Stereoselective synthesis of cyclohexa-2,4-dien-1-ones and cyclohex-2-en-1-ones from phenols

Article abstract of DOI:10.1016/j.tetasy.2006.06.017

A convenient synthetic method for the synthesis of substituted cyclohex-2-en-1-ones by the direct alkylation of phenols has been developed. Furthermore, enantiomerically enriched 2,6-dimethyl-6-(3-methylbut-2-enyl)-cyclohexa-2,4-dienone was prepared by th

Full text of DOI:10.1016/j.tetasy.2006.06.017

Tetrahedron: Asymmetry 17 (2006) 1693–1699
Stereoselective synthesis of cyclohexa-2,4-dien-1-ones and
cyclohex-2-en-1-ones from phenols
a,b,
Martin A. Lovchik,a Andreas Goekeb,c and Georg Frater
*
´
aUniversity of Zurich, 8057 Zurich, Switzerland
bGivaudan Schweiz AG, 8600 Duebendorf, Switzerland
cShanghai Givaudan Ltd, 201203 Shanghai, China
Received 2 May 2006; accepted 5 June 2006
Abstract—A convenient synthetic method for the synthesis of substituted cyclohex-2-en-1-ones by the direct alkylation of phenols has been
developed. Furthermore, enantiomerically enriched 2,6-dimethyl-6-(3-methylbut-2-enyl)-cyclohexa-2,4-dienone was prepared by the
deprotonation of 2,6-dimethylphenol with a sparteine–lithium complex followed by alkylation with 1-chloro-3-methylbut-2-ene. 2,6-
Dimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-enone was prepared from the corresponding cyclohexa-2,4-dien-1-one by selective hydroge-
nation of the 4,5-double bond. The method was extended to 2-methyl-naphthalen-1-ol and 1-methyl-naphthalen-2-ol resulting in 2-(R)-
methyl-2-(3-methylbut-2-enyl)-2H-naphthalen-1-one and 1-(S)-methyl-1-(3-methylbut-2-enyl)-1H-naphthalen-2-one, respectively.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
During the investigation of the Lewis-acid catalyzed rear-
rangements of allyl cyclohexenones,6 we developed a conve-
nient multi-gram synthesis of olfactorily interesting tri- and
tetraalkylated cyclohex-2-en-1-ones by a simple C-alkyl-
ation/hydrogenation sequence (Table 1). This straightfor-
ward route also prompted us to investigate the possibility
of introducing optical activity in the intermediate cyclo-
hexa-2,4-dien-1-ones by deprotonation of phenols with a
chiral base. To access this novel strategy, chiral lithium
amide bases and amine complexes were applied, which have
been successfully used by other groups in a variety of enan-
tioselective deprotonation reactions.7,10
Cyclohexenones belong to the standard skeletons in
organic chemistry but short syntheses of chiral gem-disub-
stituted derivatives remain scarce. Chiral 3,6,6-trialkylated
and 3,4,4-trialkylated cyclohex-2-en-1-ones are accessible
through intramolecular aldol condensation of a,a-disubsti-
tuted-2,6-heptane-diones.1a The chemoselectivity can be
controlled by choosing appropriate reaction conditions.1b
Cyclohexa-2,4-dienones, which were used in various natu-
ral product synthesis,2 are accessible by direct alkylation
of ortho substituted phenols.3 Optically active cyclohexa-
dienones can be prepared by a multistep route involving
an asymmetric variation of the Birch reduction–alkylation
reaction.4 To the best of our knowledge, the specific and
enantioselective alkylation of phenolates leading to opti-
cally active cyclohexadienones has not been described.
We herein report the results of both the alkylation/hydro-
genation protocol and the first asymmetric alkylation of
phenols and naphthols resulting in optically active cyclo-
hexa-2,4-dien-1-ones.
2,6-Dialkylated phenoxide ions can act as ambident cyclic
ketone enolates and can be C-alkylated under aprotic condi-
tions, leading to cyclohexa-2,4-dien-1-ones with a new
quaternary stereogenic center at C(6).3 Earlier attempts to
selectively hydrogenate the 4,5-double bond generated allyl-
phenols by Pd-catalyzed sigmatropic rearrangements.5
2. Results and discussion
Substituted phenols 1a–c were deprotonated with NaH in
toluene, followed by alkylation with alkyl and benzyl chlo-
rides 2. Care had to be taken to keep the temperature at
about 15 ꢁC during the alkylation to minimize the rear-
rangement of the 6-allyl cyclohexadienones into allyl-
phenols. In order to avoid isolation of the thermally
*
Corresponding author. Tel.: +41 44 824 2371; e-mail: georg.frater@
givaudan.com
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.06.017

1694
M. A. Lovchik et al. / Tetrahedron: Asymmetry 17 (2006) 1693–1699
Table 1. Synthesis of substituted cyclohexenones by direct alkylation of
phenols
In the first attempt, a series of 11 chiral nitrogen containing
ligands, commonly used in asymmetric synthesis, and read-
ily available natural products containing secondary and ter-
tiary nitrogen atoms were tested for their potential to
enantioselectively form lithium carbanion pairs of phenols
to be alkylated by allylhalides. Chiral compounds included
(1R,2R)-(+)-1,2-diamino-cyclohexane-N,N0-bis(20-diphenyl-
phosphinobenzoyl),8a bis-quinine phthalazine (Q)2-
PHAL,8b (R,R)-(+)-bis-(a-methylbenzyl)-amine,9 (+)-2,6-
bis-[(4R)-4-phenyl-2-oxazolin-2-yl]pyridine,8c (ꢀ)-sparteine,10
a-isosparteine,11 nicotine, brucine, quinine, (R)-(+)-2,20-
bis(diphenylphosphino)-1,10-binaphthyl and (S)-N,N,N0,N0-
tetramethyl-2,20-diamino-1,10-binaphthyl.8d The alkylation
of 1a with 2a served as the model reaction for screening the
chiral ligands. The general procedure involved the treatment
of the chiral ligands with BuLi. Compound 1a was then added
to the stirred solution at 0 ꢁC, followed by the addition of 2
(Scheme 1). The mixture was warmed to 22 ꢁC and left stirring
for 15 h. The reactivity of the phenolate complex is quite low
and no conversion occurred below +20 ꢁC. The enantiomeric
enrichment of the resulting cyclohexa-2,4-dien-1-one was
determined by 1H NMR experiments with chiral shift
reagents. Under these conditions, only (ꢀ)-sparteine and a-iso-
sparteine afforded enantiomerically enriched 4 in moderate
yields and low ee (Table 2, entries 1–3). In fact, prenyl phenyl-
ether 5 was always the major product because addition of
1 or even 2 equiv of ligand decreases the polarity of the reaction
medium and therefore the amount of C-alkylation decreases
accordingly. Application of other chiral bases did not lead
to any enantiomeric enrichment (<5%). For example, ligand
8, which was successfully used by Simpkins9 and others7 for
the enantio- and diastereoselective deprotonation of ketones
led to racemic 4 in comparable yield. Although sodium is the
most effective counter ion for the non-enantioselective
C-alkylation of phenolate ions, it is not well suited for complex
formation with (ꢀ)-sparteine and consequently, no enantio-
topic discrimination was observed. Based on these results,
we propose that deprotonation of 1a with sparteine/BuLi
OH
O
1. NaH, toluene, 5-15 ºC,
(2)
2. MeOH, H2, Pd/C 10%
Cl
R3
R3
R1
R1
R2
R2
1a-g
R1
3a-g
R2
R3
Yield (%)
a
b
c
d
e
f
H
H
CH3
H
H
H
H
H
H
CH3
H
H
H
H
H
H
CH@C(CH3)2
CH@C(CH3)2
CH@C(CH3)2
C6H5
CH@CCH3C(CH3)3
CH@C(CH3)CH2CCl3
CH@C6H10
81
54
40
62
58
71
50
Traces
g
h
CH@CH2
unstable and acid sensitive dienones, an in situ hydrogena-
tion of the 4,5-double bonds seemed to be most convenient
in terms of preparative ease. This was achieved by subse-
quently adding methanol and Pd on charcoal to the reac-
tion mixture. The order of addition is important as the
addition of methanol causes sodium chloride to precipi-
tate, which renders the catalyst less reactive if added first.
Under these conditions, the hydrogen up take was quick
and exothermal, making external cooling necessary. In
the absence of methanol, no hydrogenation took place
and the dienones rearranged to give both allylphenols
and allylphenyl ethers. To an increasing degree, this holds
true for less substituted allyl substituents. For instance,
compound 3h was only identified in trace amounts. Pre-
sumably, a Pd promoted Cope rearrangement of the inter-
mediate 6-allylcyclohexadienone competes in these cases.5
The allyl cyclohexenones 3a–g (Table 1) obtained in this
way exhibited interesting olfactory properties as described
in Experimental.
N
N
OH
O
Li
Cl
1) 5/BuLi
O
*
2)
Cl
1a
4
2a
A
Pd/C 10%, H2
toluene/MeOH
2:1
1) BuLi
2) 2
80%
H
N
N
N
N
N
O
H3C
H
H
CH3
O
6
(-)-sparteine
7
*
(R,R)-8
α-isosparteine
5
3a
Scheme 1. Enantioselective alkylation of phenol resulting in cyclohexa-2,4-dien-1-one.

M. A. Lovchik et al. / Tetrahedron: Asymmetry 17 (2006) 1693–1699
Table 2. Alkylation of 2,6-dimethyl phenol with prenyl chloride
1695
OH
O
1) BuLi, sparteine,
benzene
*
Cl
2)
2a
1a
4
25
Chiral base
Yield (%)
ee (%)
½aꢁD
Li/(ꢀ)-sparteine 1 mol equiv
Li/(ꢀ)-sparteine 2 mol equiv
Li/a-isosparteine 1 mol equiv
(R,R)-8 1 mol equiv
28
14
17
29
4
8
9
0
+16
+32
+37
0
results in a chiral environment for the electrophilic attack
of 2a, as illustrated in the postulated enolate complex A.
Figure 1. ORTEP-plot of the a-isosparteine/allyl bromide salt 9. X-ray
crystallographic details for compound 9: C18H31N2þBrꢀ ꢂ 2C6H6, Mr =
511.59, monoclinic, space group P21, a = 9.6338(2), b = 8.4978(2), c =
In order to facilitate the work-up procedure of the unstable
dienone, an in situ hydrogenation of the 4,5-double bond in
4 was attempted according to the conditions used in the
racemic method (Scheme 1). However, no hydrogenation
took place. Presumably, the palladium catalyst was poi-
soned by the sparteine in the reaction mixture.12 However,
it was possible to hydrogenate pure 4 over Pd/C (10%) in a
mixture of toluene/MeOH 2:1 in 80% yield.
3
˚
˚
16.9348(4) A, b = 96.8364(9)ꢁ, V = 1376.53(5) A , Z = 2, Dx = 1.234
g cmꢀ3, T = ꢀ113 ꢁC, crystal dimensions: 0.10 · 0.20 · 0.22 mm, Nonius
˚
KappaCCD area-detector diffractometer, MoKa radiation, k = 0.71073 A,
l = 1.517 mmꢀ1, hmax = 27.5ꢁ, 31067 measured reflections, 6726 symmetry-
independent reflections, 5456 reflections with I > 2r(I), refinement on F2
with SHELXL-97,16 300 parameters, 1 restraint, R(F) [I > 2r(I) reflections] =
0.048, wR(F2) [all reflections] = 0.126, S(F2) = 1.065, Dqmax = 0.78 e A
.
ꢀ3
˚
The asymmetric unit contains one cation, one anion, and two benzene
molecules. The absolute configuration of the molecule in the crystal has
been determined independently by the diffraction experiment: absolute
structure parameter17 = 0.05(1). CCDC-603895 contains the supplemen-
tary crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
The ratio of O- versus C-alkylation of phenol strongly
depends on the solvent and has been reported to work best
in heterogeneous mixtures of the phenoxide in aprotic sol-
vents. Based on this finding, we decided to perform the
reaction in the solid state.13 Solid lithium, potassium, and
sodium phenoxides were mixed with (ꢀ)-sparteine resulting
in dark green readily stirred mixtures. The addition of 2a
afforded 4 in irreproducible yields and enantioselectivities,
which indicates a rapid interconversion between different
aggregates present in the reaction mixture.14
of the phenolate–Li complex or its low reactivity. Due to
the more extensive delocalization of charge, naphthols
are more reactive than phenols and alkylation is more
rapid (Scheme 2). 2-Methyl-1-naphthol 10 was deprotonated
with a-isosparteine/lithium complex and alkylated with 2a.
The reaction proceeded smoothly affording (R)-11 in 54%
yield and 38% enantioselectivity. The alkylation of 1-
methyl-2-naphthol 12 proceeded in a similar manner, lead-
ing to (S)-13 in 26% yield with a slightly lower ee of 30%.
(ꢀ)-Sparteine and a-isosparteine can form an intermediate
quaternary ammonium salt with an alkylating agent. Allyl
transfer from the chiral ammonium salt to the phenoxide
would then result in the observed enantiotopic discrimina-
tion. To determine whether such a mechanism is in effect,
(ꢀ)-sparteine and a-isosparteine were treated with allyl
bromide in a toluene solution.
OH
O
1) α-isosparteine
BuLi, benzene
Upon standing, allyl bromide/a-isosparteine salt 9 formed
fine colorless crystals. Analysis by X-ray crystallography
revealed that the quaternary ammonium salt was indeed
present, while the allyl moiety was attached to the convex
face of a-isosparteine resulting in inversion at the partici-
pating nitrogen atom (Fig. 1).15
Cl
2)
2a
10
(R)-11 ee 38%
25
54%
α
= + 118.8
[ ]D
Experimental results showed that if 9 was added to a solu-
tion of lithium 2,6-dimethylphenoxide in benzene at 0 ꢁC,
no products were observed even after stirring at room
temperature for 24 h. Possibly the large spartein molecule
imposes too much steric constraint at the reactive center
of the allylic moiety.
1) α-isosparteine
OH
O
BuLi, benzene
Cl
2)
2a
12
(S)-13 ee 30%
25
26%
The low enantioselectivity of the phenol alkylation is
caused by either poor facial selectivity of the symmetrically
substituted phenol 1a, by the low configurational stability
α
[ ]D = +14.87
Scheme 2. Stereoselective alkylation of naphthols.

1696
M. A. Lovchik et al. / Tetrahedron: Asymmetry 17 (2006) 1693–1699
The absolute configuration of 11 and 13 was determined by
vibrational circular dichroism (VCD) spectroscopy com-
bined with Gaussian 03 quantum chemical computations.
tilled by the ‘Kugelrohr’-method. The vacuum was
provided either by a rotary slide pump (0.05 mbar) or by
a water-jet vacuum pump (10 mbar).
4.2. 2,6-Dimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-enone
3a
3. Conclusion
Herein, we have shown that cyclohexenones can be pre-
pared in a one-pot protocol through direct alkylation of
phenolates followed by selective in situ hydrogenation of
the 4,5-double bond. This regioselective hydrogenation
can also be performed with isolated dienones using Pd/C
10% in toluene/MeOH 2:1, without any hydrogenation of
the 2,3-double bond or the allylic side chain. We have also
shown for the first time that it is possible to synthesize
enantiomerically enriched cyclohexa-2,4-dien-1-ones by
C-alkylation of phenols using a (ꢀ)-sparteine– or a-iso-
sparteine–lithium complex as chiral base. The highest enan-
tiomeric enrichment was observed in the products resulting
from the alkylation of naphthols. Contrary to the results
reported in the racemic alkylation protocols, lithium was
found to be the most suitable alkali metal ion in the asym-
metric variant of the phenol alkylation.
Sodium hydride (60%, 85 g, 2.13 mol) was added in
portions to a solution of 2,6-dimethylphenol (250 g,
2.05 mol) in 2 L of toluene at 10–15 ꢁC. The resulting sus-
pension was stirred for 45 min. The mixture was cooled to
5 ꢁC, and 1-chloro-3-methyl-but-2-ene (prenyl chloride)
(262 g, 2.13 mol, 85%) was added over 1.5 h keeping the
temperature at 5 ꢁC. The mixture was then stirred for a fur-
ther 2 h at 10–15 ꢁC. Methanol (1 L) and palladium (2.5 g,
10% on charcoal) were added and the gray suspension was
hydrogenated at 0.3 bar pressure, keeping the temperature
at 20–22 ꢁC (ice bath). The suspension was then filtered
through a pad of Celite. The yellow filtrate was washed
with water (0.5 L), aqueous sodium hydroxide (0.5 L),
and brine (0.5 L), dried (MgSO4), and concentrated in
vacuo. The residue was distilled over a 5 cm Vigreux column
to yield 318 g (81%, bp 78–82 ꢁC/0.05 Torr) of a colorless
oil. Odor: fruity, grapefruit, minty, bergamot. IR (ATR)
1
m: 2965s, 2922s, 1667vs, 1449m, 1376m, 1033m. H NMR
4. Experimental
4.1. General
(400 MHz, CDCl3) d 1.05 (s, 3H, 6-CH3); 1.59 (s, 3H, 30-
CH3); 1.70 (s, 3H, 40-H); 1.77–1.70 (m, 1H, 5b-H); 1.76
(s, 3H, 2-CH3); 1.91 (dt, J5a,5b = 13.6 Hz, J5a,4 = 6.1 Hz,
1H, 5a-H); 2.25–2.14 (m, 2H, 10H); 2.34–2.28 (m, 2H, 4-
H); 5.06–5.11 (m, 1H, 20-H); 6.62 (br s, 1H, 3-H). 13C
NMR (100 MHz, CDCl3) d 16.4 (q, 2-CH3); 17.8 (q, 30-
(CH3)b); 21.8 (q, 6-CH3); 22.9 (t, C-4); 25.9 (q, 30-
(CH3)a); 33.4 (t, C-5); 34.9 (t, C-10); 45.0 (s, C-6); 119.7
(d, C-20); 134.0, 133.9 (2s, C-2, C-30); 143.4 (d, C-3);
204.0 (s, C-1). GC/MS (EI): 192 (M+, 16), 124 (100), 109
(74), 82 (31), 69 (40), 41 (57). Anal. Calcd for C13H20O
(192.29): C, 81.20; H, 10.48. Found: C, 81.21; H, 10.47.
1H NMR and 13C NMR spectra were measured on Bruker
AC300, Bruker ARX300 (both 300 MHz) or on a Bruker
Avance DPX-400 spectrometer. Chemical shifts are given
in parts per million relative to internal TMS, while cou-
pling constants are reported in Hertz (Hz). Deuterated
chloroform and benzene were used as solvents. Multiplici-
ties are specified by abbreviations, s = singlet, d = doublet,
t = triplet, m = multiplet, and td = triplet of doublets. In
13C NMR spectra, the solvent itself served as the internal
standard: CDCl3 (d(C) = 77.00 ppm, t, JCD = 31.5 Hz).
The multiplicity is designated q (quartet) for CH3, t (trip-
let) for CH2, d (doublet) for CH, and s (singlet) for fully
substituted carbon atoms. GC/MS was measured routinely
on a HP MSD 5973 instrument with a 30m HP5/MS or
Varian VF5ms column. Mass spectra were measured in
electron impact (EI) mode at 70 eV, with a source temper-
ature of 200 ꢁC, an acceleration voltage of 5 kV, and a res-
olution of 10,000. High resolution mass spectra (HRMS)
were recorded on a Finnigan MAT 95. IR spectra were
run on Spectrum One FT-IR- and Bruker Vector 22 FT-
IR-spectrometers. The relative intensities of the absorption
bands are indicated as vs = very strong (>90%), s = strong
(70–90%), m = medium (40–70%), w = weak (<40%). Col-
umn Chromatography was performed on Silica gel Chemie
Uetikon ZEOCHEM C-Gel C-560, particle size 40–63 lm
or aluminum oxide Fluka type 5016 basic, particle size
50–150 lm; pH 9.5 0.5 Act. III (Brockmann). Standard
GC analysis was performed on a HP 5890 instrument with
HP 3396A integrator and a DB5 30m, 0.53 mm column.
The split ratio was 1:100, initial temperature 80 ꢁC, and
rate 10 ꢁC/min. Microanalyses were obtained from Ilse
Beetz, Mikroanalytisches Laboratorium, 96301 Kronach,
Postf. 1164, Germany. Most products were short path dis-
4.3. 2,4,6-Trimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-
enone 3b
A mixture of two diastereomers in a ratio of 4/1. Odor:
hesperidic, fresh, floral, grapefruit, terpenic. IR (ATR) m:
2962s, 2924s, 1670vs, 1453s, 1376s, 1035m, 986m. 1H
NMR (400 MHz, CDCl3) d 1.07/1.03 (2s, 3H, 6a,b-CH3);
1.09 (d, J = 6.8 Hz, 3H, 4-CH3); 1.59–1.55 (m, 1H, 5b-H);
1.61 (s, 3H, 30-CH3); 1.68 (s, 3H, 40-CH3); 1.71–1.67 (m,
1H, 5a-H); 1.76 (s, 3H, 2-CH3); 2.36–2.11 (m, 2H, 10-H);
2.62–2.52 (m, 1H, 4-H); 5.09–5.03 (m, 1H, 20-H); 6.43 (br
s, 1H, 3-H). 13C NMR (100 MHz, CDCl3) d 16.3 (q, 2-
CH3); 17.8 (q, 30-(CH3)b); 21.3 (q, 6-CH3); 22.3 (q, 4-
CH3); 25.9 (q, 30-(CH3)a); 27.9 (d, C-4); 36.4 (t, C-10); 41.7
(t, C-5); 44.8 (s, C-6); 120.1 (d, C-20); 133.6, 132.9 (2s, C-
2, C-30); 149.4 (d, C-3); 204.0 (s, C-1). GC/MS (EI), main
isomer: 206 (M+, 13), 164 (20), 138 (69), 123 (100), 96
(27), 69 (35), 41 (81). HRMS: 206.1679 (calcd 206.1671).
4.4. 2,3,6-Trimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-
enone 3c
Odor: agrestic, minty, fruity. IR (ATR) m: 2915s, 1659vs,
1
1638s, 1376s, 1023m, 764w. H NMR (400 MHz, CDCl3)

M. A. Lovchik et al. / Tetrahedron: Asymmetry 17 (2006) 1693–1699
1697
d 1.03 (s, 3H, 6-CH3); 1.59 (s, 3H); 1.69–1.63 (m, 1H, 5b-
H); 1.70 (s, 3H); 1.75 (s, 3H); 1.89–1.83 (m, 1H, 5a-H);
1.89 (s, 3H); 2.25–2.11 (m, 2H, 10-H); 2.33–2.29 (m, 2H,
4-H); 5.09–5.05 (m, 1H, 20-H). 13C NMR (100 MHz,
CDCl3) d 11.2 (q, 2-CH3); 17.7 (q); 21.2 (q); 22.0 (q);
25.9 (q); 29.3 (t); 32.3 (t); 35.2 (t); 43.7 (s, C-6); 119.8 (d,
C-10); 131.8, 131.4 (2s, C-2, C-30); 152.4 (s, C-3); 203.3 (s,
C-1). GC/MS (EI): 206 (M+, 9), 178 (15), 138 (100), 137
(98), 123 (97), 96 (50), 67 (52), 41 (62). HRMS: 206.1663
(calcd 206.1671).
33.7 (t); 37.4 (t); 44.8 (s); 116.1 (d); 133.9 (s); 142.1 (s);
143.3 (d); 204.2 (s). GC/MS (EI): 232 (M+, 1), 124 (100),
109 (38), 91 (12), 79 (17), 67 (35), 55 (16), 41 (20). HRMS:
232.1848 (calcd 232.1827).
4.9. 2,6-Dimethyl-6-(3-methylbut-2-enyl)cyclohexa-2,4-dien-
1-one 4
(ꢀ)-Sparteine 6 (6.00 g, 24.60 mmol) was dissolved in benz-
ene (60.0 mL) and the solution cooled to ꢀ15 ꢁC. Butyl
lithium (15.4 mL, 24.60 mmol, 1.6 M in hexane) was added
dropwise. 2,6-Dimethyl phenol 1a (3.00 g, 24.59 mmol) was
added as a solution in toluene (15.0 mL) to the bright yel-
low reaction mixture. The mixture was stirred at room tem-
perature for 1 h. Prenyl chloride (3.50 g, 24.60 mmol) was
added dropwise to the stirred solution. After stirring at
0 ꢁC for 1 h, the reaction mixture was left stirring at room
temperature for 15 h. The reaction was then quenched with
water (100.0 mL) and extracted with ether. The organic
layers were washed with a Claisen base (satd KOH/MeOH)
to remove phenolic by-products, then with water and brine.
The crude product was purified by chromatography over
basic aluminum oxide [hexane/MtBE 95:5] and dried in
4.5. 6-Benzyl-2,6-dimethylcyclohex-2-enone 3d
Odor: Fruity, minty, saffron, rosy, apple. IR (ATR) m:
2923s, 1666vs, 1452s, 1375m, 1027m, 702s. 1H NMR
(400 MHz, CDCl3) d 1.06 (s, 3H, 6-H); 1.91–1.60 (m, 2H,
5-H); 2.40–2.29 (m, 2H, 4-H); 2.74 (d, J = 15 Hz,
CHHbPh); 2.97 (d, J = 15 Hz, 1H, CHaHPh); 6.65 (br s,
1H, 3-H); 7.28–7.09 (m, 5H, Ar–H). 13C NMR
(100 MHz, CDCl3) d 16.6 (q); 22.2 (q); 22.9 (t); 33.0 (t);
42.7 (t); 45.4 (s); 126.2 (d); 127.8 (2d); 130.7 (2d); 134.8
(s); 137.8 (d); 143.6 (d); 203.7 (s). GC/MS (EI): 214 (M+,
27), 186 (37), 123 (44), 95 (13), 91 (100), 82 (91), 77 (10),
65 (18), 54 (25), 39 (20). HRMS: 214.1343 (calcd 214.1358).
vacuo. Compound 4 (0.45 g, 28% yield, 4% ee) was obtained
25
as a colorless liquid: ½aꢁD ¼ þ16:6 (c 1.3, EtOH). IR (ATR)
4.6. 2,6-Dimethyl-6-(3,4,4-trimethylpent-2-enyl)-cyclohex-2-
enone 3e
m: 3034w, 2969m, 2923m, 1627vs, 1642s, 1582w, 1450m,
1
1377m, 742m. H NMR (300 MHz, C6D6) d 1.14 (s, 3H);
1.51 (s, 3H); 1.54 (d, J = 1.1 Hz, 3H); 1.84 (m, 3H); 2.12
(m, 1H); 2.7 (m, 1H); 5.05 (m, 1H); 5.76 (dd, J = 5.9,
9.5 Hz, 1H); 5.90 (m, 1H); 6.27 (m, 1H). 13C NMR
(75 MHz, CDCl3) d 15.3 (q); 17.8 (q); 24.0 (q); 25.6 (q);
38.9 (t); 51.1 (q); 118.8 (d); 120.1 (d); 133.0 (s); 134.1 (s);
137.8 (d); 145.1 (d); 206 (s). EI-MS (GC/MS): 190 (M+,
1), 175 (4), 122 (100), 107 (28), 91 (14), 69 (25), 41 (29).
IR (ATR) m: 2915s, 1659vs, 1638s, 1376s, 1023m, 764w,
1
1029m. H NMR (400 MHz, CDCl3) d 1.02 (s, 9H, 40-
(CH3)3); 1.05 (s, 3H, 6-CH3); 1.60 (s, 3H); 1.77 (s, 3H);
1.77–1.70 (m, 1H); 1.92–183 (m, 1H); 2.22 (d, J = 7.6 Hz,
2H, 10-H); 5.18–5.15 (m, 1H, 20-H); 6.62 (br s, 1H, 3-H);
2.34–2.28 (m, 2H, 4-H). 13C NMR (100 MHz, CDCl3) d
12.8 (q); 16.4 (q); 21.8 (q); 22.8 (t); 29.0 (3q); 33.4 (t);
34.8 (t); 36.3 (s); 45.1 (s); 116.0 (d); 134.0 (s); 143.3 (d);
154.4 (s); 204.2 (s). GC/MS (EI): 234 (M+, 8), 177 (5),
124 (100), 109 (31), 95 (20), 69 (38), 55 (35), 41 (38).
HRMS: 234.1982 (calcd 234.1937).
4.10. a-Isosparteine 7
Neutral, dry aluminum oxide (18.00 g) was mixed with alu-
minum chloride (7.56 g, 56.80 mmol) under an inert atmo-
sphere. The mixture was sealed in glass ampoules and
heated at 230 ꢁC for 6 h. The a-isosparteine was isolated
by acid–base extraction and crystallized as its hydrate from
wet acetone. The required amounts of a-isosparteine 7 for
the experiments were dehydrated by short path distillation
(120 ꢁC, 0.05 mbar) immediately before use. a-Isosparteine
hydrate can be stored in the refrigerator for extended
4.7. 6-(5,5,5-Trichloro-3-methylpent-2-enyl)-2,6-dimethyl-
cyclohex-2-enone 3f
IR (ATR) m: 2923m, 1667s, 1450m, 1377m, 1029m, 761s,
1
704vs. H NMR (400 MHz, CDCl3) d 1.10 (s, 3H); 1.33–
1.14 (m, 2H); 1.77 (s, 3H); 1.87 (s, 3H); 2.03–1.74 (m,
2H); 2.37–2.23 (m, 4H); 3.37 (s, 2H); 5.55–5.50 (m, 1H);
6.64 (br s, 1H). 13C NMR (100 MHz, CDCl3) d 16.4 (q);
17.9 (q); 21.7 (q); 22.7 (t); 33.3 (t); 35.3 (t); 45.0 (s); 63.6
(t); 99.2 (s); 130.5 (s); 131.0 (d); 133.8 (s); 143.6 (d); 203.6
(s). GC/MS (EI): 309 (M+, 3), 191 (34), 163 (11), 123
(100), 109 (32), 95 (35), 82 (60), 67 (21), 53 (26), 39 (23).
periods of time. Mp: 108–110 ꢁC [lit. 104–105 ꢁC].
25
½aꢁD ¼ ꢀ55:0 (c 1.275, MeOH) [lit. ꢀ32.6].11
4.11. 2,6-Dimethyl-6-(3-methylbut-2-enyl)cyclohexa-2,4-
dien-1-one 4 using a-isosparteine/Li as chiral base
a-Isosparteine 7 (0.60 g, 2.46 mmol) was dissolved in tolu-
ene (6.0 mL). The solution was then cooled to ꢀ10 ꢁC and
BuLi (1.5 mL, 2.46 mmol, 1.6 M in hexane) was added
dropwise. The originally colorless solution turned bright
yellow. After stirring at ꢀ10 ꢁC for 30 min, 1a (300 mg,
2.46 mmol) was added dropwise as a solution in toluene
(1.5 mL). The solution discolored immediately after the
addition and then turned yellow again upon stirring for
30 min at ꢀ10 ꢁC. Prenyl chloride (256 mg, 2.46 mmol)
was added and the mixture was slowly warmed to rt and
4.8. 6-(2-Cyclohexylideneethyl)-2,6-dimethylcyclohex-2-
enone 3g
IR (ATR) m: 2924s, 2852m, 1667s, 1447m, 1373m, 1027m.
1H NMR (400 MHz, CDCl3) d 1.05 (s, 3H); 1.56–1.45
(m, 6H); 1.76 (br s, 3H); 1.77–1.69 (m, 1H); 1.94–1.86
(m, 1H); 2.34–2.04 (m, 8H); 5.05–5.50 (m, 1H); 6.63–6.61
(m, 1H). 13C NMR (100 MHz, CDCl3) d 16.4 (q); 21.7
(q); 22.9 (t); 26.7 (t); 27.6 (t); 28.6 (t); 28.7 (t); 33.3 (t);

1698
M. A. Lovchik et al. / Tetrahedron: Asymmetry 17 (2006) 1693–1699
stirred for 14 h. After chromatography over basic alumi-
num oxide [hexane/MtBE 95:5] and short path distillation
1-methyl-naphthalen-2-ol 12 (647 mg, 4.1 mmol) was
added as solution in benzene (3.0 mL). The bright yellow
a-isosparteine lithium complex discolored and some solids
precipitated. After 30 min at 0–5 ꢁC prenyl chloride
(533 mg, 4.10 mmol) was added in one portion. The reac-
tion mixture was stirred for 15 h, gradually reaching room
temperature. TLC analysis showed that the reaction had
reached completion. Silica gel and hexane were added to
the reaction mixture and the solids were removed from
the suspension by filtration and washed with hexane/MtBE
1:1. The filtrate was concentrated and the residue separated
by chromatography over basic aluminum oxide [hexane/
MtBE 9:1]. After short path distillation (120 ꢁC, 0.05
(ꢃ50 ꢁC, 0.05 mbar) 4, (80 mg, 17% yield, 9% ee) was
25
obtained as yellow oil: ½aꢁD ¼ þ37:0 (c 0.8, EtOH).
4.12. 2-(R)-Methyl-2-(3-methylbut-2-enyl)-2H-naphthalen-
1-one (R)-11
A solution of a-isosparteine 7 (440 mg, 1.80 mmol) in tolu-
ene (5.0 mL) was cooled to ꢀ10 ꢁC. Butyl lithium (1.1 mL,
1.80 mmol, 1.6 M in hexane) was added dropwise. A bright
yellow solution was obtained and stirred for 30 min at
ꢀ10 ꢁC. 2-Methyl-naphthalen-1-ol 10 (284 mg, 1.80 mmol)
was added dropwise as a solution in toluene (2.0 mL).
After stirring at ꢀ10 ꢁC for 30 min, the solids precipitated
and the mixture turned gray/green. Additional toluene
(2.0 mL) was added to maintain a movable suspension.
Prenyl chloride (234 mg, 1.80 mmol) was added causing
the mixture to turn darker. The reaction was left stirring
at rt for 15 h. More solids formed and analysis of the reac-
tion mixture by TLC showed that all the starting materials
had been consumed. Silica gel and hexane were added to
the reaction mixture. The solids were removed by filtration
and washed with hexane/MtBE 1:1. The filtrate was con-
centrated and the residue was purified by chromatography
over aluminum oxide [hexane/MtBE 95:5]. Short path dis-
mbar), 13 (240 mg, 26% yield, 30% ee) was obtained as
25
a light yellow oil: ½aꢁD ¼ þ14:9 (c 1.0, EtOH). The CD
spectrum of 13 in acetonitrile contains a broad asymmetric
positive band with two maxima above 320 nm and a nega-
tive one near 300 nm. The
sign pattern is compatible
with an M-helicity of the enone chromophore. If assuming
the axial position of the methyl group, this gives rise to an
(S)-configuration. IR (neat) m: 2970w, 2913w, 1655vs,
1621w, 1597w, 1449m, 1397w, 1376w, 1299w, 1239w,
1
1207w, 835m, 755s. H NMR (300 MHz, CDCl3) d 1.40
(s, 3H); 1.47 (s, 3H); 1.49 (m, 3H); 2.45 (m, 1H); 2.77 (m,
1H); 4.66 (m, 1H); 6.14 (d, J = 9.9 Hz, 1H); 7.42–7.23
(m, 5H). 13C NMR (75 MHz, CDCl3) d 25.8, 17.9 (3q);
41.8 (t); 52.03 (s); 129.9, 129.4, 126.9, 126.7, 125.4, 118.8
(6d); 130.0 (s); 134.7 (s); 145.0 (d); 146.3 (s); 204.4 (s).
EI-MS (GC/MS): 226 (M+, 1), 211 ([MꢀCH3]+, 1), 158
(100), 128 (22), 115 (9), 69 (20), 41 (20).
tillation (120 ꢁC, 0.05 mbar) afforded 11 (220 mg, 54%
25
yield, 38% ee) as a light-yellow oil: ½aꢁD ¼ þ118:8 (c 1.0,
EtOH). The absolute configuration was determined by
VCD spectroscopy. Due to the high conformational mobil-
ity of the side chain, only VCD signals resulting from
stretching vibrations of the C@O group and the C@C dou-
ble bonds (the 1750–1550 cmꢀ1 region) can be interpreted.
The CD spectrum of 11 in acetonitrile contains only posi-
tive bands with fine structures in the 250–400 nm region.
Below 250 nm, the spectrum is governed by the positive
1La band at ꢃ230 nm and a negative one below 200 nm.
These bands mostly result from the phenyl chromophore.
Applying the sector rule of the saturated ketones to the po-
sitive long-wavelength band at 333 nm resulted in an (R)-
configuration of the stereogenic center assuming the axial
position of the Me group. IR (ATR) m: 2968w, 1673s,
1644w, 1598m, 1483w, 1317w, 1268w, 981w, 790vs, 691m.
1H NMR (300 MHz, C6D6) d 1.20 (s, 3H); 1.43 (d,
J = 1.1 Hz, 3H); 1.51 (s, 3H); 2.19 (m, 1H); 2.78 (dd,
J = 8.0, 14.0 Hz, 1H); 5.09 (m, 1H); 5.84 (d, J = 9.9 Hz,
1H); 6.30 (d, J = 9.7 Hz, 1H); 6.82 (m, 1H); 6.93 (m,
1H); 7.08 (m, 1H); 8.26 (m, 1H). 13C NMR (75 MHz,
C6D6) d 17.9 (3q); 25.6, 24.5, 39.0 (3t); 49.6 (s); 127.9,
127.2, 127.0, 214.1, 119.6 (5d); 130.0 (s); 134 (d); 134.2
(s); 138.5 (s); 140.1 (d); 202.1 (s). EI-MS (GC/MS): 226
(M+, 1), 211 ([MꢀCH3]+, 1), 158 (100), 128 (24), 115
(10), 69 (19), 41 (20). Anal. Calcd for C16H18O (226): C,
84.91; H, 8.02. Found: C, 84.96; H, 8.26.
4.14. 2,6-Dimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-en-1-
one 3a
2,6-Dimethyl-6-(3-methylbut-2-enyl)cyclohexa-2,4-dien-1-
one 4 (2.50 g, 9.90 mmol) was mixed with toluene
(10.0 mL) and methanol (5.0 mL). Palladium 10% on acti-
vated carbon (10 mg) was added and the suspension hydro-
genated at atmospheric pressure for 3 h at room
temperature. The catalyst was removed by filtration over
Celite and the crude product was purified by chromato-
graphy over silical gel [hexane/MtBE 8:2]. 2,6-Dimethyl-
6-(3-methyl-but-2-enyl)-cyclohex-2-en-1-one 3a (1.53 g, 80%
yield) was isolated as a colorless liquid. IR (CCl4) m:
2966m, 2922m, 1665s, 1449m, 1375m, 1356m, 1189w,
1074w, 1032m, 979w, 942w, 876w, 840w. 1H NMR
(400 MHz, CDCl3) d 1.09 (s, 3H); 1.47 (m, 1H); 1.54 (s,
3H); 1.67 (s, 3H); 1.73 (m, 1H); 1.91–1.83 (m, 5H); 2.33
(m, 2H); 5.25 (m, 1H); 6.11 (m, 1H). 13C NMR (75 MHz,
CDCl3) d 16.5 (q); 17.9 (q); 21.9 (q); 23.0 (t); 26.0 (q);
33.5 (t); 35.0 (t); 45.1 (s); 119.8 (d); 134.0 (s); 134.1 (s);
143.4 (d); 204.3 (s). CI-MS (GC/MS, NH3): 193.1
([M+H]+, 100), 194.1 (14). HRMS: (192.1514) (calcd
192.1513).
4.13. (S)-1-Methyl-1-(3-methylbut-2-enyl)-1H-naphthalen-2-
one (S)-13
Acknowledgments
a-Isosparteine 7 (1.00 g, 4.10 mmol) was first dissolved in
benzene (10.0 mL). The solution was then cooled to 0 ꢁC
and BuLi (2.56 mL, 4.10 mmol, 1.6 M in hexane) was
added dropwise. After stirring at 0 ꢁC for 30 min,
Funding from Givaudan is gratefully acknowledged. We
would like to thank Professor Dr. Heinz Heimgartner
and his group from the University of Zurich for the many
valuable discussions. We also thank Dr. Anthony Linden

M. A. Lovchik et al. / Tetrahedron: Asymmetry 17 (2006) 1693–1699
1699
2846–2847; (b) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.;
Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.;
Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org.
Chem. 1992, 57, 2768–2771; (c) Evans, D. A.; Kozlowski, M.
C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B.
T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669–685; (d)
Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345–350;
Rosini, C.; Franzini, L.; Luliano, A.; Pini, D.; Salvadori, P.
Tetrahedron: Asymmetry 1991, 2, 363–366.
from the University of Zurich for performing the X-ray
´
diffraction crystallography and Dr. Elemer Vass from
´
the Eo¨tvo¨s Lorand University in Budapest for the VCD
measurements and computations.
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