clinique, 1972),
‘Polo’ (Ralph Lauren, 1978), ‘Chance’ (Chanel, 2002), and
‘2 Man’ (Comme des Garçons, 2004), is based on the con-
trast between a fresh citrus accord and a mossy-woody
foundation.[2] Whereas patchouli oil is more typical for the
woody part of a Chypre fragrance, vetiver often contributes
markedly to their characteristic dry base note. The pre-
ferred citrus component of Chypre fragrances is bergamot,
and so we find bergamot and vetiver in most of the many
fragrances that bear the ‘vetiver’ designation in their
name.[3] The harmony of ‘bergamot and vetiver’, however,
is also employed in totally unrelated olfactory families, such
as in floral-aldehydic fragrances around ‘Chanel N°5’.[4]
Roughly about one third of all fragrances on the market
feature the ‘bergamot–vetiver’ complex. Although the im-
portant odor vectors of bergamot oil, linalyl acetate (22–
36%),[5] linalool (3–16%),[5] and limonene (30–45%)[5] are
today inexpensive commodities, no synthetic vetiver odor-
ant is commercially available. There is not even a consensus
about which constituents contribute to its distinct and char-
acteristic suave and sweet woody-earthy odor with green,
Bergamot and vetiver
Run through my head and fall away”
R.E.M., ‘Find The River’[1]
Introduction
The concept of the Chypre fragrance family, which origi-
nated from the classical ‘Chypre’ of Coty (1917) and com-
[a] Givaudan Schweiz AG, Fragrance Research,
Überlandstrasse 138, 8600 Dübendorf, Switzerland
Fax: +41-44-824-29-26
E-mail: philip.kraft@givaudan.com
Homepage: www.givaudan.com
[‡] Master’s thesis of Natacha Denizot, Université Joseph Fourier,
Grenoble, France, carried out during her 8-month stay within
the Givaudan Fragrance Research Center, Switzerland.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201318.
Eur. J. Org. Chem. 2013, 49–58
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P. Kraft, N. Denizot
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grapefruit, and rhubarb-type facets.[6] The norsesquiterpene zizaanes, this scission should preserve the overall molecular
(–)-khusimone [12-norziza-6(13)-en-2-one, 1, Figure 1], shape, while simplifying its synthetic access.
which constitutes only up to 2% of the essential oil,[7] is the
Our retrosynthetic analysis of target structure 2 is
only component that is agreed to possess a typical vetiver delineated in Scheme 1. A concluding 1,4-conjugate ad-
odor and, thus, is the only concrete lead structure.[6] Yet, dition of a vinyl Gilman reagent to enone 6 would proceed
by synthesis of novel spiro[4.5]decan-2-ones, together with via an enolate intermediate, which could enable the con-
the vetiver constituents khusimone (1), eremophiladienal, comitant closure of the spirocyclic ring in the presence of a
and 1,7-cyclogerma-1(10),4-dienal,[8] a vetiver rule could be suitable leaving group X (Scheme 1, route A). Enones 6
postulated,[2,3] according to which a vetiver odorant should could be prepared by simple aldol condensation of cyclo-
bear one α-branched carbonyl osmophore in a distance of pentanone (7) with suitably substituted aldehyde 8 with
5.0Ϯ0.5 Å to a bulky group, while possessing an overall subsequent isomerization[13] of the resulting exocyclic
dimension of 13–16 carbon atoms (Figure 1).
double bond into the endocyclic position. Pd-catalyzed
Negishi cross-coupling[14] of 2-iodocyclopen-2-en-1-one
(9)[15] with a suitably protected vinylic, allylic, or homoall-
ylic organozinc reagent of type 10 (PG = protecting group)
would avoid such an isomerization but would necessitate
a very tricky and selective hydrogenation of the side-chain
double bond.
Figure 1. The vetiver rule applied to the design of spirocyclic core
structure 2 from the natural lead (–)-khusimone (1) and related
spirocyclic odorants 3–5 with patchouli and woody-ambery odor
characteristics.
Any tricyclic skeleton with a zero-bridge to one bridge-
head atom by definition contains a spirocyclic ring sys-
tem.[2] It is this spirocyclic frame, highlighted in the struc-
ture of (–)-khusimone (1) in Figure 1, that determines the
molecular shape of such tricyclic compounds. The woody
odorants of nature are almost exclusively tricyclic sesquiter-
penoids, and it is therefore not surprising that many syn-
thetic spirocycles possess potent woody odors. Spirocyclic
ketol 3[9] and its ring-inverted methyl carbinol derivative
Scheme 1. Retrosynthetic analysis of target structure 2.
Inspired by Noyori’s three-component prostaglandin
synthesis,[17] introduction of an auxiliary hydroxy function
into target structure 2 would, however, allow the directed
aldol reaction of protected hydroxy aldehyde 13 with
trapped enolate 12 from the conjugate addition of a vinyl
Gilman reagent to cyclopentenone. Albeit less elegant, this
seems synthetically more sound, as there is a very good
chance that the desired 5-exo-tet cyclization would energeti-
cally win over the 7-exo-tet alternative, after reductive re-
moval of the hydroxy function of 11 and exchange of the
protecting group for a leaving group (Scheme 1, route B).
These two additional synthetic operations, however, seem a
bit cumbersome at first sight.
4
[10] for instance are closely reminiscent in odor to the tricy-
clic sesquiterpene (–)-patchoulol, the odorous principal of
patchouli oil. Spirocyclic ketol 3 possesses an odor thresh-
old that is more than 30 times lower than that of (–)-patch-
oulol.[3] In the family of woody-ambery odorants, para-
linked acetyl-1-oxaspiro[4.5]decane 5 resembles Iso E Super
closely in odor,[11] but it is much more water soluble and
bioavailable.
Given that the synthesis of zizaanes poses some synthetic
challenges and is industrially unfeasible,[12] and because
(–)-khusimone (1), with an odor threshold of 4.7 ngL–1 air,
is not very intense, similar spirocyclic structures might exhi-
bit improved olfactory properties. Therefore, it seemed
highly interesting to challenge the vetiver rule in the design
of a new spirocyclic odorant devised by dissecting the bond
between the methylene and the gem-dimethyl unit of 1 (Fig-
Results and Discussion
Both routes A and B require 3-substituted 1,4-bifunc-
ure 1). As the spiro[4.4]nonyl core conformationally con- tional building blocks 8 and 13, which could be accessible
strains the tricyclo[6.2.1.01,5]undecyl framework of the by oxidative degradation of γ,δ-unsaturated carbonyl com-
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Spirocyclic Seco Structure of a Vetiver Odorant
pounds, that is, Claisen rearrangement products. The Ire-
Building block 8 (X = Br) for the aldol reaction with
land–Claisen modification is particularly appealing and led cyclopentanone (7) was prepared by standard Appel
to allyl isovalerate (16) as an easily accessible starting mate- bromination[20] of alk-4-enol 19 with tetrabromomethane
rial. As illustrated in Scheme 2, allyl ester 16 was prepared and triphenylphosphane in dichloromethane at room tem-
by Steglich esterification[18] of 3-methylbutanoic acid (iso- perature for 1 d. After chromatographic purification, re-
valeric acid, 14) and prop-2-en-1-ol (allyl alcohol, 15) in sulting 5-bromo-4-isopropylpent-1-ene (22) was isolated in
anhydrous diethyl ether. After silica gel flash chromatog- 92% yield. Ozonolysis of 22 with reductive workup by em-
raphy, 16, possessing a fruity-green odor reminiscent of ploying thiourea then provided γ-bromo aldehyde 23 in
pineapples, was isolated in 94% yield. For the subsequent moderate 31% yield.
Ireland–Claisen rearrangement, we followed a procedure
Following the supposedly shorter retrosynthetic route A,
previously used in the synthesis of a constitutional nerol siloxy aldehyde 21 was slowly added with the use of a sy-
isomer.[19] Allyl ester 16 was deprotonated with lithium ringe pump to a solution of cyclopentanone (7) and potas-
cyclohexylisopropylamine (LICA) in THF at –78 °C, the sium hydroxide in ethanol, in analogy to a procedure by
corresponding lithium enolate was trapped with trimethyl- Sarpong and co-workers.[21] After standard workup and
silyl chloride, and the resulting silyl ester enolate 17 was chromatographic purification, corresponding aldol conden-
stirred at 0 °C for 45 min, and then overnight at room tem- sation product 24 was obtained in 47% yield. The acid-
perature. Mild hydrolysis afforded 2-isopropylpent-4-enoic catalyzed kinetic isomerization of an exocyclic cyclopen-
acid (18) in 72% yield after chromatographic isolation. tenone double bond into the endocyclic position is the key
Standard lithium aluminum hydride (LAH) reduction of step in the commercial synthesis of Hedione,[3] that is, the
γ,δ-unsaturated acid 18 in ether provided corresponding isomerization of 2-pentylidenecyclopentanone into 2-pent-
alcohol 19 in 91% yield, without any need for further puri- ylcyclopent-2-enone.[13] Treatment of 24 with hydrochloric
fication.
acid in butanol, however, led to 4-isopropyltetrahydrofuran-
2-yl system 25 by deprotection and cyclization. The same
result was obtained when rhodium trichloride in ethanol[22]
was employed in the isomerization reaction of 3-isopropyl-
butylidene cyclopentanone 24, although that reaction was
expected to proceed under much milder conditions. Instead
of varying the protecting group of aldehyde building block
21, we believed bromo aldehyde 23 could be employed di-
rectly in the aldol condensation reaction with 7 by em-
ploying 5% aqueous NaOH as the base.[16] Yet, not so sur-
prisingly, the corresponding bromo-substituted aldol ad-
duct reacted further, and following elimination of hydrogen
bromide, cyclopropylmethylene derivative 26 was formed.
Therefore, we switched to the alternative retrosynthetic
strategy B, starting from cyclopent-2-en-1-one (27), as de-
lineated in Scheme 4. Conjugate 1,4-addition of the vinyl
Gilman reagent, prepared in situ by transmetalation of the
vinyl Grignard reagent with tert-butyllithium and copper
iodide to enone 27, provided the lithium 3-vinylcyclopent-
1-enolate, which was trapped by trimethylsilyl chloride ac-
cording to a procedure of Snider and Yang[23] to afford 12
in 60% yield after Kugelrohr distillation. The 3-vinylcy-
clopent-1-enolate was released by reaction of 12 with butyl-
lithium. Subsequent reaction of this enolate with aldehyde
21 in the presence of zinc(II) chloride led, however, with
elimination of the hydroxy function, to a complex mixture
of exo/endocyclic and unconjugated double bond isomers.
To prevent the elimination of the hydroxy function from
the aldol adduct, the reaction was then conducted under
Mukaiyama conditions.[24] Trapped 1-trimethylsiloxy-3-
Scheme 2. Synthesis of building blocks 21 and 23 by Ireland–
Claisen rearrangement of allyl isovalerate (16) to 2-isopropylpent-
4-enoic acid (18) and subsequent functionalization of correspond-
ing alcohol 19.
En route to building block 13 (PG = TBS), the hydroxy vinylcyclopent-1-ene (12) was thus added to a solution of
function of 19 was then protected as a tert-butyldimethyl- aldehyde 21 in dichloromethane in the presence of titani-
silyl (TBS) ether by reaction with TBSCl in DMF at room um(IV) chloride at –78 °C. Although the Mukaiyama aldol
temperature, and 19 was isolated by flash chromatography reaction itself went smoothly, the formation of hydrochloric
in 97% yield. Ozonolysis of 19 with reductive workup by acid from titanium(IV) chloride upon quenching, even
employing thiourea then afforded TBS-protected γ-hydroxy when employing aqueous buffer systems, led to deprotec-
aldehyde 21 in 68% yield.
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P. Kraft, N. Denizot
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tion and cyclization to form the diastereomeric 3-vinyl-sub- 29. This reduction proceeds through palladium-catalyzed
stituted analogs of 25 (Scheme 3).
hydrostannylation in the presence of an activating Lewis
acid, in this case, zinc(II) chloride. The stereochemical out-
come of this reduction[34] is determined by the tendency of
2,3-disubstituted cyclopentene-derived enols to afford the
thermodynamically favored trans product following proton-
ation.[35] Thus, conjugate palladium-catalyzed tin hydride
reduction of enone 28 in the presence of zinc(II) chloride
after 2 h afforded 2,3-trans-configured cyclopentanone 29
in 82% yield after chromatography on potassium carbon-
ate/silica (10% w/w) to remove all organotin impurities to
levels below 15 ppm.[36] Attempts to improve the yield by
forcing the reaction conditions, for instance by increasing
the amount of [Pd(PPh3)4], led to reduction of the vinyl
moiety as well, the resulting product of which proved diffi-
cult to separate by chromatography.
Scheme 3. Synthetic attempts towards target structure 2 according
to retrosynthetic analysis route A.
With 3-vinyl-substituted bromo ketone 29 in hand, the
stage was now set for the final cyclization of lithium enolate
If this elimination of the hydroxy function from the aldol 30 to target structure 2. As the C-2 stereocenter of 29 was
adduct could not be restrained, and if the aldol hydroxy flattened in enolate intermediate 30, the relative trans
group subsequently could not be removed reductively, for stereochemistry of 29 was irrelevant. However, as indicated
instance through Barton–McCombie deoxygenation[25,26] of in suggested transition state 30 in Scheme 4, we hoped that
the corresponding O-phenoxythiocarbonyl derivative, a 2- the vinyl moiety would sterically shield the Si face, which
tetrahydrofuran-2Ј-ylcyclopentanone derivative threatened would thus lead to anti selectivity of the nucleophilic substi-
to be the dead end of route B as well. Therefore, a Mukai- tution on the Re face of the cyclopentenolate ring. Indeed,
yama-type aldol reaction with a Lewis acid that would not treatment of bromo ketone 29 with freshly prepared lithium
form a strong Brønsted acid upon hydrolysis was in de- diisopropylamine (LDA) at –78 °C in THF/DMPU (5:1)
mand, and the BF3·OEt2-catalyzed variant of Evans nicely afforded only one single pair of diastereoisomers in
et al.[27] seemed to be the method of choice; yet, even these 56% yield, the like-configured (4R*,5R*)-7-isopropyl-4-
conditions led to the aldol condensation product rather vinylspiro[4.4]nonan-1-one [(4R*,5R*)-2], isomeric only in
than the expected β-hydroxy ketone.
the configuration of the 7-isopropyl group. The stereochem-
However, it seemed possible that the mild reaction condi- istry of the (4R*,5R*,7R*)-diastereomer of 2 was tenta-
tions of the Evans’ variant of the Mukaiyama aldol reac- tively assigned by nuclear Overhauser effects between 4-Hax
tion would tolerate a bromine substituent, and thus, build- and 6-Hb, as well as between 6-Hb and 2ЈЈ-H and between
ing block 23 was directly subjected to an aldol reaction with 6-Ha and 1ЈЈ-Me in the 1H–1H NOESY spectrum. The rela-
1-trimethylsiloxy-3-vinylcyclopent-1-ene (12). Indeed, drop- tive (4R*,5R*) configuration was unequivocally proven by
wise addition of BF3·OEt2 to a solution of 12 and 23 in
freshly distilled dichloromethane furnished (4Ј-bromo-3Ј-
isopropylbutylidene)-3-vinylcyclopentanone (28) as a dia-
stereomeric mixture in 61% yield after chromatographic
purification. As was deduced from the strong nuclear
Overhauser effect between 3-H and 2Ј-H in the 1H–1H
NOESY spectrum, both diastereoisomers were un-
equivocally [2(1Ј)E]-configured.
The problem of the reductive removal of the aldol hy-
droxy group of 11 thus shifted to that of the selective re-
duction of the (E)-configured conjugated double bond of
28. For this synthetic operation, a number of practical
methods are available, for instance, Stryker’s method[28]
with copper(I) hydride cluster [(PPh3)CuH]6, which we had
used earlier in the synthesis of linear musks,[29] or the cata-
cholborane procedure of Evans and Fu,[30] which we had
recently applied in the synthesis of orris odorants.[31] As
neither Stryker’s method[28] nor catacholborane[30] fur-
nished any reduction product 29, and because there was
precedence on a related system,[32] the palladium-catalyzed
Scheme 4. Concluding steps in the synthesis of (4R*,5R*)-config-
ured target structure 2 from cyclopent-2-en-1-one (27) by retrosyn-
tin hydride reduction of Keinan and Gleize[33] was selected
for the conjugate reduction of enone 28 to bromo ketone thetic route B.
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Spirocyclic Seco Structure of a Vetiver Odorant
the distinct and characteristic NOE cross-peak between 4- ral stationary GC phases were also employed, but only the
Hax and 6-Hb in both diastereoisomers. Together with enantiomers of (4R*,5R*)-2 were separable, whereas the 7-
chemical shift correlations and mechanistic considerations, diastereoisomers co-eluted.
the other diastereomer was tentatively assigned
a
The relative (4R*,5R*) stereochemistry, however, nicely
(4R*,5R*,7S*) configuration. To our great disappointment, matched that of natural (–)-khusimone (1), as can also be
the diastereoisomers of (4R*,5R*)-2 proved inseparable by seen in the superposition analyses of compounds 1 and
all chromatographic means, including preparative GC. Chi- (4R,5R,7R)-2 in Figure 2 with the MOE 2011.10 soft-
ware.[37] Thus, we successfully concluded the synthesis of
our target molecule in only 10 steps from isovaleric acid
(14) and allyl alcohol (15). Although we could not separate
the C-7 diastereomers, the correct relative (4R*,5R*) stereo-
chemistry still allows meaningful insights, especially if syn-
thesized racemic 7,8-seco-/6-epi-7,8-secokhusimone mixture
(4R*,5R*)-2 displays no woody-vetiver character, which is
the case.
Olfactory Properties, Superposition Analyses, and
Conclusions
Whereas (–)-khusimone (1) with an odor threshold of
4.7 ngL–1 air indeed possesses a typical woody, vetiver-type
note with green-rooty, woody-ambery facets accompanied
by a slight grapefruit nuance, β-/epi-β-vetivone (31) with
a spiro[4.5]dec-6-en-8-one skeleton is clearly reminiscent of
grapefruit and rhubarb, with a vegetal, metallic connota-
tion but without much woody character. β-/epi-β-Vetivone
(31) recalls the citrusy aspects of decatone [6-isopropyloc-
tahydronaphthalen-2(1H)-one] and possesses an odor
threshold of 5.0 ngL–1 air, so it is comparable in odor
strength to (–)-khusimone (1). β-Vetivone makes up 4–10%
of vetiver oils, but contributes to the less-desired grapefruit
aspects of the essential oil rather than to its elegant woody
note.
The synthesized racemic 7,8-seco-/6-epi-7,8-secokhusi-
mone mixture (4R*,5R*)-2 has an odor threshold of
42.0 ngL–1 air, which is almost 10 times less intense than
that of both (–)-khusimone (1) and β-/epi-β-vetivone (31),
and to our great disappointment shares neither of their
odor characteristics. Instead it has a floral, rosy, green, ge-
ranium-type odor in the direction of Petalia [32, 2-cyclohex-
ylidene-2-(o-tolyl)acetonitrile] and Magnolan (2,4-dimethyl-
4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine) with some
slightly fatty-metallic facets (Figure 2). So it is devoid of
any woody-vetiver character, and it does not smell like any-
thing in a woody direction. GC-Olfactometry analysis with
a chiral Hydrodex β-6TBDM [heptakis(2,3-di-O-methyl-6-
O-tert-butyldimethylsilyl)-β-cyclodextrin] phase indicated
compound (4R*,5R*)-2 (gold), β-/epi-β-vetivone (31), and Petalia that the odor of the (4R*,5R*)-2 mixture was mainly a re-
Figure 2. Olfactory properties of (–)-khusimone (1, black), target
(32, silver) in comparison, as well as superposition analyses of nat-
sult of the more intense first eluting diastereomeric peak of
ural template 1 on (4R,5R,7R)-2 in biflexible alignment mode with
enantiomers with a floral, rosy, green, powdery odor,
CCG’s Molecular Operating Environment MOE2011.10,[37] within
whereas the second diastereomeric pair of enantiomers was
weaker, floral-herbaceous, slightly celery-like, and some-
what reminiscent of cis-jasmone.
a conformational space of 15 kcalmol–1. E potential energy above
the global minimum-energy conformer (MMFF94x); Estrain strain
energy component; F feature overlap describing the configurational
similarity as negative value of the probability-density overlap func-
tion, with lower values indicating greater similarity; score grand
alignment score of the probability-density overlap, and the average
strain energy of the molecules in alignment, with lower values indi-
cating better alignments.
In the generation of computational structure–activity
models, it is generally assumed that a receptor can induce
a fit of an agonist within a conformational space of
20 kcalmol–1.[38] Restricting the conformational space even
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P. Kraft, N. Denizot
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more conservatively to about 15 kcalmol–1 above the global enantiomers of 19 or related alk-4-enols for the construc-
energy minima, Figure 2 details the five best superposition tion of further analogs of our target compound 2.
alignments for 1 and (4R,5R,7R)-2, as calculated with the
Besides the synthesis of new vetiver odorants, the pre-
MOE 2011.10 software package.[37] Unsurprisingly, (–)- sented sequence will also be of general synthetic value for
khusimone (1) remains rather rigid in these biflexible align- the spiroannulation of cyclic and open-chain ketones.
ments, and a maximum of 2.18 kcalmol–1 is induced in the
superposition scored at –50.8, all of which is in the form of
strain energy. It thus seems to be a valid template for the
receptor binding site of vetiver odorants.
Experimental Section
General Methods: IR spectra were recorded with
a Bruker
Seco structure (4R,5R,7R)-2 is far more flexible and pop-
ulates, for instance, a conformer that is 14.5 kcalmol–1
above the global energy minimum in the superposition
scored at –50.8. Generally, only 70–80% of the total energy
of the delineated conformers of 2 is transformed into strain
energy, and the vinyl moiety avoids some steric interactions
by rotating out. The bulky gem-dimethyl group of (–)-khusi-
mone (1) and the (7R)-isopropyl moiety of 2, however, gen-
erally overlap well, despite the puckering of the spirocyclic
cyclopentyl ring, and because both carbonyl osmophores
are α-branched, the vetiver rule should have been served
adequately.
The good superposition of 1 on 2 depicted in Figure 2 is,
of course, only valid for the (4R,5R,7R)-enantiomer of 2,
so the floral rosy-green, geranium odor of (4R*,5R*)-2
could very well originate mainly from another isomer. Be-
cause the correct (4R,5R,7R)-enantiomer of 2 is also con-
tained in the mixture, and no vetiver character was ob-
served at all, these results still disprove the vetiver rule,[2] at
least in its genuine wording. This is also in agreement with
the rather high threshold of (4R*,5R*)-2, which indicates a
less specific fit to the olfactory receptor(s).
In the superposition analyses in Figure 2, the 4-vinyl
moiety is somewhat displaced from its original position in
(–)-khusimone (1). It is therefore possible that the precise
relative orientation of this double bond as constrained by
the tricyclic skeleton of 1 is of utmost importance for the
characteristic odor of vetiver. In any case, the structural
requirements are certainly more complex than suggested by
the vetiver rule in Figure 1,[2] and further derivatives of
(–)-1 and probably also (4R*,5R*)-2 are required to gain
the necessary insight into the structural requirements for a
targeted design of new vetiver odorants.
The presented 10-step synthetic sequence to (4R*,5R*)-2
consisting of Steglich esterification of allyl alcohol (15) and
isovaleric acid (14), Ireland–Claisen rearrangement of
formed allyl isovalerate (16), LAH reduction of the re-
sulting γ,δ-unsaturated acid, Appel bromination, ozonoly-
sis, Evans’ variant of the Mukaiyama aldol reaction with
trapped 1-trimethylsiloxy-3-vinylcyclopent-1-ene (12), pal-
ladium-catalyzed conjugate tin hydride reduction of inter-
mediate enone 28, and LDA-mediated 5-exo-tet cyclization
to the [4.4]-spirocyclic target compound allows further
structural modifications of the target structure rather easily.
A C-7 stereocenter could be introduced into these spiro-
[4.4]nonan-1-ones by asymmetric allylation of chiral imide
enolates according to Evans et al.,[39] which after LAH re-
duction of the resulting oxazolidinones should afford the
VECTOR 22/Harrick SplitPea micro ATR, Si. NMR spectra were
recorded with a Bruker Avance DPX-400, Bruker Avance 500
(TCI), or Bruker Avance 600 spectrometer with tetramethylsilane
as an internal standard (δ = 0 ppm). MS was performed with an
HP Chemstation 6890 GC/5973 Mass Sensitive Detector. HRMS
was performed with a Finnigan MAT 95 (EI: 70 eV). Flash
chromatography was performed with Merck Kieselgel 60 (40–
63 μm). TLC was carried out with Merck Kieselgel 60 F254 (particle
size 5–20 μm, layer thickness 250 μm on glass, 5 cmϫ10 cm), and
phosphomolybdic acid spray and plunge solution (Fluka 02553)
was used for visualization. Unless otherwise stated, all reactions
were performed under an atmosphere of N2 with reagents and sol-
vents (puriss. or purum) from SAFC, which were used without fur-
ther purification.
The odor thresholds were determined by GC-Olfactometry: Dif-
ferent dilutions of the sample substance were injected into a gas
chromatograph in descending order of concentration until the pan-
elist failed to detect the respective substance at the sniffing port.
The panelist smelled in blind and pressed a button on perceiving
an odor. If the recorded time matched the retention time, the sam-
ple was further diluted. The last concentration detected at the cor-
rect retention time was the individual odor threshold. The reported
threshold values are the geometrical mean values of the individual
odor thresholds of the different panelists.
Allyl-3-methyl Butanoate (16): Isovaleric acid (14; 10.2 g,
100 mmol), prop-2-en-1-ol (15; 5.81 g, 100 mmol), and 4-dimethyl-
aminopyridine (DMAP; 1.22 g, 10.0 mmol) were dissolved in Et2O
(100 mL). At 0 °C, a solution of 1,3-dicyclohexylcarbodiimide
(DCC, 22.7 g, 110 mmol) in Et2O (50.0 mL) was added, and the
mixture was stirred at room temperature overnight prior to fil-
tration of the insoluble material and concentration of the filtrate
under reduced pressure. The resulting residue was purified by silica
gel flash chromatography (FC; pentane/Et2O = 96:4, Rf = 0.4) to
provide 16 (13.3 g, 94%). IR (neat): ν = 3087 (w, ν=CH ), 1735 (s,
˜
2
νC=O), 1649 (w, νC=C), 1170 (s, νCO–O), 991 (δCH=CH2) cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.96 (d, J = 7.0 Hz, 6 H, 3-Me2),
2.12 (ddq, J = 13.5, 8.0, 7.0 Hz, 1 H, 3-H), 2.22 (d, J = 7.0 Hz, 2
H, 2-H2), 4.57 (dt, J = 5.5, 1.0 Hz, 2 H, 1Ј-H2), 5.23 (dq, J = 10.5,
1.0 Hz, 1 H, 3Ј-HE), 5.31 (dq, J = 17.5, 1.0 Hz, 1 H, 3Ј-HZ), 5.92
(ddt, J = 17.5, 10.5, 5.5 Hz, 1 H, 2Ј-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 22.3 (2 q, 3-Me2), 25.7 (d, C-3), 43.3 (t, C-2), 64.8 (t,
C-1Ј), 118.0 (t, C-3Ј), 132.3 (d, C-2Ј), 172.7 (s, C-1) ppm. MS (EI,
70 eV): m/z (%) = 142 (1) [M]+, 100 (11) [M – C3H6]+, 85 (70) [M –
C4H9]+, 57 (100) [C4H9]+, 41 (75) [C3H5]+, 29 (11) [CHO]+.
2-Isopropylpent-4-enoic Acid (18): At 0 °C under a N2 atmosphere,
N-isopropylcyclohexylamine (15.4 mL, 92.0 mmol) was added to a
stirred solution of nBuLi (1.6 m in hexane, 57.5 mL, 92.0 mmol).
The solvent was evaporated at room temperature with a vacuum
line, and the yellowish residue was taken up in anhydrous THF
(120 mL). At –78 °C,
a solution of 1,3-dimethyltetrahydro-
pyrimidin-2(1H)-one (DMPU; 5.50 mL, 46.2 mmol) and allyl-3-
methyl butanoate (16, 10.7 g, 75.2 mmol) in THF (30 mL) was
54
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 49–58

Spirocyclic Seco Structure of a Vetiver Odorant
added dropwise with stirring over a period of 30 min, prior to the
dropwise addition of Me3SiCl (22.0 mL, 175 mmol) at the same
temperature. After stirring at 0 °C for 45 min, and then overnight
at room temperature, the reaction was carefully quenched at –20 °C
by slow addition of acetic acid (15.0 mL, 0.26 mol), followed by
the dropwise addition of water (85 mL). The aqueous layer was
extracted with Et2O, and the combined organic extracts were
washed with water and brine, dried (Na2SO4), and concentrated
under reduced pressure. Chromatography of the resulting residue
(pentane/Et2O = 19:1, Rf = 0.20) afforded 18 (7.70 g, 72%). IR
δCH2, CH3), 1388/1362 (m, δCH3), 1252 [m, νC(CH3)3], 1083 (s,
νSi–O–C), 833 (s, νSi–CH3), 772 (s, δSi–CH3) cm–1. 1H NMR
(400 MHz, CDCl3): δ = 0.03 (s, 6 H, SiMe2), 0.86 (s, 9 H, CMe3),
0.89/0.90 (2 d, J = 7.0 Hz, 3 H, 1Ј-Me, 3Ј-Me), 1.33 (dddt, J = 8.0,
5.0, 5.0, 5.0 Hz, 1 H, 2-H), 1.78 (sept.d, J = 7.0, 5.0 Hz, 1 H, 2Ј-
H), 2.00 (dddt, J = 14.5, 8.0, 7.0, 1.5 Hz, 1 H, 3-Hb), 2.07 (dddt, J
= 14.5, 7.0, 5.0, 1.5 Hz, 1 H, 3-Ha), 3.50 (dt, J = 10.0, 5.0 Hz, 2
H, 1-H2), 4.93 (ddt, J = 10.0, 2.5, 1.5 Hz, 1 H, 5-HE), 4.97 (ddt, J
= 17.0, 2.5, 1.5 Hz, 1 H, 5-Hz), 5.75 (dddd, J = 17.0, 10.0, 7.0,
7.0 Hz, 1 H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ = –5.5 (q,
SiMe2), 18.2 (s, CMe3), 19.4 (2 q, C-1Ј, C-3Ј), 25.9 (q, CMe3), 27.6
(neat): ν = 2963 (br. m, νCOO–H), 1702 (s, νC=O), 1643 (w,
˜
νC=C), 1468/1439 (w, δCH2, CH3), 1390/1372 (w, δCH3), 914 (s, (d, C-2Ј), 32.4 (t, C-3), 46.3 (d, C-2), 62.9 (t, C-1), 115.3 (t, C-5),
δCH=CH2) cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.97/0.99 (2 d, 138.2 (d, C-4) ppm. MS (EI, 70 eV): m/z (%) = 242 (1) [M]+, 185
J = 7.0 Hz, 6 H, 1Ј-Me, 3Ј-Me), 1.92 (oct., J = 7.0 Hz, 1 H, 2Ј-H), (27) [M – C4H9]+, 155 (13) [M – C6H15]+, 129 (29) [C8H17O]+, 101
2.24 (ddd, J = 10.0, 7.0, 4.5 Hz, 1 H, 2-H), 2.31 (ddddt, J = 14.0,
10.0, 7.0, 4.5, 1.0 Hz, 1 H, 3-Hb), 2.32 (ddddt, J = 14.0, 10.0, 7.0,
4.5, 1.0 Hz, 1 H, 3-Ha) 5.02 (dquint., J = 10.0, 1.0 Hz, 1 H, 5-HE),
5.08 (dq, J = 17.0, 1.0 Hz, 1 H, 5-Hz), 5.78 (ddt, J = 17.0, 10.0,
7.0 Hz, 1 H, 4-H), 11.65 (s, 1 H, OH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 20.1 (2 q, C-1Ј, C-3Ј), 29.9 (d, C-2Ј), 33.5 (t, C-3), 52.2
(d, C-2), 116.6 (t, C-5), 135.5 (d, C-4), 181.5 (s, C-1) ppm. MS (EI,
70 eV): m/z (%) = 142 (1) [M]+, 127 (1) [M – CH3]+, 99 (100) [M –
C3H7]+, 81 (20) [C6H9]+, 71 (12) [C4H7O]+, 55 (49) [C4H7]+, 43 (50)
[C3H7]+, 41 (44) [C3H5]+, 39 (27) [C3H3]+, 27 (13) [C2H3]+.
(13) [C4H9OSi]+, 89 (16) [C5H13O]+, 75 (100) [C2H7OSi]+, 59 (10)
[C3H7O]+, 41 (9) [C3H5]+.
4-(tert-Butyldimethylsiloxy)-3-isopropylbutanal (21): At –78 °C un-
der a N2 atmosphere, ozone was bubbled through a solution of
siloxy alkene 20 (5.23 g, 21.6 mmol) in MeOH (15 mL) and CH2Cl2
(60 mL) until a deep blue color persisted. Thiourea (2.46 g,
32.4 mmol) was then added, and the solution was warmed to room
temperature and stirred at this temperature for 2 h prior to fil-
tration through a pad of Celite. The filter cake was washed with
water. The aqueous layer was extracted with Et2O, and the com-
bined organic extracts were washed with brine, dried (Na2SO4),
and concentrated under reduced pressure. The resulting residue was
purified by silica gel FC (pentane/Et2O = 95:5, Rf = 0.70) to pro-
2-Isopropylpent-4-en-1-ol (19): At room temperature, lithium alumi-
num hydride (LAH; 1.50 g, 40.4 mmol) was dissolved in dry diethyl
ether (160 mL). The solution was cooled down to 0 °C, and acid 18
(5.70 g, 40.4 mmol) dissolved in diethyl ether (40 mL) was carefully vide 21 (3.58 g, 68%) as a colorless oil. IR (neat): ν = 1726 (s,
˜
added dropwise. After stirring at this temperature for 15 min and
then at room temperature for 2 h, the solution was carefully
quenched by slow addition of a satd. aq. solution of NH4Cl
(80 mL). The aqueous layer was extracted with Et2O, and the com-
bined organic extracts were washed with water and brine, dried
(Na2SO4), and concentrated under reduced pressure to afford
alcohol 19 (4.70 g, 91%), which was used in the next step without
νC=O), 1471 (m, νCH2, CH3), 1252 [m, ν C(CH3)3], 1101 (s, νSi–
O–C), 833 (s, νSi–CH3), 774 (s, δSi–CH3) cm–1. 1H NMR
(400 MHz, CDCl3): δ = 0.02 (s, 6 H, SiMe2), 0.87 (s, 9 H, CMe3),
0.88/0.90 (2 d, J = 7.0 Hz, 6 H, 1Ј-Me, 3Ј-Me), 1.76 (sept.d, J =
7.0, 5.0 Hz, 1 H, 1Ј-H), 2.04 (tdt, J = 8.0, 5.0, 5.0 Hz, 1 H, 3-H),
2.33 (ddd, J = 16.0, 5.0, 2.0 Hz, 1 H, 2-Hb), 2.38 (ddd, J = 16.0,
8.0, 5.0 Hz, 1 H, 2-Ha), 3.48 (dd, J = 10.0, 8.0 Hz, 1 H, 4-Hb), 3.65
(dd, J = 10.0, 5.0 Hz, 1 H, 4-Ha), 9.75 (dd, J = 3.0, 2.0 Hz, 1 H,
further purification. IR (neat): ν = 3332 (br. m, νO–H), 3076 (w,
˜
ν=CH2), 1639 (m, νC=C), 1466/1440 (m, δCH2, CH3), 1386/1368 1-H) ppm. 13C NMR (100 MHz, CDCl3): δ = –5.6 (q, SiMe2), 18.2
(m, δCH3), 1040 (s, νCH2–OH), 908 (s, δCH=CH2) cm–1. 1H NMR
(400 MHz, CDCl3): δ = 0.91/0.92 (2 d, J = 7.0 Hz, 3 H, 1Ј-Me, 3Ј-
Me), 1.42 (dddt, J = 8.0, 5.0, 5.0, 5.0 Hz, 1 H, 2-H),1.81 (sept.d, J
= 7.0, 5.0 Hz, 1 H, 2Ј-H), 2.04 (tddt, J = 8.0, 8.0, 7.0, 1.5 Hz, 1 H,
3-Hb), 2.17 (tddt, J = 8.0, 7.5, 5.0, 1.5 Hz, 1 H, 3-Ha), 3.50 (dd, J
= 11.0, 5.0 Hz, 1 H, 1-Ha), 3.61 (dd, J = 11.0, 5.0 Hz, 1 H, 1-Hb),
5.01 (ddt, J = 10.0, 3.0, 1.5 Hz, 1 H, 5-HE), 5.06 (ddt, J = 17.0,
3.0, 1.5 Hz, 1 H, 5-Hz), 5.84 (dddd, J = 17.0, 10.0, 7.5, 7.0 Hz, 1
H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.3/19.8 (2 q, C-
1Ј, C-3Ј), 27.8 (d, C-2Ј), 32.9 (d, C-3), 46.4 (d, C-2), 63.6 (t, C-1),
115.7 (t, C-5), 138.0 (d, C-4) ppm. MS (EI, 70 eV): m/z (%) = 128
(1) [M]+, 113 (1) [M – CH3]+, 110 (7) [M – H2O]+, 95 (77)
[C7H11]+, 86 (15) [M – C3H6]+, 81 (19) [C6H9]+, 69 (52) [C5H9]+, 55
(94) [C4H7]+, 45 (32) [C2H5O]+, 41 (100) [C3H5]+, 31 (13) [CH3O]+,
29 (16) [C2H5]+. Odor description: powerful and pungent minty-
camphoreous, with aspects of rotten wood and a meaty character.
(s, CMe3), 19.3/20.1 (2 q, C-1Ј, C-3Ј), 25.8 (q, CMe3), 28.5 (d, C-
2Ј), 42.4 (d, C-3), 43.8 (t, C-2), 64.4 (t, C-4), 203.0 (d, C-1) ppm.
MS (EI, 70 eV): m/z (%) = 244 (1) [M]+, 229 (1) [M – CH3]+, 200
(1) [M – C2H4O]+, 187 (20) [M – C4H9]+, 169 (5) [C9H17OSi]+, 157
(28) [C8H17OSi]+, 143 (6) [C7H15OSi]+, 131 (63) [C6H15OSi]+, 115
(11) [C6H15Si]+, 101 (34) [C6H13O]+, 95 (50) [C7H11]+, 75 (100)
[C2H7OSi]+, 59 (22) [C2H7Si]+, 41 (16) [C3H5]+.
5-Bromo-4-isopropylpent-1-ene (22): Triphenylphosphane (24.0 g,
91.0 mmol) was added portionwise at room temperature to a solu-
tion of 2-isopropylpent-4-en-1-ol (19; 7.81 g, 60.9 mmol) and tetra-
bromomethane (30.3 g, 91 mmol) in CH2Cl2 (180 mL), and the re-
sulting mixture was stirred overnight at ambient temperature. The
solvent was removed under reduced pressure, and the residue was
diluted with pentane/Et2O (1:1, 400 mL) and filtered. The filter
cake was washed with pentane/Et2O (1:1, 400 mL), and the com-
bined filtrates were concentrated under reduced pressure. Repeated
silica gel FC (pentane, 100%, Rf = 0.86) of the resulting residue
1-(tert-Butyldimethylsiloxy)-2-isopropylpent-4-ene (20): At room
temperature under a N2 atmosphere, alcohol 19 (4.40 g, 34.3 mmol)
and imidazole (7.00 g, 103 mmol) were dissolved in anhydrous
DMF (5 mL), prior to the addition of tert-butyldimethylsilyl chlor-
ide (TBSCl; 7.70 g, 51.5 mmol). After stirring overnight, the solu-
tion was diluted with water (60 mL), and the aqueous layer was
extracted with pentane. The organic extracts were dried (Na2SO4)
and concentrated under reduced pressure. Chromatography of the
resulting product (pentane, Rf = 0.54) afforded 20 (8.07 g, 97%).
afforded 22 (10.7 g, 92%). IR (neat): ν = 3077 (w, ν=CH ), 1835
˜
2
(w, δ = CH2 oop), 1639 (w, νC=C), 1463/1436 (m, δCH2, CH3),
1
1386/1369 (m, δCH3), 992 (s, δCH=CH2), 669 (s, δC–Br) cm–1. H
NMR (400 MHz, CDCl3): δ = 0.92/0.93 (2 d, J = 7.0 Hz, 6 H, 1Ј-
Me, 3Ј-Me), 1.50 (dddt, J = 8.0, 7.0, 5.0, 5.0 Hz, 1 H, 4-H), 1.84
(oct., J = 7.0 Hz, 1 H, 2Ј-H), 2.09 (dddt, J = 14.0, 8.0, 8.0, 1.0 Hz,
1 H, 3-Hb), 2.27 (dddt, J = 14.0, 6.5, 5.0, 1.5 Hz, 1 H, 3-Ha), 3.44
(dd, J = 10.0, 5.0 Hz, 1 H, 5-Hb), 3.47 (dd, J = 10.0, 5.0 Hz, 1 H,
IR (neat): ν = 3077 (w, ν=CH ), 1640 (w, νC=C), 1471/1441 (m, 5-Ha), 5.06 (ddt, J = 10.0, 2.0, 1.0 Hz, 1 H, 1-HE), 5.10 (ddt, J =
˜
2
Eur. J. Org. Chem. 2013, 49–58
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
55

P. Kraft, N. Denizot
FULL PAPER
17.0, 2.0, 1.5 Hz, 1 H, 1-HZ), 5.73 (dddd, J = 17.0, 10.0, 8.0, 6.5 Hz,
(0.5 mL) was added to
a
solution of ketone 24 (210 mg,
1 H, 2-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.3/19.9 (2 q, 0.677 mmol) in EtOH (6.0 mL). The resulting mixture was heated
C-1Ј, C-3Ј), 28.9 (d, C-2Ј), 33.8 (t, C-3), 36.9 (t, C-5), 45.9 (d, C- at reflux overnight and allowed to cool to room temperature prior
4), 116.8 (t, C-1), 136.5 (d, C-2) ppm. MS (EI, 70 eV): m/z (%) =
to pouring into ice/water (1:1, 10 mL). The aqueous layer was ex-
tracted with Et2O (3ϫ 10 mL), and the combined organic extracts
191/189 (1) [M]+, 150/148 (11) [M – C3H5]+, 111 (3) [M – Br]+, 95
(6) [C7H11]+, 69 (100) [C5H9]+, 55 (21) [C4H7]+, 41 (47) [C3H5]+, 27 were washed with satd. aq. Na2CO3 and brine, dried (Na2SO4),
(6) [C2H3]+. Odor description: agrestic, terpenic odor with aspects
of wet soil, and leathery facets recalling shoe wax.
and concentrated under reduced pressure. The resulting residue was
purified by silica gel FC (pentane/Et2O = 19:1, Rf = 0.89) to afford
25 (20 mg, 15%) as a colorless oil. IR (neat): ν = 1737 (s, νC=O)
˜
4-Bromo-3-isopropylbutanal (23): At –78 °C under a N2 atmo-
sphere, ozone was bubbled through a solution of bromoalkene 22
(5.54 g, 29.0 mmol) in CH2Cl2 (100 mL) and MeOH (20 mL) until
a deep blue color persisted. Thiourea (3.31 g, 43.5 mmol) was then
added, and the solution was warmed to room temperature and
stirred at this temperature for 2 h prior to filtration through a pad
of Celite. The filter cake was washed with water. The aqueous layer
was extracted with Et2O, and the combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated under re-
duced pressure. The resulting residue was purified by silica gel FC
(pentane/Et2O = 95:5, Rf = 0.35) to provide 23 (1.68 g, 30%) as a
1
cm–1. H NMR (600 MHz, C6D6): δ = 0.66 (mc, 3 H, 3ЈЈ-H3), 0.76
(mc, 3 H, 1ЈЈ-H3), 1.06 (q, J = 8.0 Hz, 1 H, 3Ј-Hb), 1.17 (mc, 1 H,
2ЈЈ-H), 1.25 (mc, 2 H, 4-H2), 1.44 (mc, 1 H, 4Ј-H), 1.74 (mc, 2 H,
3-H2), 1.87 (mc, 1 H, 3Ј-Ha), 1.88 (mc, 1 H, 2-H), 1.90 (mc, 2 H, 5-
H2), 3.17 (t, J = 8.5 Hz, 1 H, 5Ј-Hb), 3.86 (t, J = 8.5 Hz, 1 H, 5Ј-
Ha), 4.20 (mc, 1 H, 2Ј-H) ppm. 13C NMR (150 MHz, C6D6): δ =
21.0 (t, C-4), 21.5/21.6 (2 d, C-1ЈЈ, C-3ЈЈ), 25.0 (t, C-3), 32.3 (d, C-
2ЈЈ), 36.3 (t, C-3Ј), 38.8 (t, C-5), 47.6 (d, C-4Ј), 52.9 (d, C-2), 72.4
(t, C-5Ј), 79.0 (d, C-2Ј), 216.4 (C-1) ppm. MS (EI, 70 eV): m/z (%)
= 196 (5) [M]+, 153 (5) [M – C3H7]+, 113 (100) [C7H13O]+, 95 (72)
[C6H7O]+, 83 (13) [C5H7O]+, 69 (59) [C5H9]+, 55 (37) [C4H7]+, 43
(52) [C3H7]+, 27 (12) [C2H3]+. Odor description: woody, recalling
Atlas cedarwood [Cedrus atlantica (Endl.) Manetti], and green-flo-
ral note with jasminic aspects, and a slight mushroom character.
yellowish oil. IR (neat): ν = 1721 (s, νC=O), 1465/1438 (w, δCH ,
˜
2
CH3), 1388/1370 (m, δCH3), 653 (w, δC–Br) cm–1. 1H NMR
(400 MHz, CDCl3): δ = 0.91/0.93 (2 d, J = 7.0 Hz, 6 H, 1Ј-Me, 3Ј-
Me), 1.84 (oct., J = 7.0 Hz, 1 H, 2Ј-H), 2.17 (tddd, J = 7.0, 6.5,
5.5, 4.5 Hz, 1 H, 3-H), 2.55 (ddd, J = 17.5, 5.5, 1.5 Hz, 1 H, 2-Hb),
2.68 (ddd, J = 17.5, 7.0, 1.5 Hz, 1 H, 2-Ha), 3.44 (dd, J = 10.0,
6.5 Hz, 1 H, 4-Hb), 3.52 (dd, J = 10.0, 4.5 Hz, 1 H, 4-Ha), 9.81 (t,
J = 1.5 Hz, 1 H, 1-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
19.3/19.7 (2 q, C-1Ј, C-3Ј), 29.7 (d, C-2Ј), 36.9 (t, C-4), 40.6 (d, C-
3), 44.7 (t, C-2), 201.2 (d, C-1) ppm. MS (EI, 70 eV): m/z (%) =
193/191 (1) [M]+, 150/148 (11) [M – C2H4O]+, 95 (26) [C7H11]+, 69
(100) [C5H9]+, 55 (12) [C3H3O]+, 41 (54) [C3H5]+, 29 (5) [CHO]+.
[2(1Ј)E]-2-[(2Ј-Isopropylcyclopropyl)methylene]cyclopentanone (26):
At 40 °C, a 5% aq. NaOH solution (100 mL, 125 mmol) was added
dropwise to a solution of aldehyde 23 (240 mg, 1.24 mmol) and
cyclopentanone (7, 150 mg, 1.86 mmol) in distilled water (200 mL).
The resulting mixture was stirred for 1 h at 40 °C, allowed to cool
down to room temperature, and extracted with Et2O (3ϫ 150 mL).
The combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated under reduced pressure. Chromatog-
raphy on silica gel (pentane/Et2O = 19:1, Rf = 0.25) provided 26
[2(1Ј)E]-[4Ј-(tert-Butyldimethylsiloxy)-3Ј-isopropylbutylidene]cyclo-
pentanone (24): At room temperature under a N2 atmosphere, a
solution of aldehyde 21 (1.0 g, 4.09 mmol) in EtOH (7.0 mL) was
added by syringe pump over a period of 60 min to a solution of
cyclopentanone (7, 340 mg, 4.09 mmol) and potassium hydroxide
(230 mg, 4.09 mmol) in EtOH (7.0 mL) and CH2Cl2 (5.0 mL). The
resulting mixture was stirred for 2 h at this temperature, quenched
by addition of half-satd. aq. NH4Cl solution (50 mL), and ex-
tracted with Et2O (3ϫ 50 mL). The combined organic extracts
were washed with brine, dried (Na2SO4), and concentrated under
reduced pressure. Silica gel FC (pentane/Et2O = 9:1, Rf = 0.41) of
the resulting residue afforded 24 (600 mg, 47%) as a yellowish oil.
(60.0 mg, 27%) as a yellowish oil. IR (neat): ν = 1712 (s, νC=O),
˜
1
1633 (s, νC=C), 1464 (w, νCH2, CH3) cm–1. H NMR (400 MHz,
CDCl3): δ = 0.79–0.92 (m, 3 H, 2ЈЈ-H, 3ЈЈ-H2), 0.97/0.98 (2 d, J =
7.5 Hz, 6 H, 1ЈЈЈ-Me, 3ЈЈЈ-Me), 1.04 (mc, 1 H, 1ЈЈ-H), 1.26 (sept.d,
J = 7.5, 5.0 Hz, 1 H, 2ЈЈЈ-H), 1.90–2.01 (m, 2 H, 4-H2), 2.32 (t, J
= 8.0 Hz, 2 H, 5-H2), 2.70 (tt, J = 7.0, 3.0 Hz, 2 H, 3-H2), 6.01 (dt,
J = 11.0, 2.5 Hz, 1 H, 1Ј-H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 15.6 (t, C-3ЈЈ), 19.8 (d, C-1ЈЈ), 19.9 (t, C-4), 21.7/21.9 (2 d, C-
1ЈЈЈ, C-3ЈЈЈ), 26.7 (t, C-3), 31.4 (d, C-2ЈЈ), 32.8 (d, C-2ЈЈЈ), 38.4 (t,
C-5), 134.2 (s, C-2), 141.4 (d, C-1Ј), 206.4 (s, C-1) ppm. MS (EI,
70 eV): m/z (%) = 178 (6) [M]+, 121 (100) [C8H9O]+, 107 (7)
[C7H7O]+, 69 (19) [C5H9]+, 55 (10) [C4H7]+, 41 (18) [C3H5]+, 27
(4) [C2H3]+. Odor description: fruity, butyric-sweaty, reminiscent of
overripe pineapple and durian fruit.
IR (neat): ν = 1721 (m, νC=O), 1649 (m, νC=C), 1471 (w, νCH ,
˜
2
CH3), 1251 [m, ν C(CH3)3], 1094 (s, νSi–O–C), 834 (s, νSi–CH3),
773 (s, δSi–CH3) cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.02 (s, 6
H, SiMe2), 0.88 (s, 9 H, CMe3), 0.89/0.90 (2 d, J = 7.0 Hz, 6 H,
1ЈЈ-Me, 3ЈЈ-Me), 1.50 (tddd, J = 7.5, 7.0, 6.0, 5.0 Hz, 1 H, 3Ј-H),
1.78 (sept.d, J = 6.5, 5.5 Hz, 1 H, 2ЈЈ-H), 1.88–1.97 (m, 2 H, 4-H2),
2.12–2.17 (m, 2 H, 2Ј-H2), 2.33 (t, J = 8.0 Hz, 2 H, 5-H2), 2.60 (ttd,
J = 10.0, 5.0, 3.0 Hz, 2 H, 3-H2), 3.49 (dd, J = 10.0, 6.0 Hz, 1 H,
4Ј-Hb), 3.55 (dd, J = 10.0, 5.0 Hz, 1 H, 4Ј-Ha), 6.59 (tt, J = 7.5,
3.0 Hz, 1 H, 1Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = –5.5 (2
q, SiMe2), 18.2 (s, CMe3), 19.7/19.8 (2 q, C-1ЈЈ, C-3ЈЈ), 19.9 (t, C-
4), 25.9 (3 q, CMe3), 26.8 (t, C-3), 28.0 (d, C-2ЈЈ), 28.4 (t, C-2Ј),
38.6 (t, C-5), 46.7 (d, C-3Ј), 63.2 (t, C-4Ј), 136.1 (d, C-1Ј), 137.6 (s,
C-2), 206.9 (s, C-1) ppm. MS (EI, 70 eV): m/z (%) = 310 (1) [M]+,
295 (1) [M – CH3]+, 253 (54) [M – C4H9]+, 197 (20) [C12H21O2]+,
169 (41) [C9H17OSi]+, 161 (20) [C11H13O]+, 133 (13) [C9H9O]+, 75
(100) [C2H7OSi]+, 69 (11) [C5H9]+, 55 (18) [C3H3O]+, 41 (15)
[C3H5]+.
1-Trimethylsiloxy-3-vinylcyclopent-1-ene (12): At –78 °C under a N2
atmosphere, a solution of tBuLi (1.7 m in THF, 100 mL, 170 mmol)
was added dropwise to a stirred solution of vinylmagnesium brom-
ide (1 m in THF, 85 mL, 85 mmol), diluted by additional THF
(150 mL). Stirring was continued at this temperature for 1 h, prior
to rapid addition of CuI (8.10 g, 42.5 mmol). The resulting mixture
was warmed to 0 °C over 10 min and then cooled back down to
–78 °C prior to the dropwise addition of a solution of cyclopen-2-
en-1-one (27; 3.46 g, 42.1 mmol) in THF (20 mL). After 45 min at
the same temperature, a solution of chlorotrimethylsilane (1.0 m in
THF, 6.46 g, 59.5 mmol) was added within 5 min, and the resulting
mixture was warmed to 0 °C and stirred at this temperature for 1 h,
prior to quenching with a half-satd. NaHCO3 solution (50 mL).
After filtration through a pad of Celite and extraction with pentane
(2ϫ 50 mL), the combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated under reduced pressure.
Kugelrohr distillation of the resulting residue afforded 12 (4.60 g,
2-(4Ј-Isopropyltetrahydrofuran-2Ј-yl)cyclopentanone (25): At room
temperature, a solution of RhCl3 (6.7 mg, 0.03 mmol) in water
56
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 49–58

Spirocyclic Seco Structure of a Vetiver Odorant
60%) as a colorless liquid. IR (neat): ν = 1640 (s, νC=C), 867 (s,
C6D6): δ = 0.74/0.75/0.76/0.77 (4 d, J = 7.0 Hz, 6 H, 1ЈЈЈ-,3ЈЈЈ-Me),
1.05 (mc, 1 H, 4-Hb), 1.16 (mc, 1 H, 3Ј-H), 1.33 (mc, 1 H, 2Ј-Hb),
1.35 (mc, 1 H, 1Ј-Hb), 1.38 (mc, 1 H, 2Ј-Ha), 1.40/1.42 (2 mc, 1 H,
2-H), 1.46 (mc, 1 H, 1Ј-Ha), 1.55 (mc, 1 H, 4-Ha), 1.64/1.66 (2 mc,
1 H, 5-Hb), 1.73/1.74 (2 mc, 1 H, 2ЈЈЈ-H), 1.94/1.98 (2 mc, 1 H, 5-
Ha), 1.99/2.01 (2 mc, 1 H, 3-H), 3.18/3.22 (2 mc, 2 H, 4Ј-H2), 4.51/
4.71 (2 mc, 2 H, 2ЈЈ-H2), 5.44/5.46 (2 mc, 1 H, 1ЈЈ-H) ppm. 13C
NMR (150 MHz, C6D6): δ = 19.4/19.5/19.6/19.7 (4 q, C-1ЈЈЈ,-3ЈЈЈ),
˜
νSi–CH3) cm–1. 1H NMR (400 MHz, C6D6): δ = 0.14 (s, 9 H,
SiMe3), 1.39 (dddd, J = 13.0, 9.5, 7.0, 5.5 Hz, 1 H, 4-Hb), 1.84 (dtd,
J = 13.0, 8.0, 4.5 Hz, 1 H, 4-Ha), 2.12 (dddt, J = 17.0, 8.0, 7.0,
2.0 Hz, 1 H, 5-Hb), 2.16 (dddt, J = 17.0, 9.5, 8.0, 2.0 Hz, 1 H, 5-
Ha), 3.12 (ddddt, J = 7.0, 5.5, 4.5, 2.0, 1.0 Hz, 1 H, 3-H), 4.53 (q,
J = 2.0 Hz, 1 H, 2-H), 4.78 (ddd, J = 10.0, 2.0, 1.0 Hz, 1 H, 2Ј-
HZ), 4.91 (ddd, J = 17.0, 2.0, 1.0 Hz, 1 H, 2Ј-HE), 5.68 (ddd, J =
17.0, 10.0, 7.0 Hz, 1 H, 1Ј-H) ppm. 13C NMR (100 MHz, C6D6): δ 25.3/25.8 (2 t, C-1Ј), 26.5/26.6 (2 t, C-4), 27.6/27.7 (2 t, C-2Ј), 29.4/
= –0.32 (s, SiMe3), 28.8 (t, C-4), 33.4 (t, C-5), 46.2 (d, C-3), 104.6
(d, C-2), 111.9 (t, C-2Ј), 143.8 (d, C-1Ј), 156.1 (s, C-1) ppm. MS
(EI, 70 eV): m/z (%) = 182/181 (77) [M]+, 167 (17) [M – CH3]+, 155
29.5 (2 d, C-2ЈЈЈ), 37.1/37.2 (2 t, C-4Ј), 37.3 (t, C-5), 46.5/46.6 (2 d,
C-3), 47.1 (d, C-3Ј), 54.1/54.2 (2 d, C-2), 115.0/115.1 (2 t, C-2ЈЈ),
141.2/141.3 (2 d, C-1ЈЈ), 216.6/216.7 (2 s, C-1) ppm. MS (EI, 70 eV):
(22) [M – C2H3]+, 151 (5) [C9H15OSi – CH3]+, 139 (3) [C8H15OSi – m/z (%) = 259 (1) [M – C2H3]+, 207 (5) [M – Br]+, 189 (5)
CH3]+, 111 (2) [C7H10O]+, 75 (32) [C2H7OSi]+, 73 (100) [C3H9Si]+, [C14H21]+, 163 (2) [C11H16O]+, 137 (3) [C9H13O]+, 123 (3)
59 (5) [C3H7O]+, 45 (15) [C2H5O]+, 39 (4) [C3H3]+, 27 (2) [C2H3]+. [C8H11O]+, 110 (100) [C7H10O]+, 95 (13) [C6H7O]+, 79 (8) [Br]+, 67
(11) [C5H7]+, 55 (11) [C4H7]+, 41 (11) [C3H5]+, 27 (2) [C2H3]+.
[2(1Ј)E]-(4Ј-Bromo-3Ј-isopropylbutylidene)-3-vinylcyclopentanone
(28): At –78 °C under an Ar atmosphere, BF3·OEt2 (2.21 g,
15.5 mmol) was added dropwise to a solution of silyl enolate 12
(4.20 g, 23.0 mmol) and bromo aldehyde 23 (3.00 g, 15.5 mmol) in
HRMS (EI): calcd. for C14H23O79Br [M]+ 286.09323; found
286.09191. HRMS (EI): calcd. for C14H23O81Br [M]+ 288.09118;
found 288.09147.
freshly distilled CH2Cl2 (80 mL). The resulting mixture was stirred
at the same temperature for 2 h and quenched by the dropwise
addition of half-satd. NaHCO3 solution (50 mL). The solution was
then warmed up to room temperature, and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were dried
with Na2SO4 and concentrated under reduced pressure. Silica gel
FC (pentane/Et2O = 8:2, Rf = 0.12) of the resulting mixture af-
forded diastereoisomeric mixture 28 (2.70 g, 61%) as brownish oil.
(4R*,5R*)-7-Isopropyl-4-vinylspiro[4.4]nonan-1-one [(4R*,5R*)-2]:
At –78 °C under an Ar atmosphere, a solution of nBuLi (2.7 m
in heptane, 0.80 mL, 2.09 mmol) was added dropwise to a stirred
solution of diisopropylamine (0.30 mL, 2.09 mmol) in THF/
DMPU (5:1, 6.0 mL). The resulting mixture was warmed to 0 °C
over 10 min and cooled back down to –78 °C prior to the dropwise
addition of a solution of bromo ketone 29 (400 mg, 1.39 mmol) in
THF (4.0 mL). The solution was stirred at the same temperature
for 1 h, and then allowed to slowly warm up to room temperature
over 4 h. The reaction mixture was then poured into water (50 mL),
and the aqueous layer was extracted with Et2O (2ϫ 10 mL). The
combined organic extracts were washed with brine, dried (Na2SO4),
and concentrated under reduced pressure. Silica gel FC of the re-
IR (neat): ν = 1719 (s, νC=O), 1645 (s, νC=C), 914 (s, δCH=CH ),
˜
2
648 (w, δC–Br) cm–1. 1H NMR (400 MHz, C6D6): δ = 0.63 [tt, J =
7.0, 3.0 Hz, 6 H, 3Ј-CH(CH3)2], 0.84/1.10 (mc, 1 H, 3Ј-H), 1.36/
1.58 (2 mc, 2 H, 4Ј-H2), 1.58 [mc, 1 H, 3Ј-CH(CH3)2], 1.97/2.08 (2
mc, 2 H, 5-H2), 2.13 (mc, 2 H, 2Ј-H2), 2.98/3.10 (2 dd, J = 10.5/
10.5, 7.0/5.0 Hz, 2 H, 4-H2), 3.21/3.48 (mc, 1 H, 3-H), 4.88 (mc, 2
H, 2ЈЈ-H2), 5.57 (ddd, J = 15.0, 10.0, 7.0 Hz, 1 H, 1ЈЈ-H), 6.62/6.69
(2 ddd, J = 9.5/8.0, 6.5/7.0, 2.0/2.5 Hz, 1 H, 1Ј-H) ppm. 1H–1H
NOESY (C6D6): 3-Hϫ2Ј-H. 13C NMR (100 MHz, C6D6): δ =
19.1/19.2 [2 q, CH(CH3)2-3Ј], 19.4/19.5 [2 q, CH(CH3)2-3Ј], 26.4/
26.5 (2 t, C-2Ј), 29.0/29.4 (2 t, C-4Ј), 29.2/29.4 [2 d, CH(CH3)2-3Ј],
35.9 (t, C-5), 36.5/37.1 (2 t, C-4), 42.6/42.7 (2 d, C-3), 45.7/46.2 (2
d, C-3Ј), 114.2/114.4 (2 t, C-2ЈЈ), 135.4/135.5 (2 d, C-1ЈЈ), 139.5/
139.7 (2 d, C-1Ј), 139.9/140.1 (2 s, C-2), 203.6/203.7 (2 s, C-1) ppm.
MS (EI, 70 eV): m/z (%) = 284 (15) [M]+, 241 (100) [M – C3H7]+,
205 (32) [M – Br]+, 191 (11) [C14H21O – CH2]+, 161 (30)
[C11H14BrO – HBr]+, 147 (19) [C11H13O – CH2]+, 135 (77)
[C11H13O – C2H3]+, 121 (44) [C3H7Br]+, 79 (85) [Br]+, 69 (43)
[C5H9]+, 55 (36) [C3H3O]+, 41 (50) [C3H5]+, 27 (11) [C2H3]+.
HRMS (EI): calcd. for C14H23OBr [M]+ 284.07758; found
284.07655. HRMS (EI): calcd. for C14H23O81Br [M]+ 286.07553;
found 286.07476.
sulting product (pentane/Et2O
= 19:1, Rf = 0.32) afforded
(4R*,5R*)-2 (160 mg, 56%) as a yellowish odoriferous liquid. IR
(neat): ν = 1735 (s, νC=O), 1638 (w, νC=C), 914 (s, δCH=CH )
˜
2
cm–1.
Tentative (4R*,5R*,7R*)-Diastereomer: 1H NMR (600 MHz,
C6D6): δ = 0.86/0.89 (2 d, J = 7.0 Hz, 6 H, 1ЈЈ-Me, 3ЈЈ-Me), 0.97
(dd, J = 12.5, 11.0 Hz, 1 H, 6-Hb), 1.02 (ddd, J = 23.0, 11.0, 8.0 Hz,
1 H, 8-Hb), 1.28 (dsept., J = 8.0, 7.0 Hz, 1 H, 2ЈЈ-H), 1.31 (mc, 1
H, 3-Hb), 1.38 (mc,1 H, 9-Hb), 1.50 (mc, 1 H, 9-Ha), 1.56 (mc, 1 H,
3-Ha), 1.71–1.76 (m, 1 H, 8-Ha), 1.82 (mc, 1 H, 2-Hb), 1.88 (mc, 1
H, 7-H), 2.01 (mc, 1 H, 2-Ha), 2.03 (mc, 1 H, 6-Ha), 2.06 (mc, 1 H,
4-H), 4.92 (ddd, J = 17.0, 2.5, 1.0 Hz, 1 H, 2Ј-HE), 4.98 (ddd, J =
10.0, 2.5, 1.0 Hz, 1 H, 2Ј-HZ), 5.58 (ddd, 17.0, 10.0, 7.0 Hz, 1 H,
1
1Ј-H) ppm. H–1H NOESY (C6D6): 4-Hax ϫ6-Hb, 6-Ha ϫ1ЈЈ-Me,
6-Hb ϫ2ЈЈ-H. 13C NMR (150 MHz, C6D6): δ = 21.7/21.8 (2 q, C-
1ЈЈ, C-3ЈЈ), 25.4 (t, C-3), 30.4 (t, C-9), 31.8 (t, C-8), 33.8 (d, C-2ЈЈ),
35.3 (t, C-2), 39.7 (t, C-6), 48.0 (d, C-7), 51.5 (d, C-4), 58.8 (s, C-
5), 116.3 (t, C-2Ј), 137.7 (d, C-1Ј), 220.0 (s, C-1) ppm.
2-(4Ј-Bromo-3Ј-isopropylbutyl)-3-vinylcyclopentanone (29): At room
temperature under an Ar atmosphere, a solution of ZnCl2 (1 m in
Et2O, 0.30 g, 2.26 mmol) was added to a stirred solution of dienone
28 (290 mg, 1.02 mmol) in THF (5 mL) prior to the rapid addition
Tentative (4R*,5R*,7S*)-Diastereomer: 1H NMR (600 MHz,
C6D6): δ = 0.88/0.90 (2 d, J = 7.0 Hz, 6 H, 1ЈЈ-Me, 3ЈЈ-Me), 1.28
of Pd(PPh3)4 (36.0 mg, 0.030 mmol). After stirring for 5 min at this (mc, 1 H, 3-Hb), 1.35 (mc, 2 H, 9-H2), 1.36 (mc, 1 H, 8-Hb), 1.45
temperature, Bu3SnH (0.59 mL, 2.05 mmol, 97%) was added drop-
wise with stirring, and stirring was continued for 2 h, prior to the
dropwise addition of water (5.0 mL). The aqueous layer was ex-
tracted with Et2O, and the combined organic extracts were washed
with brine, dried (Na2SO4), and concentrated under reduced pres-
(mc, 1 H, 7-H), 1.47 (mc, 1 H, 6-Hb), 1.48 (mc, 1 H, 2ЈЈ-H), 1.52
(mc, 1 H, 3-Ha), 1.60 (mc, 1 H, 8-Ha), 1.80 (mc, 1 H, 6-Ha), 1.81
(mc, 1 H, 2-Hb), 2.08 (mc, 1 H, 2-Ha), 2.12 (mc, 1 H, 4-H), 4.93
(ddd, J = 17.0, 2.5, 1.0 Hz, 1 H, 2Ј-HE), 4.99 (ddd, J = 10.0, 2.5,
1.0 Hz, 1 H, 2Ј-HZ), 5.62 (ddd, J = 17.0, 10.0, 7.0 Hz, 1 H, 1Ј-H)
sure. Chromatography on silica gel/K2CO3 (10% w/w, pentane/ ppm. 13C NMR (150 MHz, C6D6): δ = 21.8/21.9 (2 q, C-1ЈЈЈ, C-
Et2O = 19:1, Rf = 0.16) afforded bromo ketone 29 (240 mg, 82%)
3ЈЈЈ), 24.6 (t, C-3), 30.0 (t, C-9), 30.7 (t, C-8), 33.7 (d, C-2ЈЈЈ), 35.2
(t, C-2), 38.5 (t, C-6), 48.7 (d, C-7), 50.9 (d, C-4), 59.1 (s, C-5),
116.1 (t, C-2Ј), 138.0 (d, C-1Ј), 219.0 (s, C-1) ppm. MS (EI, 70 eV):
as a yellowish oil. IR (neat): ν = 1735 (s, νC=O), 1638 (w, νC=C),
˜
912 (s, δCH=CH2), 651 (w, δC–Br) cm–1. 1H NMR (600 MHz,
Eur. J. Org. Chem. 2013, 49–58
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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57

P. Kraft, N. Denizot
FULL PAPER
m/z (%) = 206 (32) [M]+, 191 (18) [M – CH3]+, 163 (45) [M –
C3H7]+, 150 (21) [C11H18]+, 135 (19) [C9H12O]+, 123 (100)
[C8H10O]+, 109 (41) [C7H9O]+, 91 (33) [C7H7]+, 84 (30) [C6H12]+,
67 (32) [C5H7]+, 55 (20) [C4H7]+, 41 (26) [C3H5]+, 27 (6) [C2H3]+.
HRMS (EI): calcd. for C14H22O [M]+ 206.16707; found 206.16672.
Odor description: floral, rosy, green, geranium-like, in the direction
of Petalia [32, 2-cyclohexylidene-2-(o-tolyl)acetonitrile] and Mag-
nolan (2,4-dimethyl-4,4a,5,9b-tetrahydroindeno[1,2-d][1,3]dioxine),
with some slightly fatty-metallic facets. Odor threshold: 42.0 ngL–1
air.
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We are indebted to Dr. Sandrine Py, Université Joseph Fourier,
Grenoble 1, for making the external Master’s thesis of N. D. pos-
sible. We gratefully thank Alain E. Alchenberger and Dominique
Lelievre for olfactory evaluations, Dr. Joachim Schmid for a sample
of (–)-khusiomone (1) and high-resolution mass spectra, Jean-
Pierre Bachmann for a sample of β-/epi-β-vetivone (31), Katarina
Grman and her panelists for the odor threshold determinations,
Dr. Gerhard Brunner and Dr. Veronika Zelenay for NMR experi-
ments, and Dr. Fabian Kuhn and Dr. Susanne Kern for mass spec-
trometric data. Proofreading of the manuscript by Dr. Andreas
Goeke is acknowledged with gratitude, as are the attempts of Heinz
Koch and Albert Feusi to separate the C-7 diastereoisomers of
(4R*,5R*)-2 by preparative GC.
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Received: October 5, 2012
Published Online: November 26, 2012
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