Asymmetric synthesis of (R)-ar-curcumene, (R)-4,7-dimethyl-l-tetralone, and their enantiomers via cobalt-catalyzed asymmetric Kumada cross-coupling

Article abstract of DOI:10.1016/j.tetasy.2015.11.009

An efficient and concise asymmetric synthesis of (R)-(+)-ar-curcumene, (R)-4,7-dimethyl-l-tetralone, and their enantiomers was accomplished. The key step to construct the stereogenic benzylmethyl centers of these natural products is the cobalt-catalyzed a

Full text of DOI:10.1016/j.tetasy.2015.11.009

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of (R)-ar-curcumene, (R)-4,7-dimethyl-l-
tetralone, and their enantiomers via cobalt-catalyzed asymmetric
Kumada cross-coupling
⇑
Lin Wu, Jiang-Chun Zhong, Shi-Kuo Liu, Fei-Peng Liu, Zi-Dong Gao, Min Wang, Qing-Hua Bian
Department of Applied Chemistry, China Agricultural University, 2 West Yuanmingyuan Road, Beijing 100193, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and concise asymmetric synthesis of (R)-(+)-ar-curcumene, (R)-4,7-dimethyl-l-tetralone, and
their enantiomers was accomplished. The key step to construct the stereogenic benzylmethyl centers of
these natural products is the cobalt-catalyzed asymmetric Kumada cross-coupling reaction of a racemic
Received 29 October 2015
Accepted 26 November 2015
Available online xxxx
a-bromo ester.
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
The stereogenic benzylmethyl center is a special subunit in
natural products, especially in (R)-ar-curcumene, (R)-4,7-
dimethyl-l-tetralone, and their enantiomers (Fig. 1). ar-Curcum-
ene, an aromatic sesquiterpene, was first separated from the
essential oil from the rhizomes of Curcuma aromatica, Salisb. by
Simonsen and Rao.1 In 1965, the absolute configuration of (À)-
ar-curcumene was confirmed as (S) via the synthesis of its enan-
tiomer from (+)-3-p-tolylbutanoic acid by Honwad and Rao.2 To
date, both (R)- and (S)-ar-curcumene have been found in Nature.3
The laboratory bioassays revealed that (S)-ar-curcumene exhibited
acetylcholinesterase (AChE) inhibitory activity,4 furthermore, it
was the main component of a sex attracting pheromone produced
by the red-shoulder stink bug, Thyanta pallidovirens.3c Recently, the
investigation of Bleeker et al. indicated that (R)-ar-curcumene
could act as a repellent to whiteflies.5 4,7-Dimethyl-l-tetralone
exists in essential oils obtained from various plants, such as
lavender, Labdanum, and Saliva.6 Lavender oil possesses cytotoxic
and antioxidant activity,7 while Saliva oil showed larvicidal activity
of mosquitoes.6c (R)-4,7-Dimethyl-l-tetralone exists in Cyperus
rotundus and exhibits antimalarial activities,8a its enantiomer was
found to coexist with (R)-1 [(S)/(R) ca. 1:1] in the Japanese
liverworts Jungermannia truncata.8b
O
O
(R)-ar-curcumene
(R)-1
(S)-ar-curcumene
(S)-1
(R)-4,7-dimethyl-
(S)-4,7-dimethyl-
l-tetralone
l-tetralone
(R)-2
(S)-2
Figure 1. Structures of (R)-ar-curcumene, (R)-4,7-dimethyl-l-tetralone, and their
enantiomers.
5-trimethylsilyl-2-cyclohexenone,9b asymmetric hydrogenations
of terminal olefins,10a asymmetric 1,6-additions of arylborox-
ines,10b asymmetric Grignard cross-coupling reactions of vinyl
bromides,10c asymmetric hydrogen esterifications of olefins,10d
asymmetric additions of arylboronic acids,10e and chemoen-
zymatic approaches.11 Compounds (R)-2 and (S)-2 could be synthe-
sized using enantioselective lithiation–borylation12a or the
conjugate addition of trimethylaluminum12b and asymmetric
induction12c or chiral source approach.12d Furthermore, they
could be inverted to some important natural product, such as
(+)-erogorgiaene,12a (S)-ar-himachalene,12b or (+)-laevigatin.12d
Despite this progress, it remains highly desirable to search for
more efficient and convenient asymmetric syntheses of (R)-ar-
curcumene, (R)-4,7-dimethyl-l-tetralone, and their enantiomers.
Transition metal-catalyzed cross-coupling reactions of Grignard
reagents with organic electrophiles (Kumada coupling) have
emerged as a powerful synthetic tool to construct carbon–carbon
bonds.13 The great deal of attention on the enantioselective
Kumada coupling stems from its capacity to synthesize tertiary
The significant biological activities of (R)-ar-curcumene,
(R)-4,7-dimethyl-l-tetralone, and their enantiomers prompted
their asymmetric synthesis. The main synthetic strategies of (R)-
1
and (S)-1 include derivation from chiral citronellal9a or
⇑
Corresponding author. Tel.: +86 010 62731356; fax: +86 010 62820325.
E-mail address: bianqinghua@cau.edu.cn (Q.-H. Bian).
http://dx.doi.org/10.1016/j.tetasy.2015.11.009
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Wu, L.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.009

2
L. Wu et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
or quaternary carbon centers.14 Recently, we developed the first
cobalt-catalyzed asymmetric Kumada cross-coupling reaction with
excellent enantioselectivity and yield (up to 97% ee and 96% yield),
O
L1
12 mol % (S,S)-
OBn
10 mol % CoI2
DIBAL-H, CH2Cl2
OBn
-78 oC to 0 o
C
4-MeC6H4MgBr
THF, -78 oC
O
Br
rac-4
93%, 91% ee
which could construct
a stereogenic benzylmethyl center
88%, 92% ee
(S)-5
directly.15 Herein, we report an expanded application of this
methodology to an efficient and concise asymmetric synthesis of
(R)-(+)-ar-curcumene, (R)-4,7-dimethyl-l-tetralone, and their
enantiomers.
OH
Br
CBr4, PPh3
CH2Cl2, 25 oC
94%, 92% ee
MgBr
Et2O, CuI, 0 o
77%
C
(S)-6
(S)-7
(1) 9-BBN, THF, 0 oC to rt
then NaOH, H2O2, 50 o
2. Results and discussion
C
CHO
(2) Dess-Martin reagent
(R)-8
CH2Cl2, 20 o
C
(R)-9
The retrosynthetic analysis of (R)-ar-curcumene and (R)-4,
7-dimethyl-l-tetralone is depicted in Figure 2. The target natural
products (R)-1 and (R)-2 contain the same stereogenic benzyl-
methyl core unit, which could be formed directly via cobalt-cat-
83% two steps
O
12 mol % (R,R)-L1
OBn
10 mol % CoI2
alyzed asymmetric Kumada cross-coupling of racemic
a-bromo
OBn
4-MeC6H4MgBr
O
ester 4. We thought to obtain (R)-ar-curcumene from Wittig olefi-
nation of aldehyde (R)-9, while (R)-4,7-dimethyl-l-tetralone could
be prepared from intramolecular Friedel–Crafts acylation of car-
boxylic acid (R)-10 derived from aldehyde (R)-9. Tandem hydrobo-
ration–oxidation/Dess–Martin oxidation from terminal olefin (R)-8
was expected to give chiral fragment (R)-9. Olefin (R)-8 would be
synthesized from Kumada cross-coupling product (S)-5, involving
cross-coupling of hydrocarbon bromide (S)-7 with vinylmagne-
sium bromide as the key step.
THF, -78 oC
89%, 92% ee
Br
-5
(R)
rac-4
O
N
O
O
O
CHO
N
N
N
Bn
Bn
Bn
Bn
L1
(S)-9
(S,S)-
(R,R)-L1
Scheme 1. Synthesis of chiral aldehydes (R)-9 and (S)-9.
Subsequent reduction with diisobutylaluminum hydride gave chi-
ral primary alcohol (S)-6 in 93% yield and with 91% ee,16 which was
converted into primary bromide (S)-7 almost quantitatively with-
out racemization via bromination with triphenylphosphine and
carbon tetrabromide.17 Terminal olefin (R)-8 was obtained
smoothly from the cross-coupling of hydrocarbon bromide (S)-7
with vinylmagnesium bromide catalyzed by CuI.18 The final tan-
dem hydroboration–oxidation19 and Dess–Martin oxidation20 from
(R)-8 resulted in the formation of key fragment (R)-9. Similarly,
(R)-1
(R)-2
O
CHO
COOH
(CH3)2CH=PPh3
aldehyde (S)-9 was prepared from chiral
(R)-5, the enantioselective Kumada cross-coupling product of race-
mic ester 4 with (R,R)-L1/CoI2 catalyst.
a-aryl carboxylic ester
(R)-10
(R)-9
(R)-8
With chiral aldehydes (R)-9 and (S)-9 in hand, the synthesis of
natural products (R)-ar-curcumene, (R)-4,7-dimethyl-l-tetralone,
and their enantiomers was accomplished (Scheme 2). The Wittig
reaction of aldehyde (R)-9 with iso-propyltriphenylphosphonium
iodide gave (R)-ar-curcumene in 79% yield and with 90% ee,21 its
spectroscopic data and specific rotation were identical to those of
natural (R)-ar-curcumene.3b Aldehyde (S)-9 was converted into
(S)-ar-curcumene in 79% yield and with 90% ee through the same
procedure. Furthermore, the oxidation of aldehyde (R)-9 with
Ag2O yielded carboxylic acid (R)-10,22 which was converted into
(R)-4,7-dimethyl-l-tetralone in 70% yield and with 90% ee via
intramolecular Friedel–Crafts acylation.23 By repeating the above
two-step protocol, (S)-4,7-dimethyl-l-tetralone was obtained from
Br
MgBr
(S)-7
O
MgBr
OBn
OBn
+
O
20 = À9.2 (c 1.7,
Br
rac-4
(S)-9 with 90% ee. The specific rotation of (S)-2 {[a]
D
25 = À10 (c 10,
(S)-5
CHCl3)} was consistent with literature value {[a]
D
CHCl3)}, its NMR spectrum also matched the literature.12c
Figure 2. Retrosynthetic analysis of (R)-ar-curcumene and (R)-4,7-dimethyl-l-
tetralone.
3. Conclusion
Our synthesis started with the preparation of chiral aldehydes
(R)-9 and (S)-9 (Scheme 1). In the presence of bisoxazoline ligand
(S,S)-L1 and CoI2, the asymmetric Kumada cross-coupling of race-
In conclusion, we have achieved an efficient and convenient
asymmetric synthesis of four natural products, (R)-ar-curcumene,
(R)-4,7-dimethyl-l-tetralone, and their enantiomers, which contain
the same stereogenic benzylmethyl core unit. The main strategies
of our approach involve the cobalt-catalyzed asymmetric Kumada
mic
a-bromo propanoate 4 with p-tolylmagnesium bromide
afforded chiral
a
-aryl carboxylic ester (S)-5 in 88% yield and with
92% ee.15 Based on the comparison with reported specific rotation
cross-coupling reaction of racemic
a-bromo ester, the Wittig
values,15 its absolute configuration was confirmed as (S).
olefination of the aldehyde, and the intramolecular Friedel–Crafts
Please cite this article in press as: Wu, L.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.009

L. Wu et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
(S)-5 (4.48 g, 88% yield, 92% ee) as a pale yellow oil. [
(c 1.2, CHCl3). Lit.15
a
]
20 = +20.0
D
n-BuLi, (CH3)2CH=PPh3
9
[
a]
20 = +12.9 (c 1.4, CHCl3) 1H NMR
(R)-
D
THF, -15 oC to rt
(300 MHz, CDCl3) d 7.34–7.11 (m, 9H), 5.14 (d, J = 12.5 Hz, 1H),
5.06 (d, J = 12.5 Hz, 1H), 3.74 (q, J = 7.2 Hz, 1H), 2.33 (s, 3H), 1.50
(d, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 174.5, 137.5,
136.8, 136.1, 129.3, 128.5, 128.0, 127.9, 127.4, 66.4, 45.2, 21.0,
18.5. HRMS (APCI-TOF) calcd for C17H19O2 [M+H]+ 255.1385, found
255.1391. Enantiomeric excess was determined by HPLC with a
Chiralcel OJ-H column (n-hexane/2-propanol 85:15, 1.0 mL/min,
220 nm); minor (R)-enantiomer tr = 12.37 min, major (S)-enan-
tiomer tr = 12.97 min.
79%, 90% ee
Ag2O, rt
1
(R)-ar-curcumene (R)-
THF/H2O
62%
PPA, 70 o
C
COOH
70%, 90% ee
O
(R)-10
(R)-4,7-dimethyl-l-tetralone (R)-2
n-BuLi, (CH3)2CH=PPh3
(S)-
9
4.2.2. (R)-Benzyl 2-p-tolylpropanoate (R)-5
THF, -15 oC to rt
76%, 90% ee
According to the similar procedure described above for (S)-5,
the cross-coupling between racemic benzyl 2-bromopropanoate
(RS)-4 (4.86 g, 20 mmol) and p-tolylmagnesium bromide (30 mL,
1.0 M in THF, 30 mmol) with (R,R)-L1 furnished (R)-5 (4.53 g, 89%
Ag2O, rt
THF/H2O
63%
(S)-ar-curcumene (S)-1
yield, 92% ee) as a pale yellow oil. [
a
]
20 = À16.5 (c 1.3, CHCl3).
D
PPA, 70 oC
71%, 90% ee
Lit.15
[a]
20 = À17.5 (c 1.6, CHCl3). 1H NMR (300 MHz, CDCl3) d
D
COOH
7.32–7.11 (m, 9H), 5.13 (d, J = 12.5 Hz, 1H), 5.05 (d, J = 12.5 Hz,
1H), 3.74 (q, J = 7.2 Hz, 1H), 2.33 (s, 3H), 1.50 (d, J = 7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3) d 174.5, 137.5, 136.8, 136.1, 129.3,
128.4, 128.0, 127.9, 127.4, 66.4, 45.1, 21.0, 18.5. HRMS (APCI-
O
(S)-10
(S)-4,7-dimethyl-l-tetralone (S)-2
Scheme 2. Synthesis of (R)-ar-curcumene, (R)-4,7-dimethyl-l-tetralone, and their
TOF) calcd for
C
17H19O2 [M+H]+ 255.1385, found 255.1384.
enantiomers.
Enantiomeric excess was determined by HPLC with a Chiralcel
OJ-H column (n-hexane/2-propanol 85:15, 1.0 mL/min, 220 nm);
major (R)-enantiomer tr = 12.26 min, minor (S)-enantiomer tr =
13.02 min.
acylation of carboxylic acid. Furthermore, we have expanded upon
the application of our asymmetric Kumada cross-coupling method-
ology, and other applications are underway in our lab.
4.2.3. (S)-2-p-Tolylpropan-1-ol (S)-6
4. Experimental
4.1. General
To a stirred solution of (S)-5 (3.81 g, 15 mmol) in anhydrous
CH2Cl2 (25 mL) was added diisobutylaluminum hydride (22 mL,
1.5 M in toluene, 33 mmol) over 15 min at À78 °C. After stirring
for 30 min at the same temperature, the reaction mixture was
warmed to 0 °C and maintained at this temperature for an addi-
tional 30 min. A solution of aqueous sodium potassium tartrate
(66 mL, 0.5 M, 33 mmol) was then added dropwise over 20 min.
The resulting mixture was stirred for 12 h at 25 °C and the organic
layer was separated. The aqueous layer was extracted with CH2Cl2
(3 Â 50 mL). The combined organic phases were dried over
anhydrous Na2SO4, and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (petroleum
ether/ethyl acetate 5:1) to afford (S)-6 (2.10 g, 93% yield, 91% ee) as
Unless otherwise indicated, all reactions were performed under
an argon atmosphere. Solvents were dried using standard proce-
dures and distilled before use. All reagents were purchased com-
mercially and used without further purification except for ester
rac-4, bisoxazoline ligands (S,S)-L1, and (R,R)-L1, which were pre-
pared according to references.24,25 1H and 13C NMR spectra were
collected at 300 and 75 MHz, respectively. High-resolution mass
spectra were conducted on an Agilent instrument with the time-
of-flight (TOF) MS technique. Optical rotations were measured on
a Perkin–Elmer 341 Polarimeter. Enantiomeric excesses (ee) were
determined on an Agilent 1200 HPLC system with a chiral column
(Daicel Chiralcel OD-H, OJ-H, or IA column) and n-hexane/2-propa-
nol as the eluent.
a colorless oil. [
a
]
20 = À21.1 (c 1.3, CHCl3). 1H NMR (300 MHz,
D
CDCl3) d 7.14 (d, J = 9.0 Hz, 2H), 7.11 (d, J = 9.0 Hz, 2H), 3.70–3.66
(m, 2H), 2.97–2.86 (m, 1H), 2.33 (s, 3H), 1.33 (t, J = 6.2 Hz, 1H),
1.26 (d, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 140.6, 136.2,
129.3, 127.3, 68.7, 42.0, 21.0, 17.7. HRMS (APCI-TOF) calcd for
10H13 [M-OH]+ 133.1017, found 133.1019. Enantiomeric excess
4.2. Experiment procedures and spectroscopic data
C
was determined by HPLC with a Chiralcel IA column (90:10
n-hexane: 2-propanol, 0.7 mL/min, 220 nm); minor (R)-enantiomer
tr = 9.32 min, major (S)-enantiomer tr = 9.83 min.
4.2.1. (S)-Benzyl 2-p-tolylpropanoate (S)-5
A 200-mL Schlenk flask was charged with anhydrous CoI2
(0.63 g, 2 mmol) and heated at 80 °C in vacuo for 30 min. After
cooling to room temperature, (S,S)-L1 (0.87 g, 2.4 mmol) and anhy-
drous THF (15 mL) were added sequentially. The resulting mixture
was stirred for 1 h at room temperature, and racemic benzyl 2-bro-
mopropanoate 4 (4.86 g, 20 mmol) was added slowly. The mixture
was then cooled to À78 °C, and p-tolylmagnesium bromide (30 mL,
1.0 M in THF, 30 mmol) was added dropwise via syringe over 2 h.
The reaction mixture was stirred for 8 h at the same temperature,
and quenched with saturated NH4Cl solution (20 mL). The aqueous
phase was extracted with Et2O (3 Â 20 mL), and the combined
organic phases were washed with saturated brine solution
(20 mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (petroleum ether/ethyl acetate 80:1) to afford
4.2.4. (R)-2-p-Tolylpropan-1-ol (R)-6
According to the similar procedure described above for (S)-6,
the reduction of (R)-benzyl 2-p-tolylpropanoate (R)-5 (3.81 g,
15 mmol) gave (R)-6 (2.12 g, 94% yield, 91% ee) as a colorless oil.
[a]
20 = +19.9 (c 1.1, CHCl3). 1H NMR (300 MHz, CDCl3) d 7.15 (d,
D
J = 9.0 Hz, 2H), 7.11 (d, J = 9.0 Hz, 2H), 3.70–3.65 (m, 2H), 2.97–
2.86 (m, 1H), 2.33 (s, 3H), 1.36 (t, J = 6.2 Hz, 1H), 1.25 (d,
J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 140.6, 136.2, 129.3,
127.3, 68.7, 42.0, 21.0, 17.7. HRMS (APCI-TOF) calcd for
C
10H13 [MÀOH]+ 133.1017, found 133.1021. Enantiomeric excess
was determined by HPLC with a Chiralcel IA column (n-hexane/
2-propanol 90:10, 0.7 mL/min, 220 nm); major (R)-enantiomer
tr = 9.30 min, minor (S)-enantiomer tr = 9.81 min.
Please cite this article in press as: Wu, L.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.009

4
L. Wu et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
4.2.5. (S)-1-(1-Bromopropan-2-yl)-4-methylbenzene (S)-7
To a solution of alcohol (S)-6 (1.50 g, 10 mmol) and triphenyl
phosphine (3.15 g, 12 mmol) in anhydrous CH2Cl2 (33 mL) was
added carbon tetrabromide (3.42 g, 10.3 mmol) portionwise. After
stirring for 4 h at room temperature, the reaction mixture was
evaporated to remove the solvent. Petroleum ether (40 mL) was
then added and filtered. The filtrate was concentrated under
reduced pressure, and the residue was purified by silica gel chro-
matography (petroleum ether) to afford (S)-7 (2.01 g, 94% yield,
4.2.9. (R)-4-p-Tolylpentanal (R)-9
To a 100-mL Schlenk reaction flask was added 9-borabicyclo
[3.3.1]nonane (26 mL, 0.5 M in THF, 13 mmol), and the terminal
olefin (R)-8 (1.60 g, 10 mmol) was then added dropwise at 0 °C
under argon. The resulting mixture was warmed to room temper-
ature and stirred for 3 h at the same temperature. After being
cooled to 0 °C, the reaction was quenched by the sequential drop-
wise addition of aqueous NaOH (5.6 mL, 3 M, 16.8 mmol) and 35%
H2O2 (5.6 mL). The biphasic solution was stirred for an additional
1 h at 50 °C and then cooled to room temperature. The mixture
was diluted with water (30 mL), and the organic phase was sepa-
rated. The aqueous layer was extracted with Et2O (3 Â 40 mL).
The combined extracts were dried over anhydrous Na2SO4, and
concentrated under reduced pressure to afford the crude primary
alcohol.
The Dess–Martin reagent (5.09 g, 12 mmol) was dissolved in
anhydrous CH2Cl2 (60 mL), after which the crude primary alcohol
in CH2Cl2 (24 mL) was added dropwise at 20 °C. The reaction mix-
ture was stirred for 30 min at the same temperature, then diluted
with Et2O (84 mL). The resulting mixture was poured into
Na2S2O3.5H2O (17.37 g, 70 mmol) in saturated aqueous NaHCO3
(240 mL) and stirred for another 10 min. The organic phase was
separated, and washed with saturated aqueous NaHCO3 and water
sequentially. The combined organic layers were dried over anhy-
drous Na2SO4 and concentrated under reduced pressure. The resi-
due was purified by silica gel chromatography (petroleum ether/
ethyl acetate 20:1) to obtain (R)-9 (1.46 g, 83% yield over two
92% ee) as a yellow oil. [
a]
20 = À22.7 (c 1.3, CHCl3). 1H NMR
D
(300 MHz, CDCl3) d 7.15 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H),
3.58 (dd, J = 9.8, 6.1 Hz, 1H), 3.46 (dd, J = 9.8, 8.0 Hz, 1H), 3.17–
3.04 (m, 1H), 2.33 (s, 3H), 1.40 (d, J = 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 140.7, 136.6, 129.3, 126.9, 41.8, 40.2, 21.1,
20.0. HRMS (APCI-TOF) calcd for C10H14Br [M+H]+ 213.0279, found
213.0282. Enantiomeric excess was determined by HPLC with a
Chiralcel OJ-H column (n-hexane/2-propanol 97:3, 0.5 mL/min,
220 nm); minor (R)-enantiomer tr = 12.15 min, major (S)-enan-
tiomer tr = 13.19 min.
4.2.6. (R)-1-(1-Bromopropan-2-yl)-4-methylbenzene (R)-7
According to the similar procedure described above for (S)-7,
the bromination of (R)-2-p-tolylpropan-1-ol (R)-6 (1.50 g,
10 mmol) gave (R)-7 (2.00 g, 94% yield, 90% ee) as a yellow oil.
[a]
20 = +19.3 (c 1.8, CHCl3). 1H NMR (300 MHz, CDCl3) d 7.14 (d,
D
J = 8.3 Hz, 2H), 7.10 (d, J = 8.3 Hz, 2H), 3.56 (dd, J = 9.8, 6.1 Hz,
1H), 3.46 (dd, J = 9.8, 8.0 Hz, 1H), 3.16–3.04 (m, 1H), 2.33 (s, 3H),
1.40 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 140.7, 136.6,
129.3, 126.9, 41.8, 40.2, 21.1, 20.0. HRMS (APCI-TOF) calcd for
steps) as a colorless oil. [
a
]
20 = À25.4 (c 1.8, CHCl3). 1H NMR
D
(300 MHz, CDCl3) d 9.67 (s, 1H), 7.11 (d, J = 8.1 Hz, 2H), 7.05 (d,
J = 8.1 Hz, 2H), 2.74–2.61 (m, 1H), 2.43–2.22 (m, 5H), 1.99–1.78
(m, 2H), 1.26 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
202.2, 142.8, 135.6, 129.0, 126.7, 42.0, 38.7, 30.2, 22.1, 20.8. HRMS
(APCI-TOF) calcd for C12H15O [MÀH]+ 175.1123, found 175.1126.
C
10H14Br [M+H]+ 213.0279, found 213.0284. Enantiomeric excess
was determined by HPLC with a Chiralcel OJ-H column (n-hex-
ane/2-propanol 97:3, 0.5 mL/min, 220 nm); major (R)-enantiomer
tr = 12.32 min, minor (S)-enantiomer tr = 13.48 min.
4.2.7. (R)-1-Methyl-4-(pent-4-en-2-yl)benzene (R)-8
4.2.10. (S)-4-p-Tolylpentanal (S)-9
To a suspension of CuI (1.98 g, 10.4 mmol) and anhydrous
diethyl ether (72 mL) was added vinylmagnesium bromide
(30 mL, 1.0 M in THF, 30 mmol) over 30 min at 0 °C. After the
resulting mixture was stirred for another 10 min, hydrocarbon bro-
mide (S)-7 (2.13 g, 10 mmol) was then added. The black suspension
was stirred for another 12 h, and the reaction was quenched with
saturated aqueous NH4Cl (20 mL). The organic phase was sepa-
rated, and the aqueous layer was extracted with Et2O
(3 Â 20 mL). The combined organic phases were washed with brine
(30 mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was purified by silica gel chro-
matography (petroleum ether) to afford (R)-8 (1.23 g, 77% yield)
According to the similar procedure described above for (R)-9,
the sequential hydroboration-oxidation and Dess–Martin oxida-
tion from (S)-1-methyl-4-(pent-4-en-2-yl)benzene (S)-8 furnished
20
(S)-9 (1.41 g, 80% yield over two steps) as a colorless oil. [
a
]
D
=
+17.9 (c 1.4, CHCl3). 1H NMR (300 MHz, CDCl3) d 9.67 (s, 1H),
7.11 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 2.74–2.60 (m, 1H),
2.36–2.28 (m, 5H), 1.99–1.78 (m, 2H), 1.26 (d, J = 6.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 202.2, 142.8, 135.6, 129.0, 126.7, 42.0,
38.7, 30.2, 22.2, 20.8. HRMS (APCI-TOF) calcd for C12H15O [MÀH]+
175.1123, found 175.1124.
4.2.11. (R)-ar-Curcumene (R)-1
as a colorless oil. [
a]
20 = À23.0 (c 0.9, CHCl3). 1H NMR (300 MHz,
To a stirred suspension of iso-propyltriphenylphosphonium
iodide (2.59 g, 6 mmol) in dry THF (6.5 mL) was added n-BuLi
(2.4 mL, 2.5 M in n-hexane, 6 mmol) at À15 °C over 5 min under
argon. The resulting mixture turned dark and was stirred for
another 30 min at the same temperature. Aldehyde (R)-9 (0.35 g,
2 mmol) in THF (1 mL) was added slowly at 0 °C. The reaction solu-
tion was warmed to room temperature and stirred for 30 min. The
reaction was quenched with saturated aqueous NH4Cl (20 mL), and
the organic phase was separated. The aqueous layer was extracted
with Et2O (5 Â 20 mL). The combined organic phases were washed
with brine (100 mL), dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. The residue was purified by silica
gel chromatography (petroleum ether) to afford (R)-1 (0.32 g,
D
CDCl3) d 7.11(d, J = 8.8 Hz, 2H), 7.07(d, J = 8.8 Hz, 2H), 5.78–5.64
(m, 1H), 5.02–4.93 (m, 2H), 2.81–2.69 (m, 1H), 2.39–2.21 (m,
5H), 1.23 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 143.9,
137.1, 135.2, 128.8, 126.7, 115.6, 42.5, 39.2, 21.4, 20.8. HRMS
(APCI-TOF) calcd for C12H17 [M+H]+ 161.1330, found 161.1337.
4.2.8. (S)-1-Methyl-4-(pent-4-en-2-yl)benzene (S)-8
According to the similar procedure described above for (R)-8,
the cross-coupling between (R)-1-(1-bromopropan-2-yl)-4-
methylbenzene (R)-7 (2.13 g, 10 mmol) and vinylmagnesium bro-
mide (30 mL, 1.0 M in THF, 30 mmol) afforded (S)-8 (1.25 g, 78%
yield) as a colorless oil. [a]
20 = +19.9 (c 1.3, CHCl3). 1H NMR
D
(300 MHz, CDCl3) d 7.11 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H),
5.78–5.64 (m, 1H), 5.01–4.93 (m, 2H), 2.81–2.69 (m, 1H), 2.41–
2.23 (m, 5H), 1.23 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
143.9, 137.1, 135.2, 128.8, 126.7, 115.6, 42.5, 39.2, 21.4, 20.8.
79% yield, 90% ee) as a colorless oil. [
a
]
20 = À44.6 (c 1.2, CHCl3).
D
Lit.21
[
a]
24 = À44.5 (c 1.1, CHCl3). 1H NMR (300 MHz, CDCl3) d
D
7.10 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 5.11–5.06 (m, 1H),
2.71–2.60 (m, 1H), 2.32 (s, 3H), 1.92–1.81 (m, 2H), 1.65 (s, 3H),
1.63–1.55 (m, 2H), 1.52 (s, 3H), 1.21 (d, J = 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 144.7, 135.1, 131.3, 128.9, 126.9, 124.6, 39.0,
HRMS (APCI-TOF) calcd for
161.1333.
C
12H17 [M+H]+ 161.1330, found
Please cite this article in press as: Wu, L.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.009

L. Wu et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
38.5, 26.2, 25.7, 22.4, 21.0, 17.7. HRMS (APCI-TOF) calcd for C15H23
[M+H]+ 203.1800, found 203.1805. Enantiomeric excess was deter-
mined by HPLC with a Chiralcel OJ-H column (n-hexane/2-propa-
nol 99.9:0.1, 0.3 mL/min, 220 nm); minor (S)-enantiomer
tr = 16.22 min, major (R)-enantiomer tr = 17.06 min.
ee) as a pale yellow oil. [
a
]
20 = +12.8 (c 1.3, CHCl3). 1H NMR
D
(300 MHz, CDCl3) d 7.84 (d, J = 1.3 Hz, 1H), 7.34–7.21 (m, 2H),
3.11–2.99 (m, 1H), 2.83–2.73 (m, 1H), 2.63–2.53 (m, 1H), 2.36 (s,
3H), 2.28–2.18 (m, 1H), 1.93–1.82 (m, 1H), 1.38 (d, J = 7.0 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 198.4, 145.9, 135.9, 134.3,
131.5, 127.1, 36.3, 32.3, 30.6, 20.7, 20.5. HRMS (APCI-TOF) calcd
for C12H15O [M+H]+ 175.1123, found 175.1124. Enantiomeric
excess was determined by HPLC with a Chiralcel OD-H column
(n-hexane/2-propanol 99:1, 0.5 mL/min, 220 nm); minor (S)-enan-
tiomer tr = 13.63 min, major (R)-enantiomer tr = 14.80 min.
4.2.12. (S)-ar-Curcumene (S)-1
According to the similar procedure described above for (R)-1,
the Wittig reaction between (S)-4-(p-tolyl)pentanal (S)-9 (0.35 g,
2 mmol) and iso-propyltriphenylphosphonium iodide (2.59 g,
6 mmol) gave (S)-ar-curcumene (S)-1 (0.31 g, 76% yield, 90% ee)
as a colorless oil. [
a
]
20 = +36.8 (c 1.3, CHCl3). Lit.3a
[
a
]
20 = +37.7 (c
D
4.2.16. (S)-4, 7-Dimethyl-l-tetralone (S)-2
D
0.7, CHCl3). 1H NMR (300 MHz, CDCl3) d 7.10 (d, J = 8.6 Hz, 2H),
7.07 (d, J = 8.6 Hz, 2H), 5.11–5.06 (m, 1H), 2.69–2.60 (m, 1H),
2.32 (s, 3H), 1.92–1.84 (m, 2H), 1.67 (s, 3H), 1.67–1.55 (m, 2H),
1.52 (s, 3H), 1.21 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
144.7, 135.1, 131.3, 128.9, 126.9, 124.6, 39.0, 38.5, 26.2, 25.7,
According to the similar procedure described above for (R)-2,
the Friedel–Crafts reaction of (S)-4-(p-tolyl)pentanoic acid (S)-10
furnished (S)-2 (0.62 g, 71% yield, 90% ee) as a pale yellow oil.
[a
]
D
20 = À9.2 (c 1.7, CHCl3). Lit.12c
[a
]
D = À10 (c 10, CHCl3). 1H
NMR (300 MHz, CDCl3) d 7.84 (d, J = 1.4 Hz, 1H), 7.34–7.21 (m,
2H), 3.10–2.99 (m, 1H), 2.83–2.73 (m, 1H), 2.63–2.52 (m, 1H),
2.35 (s, 3H), 2.28–2.17 (m, 1H), 1.93–1.82 (m, 1H), 1.38
(d, J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 198.4, 145.9,
135.9, 134.4, 131.4, 127.1, 36.3, 32.3, 30.6, 20.7, 20.5. HRMS
(APCI-TOF) calcd for C12H15O [M+H]+ 175.1123, found 175.1125.
Enantiomeric excess was determined by HPLC with a Chiralcel
OD-H column (n-hexane/2-propanol 99:1, 0.5 mL/min, 220 nm);
major (S)-enantiomer tr = 13.60 min, minor (R)-enantiomer
tr = 14.84 min.
22.5, 21.0, 17.7. HRMS (APCI-TOF) calcd for
C
15H23 [M+H]+
203.1800, found 203.1806. Enantiomeric excess was determined
by HPLC with a Chiralcel OJ-H column (n-hexane/2-propanol
99.9:0.1,
0.3 mL/min,
220 nm);
major
(S)-enantiomer
tr = 16.42 min, minor (R)-enantiomer tr = 17.27 min.
4.2.13. (R)-4-p-Tolylpentanoic acid (R)-10
To a mixture solution of THF and H2O (THF/H2O 3:1, 30 mL) was
added aldehyde (R)-9 (1.76 g, 10 mmol). A solution of AgNO3 (2.6 g,
15.3 mmol) in H2O (100 mL) was then added. The resulting mix-
ture was stirred and aqueous NaOH (50 mL, 10%) was added drop-
wise at room temperature. After stirring for 2 h at the same
temperature, the reaction mixture was filtered and washed with
water. The filtrate was extracted with Et2O (150 mL) and the
organic layer was separated. The aqueous phase was acidified to
pH = 1 with hydrochloric acid (12 mol LÀ1) at 0 °C and extracted
with CH2Cl2 (4 Â 150 mL). The combined extracts were dried over
anhydrous Na2SO4, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (petroleum
Acknowledgments
We are grateful to New Century Excellent Talents in University
(NCET-12-0528) and the National Key Technology Research and
Development Program (No. 2015BAK45B01) for their financial
support.
References
ether/ethyl acetate 2:1) to give (R)-10 (1.19 g, 62% yield) as a yel-
1. Rao, B. S.; Simonsen, J. L. J. Chem. Soc. 1928, 2496–2505.
low oil. [
a]
= À28.3 (c 2.1, CHCl3). 1H NMR (300 MHz, CDCl3) d
20
2. Honwad, V. K.; Rao, A. S. Tetrahedron 1965, 21, 2593–2604.
3. (a) Uhde, G.; Ohloff, G. Helv. Chim. Acta 1972, 55, 2621–2625; (b) Maurer, B.;
Grieder, A. Helv. Chim. Acta 1977, 60, 2177–2190; (c) McBrien, H. L.; Millar, J. G.;
Rice, R. E.; McElfresh, J. S.; Cullen, E.; Zalom, F. G. J. Chem. Ecol. 2002, 28, 1797–
1818.
4. Fujiwara, M.; Yagi, N.; Miyazawa, M. J. Agric. Food Chem. 2010, 58,
2824–2829.
5. Bleeker, P. M.; Diergaarde, P. J.; Ament, K.; Schuetz, S.; Johne, B.; Dijkink, J.;
Hiemstra, H.; de Gelder, R.; de Both, M. T. J.; Sabelis, M. W.; Haring, M. A.;
Schuurink, R. C. Phytochemistry (Elsevier) 2011, 72, 68–73.
6. (a) Kaiser, R.; Lamparsky, D. Helv. Chim. Acta 1983, 66, 1843–1849; (b)
Weyerstahl, P.; Marschall, H.; Weirauch, M.; Thefeld, K.; Surburg, H. Fragrance J.
1998, 13, 295–318; (c) Ali, A.; Tabanca, N.; Demirci, B.; Blythe, E. K.; Ali, Z.;
Baser, K. H. C.; Khan, I. A. J. Agric. Food Chem. 2015, 63, 447–456.
7. Imelouane, B.; Elbachiri, A.; Wathelet, J.-P.; Dubois, J.; Amhamdi, H. World J.
Chem. 2010, 5, 103–110.
D
11.40 (br s, 1H), 7.10 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H),
2.75–2.60 (m, 1H), 2.31 (s, 3H), 2.25–2.16 (m, 2H), 1.98–1.79 (m,
2H), 1.25 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 180.1,
142.8, 135.6, 129.0, 126.7, 38.7, 32.8, 32.1, 22.1, 20.8. HRMS
(APCI-TOF) calcd for C12H17O2 [M+H]+ 193.1229, found 193.1233.
4.2.14. (S)-4-p-Tolylpentanoic acid (S)-10
According to the similar procedure described above for (R)-10,
the oxidation of (S)-4-p-tolylpentanal (S)-9 afforded (S)-10
(1.21 g, 63% yield) as a yellow oil. [
[a]
D
a]
20 = +26.6 (c 1.1, CHCl3). Lit.12b
D
23 = +21.5 (c 0.8, CHCl3). 1H NMR (300 MHz, CDCl3) d 11.49 (br s,
8. (a) Thebtaranonth, C.; Thebtaranonth, Y.; Wanauppathamkul, S.; Yuthavong, Y.
Phytochemistry 1995, 40, 125–128; (b) Nagashima, F.; Asakawa, Y.
Phytochemistry 2001, 56, 347–352.
9. (a) Hagiwara, H.; Okabe, T.; Ono, H.; Kamat, V. P.; Hoshi, T.; Suzuki, T.; Ando, M.
J. Chem. Soc., Perkin Trans. 1 2002, 895–900; (b) Asaoka, M.; Shima, K.; Fujii, N.;
Takei, H. Tetrahedron 1988, 44, 4757–4766.
1H), 7.10 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 8.2 Hz, 2H), 2.75–2.60 (m,
1H), 2.31 (s, 3H), 2.26–2.19 (m, 2H), 1.98–1.79 (m, 2H), 1.25 (d,
J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 180.1, 142.8, 135.6,
129.0, 126.7, 38.7, 32.8, 32.1, 22.1, 20.8. HRMS (APCI-TOF) calcd
for C12H17O2 [M+H]+ 193.1229, found 193.1237.
10. (a) Yang, S.; Zhu, S.-F.; Guo, N.; Song, S.; Zhou, Q.-L. Org. Biomol. Chem. 2014, 12,
2049–2052; (b) Nishimura, T.; Yasuhara, Y.; Sawano, T.; Hayashi, T. J. Am. Chem.
Soc. 2010, 132, 7872–7873; (c) Tamao, K.; Hayashi, T.; Matsumoto, H.;
Yamamoto, H.; Kumada, M. Tetrahedron Lett. 1979, 20, 2155–2156; (d) Du, Z.;
Yue, G.; Ma, J.; She, X.; Wu, T.; Pan, X. J. Chem. Res. 2004, 427–429; (e)
Yasukawa, T.; Suzuki, A.; Miyamura, H.; Nishino, K.; Kobayashi, S. J. Am. Chem.
Soc. 2015, 137, 6616–6623.
11. (a) Fuganti, C.; Serra, S. Synlett 1998, 1252–1254; (b) Fuganti, C.; Serra, S.;
Dulio, A. J. Chem. Soc., Perkin Trans. 1 1999, 279–282; (c) Kamal, A.; Malik, M. S.;
Shaik, A. A.; Azeeza, S. Tetrahedron: Asymmetry 2007, 18, 2547–2553.
12. (a) Elford, T. G.; Nave, S.; Sonawane, R. P.; Aggarwal, V. K. J. Am. Chem. Soc. 2011,
133, 16798–16801; (b) Goncalves-Contal, S.; Gremaud, L.; Alexakis, A. Angew.
Chem., Int. Ed. 2013, 52, 12701–12704; (c) Chavan, S. P.; Khatod, H. S.
Tetrahedron: Asymmetry 2012, 23, 1410–1415; (d) Chavan, S. P.; Dhondge, V. D.;
Patil, S. S.; Rao, Y. T. S.; Govande, C. A. Tetrahedron: Asymmetry 1997, 8, 2517–
2518.
4.2.15. (R)-4,7-Dimethyl-l-tetralone (R)-2
Acid (R)-10 (0.96 g, 5 mmol) was dissolved in polyphosphoric
acid (15 mL) at 70 °C. The reaction mixture turned orange and
was stirred vigorously for 2 h at the same temperature. After being
cooled to 0 °C, water (20 mL) was added dropwise. The resulting
mixture was stirred for another 30 min at the same temperature,
and then warmed to room temperature followed by extraction
with Et2O (3 Â 20 mL). The combined extracts were dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (petroleum
ether/ethyl acetate 20:1) to afford (R)-2 (0.61 g, 70% yield, 90%
Please cite this article in press as: Wu, L.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.009

6
L. Wu et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
13. (a) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374–4376;
(b) Desai, K. R. Organic Name Reactions; Jaipur India: Oxford, 2008. p 144; (c)
Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417–1492.
14. (a) Kiso, Y.; Tamao, K.; Miyake, N.; Yamamoto, K.; Kumada, M. Tetrahedron Lett.
1974, 15, 3–6; (b) Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc.
1988, 110, 8153–8156; (c) Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 1264–
1266; (d) Tollefson, E. J.; Dawson, D. D.; Osborne, C. A.; Jarvo, E. R. J. Am. Chem.
Soc. 2014, 136, 14951–14958.
17. Li, A.; Yue, G.; Li, Y.; Pan, X.; Yang, T.-K. Tetrahedron: Asymmetry 2003, 14, 75–78.
18. Lorenz, M.; Kalesse, M. Org. Lett. 2008, 10, 4371–4374.
19. Trost, B. M.; Schroeder, G. M. Chem. Eur. J. 2005, 11, 174–184.
20. Lee, T.; Jones, J. B. J. Am. Chem. Soc. 1996, 118, 502–508.
21. Song, S.; Zhu, S.-F.; Yang, S.; Li, S.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2012, 51,
2708–2711.
22. Amin, S.; Huie, K.; Hussain, N.; Balanikas, G.; Hecht, S. S. J. Org. Chem. 1985, 50,
1948–1954.
15. Mao, J.-Y.; Liu, F.-P.; Wang, M.; Wu, L.; Zheng, B.; Liu, S. Z.; Zhong, J.; Bian,
Q.-H.; Walsh, P. J. J. Am. Chem. Soc. 2014, 136, 17662–17668.
16. Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J. Am. Chem. Soc.
1990, 112, 5290–5313.
23. Phillips, D. D. J. Am. Chem. Soc. 1955, 77, 3658–3659.
24. Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.; Campos, K. R.;
Woerpel, K. A. J. Org. Chem. 1998, 63, 4541–4544.
25. DeShong, P.; Kell, D. A.; Sidler, D. R. J. Org. Chem. 1985, 50, 2309–2315.
Please cite this article in press as: Wu, L.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.11.009