Competitive Gold-Promoted Meyer-Schuster and oxy-Cope Rearrangements of 3-Acyloxy-1,5-enynes: Selective Catalysis for the Synthesis of (+)-(S)-γ-Ionone and (-)-(2S,6 R)-cis-γ-Irone

Article abstract of DOI:10.1002/chem.201502382

We report a simple, highly stereoselective synthesis of (+)-(S)-γ-ionone and (-)-(2S,6R)-cis-γ-irone, two characteristic and precious odorants; the latter compound is a constituent of the essential oil obtained from iris rhizomes. Of general interest in this approach are the photoisomerization of an endo trisubstituted cyclohexene double bond to an exo vinyl group and the installation of the enone side chain through a [(NHC)Au^I]-catalyzed Meyer-Schuster-like rearrangement. This required a careful investigation of the mechanism of the gold-catalyzed reaction and a judicious selection of reaction conditions. In fact, it was found that the Meyer-Schuster reaction may compete with the oxy-Cope rearrangement. Gold-based catalytic systems can promote either reaction selectively. In the present system, the mononuclear gold complex [Au(IPr)Cl], in combination with the silver salt AgSbF₆ in 100:1 butan-2-one/H₂O, proved to efficiently promote the Meyer-Schuster rearrangement of propargylic benzoates, whereas the digold catalyst [{Au(IPr)}₂(μ-OH)][BF₄] in anhydrous dichloromethane selectively promoted the oxy-Cope rearrangement of propargylic alcohols.

Full text of DOI:10.1002/chem.201502382

DOI: 10.1002/chem.201502382
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Terpenoids |Hot Paper|
Competitive Gold-Promoted Meyer–Schuster and oxy-Cope
Rearrangements of 3-Acyloxy-1,5-enynes: Selective Catalysis for
the Synthesis of (+)-(S)-g-Ionone and (À)-(2S,6R)-cis-g-Irone
Serena Bugoni,[a] Valentina Merlini,[a] Alessio Porta,[a] Sylvain Gaillard,[b] Giuseppe Zanoni,[a]
Steven P. Nolan,[b, c] and Giovanni Vidari*[a]
Abstract: We report a simple, highly stereoselective synthe-
sis of (+)-(S)-g-ionone and (-)-(2S,6R)-cis-g-irone, two charac-
teristic and precious odorants; the latter compound is a con-
stituent of the essential oil obtained from iris rhizomes. Of
general interest in this approach are the photoisomerization
of an endo trisubstituted cyclohexene double bond to an
exo vinyl group and the installation of the enone side chain
through a [(NHC)AuI]-catalyzed Meyer–Schuster-like rear-
rangement. This required a careful investigation of the
mechanism of the gold-catalyzed reaction and a judicious
selection of reaction conditions. In fact, it was found that
the Meyer–Schuster reaction may compete with the oxy-
Cope rearrangement. Gold-based catalytic systems can pro-
mote either reaction selectively. In the present system, the
mononuclear gold complex [Au(IPr)Cl], in combination with
the silver salt AgSbF6 in 100:1 butan-2-one/H2O, proved to
efficiently promote the Meyer–Schuster rearrangement of
propargylic benzoates, whereas the digold catalyst
[{Au(IPr)}2(m-OH)][BF4] in anhydrous dichloromethane selec-
tively promoted the oxy-Cope rearrangement of propargylic
alcohols.
Introduction
Ionones and irones are C13 and C14 norterpenoids, respectively,
which impart a powerful and pleasant violet-like scent to
blooming violet flowers and the essential oil of Iris rhizomes,
respectively.[1] Owing to their delicate odor palette, for centu-
ries they have been used extensively as important raw materi-
als for the production of many expensive fragrances, perfumes,
and cosmetics.[2] Moreover, ionones have been employed as
valuable building blocks for the preparation of more complex
natural products.[3] Ionones and irones exist in nature as three
different regioisomers (Figure 1), named a (1, 4), b (2, 5), and g
(3, 6), depending on the position of the double bond. (À)–g-
Irone 8 occurs in different Iris species, for example in iris butter
prepared from I. germanica;[4] in contrast, (+)-g-ionone 7
seems to have a restricted distribution in nature.[5] Notably, the
human nose is able to distinguish the odor of the five ionone
Figure 1. Ionone and irone regioisomers.
and ten irone isomers, so that sensory evaluations were carried
out and odor characters were established for single isomers,
when they were obtained by enantioselective syntheses or
chromatographic separations.[4–6]
[a] Dr. S. Bugoni, Dr. V. Merlini, Dr. A. Porta, Prof. G. Zanoni, Prof. G. Vidari
Dipartimento di Chimica - Sezione Chimica Organica
Università degli Studi di Pavia, Via Taramelli 12, 27100 Pavia (Italy)
E-mail: vidari@unipv.it
The (+)-(S)-g-ionone 7 is the most powerful and pleasant of
the ionone isomers for the floral, green, woody odor with
[b] Dr. S. Gaillard, Prof. Dr. S. P. Nolan
EaStCHEM School of Chemistry, University of St. Andrews
North Haugh, KY16 9ST St. Andrews (UK)
a
very natural violet tonality;[5] (À)-(2S,6R)-cis-g-irone
8
[c] Prof. Dr. S. P. Nolan
(Figure 1) has a warm floral-woody odor tonality, with some
fruity nuances, and its odor threshold by GC olfactometry was
reported to be only 0.75 ngLÀ1, significantly much lower than
that of the (2R,6S)-enantiomer.[4]
Chemistry Department, College of Science, King Saud University
P.O. Box 2455, Riyadh 11451 (Saudi Arabia)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502382.
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The syntheses of enantiopure g-ionone enantiomers report-
ed to date have mostly been based on long and tedious classi-
cal[7] or enzymatic resolution procedures.[5] Alternatively, the
chiral information was encoded by a Sharpless asymmetric di-
hydroxylation of a geraniol derivative, containing a trimethyl-
silyl group to control the regioselective formation of an exo
olefin intermediate in an elegant biomimetic cyclization.[8]
Equally challenging has been the synthesis of the g-irone
enantiomers. In a clever approach from the commercial prod-
uct Irone Alpha, Fuganti and co-workers obtained the single
stereoisomers of the three regioisomeric irones, including 8.
The process required, however, multiple lipase-mediated reso-
lutions of racemic mixtures and separation of diastereomeric
products.[4,6] Moreover, ex novo enantioselective synthesis of 8
required the invention of ingenious strategies for installing the
thermodynamically disfavored cis relationship between H2 and
H6, and enantioenriched starting materials were often difficult
to obtain. These difficulties account for the limited number of
enantioselective syntheses of irone 8 reported to date.[9]
We describe herein a straightforward approach to 7 and 8
from geranic acid 9 and (S)-epoxygeraniol 10, respectively,
which can easily be converted, in gram quantities, into enan-
tioenriched building blocks 11[3g] and 12,[9d,10] respectively. Our
common strategy to obtain both target compounds was based
on two key reactions: the photoisomerization of the endocyclic
(a) double bond to the exocyclic (g) position (11!13 and
12!14, respectively),[11] and a [(NHC)AuI]-promoted Meyer–
Schuster rearrangement[12] of a suitable propargylic derivative
(15!7 and 16!8, respectively; NHC=N-heterocyclic carbene;
Scheme 1) to deliver the enone system. The olefin photoisome-
rization protocol[11] proved, indeed, to be much simpler than
an alternative multistep route previously employed to move
the a-double bond to the g-position.[9d,11] Moreover, a recent
synthesis of (S)-a-ionone (S)-1,[12e] suggested that the
[(NHC)AuI]-catalyzed[13] Meyer–Schuster-like rearrangement of
a propargylic ester[12,14] in an aqueous medium is an attractive
alternative to the classical Horner–Wadsworth–Emmons reac-
tion to build the a,b-enone side-chain of 7[8] and 8.[9c,e] This
new method, further preserving the stereochemical integrity at
C6, exhibits other remarkable synthetic advantages, such as
good atom economy, nontoxicity of the solvent, and the small
amount of the catalyst employed.
Results and Discussion
The common synthetic strategy to give compounds 7 and 8
was at first optimized in the synthesis of a-ionone and then
extended to g-irone. Due to the volatility of (S)-a-cyclogeraniol
11 (ꢀ95% ee)[3g,10] and its acetate, optimized photoisomeriza-
tion of the double bond to the g-isomer 13 required imple-
mentation of a slightly modified Serra protocol.[11] Thus, alcohol
11[3g,10] was at first converted to the corresponding myristate
17, which was subsequently irradiated at 254 nm for 24 h in
a degassed 4:1 iPrOH/xylene mixture (Scheme 2). To our de-
light, photoisomerization of 17 to the g-isomer 19 occurred
almost quantitatively (g/aꢀ98:2 by GC). Subsequently, myris-
tate 19 was smoothly cleaved to give (S)-g-cyclogeraniol 13 (ꢀ
95% ee by chiral GC)[8,11,15] in 97% yield. Following an identical
procedure, alcohol 12 (ꢀ99% ee),[9a,d] was converted in three
steps to (2S,6R)-2-methyl-g-cyclogeraniol 14 (ꢀ99% ee by
chiral HPLC)[9a,c,d] in 74% overall yield.
Subsequently, the two alcohols 13 and 14 were separately
oxidized by stabilized 2-iodoxybenzoic acid (SIBX) in DMSO[16]
to give the corresponding unstable aldehydes 21[8] and 22,[9c]
respectively. One-pot addition of propynylmagnesium bromide
to each aldehyde followed by benzoyl chloride, afforded ben-
zoates 23 and 24, respectively, in excellent overall yields
(Scheme 3), as undetermined mixtures of diastereomers at the
carbinol center.
Scheme 2. Synthesis of (S)-g-cyclogeraniol 13 and (2S, 6R)-2-methyl-g-cyclo-
geraniol 14. Reagents and conditions: a) Me(CH2)12CO2H, N,N’-dicyclohexyl-
carbodiimide (DCC), 4-(dimethylamino)pyridine (DMAP), RT, 6 h; 94% for 17,
97% for 18; b) hn (254 nm), 4:1 iPrOH/xylene, 24 h; 88% for 19, 83% for
20.; c) K2CO3, MeOH, RT, 6 h; 97% for 13, 95% for 14.
Scheme 3. Synthesis of benzoates 23 and 24. a) SIBX, dry DMSO, RT, 2 h;
b) MeÀCꢁCMgBr, dry THF, À788C to RT, 2 h; followed by c) BzCl, DMAP, dry
THF, 08C to RT, 2 h; 68% overall yield of 23 from 13; 64% of 24 from 14.
Scheme 1. Retrosynthesis of g-ionone 7 and g-irone 8.
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Competitive gold-promoted Meyer–Schuster and oxy-Cope
rearrangements of 3-acyloxy-1,5-enynes
Ester 23 was then subjected to the gold-mediated Meyer–
Schuster-like rearrangement under the conditions that we opti-
mized for the synthesis of a-ionone,[12e] namely, 2 mol% of the
dinuclear gold complex [{Au(IPr)}2(m-OH)][BF4] (IPr=1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene) 25,[17] in a mixture of
butan-2-one-H2O, 100:1, at 608C for 12 h.
(E)-g-ionone 7 was, indeed, formed in 48% yield. However,
quite unexpectedly, it was accompanied by 16% of a mixture
of E and Z dienals 26a and 26b, in a ratio of about 1:1
(Scheme 4). The chromatographically inseparable isomers 26a
Scheme 5. Examples of [(NHC)AuI]-assisted cycloisomerization of 1,5-enynes
bearing a propargylic acyloxy group. Reagents and conditions: [(IPr)AuCl]/
AgBF4, dry DCM, RT, 5 min.
of esters such as the benzoate 23, in analogy with the gold-
catalyzed reactions of other substrates.[12b]
As far as the active catalytic gold species involved in the re-
action of benzoate 23 was concerned, NMR data supported
the hypothesis that in an aqueous medium the dinuclear gold
complex 25, further having a direct catalytic role, had the syn-
thetically useful potential to deliver, simultaneously, the gold
species [Au(IPr)][BF4] 31 and [Au(IPr)(OH)] 32 (Scheme 6).[17a]
Scheme 4. Gold-promoted rearrangements of benzoate 23. Reagents and
conditions: [{Au(IPr)}2(m-OH)][BF4] 25, 100:1 butan-2-one/H2O, 608C, 12 h.
and b were fully characterized by NMR spectroscopy after sep-
aration from 7 on a RP-18 column eluted with MeCN/H2O (7:3).
The overall yield and the ratio between 7 and 26a and b did
not change significantly by increasing the amount of H2O in
the solvent mixture, up to a ratio between butan-2-one and
H2O of 100:6. However, the reaction was much faster, going to
completion in 6 h. Instead, the ratio between 7 and 26a and
b slightly increased to 4:1 when the reaction was performed in
butan-2-one/5% aqueous NaHCO3 (100:5). However, under
stronger basic conditions, namely in butan-2-one/1m aqueous
NaOH (100/5), only extensive hydrolysis of the benzoate group
was observed after heating at 608C for 48 h.[18]
Compounds 7 and 26a and b appeared to derive from two
different [3.3]-sigmatropic rearrangements of benzoate 23. Ac-
tually, enone 7 corresponded to the expected product of the
gold-promoted Meyer–Schuster rearrangement of propargylic
esters,[12,14] while 26a and b could be considered as the prod-
ucts of a formal gold-promoted oxy-Cope rearrangement[19] of
a 3-acyloxy-1,5-enyne.[20]
Scheme 6. Equilibrium between dinuclear and mononuclear gold complexes
in an aqueous medium.
Remarkably, the former complex is an efficient cationic s-
and p-system-activating agent, whereas the mononuclear gold
species 32 has the characteristics of a strong Brønsted base,[17d]
Thus, a synergistic effect can result, leading to enhanced cata-
lytic activity.
On this basis, we envisioned, as a working mechanistic hy-
pothesis, different accessible pathways leading to enone 7 and
aldehydes 26a and b through competitive rearrangements of
benzoate 23 (Scheme 7). A push–pull SN2’-like mechanism (rou-
tes a and a’ in Scheme 7) could be involved in the formation of
the Meyer–Schuster rearrangement product 7. In accordance
with this hypothesis, the nucleophilic hydroxyl–gold complex
32 would attack the distant carbon of the propargylic group of
alkyne 23 with concomitant removal of the benzoate group to
deliver the gold allenolate 35. Moreover, coordination of the
benzoate group to a cationic gold species, most likely complex
31, appeared to be necessary to facilitate its expulsion and the
entrance of the nucleophilic group, as shown in the TS 33. In
fact, the sole gold species 32 was shown to exhibit poor effica-
cy in enabling the Meyer–Schuster rearrangement of esters.[18]
A double activation of the leaving group was also possible, in
which not only the gold cation 31 but also the proton of the
hydroxy group of the species 32, intramolecularly transferred
to the inner oxygen atom of the acyl group, would accelerate
the release of the benzoate from the incipient allene system
The formation of structures such as 26a and b was in strik-
ing contrast with previous findings on the [(NHC)AuI]-assisted
cycloisomerization of 1,5-enynes bearing a propargylic acyloxy
group. Thus, [(NHC)AuCl]/AgBF4 in dry DCM promoted the con-
version of acetate 27 to the bicyclo[3.1.0]hexane derivative
28,[21] whereas replacing the alkene moiety with an aryl ring, as
in ester 29, led to a substituted indene 30 (Scheme 5).[12b]
Although rather unexpected, our results confirmed previous
findings for gold-catalyzed reactions, indicating that, in addi-
tion to the steric and electronic features of the substrate, the
nature of the ligands on the gold center, as well as the coun-
terion and the solvent, have a dramatic effect on the structures
of products. In particular, the presence of H2O in the solvent
mixture appeared to play a crucial role in the rearrangement
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have proposed a stepwise mechanism. However, at
this stage of our studies, we cannot rule out a con-
certed process with exclusion of carbocation inter-
mediates.
Selective Au catalysis for the Meyer–Schuster rear-
rangement of 3-benzoyloxy-1,5-enynes: Synthesis
of (S)-g-ionone, (2S,6R)-g-irone, and (S)-a-ionone
A few key experiments nicely supported our pro-
posed mechanism (Scheme 7). In a first instance, we
changed the gold catalyst, using, instead of the com-
plex 25, the mononuclear gold complex [Au(IPr)Cl] in
combination with the silver salt AgSbF6. This catalyst
has been shown to efficiently promote the Meyer–
Schuster rearrangement of propargylic acetates in
aqueous THF to afford the corresponding enones.[12b]
After preliminary experiments in different solvents,
benzoate 23 (0.1m) was finally exposed to 2 mol%
[Au(IPr)Cl] and 2 mol% AgSbF6 in 100:1 butan-2-one/
H2O to deliver (S)-g-ionone 7[8] as the (E)-isomer, in
55% yield (Scheme 8).
Scheme 7. Proposed mechanism for the gold-catalyzed formation of the Meyer–Schuster
and the oxy-Cope rearrangement products 7 and 26a,b, respectively.
To our delight, enals 26a and b were not formed.
Subsequently, by subjecting esters 24 and 39[12e] to
(TS 34). To complete the catalytic cycle, water would finally
add to intermediate 35 to deliver the enone 7 and regenerate
[Au(IPr)(OH)] 32 (Scheme 7).[12b]
Alternative mechanisms for the Meyer–Schuster rearrange-
ment involving the coordination of a cationic gold species to
the triple bond of alkyne 23 appeared to be energetically less
favored than the routes a and a’ (Scheme 7). In fact, Nolan, Ma-
seras and co-workers calculated that, of the three possible
complexes that a cationic NHC–gold species such as 31 can
form with a propargylic ester such as the benzoate 23, the
most stable one involves the coordination of gold to the alco-
holic oxygen atom of the ester and not to the triple bond, as
might be expected.[12b]
Scheme 8. Meyer–Schuster rearrangement of benzoates 23, 24, and 39 to
(S)-g-ionone 7, (2S,6R)-cis-g-irone 8, and (S)-a-ionone 40, respectively. Re-
agents and conditions: 23, 24, or 39 (0.1m), [(IPr)AuCl] (2 mol%), AgSbF6
(2 mol%), 100:1 butan-2-one/H2O, RT, 3 h, 608C, 3 h. Yields=55% 7; 65% 8,
66% 40.
Enals 26a and b, the minority products of the 25-induced
rearrangement of enyne 23, possibly ensued from electrophilic
activation of a cationic Au-coordinated triple bond (route b in
Scheme 7), although such a gold complex was estimated to be
less stable than the Au–benzoate one.[12b] In this context, con-
sidering the softer Lewis acid characteristics of the gold spe-
cies occurring in the reaction medium (Scheme 6), the dinu-
clear gold complex 25 should play a more important activating
effect on the triple bond than the mononuclear cation 31. The
resulting loss in electron density from the p-system of the
triple bond would thus promote the nucleophilic 6-endo-dig-
like addition of the exo double bond of enyne 23 to the more
electrophilic end of the alkyne, affording the cyclocarbenium
ion 37. Subsequently, a Grob-type fragmentation in 37 would
give rise to the more stable oxonium ion 38, which would be
rapidly cleaved by water to produce 26a and b and regenerate
the gold catalyst (route b in Scheme 7).
the same reaction conditions, (2S,6R)-g-irone 8[7] and (S)-a-
ionone 40[12e] were produced in good yields (Scheme 8). Nota-
bly, no products derived from an oxy-Cope-like rearrangement
were detected in these experiments. However, whereas 7 and
8 were stereochemically homogeneous, 40 was a mixture of E
and Z stereoisomers. At present, we do not have a clear ex-
planation for this different diastereoselecivity. GC and HPLC
analyses indicated 95% ee for 7 and ꢀ99% ee for 8.
The selective Meyer–Schuster rearrangement promoted by
the gold-catalyst [Au(IPr)Cl]/AbSbF6, with suppression of the
oxy-Cope rearrangement further supported our hypothesis
that the dinuclear gold species 25 played a key role in catalyz-
ing the conversion of propargylic benzoate 23 to enals 26a
and b.
The overall process from benzoate 23 to 38 thus corre-
sponds to a formal 1,5-enyne oxy-Cope rearrangement.[19] We
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Selective Au catalysis for the oxy-Cope rearrangement of 3-
hydroxy-1,5-enynes
To this end, each of the model 3-hydroxy-1,5-enynes 45–50
(0.1m in anhydrous DCM) was treated with 2 mol% of 25
(Table 1). All reactions proceeded smoothly at room tempera-
ture, reaching completion in ca. 30 min, with the exception of
the reaction of alcohol 49, that required 4 h.
The compounds formed by the oxy-Cope rearrangement
were the main isolated products, whereas the Meyer–Schuster
rearrangement product (<10%) was formed only in the reac-
tion of bicyclic alcohol 49.
As expected on the basis of the proposed mechanism
(Scheme 9), yields of the isolated rearrangement products
ranged from good to excellent for substrates 45–49. In con-
trast, the monosubstituted olefin 50 gave 56 in low yield, ac-
companied by the bicyclo[3.1.0]hexane derivative 57. Accord-
ing to the proposed reaction mechanism (Scheme 9), these re-
sults nicely reflect the higher stability of tertiary carbocation in-
termediates arising from substrates 45–49, rather than the sec-
ondary analogue resulting from enyne 50. Moreover, the
slightly lower yields of the oxy-Cope rerrangement products
In another series of experiments, propargylic alcohol 41, readi-
ly obtained by addition of propynylmagnesium bromide to al-
dehyde 21, was exposed to 2 mol% of [{Au(IPr)}2(m-OH)][BF4]
25 in dry DCM. Indeed, water appeared to play a crucial role in
different steps of the Meyer–Schuster rearrangement promot-
ed by the gold complex 25, mainly by producing the catalyti-
cally active nucleophilic species 32 (routes a and a’ in
Scheme 7). By excluding water from the reaction mixture, we
thus expected to increase the Lewis acid character of the gold
complex and to force the gold-catalyzed transformations of al-
cohol 41 selectively towards the oxy-Cope rearrangement
products 26a and b.
Upon exposure of alcohol 41 to catalyst 25 in anhydrous
DCM, the two isomeric E and Z aldehydes 26a and 26b were
smoothly formed in combined 99% yield in less than 30 min at
room temperature. Notably, the Meyer–Schuster rearrange-
ment product, namely enone 7, was not detected (Scheme 9).
Table 1. Gold catalyzed oxy-Cope rearrangement of propargylic alco-
hols.[a,b]
Starting compound
Product (yield)[c]
Scheme 9. Oxy-Cope rearrangement of propargylic alcohol 41. Reagents and
conditions: 41 (0.1m), 25 (2 mol%), dry DCM, RT, 30 min. Yield=99%.
The proposed mechanism for the formation of aldehydes
26a and b under these conditions (Scheme 9) closely resem-
bles route b in Scheme 7. Thus, gold coordination to the triple
bond would induce electrophilic addition of the exocyclic
double bond to give the bicyclic carbocation 42. Grob-type
fragmentation of this intermediate (Scheme 9, route a) would
then afford aldehydes 26a and b and regenerate the gold cat-
alyst. This rearrangement is more likely initiated by deprotona-
tion of the hydroxy group (Scheme 9, route a) than by gold de-
tachment from the cyclohexene double bond (Scheme 9,
route b) to give allenol 44. In the latter case, ring fragmenta-
tion would proceed through a high-energy cyclic TS containing
an incipient allene system (TS 43 in Scheme 9).
The oxy-Cope reaction has found widespread use in organic
synthesis[19] and dienals such as 26a and b are versatile elec-
trophilic reagents. This prompted us to extend the reaction
conditions optimized for the rearrangement of alcohol 41 to
other secondary propargylic alcohols, to find the limits and ap-
plicability of our gold-mediated procedure in synthetic organic
chemistry.
[a] Reaction conditions: Propargylic alcohol (0.1m), [[(IPr)Au]2 (m-OH)][BF4]
25 (2 mol%), dry DCM, RT, 30 min; [b] alcohols 45 and 50 were known
compounds, whereas 46–49 were prepared by the addition of 1-propy-
nylmagnesium bromide to aldehydes; [c] yields refer to isolated product;
[d]ꢀ95% E-stereoisomer; [e] the reaction went to completion in 4 h.
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a degassed 4:1 iPrOH/xylene solvent mixture (6.8 mL/1.7 mL) in
a sealed quartz vessel was irradiated in a Rayonet photochemical
reactor equipped with four 254 nm high-pressure Hg lamps. The
reaction was monitored by GC-MS and the irradiation was inter-
rupted after 24 h, when the starting compound was completely
consumed. The reaction mixture was then concentrated under re-
duced pressure and the residue was purified by chromatography
on a column (150 mm”30 mm) of silica gel (15 g). Elution with
98:2 hexane/Et2O afforded g-ester 19 (273 mg, yield=88%) as
a yellow oil. [a]2D0 =À1.6 (c=0.84, CH2Cl2); TLC (SiO2): Rf =0.33
51 and 52 compared to 26 and 53–54, likely depended on the
higher molecular steric strain required by overlapping the
alkyne p-electrons with an endo double bond than with an exo
olefin.
In striking contrast, but according to our expectations, in
analogy with esters 23, 24, and 39, benzoates of alcohols 46,
49, and 50 gave the corresponding products of the Meyer–
Schuster rearrangement upon exposure to [Au(IPr)Cl] and
2 mol% AgSbF6 in 100:1 butan-2-one/H2O (data not included).
Notably, in the absence of the gold catalyst 25, no rearrange-
ment occurred, even upon heating a propargylic alcohol in dry
DCM at 358C for a few hours. This result confirmed the catalyt-
ic effects of this unique gold complex.
1
(hexane/Et2O, 98:2); H NMR (300 MHz, CDCl3): d (ppm)=4.85 (brs,
1H), 4.60 (brs, 1H), 4.30–4.15 (m, 2H), 2.25 (t, J=7.5 Hz, 2H), 2.23–
2.20 (m, 2H), 2.18–2.02 (m, 1H), 1.64–1.55 (m, 4H), 1.42–1.23 (m,
22H), 0.99 (s, 3H), 0.90–0.87 (overlapped s + t, 2”3H); 13C NMR
(75 MHz, CDCl3): d (ppm)=173.9 (s), 147.1 (s), 109.7 (t), 62.6 (t),
52.2 (d), 37.8 (t), 34.4 (t), 34.3 (s), 33.3 (t), 31.9 (t), 29.6 (t), 29.6 (t),
29.4 (t), 29,3 (t), 29.2 (t), 29.1 (t), 28.7 (q), 25.1 (q), 25.0 (t), 23.4 (t),
22.7 (t), 14.1 (q); IR (neat product): n˜ =2925, 2854, 1737, 1466,
Conclusion
1170, 891 cmÀ1
364.3345.
; HRMS: calcd for C24H44O2 364.3341; found
In summary, we have described a novel and highly enantiose-
lective synthesis of naturally occurring (S)-g-ionone 7 and
(2S,6R)-g-irone 8, which are characteristic and valuable compo-
nents of expensive perfumes and fragrances. These efficient
syntheses started from easily accessible, almost enantiopure,
starting materials and were based on the photoisomerization
of an endocyclic cyclohexene olefin to an exo double bond,
followed by a gold-catalyzed Meyer–Schuster rearrangement
of a propargylic benzoate to deliver the characteristic enone
side-chain. The latter procedure proved to be an efficient eco-
friendly alternative to the classical Wittig-type olefination
methodology used in previous syntheses of these compounds.
In the course of these studies, we examined the competition
of the gold-assisted Meyer–Schuster rearrangement of 3-acy-
loxy-1,5-enynes with the oxy-Cope rearrangement. Under con-
trolled conditions, highly divergent reaction pathways can be
implemented. Specifically, upon exposure of 3-benzoyloxy-1,5-
enynes to the mononuclear gold complex [Au(IPr)Cl]/AbSbF6 in
100:1 butan-2-one/H2O, only the products of the Meyer–Schus-
ter rearrangement were obtained, whereas the digold catalyst
[{Au(IPr)}2(m-OH)][BF4] 25 in anhydrous DCM catalyzed the se-
lective oxy-Cope rearrangement of the corresponding 3-hy-
droxy-1,5-enynes. With 1,5-enynes incorporating a double
bond endo or exo to a ring, the oxy-Cope rearrangement pro-
ceeded rapidly under very mild conditions, affording a,b,d,e-di-
enals in yields ranging from good to excellent.
The g/a ratio (ꢀ98:2) was determined by GC analysis on a capillary
HP5 column (30 m, 0.25 mm i.d., 0.25 mm f.t.); carrier gas=He,
flow=1 mLminÀ1
; injector temperature=2508C; detector: MS;
temperature program: 808C (1 min), then 108CminÀ1 to 2808C
(5 min); tR of a-ester 17=19.67 min; tR of g-ester 19=19.80 min.
Selective Meyer–Schuster rearrangement: General proce-
dure
(S,E)-4-(2,2-dimethyl-6-methylenecyclohexyl)but-3-en-2-one [(S)-g-
ionone (7)]: [Au(IPr)Cl] (3.4 mg, 5.4”10À3 mmol, 0.02 equiv) and
AgSbF6 (1.9 mg, 5.4”10À3 mmol, 0.02 equiv) were added to a solu-
tion of 23 (81 mg, 0.27 mmol, 1.0 equiv) in 100:1 butan-2-one/H2O
(2.7 mL/0.027 mL). The mixture was stirred at RT for 3 h and then
warmed at 608C for 3 h. The solvent was then removed under re-
duced pressure (p>80 mmHg). The residue, comprising only the E-
isomer, was purified by chromatography on a column (150 mm”
15 mm) of silica gel (8 g). Elution with 98:2 pentane/Et2O afforded
1
(E,S)-g-ionone 7 (29 mg, yield=55%) as a pale yellow oil. H NMR
and 13C NMR data of compound 7 are identical to those reported
in the literature.[8]
Selective Oxy-Cope rearrangement. General procedure
(E)- and (Z)-4-(3,3-dimethylcyclohex-1-en-1-yl)-3-methylbut-2-enal
(26a and b): [{Au(IPr)}2(m-OH)][BF4] 25 (6.8 mg, 5.0”10À3 mmol,
0.02 equiv) was added to a solution of propargylic alcohol 41
(51 mg, 0.26 mmol, 1.0 equiv) in dry CH2Cl2 (2.6 mL). After stirring
at RT for 30 min, the solvent was removed under reduced pressure
(p>80 mmHg). The residue was purified by chromatography on
a column (150 mm”15 mm) of silica gel (5 g). Elution with 98:2
pentane/Et2O afforded a 2:1 mixture of inseparable (E)- and (Z)-al-
dehydes 26a and 26b (50 mg, combined yield=99%). TLC (SiO2):
We think that this methodology will add to the great array
of remarkable gold-catalyzed reactions discovered in the last
decade, furnishing organic chemists with another useful tool
for accomplishing directed syntheses. Moreover, our results
have clearly proven the different reaction mechanisms trig-
gered by the various gold-based catalytic systems and the im-
portance of a judicious selection of the gold species for selec-
tive synthesis.
Rf =0.29 (pentane/Et2O, 98:2); 1H NMR (300 MHz; CD2Cl2):
d
(ppm)=10.00 (d, J=7.9 Hz, 0.5H); 9.98 (d, J=8.1 Hz, 1H), 5.97 (d,
J=8.2 Hz, 1H), 5.94 (d, J=8.1 Hz, 1H); 5.36 (brs, 0.5H), 5.29 (brs,
1H); 3.21 (s, 2H), 2.83 (s, 1H); 2.12 (s, 1.5H), 1.93 (s, 3H); 1.82–1.87
(m, 3H); 1.64–1.69 (m, 3H); 1.40–1.44 (m, 3H); 1.01 (s, 9H);
13C NMR (75 MHz, CD2Cl2): d (ppm)=191.8 (d), 191.5 (d), 163.1 (s),
162.8 (s), 136.9 (d), 136.1 (d), 132.4 (s), 132.1 (s), 130.1 (d), 129.0 (d),
50.0 (t), 41.4 (t), 37.7 (t), 32.6 (s), 30.4 (q), 30.3 (q), 29.0 (t), 28.8 (t),
25.2 (q), 20.6 (t), 17.5 (q); IR (neat product): n˜ =3480, 2950, 2932,
2855, 1673, 1456, 1170 cmÀ1; HRMS: calcd for C13H20O 192.1514;
found 192.1518.
Experimental Section
Photoisomerization of the double bond: General procedure
(S)-(2,2-dimethyl-6-methylenecyclohexyl)methyl
tetradecanoate
(19): A solution of a-ester 17 (309 mg, 0.84 mmol, 1.0 equiv) in
Chem. Eur. J. 2015, 21, 14068 – 14074
www.chemeurj.org
14073
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
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We thank the Italian MIUR (funds PRIN) for financial support,
and Professor Mariella Mella for NMR spectroscopic measure-
ments. For work conducted in the Nolan group, S.P.N. acknowl-
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Keywords: fragrances
· gold · homogeneous catalysis ·
sigmatropic rearrangement · terpenoids
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Received: June 19, 2015
Published online on August 28, 2015
Chem. Eur. J. 2015, 21, 14068 – 14074
www.chemeurj.org
14074
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim