Electrophilic Cyclization of 1,6-Dienes Containing an Allylsilane Moiety - Enantioselective Synthesis of cis- and trans-γ-Irone

Article abstract of DOI:10.1002/ejoc.200300276

In this paper, we report the first examples of Lewis acid and mercuric trifluoroacetate promoted cyclizations of 1,6-dienes containing an allylsilane moiety. Mercuric trifluoroacetate has been proved to be the reagent of choice leading to methylenecyclohexane derivatives in good yields and with complete regioselectivity albeit with poor diastereoselectivity. Using this methodology a stereodivergent synthesis of enantiomerically pure (-)-(2S,6R)-cis-γ -irone and (-)-(2S,6S)-trans-γ-irone, two precious aroma constituents, has been accomplished. This represents an innovative approach with respect to previous syntheses of γ-irones. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300276

FULL PAPER
Electrophilic Cyclization of 1,6-Dienes Containing an Allylsilane Moiety ؊
Enantioselective Synthesis of cis- and trans-γ-Irone
Stephen Beszant,[a] Elios Giannini,[a] Giuseppe Zanoni,[a] and Giovanni Vidari*[a]
Keywords: Fragrances / Terpenoids / Total synthesis / Synthetic methods / Cyclization
In this paper, we report the first examples of Lewis acid and
mercuric trifluoroacetate promoted cyclizations of 1,6-dienes
antiomerically pure (−)-(2S,6R)-cis-γ-irone and (−)-(2S,6S)-
trans-γ-irone, two precious aroma constituents, has been ac-
containing an allylsilane moiety. Mercuric trifluoroacetate complished. This represents an innovative approach with re-
has been proved to be the reagent of choice leading to
methylenecyclohexane derivatives in good yields and with
complete regioselectivity albeit with poor diastereoselectiv-
spect to previous syntheses of γ-irones.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ity. Using this methodology a stereodivergent synthesis of en- Germany, 2003)
Introduction
In the γ-series, (Ϫ)-(2S,6R)-cis-irone (4) is considered to
have the strongest and finest aroma of the four isomers,[3,4l]
Irones are C14 norterpenoid ketones, responsible for the whereas the threshold value of (Ϫ)-(2S,6S)-trans-irone (5)
powerful and pleasant violet-like scent of the essential oil is four times higher than that of the (ϩ)-enantiomer.[2f]
of Iris rhizomes and precious constituents of expensive ar-
Chemists have struggled with the synthesis of γ-irones for
omas, perfumes, and other cosmetics.[1] Most Iris oils con- a long time,[4] the first syntheses of the single enantiomers
tain the three α-, β-, and γ-double-bond isomers 1Ϫ3 in having appeared in the literature only recently.[2f,3,4d,4l,4m]
different proportions.[2] In the natural oils cis-α-irone and On the other hand, even the synthesis of each diastereomer
cis-γ-irone are the major components, but trans-α-irone is turns out to be troublesome; indeed, literature data reveal
also found and, on one occasion, traces of (Ϫ)-trans-γ-irone that cis-γ-irone is the more difficult to achieve due to the
have been detected.[2b][2f] In addition, enantiomeric irones severe 1,3-allylic interaction[5] between the exocyclic double
can be isolated from Iris plants of different geographical bond and the nearby side chain.
origin. The olfactory properties of the three regioisomers
We envisioned that an innovative approach for the en-
are remarkably different and even for the single regioisomer, antioselective synthesis of γ-irone diastereomers, namely
intensity and characters of the Iris-like notes are dramati- (Ϫ)-(2S,6R)-cis-γ-irone (4) and (Ϫ)-(2S,6S)-trans-γ-irone
cally dependent on the relative and absolute stereochem- (5), could be based on an intramolecular electrophilic cycli-
istry.[2g]
zation[6] of the chiral allylsilane 6 (Scheme 1). In fact, we
expected that the allylsilyl moiety would allow the regiose-
lective formation of the exocyclic double bond[7] of γ-irones,
whereas the absolute configuration of the allylsilane 6, de-
rived from the chiral pool (vide infra), would dictate the
absolute stereochemistry of the cyclized product. Two cru-
cial issues of the reaction remained, however, to be ex-
plored, namely the preference of the electrophilic species for
the distal double bond with respect to the trisubstituted one
and the role of different factors affecting the cyclization dia-
stereoselectivity. Indeed, it must be stressed that, in contrast
Figure 1. Components of Iris oil
[a]
`
Dipartimento di Chimica Organica, Universita di Pavia,
Via Taramelli 10, 27100 Pavia, Italy
Fax: (internat.) ϩ 39-0382/507323
E-mail: vidari@chifis.unipv.it
Scheme 1. Retrosynthesis of γ-irone
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DOI: 10.1002/ejoc.200300276
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Electrophilic Cyclization of 1,6-Dienes Containing an Allylsilane Moiety
FULL PAPER
with the intramolecular electrophilic cyclizations of simple cedure[14] for the synthesis of terpenoid allylsilanes secured
1,5- and 1,6-dienes,[6,8] annulations of 1,6-dienes containing compound 15 with (Z)/(E) stereoselectivity Ͼ 50:1, in 42%
an allylsilane moiety of type 6 were unknown at the onset overall yield over 3 steps.
of our work.
Results and Discussion
Cyclization Studies
The required allylsilane 6 was synthesized (Scheme 2)
starting from the commercially available chiral building
block methyl (S)-(ϩ)-3-hydroxy-2-methylpropionate (8) (ee
Ͼ 99%), which already contained the C-2 stereogenic center
of irones. Reaction of 8 with methylmagnesium bromide
furnished diol 9, which was selectively protected as its pri-
mary p-toluenesulfonate 10.[9] Regioselective elimination of
Scheme 3. a) Na/Li methyl acetoacetate dianion, THF, 0 °C to
the tertiary hydroxy group was then easily accomplished[10]
room temp., 1 h; b) ClP(O)(OEt)2, 0 °C to room temp., 1.5 h; c)
by exposure of 10 to mesyl chloride followed by in situ elim-
ination of the corresponding tertiary methanesulfonate
group with excess Et3N to give the terminal olefin 11[11] in
66% overall yield (3 steps), without traces of the internal
∆2-olefin (1H NMR spectrum). Exchange of the tosylate
group with LiI furnished the more reactive iodide 12, which
was readily alkylated with the Na/Li methyl acetoacetate
dianion[12] to give the γ-alkylated β-oxo ester 13 in 40%
unoptimized overall yield (2 steps). The allylsilyl moiety
was then introduced with a tandem reaction[7c] via the inter-
mediate enol phosphate 14 to give the required allylsilane 6
in 70% overall yield over 2 steps. The (Z)/(E) stereoselectiv-
Me3SiCH2MgCl, cat. Ni(acac)2, THF, 0 °C, 1 h, 42% yield (3 steps)
With dienes 6 and 15 in hand, we reasoned that the elec-
tronic properties of their two double bonds were similar to
those of previously investigated allylic 1,5-dienylsilanes
which require a strong Lewis acid or a species able to gener-
ate a bridged cation, to promote the electrophilic cycliza-
tion.[7b][7c]
At first, different Lewis acids and a number of reaction
conditions were tested for the cyclization of achiral allylic
dienylsilane 15 in order to avoid protodesilylation and shift
of the double bond in the cyclized product 7, resulting in
an unfruitful mixture of regioisomeric olefins.
Eventually, cyclization of 15 with SnCl4 (4 equiv.) in wet
CH2Cl2 at Ϫ30/Ϫ20 °C readily afforded the desired exo-
olefin 7,[15] albeit as a 1:1.5 mixture of chromatographically
inseparable cis-/trans-7 stereoisomers,[16] in 85% yield
(Scheme 4, route a). Noteworthy, this ratio was quite differ-
ent from the thermodynamic equilibrium ratio, which PM3
1
ity was estimated from the H and 13C NMR spectra of
ester 6 to be greater than 50:1.
Scheme 2. a) MeMgBr, Et2O, 0 °C, 1.5 h; b) TsCl, pyridine, 0 °C,
15 h; c) CH3SO2Cl, Et3N, Et2O, 0 °C to room temp., 15 h, 66%
yield (3 steps); d) LiI, THF, reflux, 2 h; e) Na/Li methyl acetoacet-
ate dianion, THF, 0 °C to room temp., 1.5 h, 40% yield (2 steps,
unoptimized); f) NaH, THF, 0 °C, 15 min, then ClP(O)(OEt)2, 0
°C to room temp., 1.5 h; g) Me3SiCH2MgCl (1  in THF), cat.
Ni(acac)2, 0 °C, 1 h, 69% yield (2 steps)
Scheme 4. a) SnCl4, wet CH2Cl2, Ϫ30 to Ϫ20 °C, 2 h, 85% yield;
b) SnCl4, wet CH2Cl2, Ϫ30 to Ϫ20 °C, 1 h, 92% yield or TiCl4, dry
CH2Cl2, Ϫ30 to Ϫ20 °C, 1 h, 87% yield; c) Hg(OCOCF3)2,
CH3CN, 0 °C, 45 min; then satd. aq. NaCl, 0 °C, 30 min; then
NaBH4, NaOH 15%, 0 °C, 30 min, 82% yield; d) Hg(OCOCF3)2,
CH3CN, Ϫ40 °C, 45 min; then satd. aq. NaCl, 0 °C, 30 min; then
The corresponding racemic reference series was prepared
from the achiral allylic silane 15 which, by analogy with 6,
was synthesized from methyl acetoacetate and the readily
accessible bromide 16[13] via β-oxo ester 17 and enol phos-
phate 18 (Scheme 3). Our recently discovered one-pot pro- NaBH4, NaOH 15%, 0 °C, 30 min, 57% yield
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FULL PAPER
Table 1. Electrophilic cyclizations of diene (S)-6; composition of the reaction mixtures
Compound
% after 30 min[a]
% after 30 min[b]
% after 60 min[a]
% after 60 min[b]
ee after 60 min[a]
ee after 60 min[b]
cis-7
trans-7
(S)-6
15
25.6
17.3
49.7
7.4
47.5
23.7
28.8
Ͻ 5
58.5
34.2
3.2
57.2
29.5
2.2
40
45
[c]
[c]
2.5
1.0
[a]
[b]
[c]
SnCl4 was used as Lewis acid. TiCl4 was used as Lewis acid. No GC base separation was observed for the trans enantiomers.
methods estimated to be about 1:9, thus indicating that the demercuration of mercurial products, diene 6 readily pro-
main factor controlling the cyclization diastereoselectivity duced the exocyclic product 7, without traces of the endo-
was the comparable activation energy of competing tran- cyclic olefin 7a, in 82% isolated yield and Ͼ 99% GC purity
sition states.
(Scheme 4, route c). A small amount (4.5%) of the open-
Cyclization of optically active diene 6 (Scheme 4, route chain product 19, resulting from mercury desilylation of the
b) under the above condition proved, however, to be unfeas- allylsilane moiety, was also isolated. A GC analysis showed
ible. Actually, besides a disappointingly low cis/trans dia- that, once again, the diastereoselectivity of the cyclization
stereoselectivity, we noticed a severe loss of stereochemical was disappointingly low (cis-7/trans-7 ഠ 1:1), similar to the
integrity for the C-2 stereogenic center in product 7. The stereoselectivity of acid-mediated cyclizations of trimethyl-
same result was observed with TiCl4 (2 equiv.) in dry silyl-unsubstituted 1,6-dienes;[8a,8b] however, each dia-
CH2Cl2 at Ϫ30/Ϫ15 °C. In fact, the enantiomeric excess of stereomer 7 was enantiomerically pure, confirming the cru-
cis-7, estimated by enantioselective GC analysis, was only cial role of the bridged mercurinium ion 6a in preventing
40 and 45%, respectively. It was interesting to compare the erosion of the stereochemistry of diene 6. It was not im-
composition of the reaction mixtures after 30 and 60 min mediately apparent what the controlling factors were in the
(see Table 1). After 60 min, cyclization yields (GC) reached competing transition states leading to cis- and trans-7,
92% with SnCl4 and 86.7% with TiCl4, favoring the cis-7 though we expected that the allylic strain[5] between the
isomer in both cases (cis/trans ϭ 1.7:1 with SnCl4 and 1.9:1 methoxycarbonyl group and the developing exocyclic
with TiCl4).
double bond could play an important role. In order to test
Moreover, the ratio of the two diastereomers did not this hypothesis and a possible influence of electronic factors
change significantly with time, a clear indication that it was on the cyclization diastereoselectivity, we prepared other di-
kinetically controlled with both Lewis acids. To account for enes (20aϪd, Scheme 5) and investigated their reactions
the dramatic erosion of the enantiomeric purity of com- with Hg(OCOCF3)2 in propionitrile at Ϫ78 °C.
pound 7 with respect to 6, the presence of compound 15 in
the reaction mixtures proved that, before cyclization, the
terminal 1,1-disubstituted double bond of diene 6 under-
went a significant isomerization to the more stable tetrasub-
stituted olefin, probably by a rapid [1,2]-H shift between the
C-6 and C-7 carbocationic centers, so that the actual cycliz-
ing substrate was a mixture of the chiral allylsilane 6 and
the achiral allylsilane 15. The same kind of racemization
was observed to occur in the Lewis acid promoted cycliza-
tion of simple 1,6-dienes.[8a] Thus, it appeared that though
the allylic silane moiety should furnish a more nucleophilic
double bond with respect to trimethylsilyl-unsubstituted
1,6-dienes, cyclization of compound 6 was still a relatively
slow process and likely proceeded through a non-con-
certed mechanism.
Scheme 5. a) DIBALH, Et2O, 0 °C, 1 h, 85% yield; b) RCOCl,
These results strongly suggested to perform cyclization of
diene 6 via an intermediate ‘‘onio’’ species in order to avoid
a shift of the distal double bond.[17] To this aim mercury
salts appear to be unique in maintaining the stereochemical
integrity of double bonds and, among them, as an ad-
pyridine, cat. DMAP, CH2Cl2, 1 h, 85% (20b), 98% (20c), 99%
(20d); c) Hg(OCOCF3)2, CH3CH2CN, Ϫ78 °C, 45 min; then satd.
aq. NaCl, 0 °C, 30 min; then NaBH4, NaOH 15%, 0 °C, 30 min
The cyclizations still proceeded readily leading to the ex-
ditional benefit, mercury trifluoroacetate proved to be an pected products 21aϪd, but without any appreciable im-
efficient initiator of electrophilic olefin cyclizations though, provement of the diastereoselectivity (Table 2).
to the best of our knowledge, 1,6-dienes appear to have
It was interesting to compare the Hg(OCOCF3)2-pro-
moted cyclizations of 1,6-dienes 6 and 20aϪd with the reac-
never been used before as substrates.[6a][7b,18]
As expected, on exposure to Hg(OCOCF3)2 (1.05 equiv.) tion of 1,5-diene 15. Indeed, when the reaction of com-
in deoxygenated acetonitrile at 0 °C, followed by reductive pound 15 was performed at Ϫ18 °C, the cyclized compound
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Electrophilic Cyclization of 1,6-Dienes Containing an Allylsilane Moiety
FULL PAPER
Table 2. Results of the Hg(OCOCF3)2-promoted cyclizations of dienes (S)-6, 15, and 20aϪd
Substrate
Product (% isolated yield)
Product purity (%, GC)
cis/trans ratio of cyclized product (GC)
(S)-6
15[a]
20a
20b
20c
7 (82)
Ͼ 99
92[a]
90
82
96
1:1
7 (57)
7:1[a]
1:1
21a (61)
21b (74)
21c (87)
21d (76)
1:1
1:1
1:1.25
20d
81
[a]
The reaction was run at Ϫ40 °C.
7 accounted for only 55% of the product mixture; the dia- sulting in a deterioration of the cyclization diastereoselec-
stereoselectivity was, however, significantly higher than for tivity.
1,6-dienes, corresponding to a ratio of cis-7/trans-7 ϭ 5:1,
which improved to 7:1 at Ϫ40 °C (Scheme 4, route d). By
Synthesis of (؊)-(2S,6R)-cis-γ-Irone (4) and (؊)-(2S,6S)-
contrast, the desilylated product 22 accounted for about
trans-γ-Irone (5)
17% of the reaction mixture, significantly more than the
corresponding desilylated product 19 produced in the reac-
tion of olefin (S)-6.
Compounds cis- and trans-7 are key intermediates[4] in
the synthesis of cis- and trans-γ-irone, respectively; there-
This result indicated that, with respect to 6, the higher fore, given the easy accessibility to these two diastereomers
steric hindrance near the distal tetrasubstituted double in enantiomerically pure form, we considered it worthy of
bond of diene 15 forced the large HgII species to add, at interest to pursue a divergent synthesis of both irones if
least in part, to the internal allylsilane moiety. Moreover, it esters 7 or derivatives could be readily separated. To this
appears that, with respect to 1,5-dienes, the additional sp3- aim, the above 1:1 mixture of isomers 7 was reduced with
carbon atom between the two double bonds of the 1,6-di- DIBALH[19] to give a 48:52 mixture of the corresponding
enes confers a higher flexibility to the acyclic chain, re- cis- and trans-alcohol 21a in 92% yield.
Scheme 6. a) DIBALH, Et2O, 0 °C, 45 min, 92% yield; b) tBuOOH, VO(acac)2, CH2Cl2, Ϫ20 °C, 22 h; 85% isolated yield of compounds
24؊26 in a ratio of 56:38:6, Ͻ 2% (GC) of compound 23
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FULL PAPER
Scheme 7. a) [Bu3SnAlMe3]Li, CH2Cl2, 0 °C, 2 h, 70% yield; b) Swern oxidation, 86% yield; c) DessϪMartin periodinane reagent,[23]
CH2Cl2, room temp., 2 h, 96% yield; d) (EtO)2POCH2COCH3, Ba(OH)2·8H2O, THF/H2O ϭ 40:1, room temp., 18 h; 4 70% yield, 5
72% yield
It is reported in the literature that these diastereomeric
Finally, each of the two highly epimerizable, base-sensi-
alcohols can be separated only by preparative GC.[4b] In tive aldehydes 27 and 28 was submitted to the barium hy-
search of a more practical method of separation, we first droxide promoted HornerϪWadsworthϪEmmons (HWE)
attempted the kinetic separation of alcohols 21a through a reaction, according to the procedure previously reported by
Sharpless asymmetric epoxidation.[20] In the event, at 53% Monti,[4m] to give enantiomerically pure γ-irones 4 and 5,
conversion after 22 h at Ϫ20 °C, (ϩ)-DIPT afforded a 47% respectively.
yield of a trans/cis ϭ 4.4:1 mixture of unchanged alcohols
Our sample of (Ϫ)-cis-γ-irone (4) showed de ϭ 93%
21a, while, under similar conditions, (Ϫ)-DIPT afforded, at (GC), ee ϭ 100% (chiral GC), and [α]2D0 ϭ Ϫ6.4 (c ϭ 1.06,
56% conversion, 44% yield of a trans/cis ϭ 10:1 mixture of CH2Cl2),[24] whereas our sample of (Ϫ)-trans-γ-irone (5)
starting material.
showed de ϭ 97% (GC), ee ϭ 100% (chiral HPLC), and
Although (Ϫ)-DIPT proved to be more selective, dia- [α]2D0 ϭ Ϫ58.4 (c ϭ 0.37, CH2Cl2).[25]
stereomerically pure trans-21a could be obtained only by
forcing the epoxidation up to a conversion of 65Ϫ70%.
Conclusion
Eventually, we succeeded in the separation of the two
series by resorting to a VO(acac)2-catalyzed epoxidation[21]
(Scheme 6) of the mixture of homoallylic alcohols 21a.
In the event, reaction of 21a with tBuOOH (1.5 equiv.)
and 5% VO(acac)2 produced the expected four epoxides
23Ϫ26, with compound 23 occurring only in traces (GC).
The cis/trans relationship between the C-2 and C-6 substitu-
ents of each epoxide was unambiguously determined by its
conversion into the original olefin (vide infra), while the
relative stereochemistry of the epoxy ring was determined
by NOE experiments. Since the mechanism of the epoxid-
ation required assistance of the alcoholic group,[21] it re-
sulted that epoxide 24 derived from the diequatorial con-
former of cis-21a, while epoxides 25 and 26 were likely
formed from the more and less stable conformations of
trans-21a, respectively. The three epoxides 24Ϫ26 were iso-
lated in 85% overall yield, in a ratio of 56:38:6.
In conclusion, we explored the Lewis acid and mercuric
trifluoroacetate promoted intramolecular cyclization of
acyclic 1,6-dienes containing an allylsilane moiety as a no-
vel synthetic method for the construction of 1,3-disubsti-
tuted 4-methylenecyclohexanes. Mercuric trifluoroacetate
proved to be superior, preventing extensive racemization of
stereogenic centers caused by an undesired double-bond
isomerization in the starting chiral dienes, which instead
was observed when Lewis acids were used. Due to the flexi-
bility of the acyclic substrate, the cyclization likely proceeds
through competitive transition states of a similar energy,
thus affording a low cis/trans product diastereoselectivity.
However, a mechanistic discussion of the reaction seems to
be premature at this stage, in absence of other precedents
in the literature on the HgII-initiated cyclizations of 1,6-
dienes and more experimental results.
The conversion of each epoxide into cis- and trans-γ-
irone is outlined in Scheme 7. At first, they were recon-
verted into the corresponding olefin according to the
OshimaϪNozaki protocol,[22] thus avoiding the protection
of the alcoholic function. Thus, on treatment with 4 equiv.
of [Bu3SnAlMe3]Li, each epoxide furnished the parent ole-
fin in ca. 70% yield. Oxidation of cis-21a was then per-
formed with the Swern protocol using DIPEA instead of
TEA,[4m] yielding the desired aldehyde 27 in 86% yield and
98% de (GC). Alcohol trans-21a was instead oxidized with
the DessϪMartin periodinane reagent[23] to aldehyde 28 in
96% yield and 98% de (GC).
An effective strategy for the ready separation of the cis
and trans products has been developed, thanks to which a
stereodivergent synthesis of enantiopure and diastereomer-
ically enriched (Ϫ)-(2S,6R)-cis-γ-irone (4) and (Ϫ)-(2S,6S)-
trans-γ-irone (5) was accomplished from the same enantio-
pure starting material.
Experimental Section
General Remarks: THF and Et2O were dried by distillation under
argon from potassium benzophenone ketyl; pyridine and CH2Cl2
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Electrophilic Cyclization of 1,6-Dienes Containing an Allylsilane Moiety
were distilled from CaH2. All other solvents were distilled under 815, 736, 685, 666 cmϪ1. H NMR: δ ϭ 0.96 (d, J ϭ 6.6 Hz, 3 H,
FULL PAPER
1
argon. MeCN was deoxygenated by bubbling argon for at least 1 h
through it and used without any drying being applied. Commer-
CH3CH), 1.12 (s, 3 H, CH3), 1.19 (s, 3 H, CH3), 1.81Ϫ1.91 (m, 1
H, CHCH3), 2.45 (s, 3 H, CH3Ar), 3.90Ϫ3.95 (m, 1 H, CHHO),
cially available reagents were used as supplied, without further puri- 4.37 (dd, J ϭ 9.2, 4.6 Hz, 1 H, CHHO), 7.34Ϫ7.81 (AAЈBBЈ sys-
fication, except MsCl and Et3N, that were distilled from CaH2 un-
der argon immediately prior to use. All reactions were performed
under a slightly positive static pressure of argon in oven-dried (140
°C for at least 3 h) glassware. Routine monitoring of reactions was
performed by using silica gel (0.20 mm thickness) aluminum-sup-
ported TLC plates. Compounds were visualized by UV irradiation
at a wavelength of 254 nm, or stained by exposure to a 0.5% vanil-
lin solution in H2SO4/EtOH (4:1), followed by heating. Preparative
liquid chromatography was accomplished with 60 Kieselgel (40Ϫ63
µm). Optical rotation values (10Ϫ1 deg cm2 gϪ1) were measured at
589 nm (D line) in the solvent and at the temperatures indicated.
Melting points were determined with a hot-stage apparatus and are
uncorrected. GCMS data were recorded using the electron impact
tem, 4 H, ArH) ppm. 13C NMR: δ ϭ 12.4 (3), 21.4 (3), 25.8 (3),
28.4 (3), 43.2 (1), 71.8 (0), 72.5 (2), 127.7 (2 ϫ 1), 129.7 (2 ϫ 1),
132.7 (0), 144.6 (0) ppm. C13H20O4S (272.36): calcd. C 57.33, H
7.40; found C 57.45, H 7.33. The 13C NMR spectrum is consistent
with the literature data.[9]
(R)-2,3-Dimethyl-3-butenyl 4-Toluenesulfonate (11): Mesyl chloride
(22.7 g, 198.4 mmol) was added dropwise to a solution of crude 10
(24.5 g, 90.2 mmol) in dry Et2O (800 mL), then the mixture was
cooled to 0 °C and Et3N (137 g, 1.35 mol) was added in 1 h; after
complete addition the solution was stirred for 15 h while warming
to room temperature. The reaction mixture was then poured into
a mixture of 1  HCl and Et2O at 0 °C under vigorous stirring;
the aqueous phase was extracted with Et2O and the combined or-
ganic layers were sequentially washed with 1  HCl, satd. aq.
NaHCO3, and brine, dried (MgSO4), and the solvents evaporated.
The crude product was purified by chromatography (SiO2; hexanes/
ethyl acetate ϭ 7:3) to give 14.8 g of product 11[11] as a colorless
oil (65% overall yield over 3 steps). [α]2D0 ϭ Ϫ6.9 (c ϭ 1.2, CHCl3).
IR ν˜ ϭ 3074, 2973, 1649, 1599, 1504, 1457, 1359, 1189, 1177, 1097,
ionization technique (70 eV, 0.5 mA). 1H NMR (300 MHz) and 13
C
NMR (75.47 MHz) spectra were obtained in CDCl3 solution at 22
°C. Chemical shifts are reported in δ units relative to CHCl3 [δH ϭ
7.26 ppm; δC (central line of t) ϭ 77.0 ppm]; the multiplicity (in
parentheses) of each carbon signal was determined by DEPT
experiments. IR spectra were obtained as liquid films. Compounds
1Ϫ5, 7, 21, 23Ϫ26, 27, and 28 have been numbered according to
carotenoid numbering.[4b]
969, 898, 839, 814, 769, 666 cmϪ1 1H NMR: δ ϭ 1.02 (d, J ϭ
.
6.7 Hz, 3 H, CH3CH), 1.62 (s, 3 H, CH3Cϭ), 1.81Ϫ1.91 (m, 1 H,
CH3CH), 2.45 (s, 3 H, CH3Ar), 3.86 (dd, J ϭ 9.4, 7.4 Hz, 1 H,
CHHO), 3.98 (dd, J ϭ 9.4, 6.6 Hz, 1 H, CHHO), 4.69 (br. s, 1
H, ϭCHH), 4.78 (br. s, 1 H, ϭCHH), 7.33Ϫ7.80 (AAЈBBЈ system,
4 H, ArH) ppm. 13C NMR: δ ϭ 17.2 (3), 21.4 (3), 22.9 (3), 41.4
(1), 74.4 (2), 113.3 (2), 129.2 (2 ϫ 1), 131.1 (2 ϫ 1), 134.4 (0), 146.0
(0), 146.2 (0) ppm. GCMS: m/z (%) ϭ 173 (5), 155 (41), 122 (3),
91 (87), 83 (27), 82 (100), 69 (27), 67 (88), 65 (48), 53 (10), 51 (9),
41 (59) ppm. C13H18O3S (254.35): calcd. C 61.39, H 7.13; found
C 61.47, H 7.25. The spectroscopic data are consistent with the
literature data.[11]
(S)-Diol 9: A solution of methyl (S)-(ϩ)-3-hydroxy-2-methylpropi-
onate [10.7 g, 90.2 mmol, ee ϭ 99% (GC)] in dry Et2O (50 mL)
was added dropwise over 30 min to a freshly prepared solution of
MeMgBr (300 mmol, 3.3 equiv.) in dry Et2O (300 mL) at room
temperature. After complete addition, stirring was continued for
further 90 min at room temperature. The reaction mixture was then
cautiously poured into a mixture of 1  HCl and Et2O at 0 °C
under vigorous stirring. The aqueous phase was extracted with
Et2O and the combined organic layers were washed with satd. aq.
NaHCO3 and brine. The acidic aqueous phase was then neutralized
and extracted in continuum with CH2Cl2 for 48 h. The Et2O and
CH2Cl2 solutions were combined, dried (MgSO4), and the solvents
evaporated to give diol 9[9] (10.5 g, 99% yield) as a viscous colorless
oil. An analytical sample was prepared by column chromatography
(SiO2; EtOAc/hexanes, 3:1). [α]2D0 ϭ Ϫ10.9 (c ϭ 0.23, EtOH). IR
ν˜ ϭ 3356, 2974, 2936, 2886, 1705, 1664, 1472, 1385, 1368, 1176,
(R)-Iodide 12: LiI (8.6 g, 64 mmol) was added in one portion to a
solution of toluenesulfonate 11 (14.8 g, 58.2 mmol) in THF
(120 mL) and the mixture was heated at reflux for 2 h. The mixture
was then filtered and the residue washed exhaustively with. Et2O.
The organic phase was then washed with satd. aq. NH4Cl and
brine, dried (MgSO4), and concentrated at room pressure to ca.
100 mL. This solution was directly used in the following reaction.
A small portion was concentrated and the residue chromato-
graphed (SiO2; hexanes/EtOAc, 95:5) to give an analytical sample.
IR: ν˜ ϭ 3075, 2965, 2925, 2870, 1645, 1455, 1375, 1277, 1186, 1165,
1102, 894 cmϪ1. 1H NMR: δ ϭ 1.16 (d, J ϭ 6.8 Hz, 3 H, CH3CH),
1.71 (s, 3 H, CH3Cϭ), 2.35Ϫ2.46 (m, 1 H, CH3CH), 3.16Ϫ3.29
(m, 2 H, CH2I) 4.77 (br. s, 1 H, ϭCHH), 4.84 (br. s, 1 H, ϭCHH)
ppm. 13C NMR: δ ϭ 13.0 (2), 19.3 (3), 19.4 (3), 43.0 (1), 111.2 (2),
146.9 (0) ppm. GCMS: m/z (%) ϭ 210 (3) [Mϩ], 169 (12), 155 (2),
127 (16), 119 (8), 83 (72), 79 (13), 77 (38), 69 (8), 67 (8), 55 (54),
41 (100). HRMS: calcd. for C6H11I [M]ϩ 209.9905; found 209.9910.
1159, 1097, 1057, 1027, 947, 905, 858 cmϪ1 1H NMR: δ ϭ 0.86
.
(d, J ϭ 7.3 Hz, 3 H, CH3CH), 1.20 (s, 3 H, CH3), 1.28 (s, 3 H,
CH3), 1.78Ϫ1.85 (m, 1 H, CHCH3), 2.54 and 2.88 (2 br. s, 2 ϫ 1
H, exchangeable with D2O, 2 OH), 3.67Ϫ3.76 (m, 2 H, CH2O)
ppm. 13C NMR: δ ϭ 12.8 (3), 23.8 (3), 29.5 (3), 43.7 (1), 65.9 (2),
74.5 (0) ppm. GCMS: m/z (%) ϭ 103 (5) [M Ϫ 15]ϩ, 85 (11), 69
(2), 59 (100), 55 (10), 45 (8), 43 (74), 42 (20), 41 (32). C6H14O2
1
(118.17): calcd. C 60.98, H 11.94; found C 61.13, H 11.83. H and
13C NMR spectra are consistent with the literature data.[9]
(S)-3-Hydroxy-2,3-dimethylbutyl 4-Toluenesulfonate (10): 4-Tolu-
enesulfonyl chloride (17.2 g, 90.2 mmol) was added to a solution
of crude diol 9 (10.64 g, 90.2 mmol) in dry pyridine (80 mL) at 0
°C and the resulting solution was stirred at 0 °C for 15 h. The
mixture was then poured into iced water, extracted with Et2O, and
the organic phase was washed with satd. aq. KHSO4, satd. aq.
NaHCO3, brine, dried (MgSO4), and the solvents were evaporated.
The crude product was used for the following reaction. An analyti-
(S)-Oxo Ester 13: A solution of methyl acetoacetate (14.8 g,
127.6 mmol) in dry THF (80 mL) was added dropwise to NaH
(60% dispersion in mineral oil, 5.7 g, 142 mmol) in THF (80 mL)
at 0 °C and the mixture was stirred for 15 min at the same tempera-
ture. BuLi (2.5  solution in hexanes, 56.8 mL, 142 mmol) was then
added dropwise and the mixture was stirred at 0 °C for an ad-
cal sample was prepared by column chromatography (SiO2; EtOAc/ ditional 15 min. To the resulting orange mixture the previously pre-
hexanes, 1:1). IR ν˜ ϭ 3342, 3418, 2976, 1598, 1494, 1466, 1357, pared solution of iodide 12 (see above) (ca. 58 mmol), diluted with
1307, 1293, 1211, 1189, 1174, 1121, 1097, 1035, 1019, 963, 840, THF (100 mL), was added and stirring was maintained for 90 min
Eur. J. Org. Chem. 2003, 3958Ϫ3968
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3963

S. Beszant, E. Giannini, G. Zanoni, G. Vidari
FULL PAPER
while warming to room temperature. The reaction mixture was then water, and the aqueous phase was extracted with hexanes. The com-
poured into a mixture of 1  HCl and Et2O at 0 °C; the aqueous bined organic layers were washed with brine, dried (Na2SO4), and
phase was extracted with Et2O and the combined organic layers the solvents evaporated. Chromatographic purification of the resi-
were washed with brine, dried (Na2SO4), and concentrated. The
residue was chromatographed (SiO2; hexanes/EtOAc, 95:5 Ǟ
90:10) to give 4.57 g of product 13 as a colorless oil (40% yield over
2 steps, not optimized). [α]2D0 ϭ Ϫ0.62 (c ϭ 0.90, CH2Cl2). IR: ν˜ ϭ
due (SiO2; hexanes/EtOAc, 98:2 Ǟ 95:5) and concentration of the
fractions at room pressure, afforded 41.6 mg (4.5% yield) of diene
19 [1H NMR: δ ϭ 1.02 (d, J ϭ 6.9 Hz, 3 H), 1.25Ϫ1.75 (m, 3 H),
1.65 (s, 3 H), 2.0Ϫ2.25 (m, 2 H), 3.05 (s, 2 H), 3.74 (s, 3 H), 4.70
3072, 2960, 2875, 1751, 1718, 1646, 1449, 1438, 1407, 1376, 1322, (br. s, 2 H), 4.87 (s, 1 H), 4.90 (s, 1 H) ppm] and 765 mg of product
1241, 1196, 1153, 1066, 1006 cmϪ1
6.8 Hz, 3 H, CH3CH), 1.65 (br. s, 3 H, CH3Cϭ), 1.61Ϫ1.71 (m, 2
.
1H NMR: δ ϭ 1.04 (d, J ϭ
7 as a colorless oil with a pleasant fragrance (82% yield, GC purity
Ͼ 99%, cis/trans, 49:51). [α]2D0 ϭ Ϫ42.2 (c ϭ 1.27, CH2Cl2). IR: ν˜ ϭ
H, 5-H2), 2.11Ϫ2.25 (m, 1 H, 6-H), 2.49 (t, J ϭ 7.5 Hz, 2 H, 4- 3074, 2960, 2882, 2861, 1736, 1648, 1458, 1436, 1391, 1377, 1367,
H2), 3.46 (s, 2 H, 2-H2), 3.76 (s, 3 H, OCH3), 4.70 (s, 1 H, ϭCHH), 1337, 1287, 1254, 1231, 1190, 1152, 1137, 1089, 1045, 1025, 952,
4.74 (s, 1 H, ϭCHH) ppm. 13C NMR: δ ϭ 18.4 (3), 19.5 (3), 27.9
895, 865, 772, 743, 685, 645 cmϪ1. C12H20O2 (196.29): calcd. C
(2), 40.3 (1), 40.8 (2), 49.0 (2), 51.2 (3), 110.3 (2), 148.6 (0), 167.5 73.43, H 10.27; found C 73.40, H 10.31. cis Isomer: 1H NMR: δ ϭ
(0), 202.6 (0) ppm. GCMS: m/z (%) ϭ 198 (4) [Mϩ], 181 (42), 180
0.86 (d, J ϭ 6.4 Hz, 3 H, 2-CH3), 0.92 (s, 3 H, 1-CH3), 0.98 (s, 3
(25), 167 (9), 149 (9), 139 (2), 129 (16), 125 (14), 124 (15), 121 (18), H, 1-CH3), 1.27Ϫ1.72 (m, 2 H), 2.04Ϫ2.23 (m, 2 H), 2.34 (ddd,
120 (23), 116 (12), 109 (22), 107 (25), 102 (17), 101 (18), 97 (20), J ϭ 13.4, 4.4, and 2.2 Hz, 1 H), 2.92 (s, 1 H, 6-H), 3.69 (s, 3 H,
95 (15), 83 (24), 82 (28), 81 (38), 74 (55), 69 (67), 67 (100), 59 (14),
55 (65), 43 (90), 41 (55) ppm. C11H18O3 (198.26): calcd. C 66.64, NMR: δ ϭ 14.3 (3), 16.0 (3), 27.3 (3), 32.2 (2), 36.4 (2), 38.9 (0),
OCH3), 4.67 (br. s, 1 H, ϭCHH), 4.85 (s, 1 H, ϭCHH) ppm. 13C
H 9.15; found C 66.79, H 9.27.
42.6 (1), 51.4 (3), 61.3 (1), 108.8 (2), 144.5 (0), 172.9 (0) ppm.
GCMS: m/z (%) ϭ 196 (11) [Mϩ], 181 (59), 168 (6), 153 (24), 149
(38), 139 (35), 137 (54), 136 (52), 127 (25), 125 (51), 123 (13), 121
(62), 114 (28), 112 (31), 111 (15), 107 (33), 105 (16), 99 (11), 95
(59), 93 (56), 91 (42), 83 (100), 82 (47), 81 (62), 79 (76), 77 (48), 70
(14), 69 (22), 67 (58), 65 (25), 59 (17), 55 (94), 52 (27), 43 (16), 41
(81). trans Isomer: 1H NMR: δ ϭ 0.83 (d, J ϭ 7.0 Hz, 3 H, 2-CH3),
0.79 (s, 3 H, 1-CH3), 0.98 (s, 3 H, 1-CH3), 1.20Ϫ1.64 (m, 2 H),
2.04Ϫ2.23 (m, 2 H), 2.62 (tdt, J ϭ 13.4, 5.5, and 2.0 Hz, 1 H), 2.92
(s, 1 H, 6-H), 3.65 (s, 3 H, OCH3), 4.76 (br. s, 1 H, ϭCHH), 4.85
(br. s, 1 H, ϭCHH) ppm. 13C NMR: δ ϭ 16.0 (3), 20.7 (3), 26.7
(3), 31.6 (2), 32.0 (2), 34.6 (1), 37.4 (0), 51.6 (3), 61.9 (1), 112.6 (2),
145.2 (0), 173.5 (0) ppm. GCMS: m/z (%) ϭ 196 (1) [Mϩ], 181 (1),
164 (1), 153 (13), 149 (11), 139 (13), 137 (48), 136 (63), 127 (38),
125 (48), 121 (74), 114 (25), 111 (12), 107 (28), 105 (13), 99 (10),
95 (68), 93 (46), 91 (32), 83 (93), 82 (40), 81 (54), 79 (55), 77 (37),
67 (60), 65 (18), 59 (17), 55 (100), 43 (12), 41 (46). ee Ͼ 99% for the
cis isomer {determined on an enantioselective DMePeBETACDX
column (25 m, 0.25 mm i.d., 0.25 µm f.t.); carrier gas ϭ He, 1 mL/
min; split 1:50; detector: FID; temperature program: 70 °C (0 min)
Ǟ 2°C/min Ǟ 140 °C (5 min); (2R,6S)-cis-7, tR ϭ 28.7 min;
(2S,6R)-cis-7, tR ϭ 29.3 min; no base separation was obtained for
the trans enantiomers.
(S,Z)-Ester 6: A solution of β-oxo ester 13 (2.85 g, 14.4 mmol) in
THF (10 mL) was added dropwise to NaH (60% dispersion in min-
eral oil, 633 mg, 15.8 mmol) in THF (20 mL) at 0 °C and the mix-
ture was stirred at 0 °C for 15 min. Diethyl chlorophosphate
(2.61 g, 15.1 mmol) was then added dropwise and the resulting mix-
ture was stirred for 1.5 h while warming to room temperature, fol-
lowed by a slow transfer via cannula to a mixture of Me3Si-
CH2MgCl and Ni(acac)2, prepared meanwhile from Mg (648 mg,
26.6 mmol) and Me3SiCH2Cl (3.2 g, 25.9 mmol) in dry THF
(30 mL), to which the Ni catalyst (260 mg, 1 mmol) was added
15 min before the addition of the enol phosphate. The reaction mix-
ture was then stirred at 0 °C for 1 h, poured into a mixture of 1 
HCl and tert-butyl methyl ether (MTBE) at 0 °C, and extracted
with MTBE; the combined organic layers were washed with satd.
aq. NaHCO3 and brine, dried (MgSO4), and the solvents evapo-
rated. The residue was chromatographed (SiO2; hexanes/EtOAc,
100:0 Ǟ 98:2) to give 2.67 g of product (S)-6 as a pale yellow oil
(69% yield). [α]2D0 ϭ Ϫ11.5 (c ϭ 0.97, CH2Cl2). IR: ν˜ ϭ 3072, 2955,
2906, 1715, 1625, 1458, 1435, 1373, 1249, 1235, 1189, 1159, 1060,
1031, 925, 877, 846, 769, 695, 635 cmϪ1. H NMR: δ ϭ 0.07 [s, 9
H, Si(CH3)3], 1.05 (d, J ϭ 6.9 Hz, 3 H, CH3CH), 1.47Ϫ1.59 (m, 2
H, CH2TMS), 1.68 (br. s, 3 H, CH3Cϭ), 2.03 (br. t, J ϭ 7.5 Hz, 2
1
H, 5-H2), 2.15Ϫ2.21 (m, 1 H, 6-H), 2.40Ϫ2.48 (m, 2 H, 4-H2), 3.69 (2S,6RS)-2-Methyl-γ-cyclogeraniol [(2S,6RS)-21a]: A solution of
(s, 3 H, OCH3), 4.73 (br. s, 1 H, ϭCHH), 4.76 (br. s, 1 H, ϭCHH),
esters 7 (153 mg, 0.78 mmol) in Et2O (8 mL) at 0 °C was added
5.57 (s, 1 H, 2-H) ppm. 13C NMR: δ ϭ Ϫ0.9 (3 ϫ 3), 18.7 (3), 19.6 dropwise via cannula to a solution of DIBALH (1  in hexanes,
(3), 26.5(2), 33.1(2), 38.4 (2), 40.8 (1), 50.4 (3), 110.0 (2), 110.8 (1), 1.7 mL, 1.7 mmol) and the mixture was stirred at 0 °C for 45 min.
149.1 (0), 165.0 (0), 167.6 (0) ppm. GCMS: m/z (%) ϭ 268 (1) [Mϩ],
253 (18), 240 (12), 237 (4), 225 (3), 211 (2), 195 (12), 183 (25), 171
The reaction was quenched with a 1:1 mixture of satd. aq. NH4Cl
and satd. aq. sodium potassium tartrate and the mixture was
(13), 164 (7), 149 (6), 137 (12), 136 (28), 121 (23), 107 (11), 95 (11), stirred at room temperature until clearness (ca. 30 min). After di-
89 (13), 82 (100), 73 (69), 67 (14), 59 (10), 55 (9), 45 (13), 41 (19) lution with Et2O, the mixture was washed with 1  HCl and the
ppm. C15H28O2Si (268.47): calcd. C 67.11, H 10.51; found C 67.26,
H 10.38.
aqueous phase was extracted with Et2O. The combined organic lay-
ers were washed with satd. aq. NaHCO3, followed by brine, dried
(Na2SO4), and the solvents evaporated. Chromatography of the
residue (SiO2; pentane/diethyl ether, 8:2) gave 121 mg of alcohol
21a as a colorless oil (92% yield, GC purity Ͼ 99%, cis/trans,
48:52). [α]2D0 ϭ Ϫ34.1 (c ϭ 0.79, CH2Cl2). IR: ν˜ ϭ 3385, 3070, 2961,
2931, 2880, 1649, 1451, 1389, 1365, 1246, 1195, 1170, 1067, 1046,
1019, 956, 932, 889 cmϪ1. The NMR and MS data of each stereo-
isomer are reported below.
Methyl (2S,6RS)-2-Methyl-γ-cyclogeraniate [(2S,6RS)-7]: A solu-
tion of Hg(OCOCF3)2 (2.14 g, 5 mmol) in deoxygenated CH3CN
(20 mL) was added dropwise via cannula to a solution of diene (S)-
6 (1.28 g, 4.78 mmol) in deoxygenated (Ar bubbling for 30 min)
CH3CN (25 mL) at 0 °C and the mixture was stirred at the same
temperature for 45 min. Deoxygenated brine (15 mL) was added
and the mixture was stirred for 30 min at 0 °C. Finally, a deoxygen-
ated solution of NaBH4 (360 mg, 9.56 mmol) in 15% aq. NaOH
Epoxides 24؊26: Vanadyl acetylacetonate (26.8 mg, 0.1 mmol) and
(15 mL) was added and the mixture was stirred for further 30 min, tert-BuOOH (5.5  in nonane, 0.48 mL, 2.62 mmol) were added to
then transferred into a separating funnel, diluted with abundant a solution of alcohol 21a (cis/trans, 48:52, 340 mg, 2.02 mmol) in
3964
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 3958Ϫ3968

Electrophilic Cyclization of 1,6-Dienes Containing an Allylsilane Moiety
FULL PAPER
dry CH2Cl2 (20 mL) at 0 °C. After stirring at 0 °C for 24 h, the
reaction was quenched by addition of satd. aq. Na2SO3; the mix-
tion of epoxide 24 (97.1 mg, 0.53 mmol) in dry THF (1 mL) was
added dropwise via cannula. After complete addition, stirring was
ture was stirred at room temp. for 15 min, then satd. aq. NaHCO3 continued at room temperature for 4 h. The reaction was then
was added. After separation of the two phases, the aqueous one quenched by dilution with Et2O and careful addition of satd. aq.
was extracted with CH2Cl2 and the combined organic layers were NH4Cl at 0 °C. 1  HCl was then added until two clear phases
washed with brine, dried (Na2SO4), and the solvents evaporated.
Three successive chromatographic purifications (SiO2; hexanes/
EtOAc, 90:10 Ǟ 70:30) of the mixture of epoxides afforded 162 mg
were obtained. After separation of the two phases, the aqueous
phase was extracted with Et2O and the combined organic layers
were washed with satd. aq. NaHCO3 and brine, dried (Na2SO4),
of 24 (91% yield with respect to cis-21a), 137 mg of 25 (71% yield and the solvents evaporated at atmospheric pressure. The crude
with respect to trans-21a), and 20 mg of 26 (10% yield with respect
to trans-21a) in 85% overall yield. Epoxide 24: Colorless oil, [α]2D0
ϩ13.7 (c ϭ 1.0, CH2Cl2). IR: ν˜ ϭ 3490, 2969, 2932, 2877, 2864,
product was adsorbed onto a flash silica gel column for 4 h in order
to allow complete decomposition of the intermediate β-oxystan-
nane, then it was eluted (hexanes/EtOAc, 95:5 Ǟ 90:10) to give
ϭ
1475, 1452, 1423, 1391, 1368, 1339, 1196, 1152, 1102, 1045, 1014, 62.3 mg (70% yield) of cis-21a as a dense colorless oil, [α]2D0
ϭ
1
961, 863, 833, 801, 710 cmϪ1. H NMR: δ ϭ 0.67 (s, 3 H, 1-CH3), Ϫ15.2 (c ϭ 1.0, CH2Cl2) {ref.[4b] [α]2D0 ϭ Ϫ28.5 (c ϭ 1.0, CHCl3)}.
0.88 (d, J ϭ 6.3 Hz, 3 H, 2-CH3), 1.05 (s, 3 H, 1-CH3), 1.28Ϫ1.36 IR: ν˜ ϭ 3661, 2993, 2944, 2876, 1643, 1463, 1385, 1197, 1048, 906
1
(m, 1 H), 1.38Ϫ1.50 (m, 2 H), 1.65Ϫ1.73 (m, 1 H), 1.97 (dd, J ϭ
10 and 2.9 Hz, 1 H), 1.97Ϫ2.09 (m, 1 H), 2.71 (d, J ϭ 3.7 Hz, 1
cmϪ1. H NMR: δ ϭ 0.58 (s, 3 H, 1-CH3), 0.84 (d, J ϭ 7.0 Hz, 3
H, 2-CH3), 1.04 (s, 3 H, 1-CH3), 1.19Ϫ1.34 (m, 2 H), 1.40Ϫ1.53
H), 3.17 (br., 1 H, OH), 3.22 (br. s, 1 H), 3.46 (t, J ϭ 11.2 Hz, 1 (m, 1 H), 1.56Ϫ1.66 (m, 1 H), 1.99Ϫ2.12 (m, 2 H), 2.33 (ddd, J ϭ
H, CHHOH), 3.71 (dd, J ϭ 11.2, 2.8 Hz, 1 H, CHHOH) ppm. 13
NMR: δ ϭ 14.7 (3), 15.0 (3), 26.3 (3), 29.9 (2), 35.3 (2), 37.8 (0),
C
12.8, 4.3, and 3.1 Hz, 1 H), 3.78Ϫ3.94 (m, 2 H, CH2OH), 4.68 (br.
s, 1 H, ϭCHH), 4.97 (br. s, 1 H, ϭCHH) ppm. 13C NMR: δ ϭ
41.3 (1), 50.7 (2), 51.2 (1), 59.3 (2), 61.5 (0) ppm. GCMS: m/z (%) ϭ 14.8 (3), 15.7 (3), 26.4 (3), 32.9 (2), 36.9 (2), 38.1 (0), 42.0 (1), 56.4
184 (2) [Mϩ], 169 (9), 167 (14), 166 (9), 151 (25), 137 (12), 135 (8), (1), 59.5 (2), 106.5 (2), 148.0 (0) ppm. GCMS: m/z (%) ϭ 169 (10)
123 (42), 121 (16), 113 (91), 111 (14), 109 (28), 107 (19), 97 (22),
[M ϩ1ϩ], 151 (100), 150 (42), 149 (11), 137 (20), 135 (49), 125 (12),
96 (36), 95 (55), 93 (29), 91 (27), 83 (68), 82 (37), 81 (99), 79 (49), 123 (33), 122 (14), 121 (18), 111 (19), 109 (48), 107 (51), 97 (15),
77 (25), 70 (23), 69 (51), 67 (54), 55 (69), 53 (28), 43 (44), 42 (20), 95 (89), 94 (26), 93 (31), 91 (21), 83 (72), 81 (69), 79 (39), 70 (18),
41 (100). C11H20O2 (184.28): calcd. C 71.70, H 10.94; found C 69 (23), 67 (45), 65 (16), 57 (15), 55 (66), 53 (20). The spectroscopic
71.88, H 11.13. Epoxide 25: Colorless oil, [α]2D0 ϭ Ϫ12.4 (c ϭ 1.2,
CH2Cl2). IR: ν˜ ϭ 3443, 2964, 2929, 2877, 1463, 1449, 1390, 1367,
1294, 1199, 1150, 1104, 1074, 1046, 1022, 998, 966, 938, 888, 844,
data are consistent with the literature data.[4b]
(2S,6S)-trans-2-Methyl-γ-cyclogeraniol (trans-21a): trans-21a was
prepared from epoxides 25 and 26, separately, by using the same
procedure described above for cis-21a. Compound 25 (120 mg,
0.65 mmol) gave 76.7 mg (70% yield) of trans-21a, whereas 26
(19 mg, mmol) afforded 12 mg (69% yield) of the same product;
white solid, m.p. 30Ϫ33 °C (ref.[4b] m.p. 34Ϫ38 °C). [α]2D0 ϭ Ϫ42.9
(c ϭ 0.87, CH2Cl2) {ref.[4b] [α]2D0 ϭ Ϫ34.0 (c ϭ 0.95, CHCl3)}. IR
(KBr): ν˜ ϭ 3663, 3075, 2992, 2941, 1644, 1467, 1389, 1049, 903
1
816, 752 cmϪ1. H NMR: δ ϭ 0.85 (d, J ϭ 6.4 Hz, 3 H, 2-CH3),
0.95 (s, 3 H, 1-CH3), 1.00 (s, 3 H, 1-CH3), 1.18Ϫ1.30 (m, 2 H),
1.40Ϫ1.54 (m, 2 H), 1.62Ϫ1.70 (m, 1 H), 2.10Ϫ2.24 (m, 1 H),
2.64Ϫ2.74 (m, 3 H), 3.79Ϫ3.90 (m, 1 H, CHHOH), 4.09 (br. t, J ϭ
10.2 Hz, 1 H, CHHOH) ppm. 13C NMR: δ ϭ 15.7 (3), 21.9 (3),
27.5 (3), 29.9 (2), 30.3 (2), 36.1 (1), 37.9 (0), 54.7 (1), 55.6 (2) 61.0
(0), 61.9 (2) ppm. GCMS: m/z (%) ϭ 184 (2) [Mϩ], 169 (25), 167
(21), 151 (38), 139 (10), 137 (27), 123 (72), 121 (31), 113 (82), 111
(18), 109 (26), 107 (25), 97 (22), 96 (30), 95 (52), 93 (45), 91 (36),
83 (55), 82 (20), 81 (100), 79 (73), 77 (33), 70 (25), 69 (54), 67 (56),
65 (21), 55 (66), 53 (26), 43 (42), 42 (20), 41 (96). C11H20O2
(184.28): calcd. C 71.70, H 10.94; found C 71.88, H 11.23. Epoxide
26: Colorless oil, [α]2D0 ϭ Ϫ3.8 (c ϭ 1.0, CH2Cl2). IR: ν˜ ϭ 3417,
2960, 2930, 2875, 1462, 1433, 1390, 1373, 1366, 1287, 1276, 1206,
1126, 1071, 1048, 1021, 998, 959, 922, 902, 836, 813, 740 cmϪ1. 1H
NMR: δ ϭ 0.95 (s, 3 H, 1-CH3), 0.99 (d, J ϭ 6.7 Hz, 3 H, 2-CH3),
1.02 (s, 3 H, 1-CH3), 1.47Ϫ1.83 (m, 6 H, 2-H, 3-H, 4-H, OH), 2.25
(m, 1 H, 6-H), 2.63 (d, J ϭ 4.2 Hz, 1 H, epoxide-H), 2.99 (d, J ϭ
4.2 Hz, 1 H, epoxide-HЈ), 3.65 (t, J ϭ 11.4 Hz, 1 H, CHHOH),
3.74 (dd, J ϭ 11.4, 4.3 Hz, 1 H, CHHOH) ppm. 13C NMR: δ ϭ
15.5 (3), 25.1 (3), 26.0 (3), 28.8 (2), 30.6 (2), 37.6 (0), 38.5 (1), 49.9
(1), 52.0 (2), 61.3 (2), 63.8 (0) ppm. GCMS: m/z (%) ϭ 184 (2)
[Mϩ], 169 (25), 152 (11), 151 (39), 137 (12), 127 (9), 123 (34), 121
(18), 113 (90), 111 (12), 109 (24), 107 (19), 105 (11), 97 (20), 96
(35), 95 (48), 93 (30), 91 (30), 83 (58), 82 (22), 81 (91), 79 (49), 77
(28), 71 (20), 70 (25), 69 (52), 67 (53), 65 (19), 55 (70), 53 (28), 43
(43), 42 (20), 41 (100). C11H20O2 (184.28): calcd. C 71.70, H 10.94;
found C 71.60, H 11.17.
1
cmϪ1. H NMR: δ ϭ 0.81 (s, 3 H, 1-CH3), 0.82 (d, J ϭ 7.0 Hz, 3
H, 2-CH3), 0.95 (s, 3 H, 1-CH3), 1.25Ϫ1.38 (m, 2 H), 1.50Ϫ1.63
(m, 2 H), 2.03 (dd, J ϭ 10.0, 6.1 Hz, 1 H), 2.20 (dd, J ϭ 8.6, 3.3 Hz,
2 H), 3.62Ϫ3.70 (m, 2 H, CH2OH), 4.76 (s, 1 H, ϭCHH), 4.93 (s,
1 H, ϭCHH) ppm. GCMS: m/z (%) ϭ 169 (15) [M ϩ 1ϩ], 152
(12), 151 (100), 150 (21), 137 (34), 135 (37), 125 (12), 123 (22), 122
(13), 121 (15), 109 (36), 107 (40), 95 (96), 94 (21), 93 (28), 91 (18),
83 (47), 81 (68), 79 (38), 70 (17), 69 (22), 67 (40), 57 (15), 55 (42),
53 (18). The spectroscopic data are consistent with the literature da-
ta.[4b]
(2S,6R)-cis-2-Methyl-γ-cyclocitral (27): A solution of dry DMSO
(70 mg, 0.9 mmol) in dry CH2Cl2 (2 mL) was added dropwise to a
solution of freshly distilled (COCl)2 (68.5 mg, 0.54 mmol) in dry
CH2Cl2 (5 mL) at Ϫ78 °C. The mixture was stirred at Ϫ78 °C for
15 min, then a solution of alcohol cis-21a (60.0 mg, 0.36 mmol) in
dry CH2Cl2 (3 mL) was added dropwise. The solution was stirred
at Ϫ78 °C for further 30 min, then freshly distilled DIPEA (209 mg,
1.62 mmol) was added and stirring was maintained for 2 h while
warming to Ϫ20 °C. The reaction was quenched by addition of
water; after extraction with CH2Cl2, the combined organic layers
were washed with brine, dried (Na2SO4), and the solvents evapo-
rated at 300 Torr. The crude product was purified by flash silica
gel column chromatography (pentane/Et2O, 95:5) to give aldehyde
27 (51.6 mg, 86.3% yield) as a colorless oil, [α]2D0 ϭ ϩ54 (c ϭ 1.00,
CH2Cl2) {ref.[4b] [α]2D0 ϭ ϩ24.8 (c ϭ 1.15, CCl4) for a sample of
76% ee}. IR: ν˜ ϭ 3110, 2964, 2755, 1732, 1658, 1465, 1398, 1377,
(2S,6R)-cis-2-Methyl-γ-cyclogeraniol (cis-21a): BuLi (1.6  solution
in hexanes, 1.33 mL, 2.13 mmol) was added dropwise to a solution
of bis(tributyltin) (1.23 g, 2.13 mmol) in dry THF (1.5 mL) at 0 °C.
The resulting yellow solution was stirred at 0 °C for 15 min, then
AlMe3 (2  solution in toluene, 1.06 mL, 2.12 mmol) was added
dropwise. Stirring was maintained at 0 °C for 15 min, then a solu-
1
904 cmϪ1. H NMR: δ ϭ 0.86 (d, J ϭ 7.0 Hz, 3 H, 2-CH3), 0.98
Eur. J. Org. Chem. 2003, 3958Ϫ3968
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3965

S. Beszant, E. Giannini, G. Zanoni, G. Vidari
FULL PAPER
(s, 3 H, 1-CH3), 1.00 (s, 3 H, 1-CH3), 1.17Ϫ1.45 (m, 2 H), H2), 2.25 (s, 3 H, 10-H3), 2.65 (d, J ϭ 9.1 Hz, 1 H, 6-H), 4.66 (br.
1.54Ϫ1.62 (m, 1 H), 2.10 (br. t, J ϭ 13.1 Hz, 1 H, 4-H), 2.34 (dt, s, 1 H, ϭCHH), 4.75 (br. s, 1 H, ϭCHH), 6.11 (d, J ϭ 15.7 Hz, 1
J ϭ 13.1, 3.1 Hz, 1 H, 4-HЈ), 2.55 (br. d, J ϭ 4.8 Hz, 1 H, 6-H), H, 8-H), 7.09 (dd, J ϭ 15.7, 9.1 Hz, 1 H, 7-H) ppm. 13C NMR:
4.52 (s, 1 H, ϭCHH), 4.93 (s, 1 H, ϭCHH), 9.92 (d, J ϭ 4.8 Hz,
δ ϭ 15.5 (3), 21.4 (3), 27.0 (3), 27.3 (3), 31.4 (2 ϫ 2), 36.2 (1), 37.6
1 H, CHO) ppm. 13C NMR: δ ϭ 14.9 (3), 15.2 (3), 27.1 (3), 31.5 (0), 59.5 (1), 110.4 (2), 131.8 (1), 147.4 (1), 147.9 (0), 198.3 (0) ppm.
(2), 36.0 (2), 37.9 (0), 41.6 (1), 65.2 (1), 109.4 (2), 145.1 (0), 205.3 GCMS: m/z (%) ϭ 206 (2) [Mϩ], 191 (4), 178 (8), 163 (29), 149
(1) ppm. GCMS: m/z (%) ϭ 166 (2) [Mϩ], 151 (28), 137 (17), 135
(21), 145 (9), 135 (10), 133 (6), 121 (58), 109 (28), 107 (24), 105
(16), 133 (12), 123 (32), 122 (20), 109 (43), 108 (23), 107 (22), 96 (12), 95 (9), 93 (18), 91 (26), 83 (17), 81 (38), 79 (28), 77 (23), 65
(20), 95 (100), 93 (24), 91 (26), 84 (25), 83 (42), 82 (45), 81 (64), 79
(44), 77 (26), 69 (23), 67 (55), 65 (20), 55 (81), 53 (38), 51 (17), 41
(15), 55 (39), 43 (100), 41 (42). The spectroscopic data are consist-
ent with the literature data.[4b] The ee of cis-γ-irone (4) was esti-
(92). The spectroscopic data are consistent with the literature da- mated by enantioselective GC analysis with a DMePeBETACDX
ta.[4b]
column (25 m, 0.25 mm i.d., 0.25 µm f.t.); carrier gas ϭ He, split
1:50, flow ϭ 1 mL/min; detector: FID; temperature program: 80
(2S,6S)-trans--2-Methyl-γ-cyclocitral (28): DessϪMartin periodin-
ane reagent[23] (44.8 mg, 0.10 mmol) was added to a solution of
alcohol trans-21a (14.8 mg, 0.088 mmol) in dry CH2Cl2 (2 mL) and
the solution was stirred at room temperature for 2 h. The reaction
mixture was then diluted with Et2O and filtered through a pad of
silica gel and Celite washing thoroughly with a mixture of pentane/
Et2O in a ratio of 8:2. The solution was concentrated at 300 Torr
and the residue was purified by flash silica gel column chromatog-
raphy (pentane/Et2O, 9:11 Ǟ 8:2) to give aldehyde 28 (14.0 mg,
°C (0 min), then 2°C/min to 160 °C (5 min); (2R,6S)-cis-4, tR
ϭ
39.6 min; (2S,6R)-cis-4, tR ϭ 40.0 min. The ee of trans-γ-irone 5
was estimated by enantioselective HPLC analysis with a Chiralcel
OD column (4.6 ϫ 250 mm). UV detector (254 nm); hexane/
iPrOH ϭ 99:1, 0.6 mL/min; (2R,6R)-trans-5, tR ϭ 23.6 min;
(2S,6S)-trans-5, tR ϭ 26.6 min.
Methyl (Z)-Ester 15: A solution of methyl acetoacetate (6.3 g,
54.0 mmol) in dry THF (50 mL) was added dropwise to NaH (60%
dispersion in mineral oil, 2.38 g, 59.4 mmol) in THF (100 mL) at
96% yield, GC purity Ͼ 99%, de ϭ 98%) as a colorless oil. [α]2D0
ϭ
Ϫ127 (c ϭ 0.7, CH2Cl2) {ref.[4b] [α]2D0 ϭ Ϫ82.6 (c ϭ 1.1, CCl4) for 0 °C and the mixture was stirred for 15 min at the same tempera-
a sample of 76% ee}. IR: ν˜ ϭ 3109, 2962, 2753, 1734, 1656, 1465,
ture. BuLi (2.5  solution in hexanes, 22.7 mL, 56.7 mmol) was
1400, 1375, 901 cmϪ1. 1H NMR: δ ϭ 0.83 (s, 3 H, 1-CH3), 0.88 (d, then added dropwise and the mixture was stirred at 0 °C for an
J ϭ 7.0 Hz, 3 H, 2-CH3), 1.11 (s, 3 H, 1-CH3), 1.24Ϫ1.43 (m, 1 additional 15 min. To the resulting orange solution freshly pre-
H), 1.59Ϫ1.70 (m, 1 H), 1.80Ϫ1.94 (m, 1 H), 2.26Ϫ2.37 (m, 2 H, pared bromide 16[13] (8.8 g, 54.0 mmol) was added dropwise and
4-H2), 2.75 (d, J ϭ 3.4 Hz, 1 H, 6-H), 4.77 (s, 1 H, ϭCHH), 4.95
the mixture was stirred for 1 h while warming to room temperature,
(s, 1 H, ϭCHH), 9.89 (d, J ϭ 3.5 Hz, 1 H, CHO) ppm. 13C NMR: then it was cooled to 0 °C and diethyl chlorophosphate (9.8 g,
δ ϭ 15.5 (3), 20.9 (3), 26.4 (3), 31.2 (2), 32.6 (2), 37.0 (1), 37.6 (0),
69.2 (1), 113.3 (2), 142.9 (0), 202.6 (1) ppm. GCMS: m/z (%) ϭ 166
56.7 mmol) was added dropwise. The resulting mixture was stirred
for an additional 1.5 h while warming to room temperature, then
(4) [Mϩ], 151 (8), 137 (23), 135 (28), 133 (10), 123 (20), 121 (7), it was slowly added via cannula to a mixture of Me3SiCH2MgCl
109 (31), 108 (28), 107 (15), 96 (20), 95 (100), 93 (19), 91 (22), 83
and Ni(acac)2 at 0 °C, prepared meanwhile from Mg (2.23 g,
(34), 82 (16), 81 (55), 79 (43), 77 (32), 69 (13), 67 (47), 65 (14), 55 91.8 mmol) and Me3SiCH2Cl (11.3 g, 91.8 mmol) in dry Et2O
(53), 53 (23), 51 (15), 43 (12), 41 (65). The spectroscopic data are (90 mL), to which the Ni catalyst (971 mg, 3.78 mmol) was added
consistent with the literature data.[4b]
15 min before the addition of the enol phosphate. After complete
addition (30 min), the mixture was stirred at 0 °C for 1 h and
eventually poured into a mixture of 1  aq. HCl and Et2O at 0 °C
under vigorous stirring; the separated organic phase was washed
with a further portion of 1  HCl, and the aqueous phase was
extracted with Et2O. The combined organic layers were washed
with brine, dried (Na2SO4), and the solvents evaporated. Separ-
ation of the crude product by flash silica gel column chromatogra-
phy (hexanes/EtOAc, 100:0 Ǟ 98:2) gave 6.04 g of ester 15 as a
pale yellow oil (42% yield). IR: ν˜ ϭ 2952, 2863, 1716, 1625, 1504,
(؊)-(2S,6R)-cis-γ-Irone (4) and (؊)-(2S,6S)-trans-γ-Irone (5): Alde-
hydes 27 (50 mg, 0.30 mmol) and 28 (14 mg, 0.08 mmol) were sep-
arately submitted to Monti’s procedure[4m] to afford cis-γ-irone (4)
(43.3 mg, 70% yield) and trans-γ-irone (5) (11.9 mg, 72% yield),
respectively. The cis-isomer 4 [de ϭ 94% (GC), ee Ͼ 99% (GC)]
was obtained as a colorless oil with an intense and distinctive Iris
fragrance. [α]2D0 ϭ Ϫ6.4 (c ϭ 1.06, CH2Cl2).[24] IR: ν˜ ϭ 2993, 2940,
2866, 1678, 1655, 1629, 1365, 1253, 997, 896 cmϪ1. H NMR: δ ϭ
1
1435, 1371, 1249, 1235, 1190, 1158, 1035, 926, 844, 695, 630 cmϪ1
.
0.74 (s, 3 H, 1-CH3), 0.88 (d, J ϭ 6.5 Hz, 3 H, 2-CH3), 0.89 (s, 3
H, 1-CH3), 1.26Ϫ1.62 (m, 3 H), 2.07 (br. td, J ϭ 13.4, 5.2 Hz, 1
H, 4-H), 2.30 (s, 3 H, 10-H3), 2.35 (ddd, J ϭ 13.4, 4.3, 2.5 Hz, 1
H, 4-HЈ), 2.57 (d, J ϭ 10.4 Hz, 1 H, 6-H), 4.45 (br. s, 1 H, ϭCHH),
4.81 (br. s, 1 H, ϭCHH), 6.11 (d, J ϭ 15.8 Hz, 1 H, 8-H), 6.95 (dd,
J ϭ 15.8, 10.4 Hz, 1 H, 7-H) ppm. 13C NMR: δ ϭ 14.3 (3), 15.8
(3), 27.2 (3), 27.6 (3), 31.9 (2), 36.2 (2), 38.8 (0), 42.0 (1), 57.8 (1),
108.7 (2), 133.6 (1), 147.1 (1), 148.8 (0), 198.0 (0) ppm. GCMS:
m/z (%) ϭ 206 (3) [Mϩ], 191 (5), 173 (5), 163 (22), 149 (33), 145
(8), 135 (7), 133 (8), 121 (82), 109 (24), 107 (25), 105 (12), 95 (9),
93 (18), 92 (10), 91 (28), 83 (19), 81 (35), 79 (27), 77 (22), 65 (15),
55 (39), 43 (100), 41 (44). The spectroscopic data are consistent
with the literature data.[4b] The trans isomer 5 [de ϭ 97% (GC), ee
1H NMR: δ ϭ 0.05 [s, 3 ϫ 3 H, Si(CH3)3], 1.62 [s, 3 ϫ 3 H,
CH3CϭϭC(CH3)2], 2.02Ϫ2.21 (m, 4 H, CH2CH2), 2.42 (s, 2 H,
CH2Si), 3.63 (s, 3 H, OCH3), 5.53 (s, 1 H, ϭCH) ppm. 13C NMR:
δ ϭ Ϫ1.0 (3 ϫ 3), 18.3 (3), 19.9 (3), 20.5 (3), 26.1 (2), 33.4 (2), 39.1
(2), 50.3 (3), 110.8 (1), 125.0 (0), 126.3 (0), 164.8 (0), 167.6 (0) ppm.
GCMS: m/z (%) ϭ 268 (2) [Mϩ], 253 (19), 237 (5), 194 (8), 186
(11), 171 (22), 164 (12), 149 (26), 136 (15), 122 (16), 121 (60), 120
(14), 107 (17), 93 (18), 89 (21), 83 (46), 82 (76), 73 (100), 67 (12),
59 (11), 55 (44), 45 (24), 43 (13), 41 (25). C15H28O2Si (268.47):
calcd. C 67.11, H 10.51; found C 67.22, H 10.43.
Methyl (؎)-(2RS,6RS)-2-Methyl-γ-cyclogeraniate [(؎)-cis-7 and
Ͼ 99% (HPLC)] was obtained as a colorless oil with a very weak (؎)-trans-7]. (a) Procedure A: SnCl4 (1  in CH2Cl2, 26.9 mL,
fragrance. [α]2D0 ϭ Ϫ61.4 (c ϭ 0.37, CH2Cl2).[25] IR ν˜ ϭ 2961, 2940,
26.9 mmol) was added to a solution of diene 15 (1.80 g, 6.70 mmol)
1683, 1622, 1365, 1256, 987, 895 cmϪ1 1H NMR: δ ϭ 0.83 (s, 3 in CH2Cl2 (70 mL), saturated with H2O at Ϫ30 °C. The mixture
H, 1-CH3), 0.88 (d, J ϭ 6.6 Hz, 3 H, 2-CH3), 0.90 (s, 3 H, 1-CH3), was stirred between Ϫ30 °C and Ϫ20 °C for 2 h, then quenched
1.23Ϫ1.40 (m, 1 H), 1.55Ϫ1.73 (m, 2 H), 2.21Ϫ2.27 (m, 2 H, 4- with satd. aq. NaHCO3, and stirred at room temperature for
.
3966
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3958Ϫ3968

Electrophilic Cyclization of 1,6-Dienes Containing an Allylsilane Moiety
FULL PAPER
K. Kogami, K. Hayashi, Bull. Chem. Soc., Jpn. 1985, 58,
further 15 min. The mixture was transferred into a separating fu-
nnel, diluted with CH2Cl2 and washed with 1  HCl until two clear
phases were obtained. The phases were separated, the organic
phase was washed with a further portion of 1  HCl and the aque-
ous phase was extracted with CH2Cl2; the combined organic layers
were washed with satd. aq. NaHCO3, followed by brine, dried
(Na2SO4), and the solvents evaporated at atmospheric pressure.
Purification of the crude product by flash silica gel column chroma-
tography (hexanes/EtOAc, 98:2 Ǟ 96:4) gave product (Ϯ)-7 as a
389Ϫ390. [4k] T. Kawanobe, M. Iwamoto, K. Kogami, M. Mat-
sui, Agric. Biol. Chem. 1987, 51, 791Ϫ796; ref.[2f] (Ϫ)-cis-γ-
[4l]
Irone:
T. Inoue, H. Kiyota, T. Oritani, Tetrahedron: Asym-
metry 2000, 11, 3807Ϫ3818; ref.[3] (ϩ)-cis-γ-Irone: ref.[4l] [4m] G.
Laval, G. Audran, J-M. Galano, H. Monti, J. Org. Chem. 2000,
65, 3551Ϫ3554; ref.[3]
;
(Ϯ)-cis-γ-Irone: ref.[4k]
C.
[4n]
´
Nussbaumer, G. Frater, Helv. Chim. Acta 1988, 71, 619Ϫ623.
[4o]
´
H. Monti, G. Laval, M. Feraud, Eur. J. Org. Chem. 1999,
1825Ϫ1829.
[5]
pale yellow oil (1.12 g, 85% yield; trans/cis ϭ 1.5:1). Spectroscopic
R. W. Hoffmann, Chem. Rev. 1989, 89, 1841Ϫ1860.
[6] [6a]
data match those of enantiomerically pure diastereomers reported
above. (b) Procedure B: Diene ester 15 (1.2 g, 4.5 mmol) was ex-
posed to a solution of Hg(OCOCF3)2 in deoxygenated CH3CN at
Ϫ40 °C according to the procedure described for the cyclization of
ester (S)-6 (see above). Workup of the reaction mixture and chrom-
atographic separation of the crude mixture afforded, in the order,
compound (Ϯ)-7 (0.50 g, 57% yield; trans/cis ϭ 1:7) and the desilyl-
J. K. Sutherland, ‘‘Polyene cyclizations’’ in Comprehensive
Organic Synthesis (Eds.: B. M. Trost, I. Fleming) Pergamon
Press, Oxford, New York, Seoul, Tokyo, 1991, vol. 3, p.
341Ϫ377. [6b]E. Langkopf, D. Schinzer, Chem. Rev. 1995, 95,
1375Ϫ1408.
[7a] I. Fleming, A. Pearce, R. L. Snowden, J. Chem. Soc., Chem.
[7]
Commun. 1976, 182Ϫ183. [7b] R. J. Armstrong, F. L. Harris, L.
[7c]
Weiler, Can. J. Chem. 1982, 60, 673Ϫ675.
L. Weiler, Can. J. Chem. 1983, 61, 2530Ϫ2539.
R. J. Armstrong,
1
ated ester 22 (154.3 mg, 17.5% yield), as a colorless oil. H NMR:
[7d]
G. Vidari,
δ ϭ 1.68 [s, 3 ϫ 3 H, CH3CϭC(CH3)2], 2.10Ϫ2.25 (m, 4 H,
CH2CH2), 3.12 (s, 2 H, CH2COOCH3), 3.75 (s, 3 H, OCH3), 4.90
(s, 1 H, ϭCHH), 4.95 (s, 1 H, ϭCHH) ppm. GCMS: m/z (%) ϭ
196 (2) [Mϩ], 140 (18), 136 (24), 123 (13), 121 (13), 107 (13), 83
(89), 81 (29), 67 (22), 55 (100), 41 (36).
G. Lanfranchi, F. Masciaga, J-D. Meriggi, Tetrahedron: Asym-
metry 1996, 7, 3009Ϫ3020.
[8]
For electrophilic cyclizations of dienes in irone synthesis, see:
[8a]
C. Chapuis, K. H. Schulte-Elte, Helv. Chim. Acta 1995, 78,
165Ϫ176. [8b] K. H. Schulte-Elte, H. Pamingle, A. P. Uijttewal,
R. L. Snowden, Helv. Chim. Acta 1992, 75, 759Ϫ765 and refer-
ences cited therein. [8c] S. Torii, K. Uneyama, S. J. Matsunami,
J. Org. Chem. 1980, 45, 16Ϫ20.
[9]
J. C. Hanekamp, R. B. Rookhulzen, H. J. T. Bos, L. Brandsma,
Tetrahedron 1992, 48, 5151Ϫ5162.
T. Suga, S. Ohta, T. Ohmoto, J. Chem. Soc., Perkin Trans. 1
1987, 2845Ϫ2848.
Acknowledgments
We thank the Italian MIUR (funds PRIN) and the University of
Pavia (funds FAR) for financial support, and Professor Mariella
Mella and Dr. Marina Ricci for the NMR and MS spectra, respec-
tively.
[10]
[11]
J. D. White, G. N. Reddy, G. O. Spessard, J. Chem. Soc., Perkin
Trans. 1 1993, 759Ϫ767.
[12] [12a]
S. N. Huckin, L. Weiler, J. Am. Chem. Soc. 1974, 96,
[12b]
1082Ϫ1087.
Supplement I, 303Ϫ317.
F. W. Sum, L. Weiler, Tetrahedron 1981, 37,
[13]
[14]
[15]
[16]
[1] [1a]
E. L. Clennan, X. Chen, J. Am. Chem. Soc. 1989, 111,
5787Ϫ5792.
A. Tschirsch, ‘‘Rizoma Iridis’’, in Handbuch der Pharma-
[1b]
kognosie, C. H. Tachnitz Verlag, Leipzig, 1917, p. 1143.
G.
Ohloff, in Scent and Fragrancies, Springer-Verlag, Berlin-Heid-
elberg, 1994; p. 164. [1c]L. Jaenicke, F. J. Marner, Pure Appl.
Chem. 1990, 62, 1365Ϫ1368.
S. Beszant, E. Giannini, G. Zanoni, G. Vidari, Tetrahedron:
Asymmetry 2002, 13, 1245Ϫ1255.
1
The H NMR spectrum (δ4-H ϭ 5.55 ppm; δ5-Me ϭ 1.68 ppm)
[2] [2a]
W. Krick, F. J. Marner, L. Jaenicke, Helv. Chim. Acta 1984,
revealed also the presence (ca.15%) of the endocyclic olefin 7a.
67, 318Ϫ323. [2b] V. Rautenstrauch, B. Willhalm, W. Thommen,
The relative stereochemistry of compound 7 and derivatives
[2c]
G. Ohloff, Helv. Chim. Acta 1984, 67, 325Ϫ331.
F. J.
can easily be assigned on the basis of the chemical shift values
[2d]
Marner, L. Jaenicke, Helv. Chim. Acta 1989, 72, 287Ϫ294.
[16a]
´ ´
J.-P. Pillot, G. Deleris, J. Dunog-
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F. J. Marner, T. Runge, W. A. König, Helv. Chim. Acta 1990,
[16b]
`
ues, R. Calas, J. Org. Chem. 1979, 44, 3397Ϫ3400.
M. G.
[2e]
´
A. Galfre, P. Martin, M. Petrizlka, J. Ess-
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Organ, D. D. Winkle, J. Huffmann, J. Org. Chem. 1997, 62,
5254Ϫ5266). In cis-7 these two proton signals are separated
farther than in trans-7 (δ ϭ 4.67 and 4.85 ppm vs. δ ϭ 4.76
and 4.85 ppm, respectively).
To this purpose, cyclizations promoted by ‘‘onio’’ species re-
semble those initiated by protonation of the terminal epoxide
of a polyolefin; see: ref.[6a] and: [17a] R. J. Armstrong, L. Weiler,
Can. J. Chem. 1986, 64, 584Ϫ596 and references cited therein.
[2f]
E. Brenna, C. Fuganti, S.
[2g]
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[3]
[4]
E. Brenna, M. Delmonte, C. Fuganti, S. Serra, Helv. Chim.
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(Ϫ)-trans-γ-Irone ϩ (ϩ)-trans-α-irone:
D. Helmlinger, G.
`
Frater, Helv. Chim. Acta 1989, 72, 1515Ϫ1521. (Ϫ)-trans-γ-
Irone ϩ (Ϫ)-cis-γ-irone (separated by prep. GC): [4b]C. Chap-
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trans-γ-Irone: ref.[2f] (ϩ)-trans-γ-Irone [(Z)/(E) mixture]: [4c] M.
[18] [18a]
M. Kurbanov, A. V. Semenovsky, W. A. Smit, L. V. Shme-
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Chem. 1981, 46, 3550Ϫ3552. [18d] M. Nishizawa, H. Takenaka,
Miyashita, N. Makino, M. Singh, A. Yoshikoshi, J. Chem. Soc.,
[4d]
Perkin Trans. 1 1982, 1303Ϫ1309. (ϩ)-trans-γ-Irone:
H.
H. Nishide, Y. Hayashi, Tetrahedron Lett. 1983, 24,
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[18e]
61, 6021Ϫ6023; ref.[2f] (Ϯ)-trans-γ-Irone ϩ (Ϯ)-cis-γ-irone:
[4e]
2581Ϫ2584.
M. Nishizawa, H. Takenaka, Y. Hayashi, J.
[18f]
Org. Chem. 1986, 51, 806Ϫ813.
M. Nishizawa, H. Tak-
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43, 85Ϫ92.
[4f]
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Interestingly, reduction of a cis/trans ϭ 1:2 mixture of com-
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compound 21a.
F. Leyendecker, M.-T. Comte, Tetrahedron 1987,
[4g]
P. Gosselin, A. Perrotin, S. Mille, Tetrahedron
[4h]
[19]
2001, 57, 733Ϫ738. (Ϯ)-trans-γ-Irone:
H. Favre, H. Schinz,
[4i]
Helv. Chim. Acta 1958, 41, 1368Ϫ1376.
J. Garnero, D. Jou-
lain, Bull. Soc. Chim. Fr. 1979, II-15ϪII-16. [4j]O. Takazawa,
Eur. J. Org. Chem. 2003, 3958Ϫ3968
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3967

S. Beszant, E. Giannini, G. Zanoni, G. Vidari
FULL PAPER
[20] [20a] Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. KO, H. Masa-
Available reference data: [α]2D0 ϭ Ϫ5.4 (c ϭ 1.66, CH2Cl2), ee ϭ
76%.[4b] [α]D Ͻ Ϫ2, ee ϭ 99%.[4l] [α]2D0 ϭ Ϫ6.3 (c ϭ 1.05,
CH2Cl2), ee ϭ 97%.[3]
[24]
[25]
mune, K. B. Sharpless, J. Am. Chem. Soc. 1987, 109,
[20b]
5765Ϫ5780.
V. S. Martin, S. S. Woodard, T. Kabuki, Y.
Yamada, M. Ikeda, K. B. Sharpless, J. Am. Chem. Soc. 1981,
Available reference data: [α]2D0 ϭ Ϫ43.3 (c ϭ 0.8, CH2Cl2), ee ϭ
103, 6237Ϫ6240.
K. B. Sharpless, T. R. Verhoeven, Aldrichim. Acta 1979, 12,
63Ϫ74.
S. Matsubara, T. Nonaka, Y. Okuda, S. Kanemoto, K. Oshima,
H. Nozaki, Bull. Chem. Soc. Jpn. 1985, 58, 1480Ϫ1483.
D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113,
7277Ϫ7287.
70%;[4a] [α]D20 ϭ Ϫ53.4 (c ϭ 2.34, CHCl3), ee ϭ 76%;[4b] [α]2D0
ϭ
[21]
[22]
[23]
Ϫ81 (c ϭ 1.0, CH2Cl2), ee Ͼ 99%[2e]
.
Received May 8, 2003
Early View Article
Published Online September 10, 2003
3968
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3958Ϫ3968