Synthesis of racemic Δ3-2-hydroxybakuchiol and its analogues

Article abstract of DOI:10.1002/hlca.200900243

The first synthetic approach to (±)-Δ³-2- hydroxybakuchiol (=4-[(1E,5E)-3-ethenyl-7-hydroxy-3,7-dimethylocta-1,5-dien-1- yl]phenol; 14) and its analogues 13a - 13f was developed by 12 steps (Schemes 2 and 3). The key features of the approach are the construction of the quaternary C-center bearing the ethenyl group by a Johnson - Claisen rearrangement (→6); and of an (E)-alkenyl iodide via a Takai - Utimoto reaction (→11); and an arylation via a Negishi cross-coupling reaction (→12e - 12f).

Full text of DOI:10.1002/hlca.200900243

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Synthesis of Racemic D3-2-Hydroxybakuchiol and Its Analogues
by Lei Shia)b), Xinsheng Lei*a), Jiange Zhang*b), and Guoqiang Lina)c)
a) Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 138 Yi Xue Yuan Road,
Shanghai, 200032, P. R. China (phone/fax: þ 86-21-54237756; e-mail: leixs@fudan.edu.cn)
b) Department of Medicinal Chemistry, School of Pharmaceutical Science, Zhengzhou University,
Zhengzhou 450001, P. R. China
c) Institutes of Biomedical Sciences, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032,
P. R. China
The first synthetic approach to (ꢀ)-D3-2-hydroxybakuchiol (¼4-[(1E,5E)-3-ethenyl-7-hydroxy-3,7-
dimethylocta-1,5-dien-1-yl]phenol; 14) and its analogues 13a – 13f was developed by 12 steps (Schemes 2
and 3). The key features of the approach are the construction of the quaternary C-center bearing the
ethenyl group by a Johnson – Claisen rearrangement (!6); and of an (E)-alkenyl iodide via a Takai –
Utimoto reaction (!11); and an arylation via a Negishi cross-coupling reaction (!12e – 12f).
Introduction. – The medicinal plant Psoralea corylifolia L. has been used over a
long time as Chinese traditional medicine to treat a wide variety of disorders such as
deobstruent, anthelmintic, and diuretic diseases as well as certain skin diseases such as
vitiligo [1][2]. A number of monoterpene phenols occurring in the plant have been
isolated and demonstrated to possess versatile biological activities [3 – 8] (see Fig.). For
example, bakuchiol1), a major constituent obtained from the seed of the plant [9][10],
exhibits b-secretase (BACE-1) [11] and protein tyrosine phosphatase B (PTP1B)
inhibition [12], hepatoprotective and antifibrotic effects [13], and other activities [14 –
19], which have attracted much interest of medicinal chemists [20 – 26]. In contrast to
bakuchiol, few attention has been paid to D3-2-hydroxybakuchiol (¼ 3,4-didehydro-2,3-
dihydro-2-hydroxybakuchiol)1) [27], a congener metabolized oxidatively from baku-
chiol, probably due to its scarcity and lability [28]. Most recently, Guo and co-workers
have disclosed that D3-2-hydroxybakuchiol could inhibit monoamine transporters and
regulate monoaminargic transmission, which are associated with psychogenic disorders
such as Parkinsonꢀs disease, depression, and cocaine addiction [29]. Therefore, the
natural product might be a lead compound for the development of potential
psychopharmacologic agents.
To the best of our knowledge, racemic or enantiomerically pure D3-2-hydroxyba-
kuchiol has not been synthesized so far since its first isolation and identification.
Though there are several available accesses to racemic or optically active bakuchiol
[20 – 26], there remain, however, some limitations. For instance, the general feature for
the construction of the styrene moiety of bakuchiol is to use the Grignard reaction of
the appropriate aliphatic aldehydes with (4-methoxyphenyl)magnesium bromide or (4-
1
)
Trivial atom numbering; for systematic names, see Exper. Part.
ꢁ 2010 Verlag Helvetica Chimica Acta AG, Zꢂrich

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Figure. (þ)-(S)-Bakuchiol and some of its congeners
methoxybenzyl)magnesium chloride and subsequent dehydration of the resulting
alcohols. Moreover, demethylation of 12-O-methylbakuchiol to form bakuchiol has to
be performed at a surprisingly high temperature (1808) with MeMgI. Previous research
has shown that 2,3-epoxybakuchiol derived from bakuchiol could not be chemically
converted to D3-2-hydroxybakuchiol but rather to D1-3-hydroxybakuchiol [30], despite
the evident biogenetic relationship between them. Therefore, the reported methods for
the synthesis of bakuchiol seem to be unsuitable for the preparation of the labile D3-2-
hydroxybakuchiol. Herein, we report the first synthesis of racemic D3-2-hydroxyba-
kuchiol.
Results and Discussion. – Our retrosynthetic route for the synthesis of (ꢀ)-D3-2-
hydroxybakuchiol (14) is outlined in Scheme 1. According to the designed route from 7
via 10, it was our idea not only to construct (ꢀ)-D3-2-hydroxybakuchiol but also to
modify afterwards the structure of the target compound conveniently for the
structure – activity-relationship study.
Thus, starting from commercial 2-hydroxyacetone (¼1-hydroxypropan-2-one; 1)
and ethyl (triphenylphosphoranylidene)acetate, ethyl (2E)-4-hydroxy-3-methylbut-2-
enoate (2) was prepared in 77.7% yield according to the described method [31 – 33],
and then, the corresponding a,b-unsaturated lactone 3 was obtained in 68.3% yield by

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Scheme 1. Restrosynthetic Route for Racemic D3-2-Hydroxybakuchiol (14)
subsequent saponification and intramolecular cyclization (Scheme 2). Our attempt to
construct the key intermediate 7 by using the Michael-addition reaction [34] of lactone
3 with vinylcuprate species, prepared in situ from vinylmagnesium bromide and CuI (or
CuBr· Me2S), failed, although the same strategy was successfully applied to an a,b-
unsaturated aldehyde by Liꢀs group [22] or to a cyclic a,b-unsaturated amide by
Esumiꢀs group [20] in the course of our project. Thus, we turned our attention to an
alternative approach aiming to obtain intermediate 7: Butenoate 2 was protected as
tBuPh2Si ether
4
and reduced to the allyl alcohol
5
with DIBALH
(¼diisobutylaluminium hydride) in CH2Cl2 at ꢁ 208 (yields 91.8% and 82.6%, resp.).
Then, compound 6 with the quaternary C-center bearing the ethenyl group was
constructed via a Johnson – Claisen rearrangement [35][36]. The reaction resulted in
73.4% of 6 (based on 5), when the allyl alcohol 5 was treated with an excess of triethyl
orthoacetate in the presence of catalytic amounts of propanoic acid. After removal of
the protective group and spontaneous cyclization, the key intermediate 7 was provided
in 83.7% yield from 6.
Scheme 2. Synthesis of the Key Intermediate 7
a) Ph3P¼CHCOOEt, toluene, reflux; 77.7%. b) tBuPh2SiCl, DMAP (¼ N,N-dimethylpyridin-4-amine),
1H-imidazole,CH2Cl2; 91.8%. c) DIBALH, CH2Cl2, ꢁ 208, 82.6%. d) Me(OEt)3, EtCOOH, reflux;
73.4%. e) Bu4NF, THF; 83.7%. f) NaOH (aq.); HCl (aq.).
The intermediate 7 was carefully reduced to the hemiacetal 8 in 82.4% yield, which
consisted of two stereoisomers in a ca. 1:1 ratio (Scheme 3). Wittig reaction of 8 with
Ph3P¼CHCO2Et in toluene under reflux for 2 h led to the desired 9 in 79% yield (65%
over both steps). Oxidation of 9 with IBX (¼2-iodylbenzoic acid ¼ 1-hydroxy-1l3,2-
benziodoxol-3(1H)-one 1-oxide) afforded aldehyde 10 in 94.5% yield. With the
aldehyde in hand, we tested the Wittig or Horner – Wadsworth – Emmons reaction by
treating 10 with the appropriate phosphorus ylides, prepared in situ from (4-

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methoxybenzyl)triphenylphosphonium bromide or diethyl (4-methoxybenzyl)phosph-
t
onate in the presence of various bases such as BuOK, NaH, LHMDS (¼ lithium
hexamethyldisilazide), etc., to get compound 12b. However, several efforts proved to
be unsuccessful, possibly due to the steric hindrance exerted by the quaternary C-atom
in a position.
Scheme 3. Synthesis of (ꢀ)-D3-2-Hydroxybakuchiol (14) and Its Analogues 13a – 13f
a) DIBALH, CH2Cl2, ꢁ 208; 82.4%. b) Ph3P¼CHCOOEt, toluene, reflux; 79%. c) IBX, DMSO; 94.5%.
d) CHI3,CrCl2,THF; 78.6%. e) ArBr, BuLi/ZnCl2; [Pd(OAc)2]/PPh3, THF; 47.3 – 90.1%. f) MeMgI,
Et2O/THF; 48.3 – 88.0%. g) Bu4NF, THF; 77.8%.
Fortunately, we found that the aldehyde 10 could be converted into the corre-
sponding (E)-alkenyl iodide 11 via the Takai – Utimoto reaction [37][38] in a satisfying
yield. Especially, the reaction resulted in up to 78.6% yield of 11 by using commercial
greyish CrCl2, in comparison with 42% or lower yields when greenish CrCl2 or freshly
prepared CrCl2 from CrCl3 · 6 H2O and Zn powder were used [39]. After the successful
synthesis of iodoalkene derivative 11, Suzuki reaction of 11 with various arylboronic
acids were performed. To our disappointment, the reaction led to very low conversion
(<10%) over a period of 24 h under either the standard condition ([Pd(PPh3)4]/
Na2CO3, toluene, 1108 ) [40] or Fuꢀs condition ([Pd(dba)2]/P(tBu)3/KF, THF, r.t.; dba ¼
dibenzylideneacetone ¼ 1,5-diphenylpenta-1,4-dien-3-one) [41]. Finally, Negishi reac-
tion [42][43] was selected for the transformation of 11. To our delight, the desired
cross-coupling compounds 12a – 12f were produced in good yields (47.3 – 90.1%), by
using [Pd(OAc)2] (0.05 equiv.)/PPh3 (0.10 equiv.) as the catalyst. After selective 1,2-
addition reaction with MeMgI, compounds 13a – 13f were obtained in rewarding yields
(48.3 – 88.0%). Finally, 13a (Ar¼ 4-(tBuPh2SiO)ꢁC6H4) was converted into (ꢀ)-D3-2-

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t
hydroxybakuchiol (14) in 77.8% yield after deprotection of the BuPh2Si group with
Bu4NF · 3 H2O in THF. As mentioned in the literature [28], the prepared compound
(ꢀ)D3-2-hydroxybakuchiol (14) indeed underwent decomposition at room temper-
ature, especially in CDCl3, but it was enough stable in AcOEt or (D6)-DMSO. Since
decomposition of the precursors 13a – 13f was not observed, it seems that the free
phenolic OH group might cause the lability of D3-2-hydroxybakuchiol.
Conclusions. – In summary, we have developed the first synthetic approach to (ꢀ)-
D3-2-hydroxybakuchiol (14) and its analogues. The key features of the approach
include the construction of the quaternary C-center bearing the ethenyl group by a
Johnson – Claisen rearrangement, and of an (E)-alkenyl iodide via a Takai – Utimoto
reaction, and an arylation via a Negishi cross-coupling reaction. The (ꢀ)-D3-2-
hydroxybakuchiol (14) was obtained by this approach in 12 steps and in 9.4% overall
yield. The optimized approach and asymmetric synthesis of D3-2-hydroxybakuchiol is
under way.
We thank the Fudan University and the National Natural Science Foundation of China (20872019)
for financial research support, and we are grateful to the Shanghai Institute of Organic Chemistry for
recording the EI-MS or ESI-MS, HR-MS, 1H-NMR, and 13C-NMR spectra.
Experimental Part
General. Solvents were distilled from the appropriate drying agents before use. All the reagents were
purchased from Acros, Alfa Aesar, and National Chemical Reagents Group Co. Ltd., P. R.China. Column
chromatography (CC): Commercial silica gel (Qingdao Hai Yang Chemical Group Co.; 300 – 400 mesh).
TLC: silica gel GF 254 plates (Yantai Jiangyou Silica R&D Co. Ltd., P. R. China); detection under UV
light or with I2. 1H- and 13C-NMR Spectra: Varian-Mercury-Plus (300 MHz for 1H and 75.5 MHz for 13C)
spectrometer; in CDCl3 if not stated otherwise; chemical shifts d in ppm, with residual CHCl3 (d(H) 7.26
and d(C) 77.0) as internal standard; J in Hz. EI-MS, ESI-MS and HR-MS: Finnigan-Mat-95 mass
spectrometer; in m/z.
Ethyl (2E)-4-Hydroxy-3-methylbut-2-enoate (2). To a soln. of 1-hydroxypropan-2-one (15 ml,
0.219 mol) in toluene (100 ml) was added a soln. of Ph3P¼CHCO2Et in toluene (200 ml), and the soln.
was then refluxed for 4 h. After accomplishment of the reaction monitored by TLC, the soln. was allowed
to reach r.t. and concentrated. The resulting residue was treated with Et2O (100 ml), and then the white
precipitate was removed by filtration. The resulting filtrate was washed with H2O and brine, dried
(Na2SO4), and concentrated, and the crude product purified by CC (silica gel, petroleum ether/AcOEt
1
5 :1, Rf 0.25): 24.5 g (77.7%) of 2. Colorless oil. H-NMR: 5.93 (d, J ¼ 1.2, HꢁC(2)); 4.08 – 4.15 (m,
CH2(4), MeCH2O); 2.72 (br. s, OH); 2.03 (s, MeꢁC(3)); 1.23 (t, J ¼ 7.5, MeCH2O).
Ethyl (2E)-4-{[(tert-Butyl)diphenylsilyl]oxy}-3-methylbut-2-enoate (4). To a soln. of 2 (4.85 g,
33.7 mmol), 1H-imidazole (4.58 g, 67.3 mmol), and DMAP (0.205 g, 1.68 mmol) in CH2Cl2 (60 ml) was
t
added dropwise BuPh2SiCl (12.1 ml, 47.1 mmol) within 30 min at 08, and the mixture was stirred for
another 2 h at r.t. The mixture was diluted with CH2Cl2 (40 ml) the soln. washed with H2O and brine,
dried (Na2SO4), and concentrated, and the crude product purified by CC (petroleum ether/CH2Cl2 5 :1:
Rf 0.20): 11.4 g (91.8%) of 4. Colorless oil. 1H-NMR: 7.39 – 7.68 (m, 10 arom. H); 6.02 (s, HꢁC(2)); 4.18
(q, 2 H, J ¼ 7.5, MeCH2O); 4.08 (d, J ¼ 1.2, CH2(4)); 2.00 (s, MeꢁC(3)); 1.32 (t, J ¼ 7.5, MeCH2O); 1.08 (s,
t
tBu). EI-MS: 337 ([M ꢁ OEt]þ), 325 ([M ꢁ Bu]þ).
(2E)-4-{[(tert-Butyl)diphenylsily]loxy}-3-methylbut-2-en-1-ol (5). To a soln. of 4 (5.04 g, 12.3 mmol)
in CH2Cl2 (150 ml) was added dropwise a soln. of DIBALH in hexane (12.3 ml, 25% (w/w), 15 mmol)
within 30 min at ꢁ 208. After stirring for 2 h, the reaction was quenched with MeOH (80 ml) and the
mixture warmed to r.t. and stirred for 0.5 h. The resulting mixture was filtered through Celite, the filtrate

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washed with brine (30 ml), dried (Na2SO4) and concentrated, and the residue purified by CC (petroleum
1
ether/AcOEt 10 :1, Rf 0.12): 3.73 g (82.6%) of 5. Colorless oil. H-NMR: 7.26 – 7.69 (m, 10 arom. H),
5.73 – 5.78 (m, HꢁC(2)); 4.21 (d, J ¼ 5.7, CH2(1)); 4.07 (s, CH2(4)); 1.62 (s, MeꢁC(3)); 1.40 – 1.50 (br. s,
t
OH); 1.07 (s, Bu). ESI-MS: 363.0 ([M þ Na]þ).
Ethyl 3-{{[(tert-Butyl)diphenylsilyl]oxy}methyl}-3-methylpent-4-enoate (6). A soln. of 5 (6.12 g,
18.0 mmol) and MeCH2CO2H (0.7 ml) in triethyl orthoacetate (98 ml) was refluxed overnight, and then
the excess triethyl orthoacetate was removed by evaporation. The resulting residue was purified by CC
1
(petroleum ether/Et2O 200 :1, Rf 0.20): 5.4 g (73.4%) of 6. Colorless oil. H-NMR: 7.23 – 7.57 (m, 10
arom. H); 5.78 – 6.03 (dd, J(4,5) ¼ 10.8 and 17.4, HꢁC(4)); 4.98 (d, J(4,5) ¼ 10.8, HcisꢁC(5)); 4.94 (d,
J(4,5) ¼ 17.4, HtransꢁC(5)); 3.96 (q, J ¼ 6.9, MeCH2O); 3.46 (d, Jgem ¼ 9.9, 1 H, SiOCH2ꢁC(3)); 3.39 (d,
Jgem ¼ 9.9, 1 H, SiOCH2ꢁC(3)); 2.46 (d, Jgem ¼ 12.9, 1 HꢁC(2)); 2.40 (d, Jgem ¼ 12.9, 1 HꢁC(2)); 1.07 (s,
MeꢁC(3)); 1.08 (t, J ¼ 6.9, MeCH2O); 0.97 (s, tBu). 13C-NMR: 171.9 (C¼O); 143.0; 135.7; 133.5; 129.7;
127.7; 113.4 (C(5)); 70.7 (SiOCH2ꢁC(3)); 60.0 (MeCH2O); 41.7 (C(2)); 41.6 (C(3)); 26.9 (MeꢁC(3));
20.9 (Me2C), 19.5 (Me3C), 14.3 (MeCH2O). ESI-MS: 411.0 ([M þ H]þ), 433.1 ([M þ Na]þ). HR-ESI-
MS: 433.2169 (C25H34NaO3Siþ, [M þ Na]þ; calc. 433.2167).
4-Ethenyldihydro-4-methylfuran-2(3H)-one (7). To a soln. of 6 (9.09 g, 20.8 mmol) in THF (50 ml)
was added a soln. of Bu4NF · 3 H2O (25.4 g, 83.2 mmol) in THF (100 ml) at r.t., and then stirring was
continued overnight. The reaction was quenched by addition of H2O (150 ml), the org. phase washed
with brine, dried (Na2SO4), and concentrated, and the residue purified by CC (petroleum ether/AcOEt
20 :1, Rf 0.14): 2.34 g (83.7%) of 7. Colorless oil. 1H-NMR: 5.85 – 5.95 (dd, J(1’,2’) ¼ 10.5, 17.7, HꢁC(2’));
5.16 (d, J(1’,2’) ¼ 17.7, HtransꢁC(1’)); 5.16 (d, J(1’,2’) ¼ 10.5, HcisꢁC(2’)); 4.14 (d, Jgem ¼ 9.0, 1 HꢁC(5));
4.01 (d, Jgem ¼ 9.0, 1 HꢁC(5)); 2.59 (d, Jgem ¼ 16.8, 1 HꢁC(3)); 2.35 (d, Jgem ¼ 16.8, 1 HꢁC(3)); 1.03 (s,
MeꢁC(4)). 13C-NMR: 176.1 (C(2)); 140.7 (C(1’)); 114.1 (C(2’)); 77.3 (C(5)); 42.1 (C(4)); 40.9 (C(3));
22.7 (MeꢁC(4)). EI-MS: 126 (Mþ). HR-EI-MS: 126.0682 (C7H10O2þ, Mþ; calc. 126.0681).
4-Ethenyltetrahydro-4-methylfuran-2-ol (8). To a soln. of 7 (1.11 g, 8.81 mmol) in CH2Cl2 (30 ml)
was added dropwise a soln. of DIBALH in hexane (7.97 ml, 25% (w/w)) within 30 min at ꢁ 208. Two
hours later, NH4Cl (0.642 g) was added to the soln., followed by a drop of MeOH. The resulting mixture
was stirred for 0.5 h at r.t., and then filtered through Celite. The filtrate was concentrated and the residue
purified by CC (petroleum ether/AcOEt 7:1, Rf 0.23): 0.930 g (82.4%) of 8 as a ca. 1:1 mixture of
stereoisomers. Colorless oil. 1H-NMR: 6.02 – 5.84 (m, HꢁC(1’)); 5.64 – 5.59 (m, HꢁC(2)); 5.14 – 4.98 (m,
CH2(2’)); 4.55 (br., 0.5 H, OH of one isomer); 4.44 (br., 0.5 H, OH of the other isomer); 3.92 – 3.51 (m,
CH2(5)); 2.25 – 1.70 (m, CH2(3)); 1.28 – 1.18 (m, MeꢁC(4)). 13C-NMR: 144.5; 143.3 (C(6)); 112.8, 111.5
(C(2’)); 99.2 (C(2)); 77.4 (C(5)); 47.0, 46.2 (C(3)); 45.4, 44 (C(4)); 23.5, 22.9 (MeꢁC(4)). ESI-MS: 127.1
([M ꢁ 1]ꢁ). HR-EI-MS: 128.0837 (C7H12O2þ, Mþ; calc. 128.0838).
Ethyl (2E)-5-(Hydroxymethyl)-5-methylhepta-2,6-dienoate (9). To a soln. of 8 (1.37 g, 10.7 mmol) in
dry toluene (30 ml) was added a soln. of Ph3P¼CHCO2Et (7.45 g, 21.4 mmol) in dry toluene (60 ml), and
the resulting soln. was refluxed for 2 h. The soln. was allowed to warm to r.t. and concentrated. The
resulting residue was treated with Et2O (50 ml), and then the white precipitate was removed by filtration.
The filtrate was washed with H2O and brine, dried (Na2SO4), and evaporated and the crude product
purified by CC (silica gel, petroleum ether/AcOEt 7:1, Rf 0.22): 1.67 g (79.0%) of 9. Colorless oil.
1H-NMR: 6.86 (dt, J(2,3) ¼ 15.6, J(3,4) ¼ 7.8, HꢁC(3)); 5.85 (d, J(2,3) ¼ 15.6, HꢁC(2)); 5.77 (dd,
J(6,7) ¼ 17.7 and 10.8, HꢁC(6)); 5.18 (d, J(6,7) ¼ 10.8, HcisꢁC(7)); 5.08 (d, J(6,7) ¼ 17.7, 1 H,
HtransꢁC(7)); 4.14 (q, J ¼ 7.2, MeCH2O); 3.34 (s, CH2ꢁC(5)); 2.30 – 2.12 (m, CH2(4)); 2.2 – 2.1 (br.,
OH); 1.16 (t, J ¼ 7.2, MeCH2O); 0.97 (s, MeꢁC(5)). 13C-NMR: 166.4 (C(1)); 145.4 (C(6)); 142.7 (C(3));
123.7 (C(2)); 114.9 (C(7)); 69.5 (CH2ꢁC(5)); 60.2 (MeCH2O); 42.3 (C(4)); 39.5 (C(5)); 20.2
(MeꢁC(5)); 14.1 (MeCH2O). EI-MS: 198(Mþ). HR-EI-MS: 198.1256 (C11H18Oþ3 , Mþ; calc. 198.1254).
Ethyl (2E)-5-Formyl-5-methylhepta-2,6-dienoate (10). To a soln. of IBX (7.10 g, 25.4 mmol) in
DMSO (120 ml) was added dropwise a soln. of 9 (1.68, 8.45 mmol) in DMSO (120 ml) at r.t. The reaction
was monitored by TLC until the alcohol disappeared. The mixture was diluted with CH2Cl2 (200 ml), the
soln. washed with H2O (3 ꢂ 150 ml) and brine, dried (Na2SO4), and concentrated, and the residue
purified by CC (petroleum ether/AcOEt 4 :1, Rf 0.18): 1.57 g (94.5%) of 10. Colorless oil. 1H-NMR: 9.39
(s, CHO); 6.83 (dt, J(2,3) ¼ 15.6, J(3,4) ¼ 7.8, HꢁC(3)); 5.81 (d, J(2,3) ¼ 15.6, HꢁC(2)); 5.73 (dd,
J(6,7) ¼ 17.7 and 10.5, HꢁC(6)); 5.32 (d, J(6,7) ¼ 10.5, HcisꢁC(7)); 5.15 (d, J(6,7) ¼ 17.7, HtransꢁC(7));

Helvetica Chimica Acta – Vol. 93 (2010)
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4.18 (q, J ¼ 7.5, MeCH2O); 2.57 – 2.43 (m, CH2(4)); 1.28 (t, J ¼ 7.5, MeCH2O); 1.21 (s, MeꢁC(5)).
13C-NMR: 201.0 (CHO); 165.8 (C(1)); 143.1 (C(6)); 137.2 (C(3)); 124.7 (C(2)); 118.0 (C(7)); 60.2
(MeCH2O); 52.3 (C(5)); 37.7 (C(4)); 18.0 (MeꢁC(5)); 14.1 (MeCH2O). EI-MS: 181 ([MꢁCH3]þ). HR-
EI-MS: 196.1099 (C11H16Oþ3 , Mþ; calc.196.1101).
Ethyl (2E,6E)-5-Ethenyl-7-iodo-5-methylhepta-2,6-dienoate (11). To a suspension of anh. CrCl2
(1.00 g, 8.14 mmol) in THF (20 ml) were added dropwise a soln. of CHI3 (0.791 g, 2.01 mmol) and 10
(0.263 g, 1.34 mmol) in THF (15 ml) at 08. After 2 h, the mixture was quenched with 10% aq. Na2S2O3
soln. (20 ml) (brown ! green mixture). The mixture was extracted with AcOEt, the combined org. phase
was washed with H2O and brine, dried (Na2SO4), and concentrated, and the residue purified by CC
(petroleum ether/CH2Cl2 4 :1, Rf 0.20): 0.337 g (78.6%) of 11. Colorless oil. 1H-NMR: 6.84 (dt, J(2,3) ¼
15.6, J(3,4) ¼ 7.8, HꢁC(3)); 6.53 (d, J(6,7) ¼ 15.0, HꢁC(6)); 6.08 (d, J ¼ 15.0, HꢁC(7)); 5.83 (d, J(2,3) ¼
15.6, HꢁC(2)); 5.75 (dd, J(1’,2’) ¼ 17.4, 10.5, HꢁC(1’)); 5.13 (d, J(1’,2’) ¼ 10.5, HcisꢁC(2’)); 5.04 (d,
J(1’,2’) ¼ 17.4, HtransꢁC(2’)); 4.18 (q, J ¼ 7.5, MeCH2O); 2.31 (d, J(3,4) ¼ 7.8, CH2(4)); 1.30 (t, J ¼ 7.5,
MeCH2O); 1.12 (s, MeꢁC(5)). 13C-NMR: 166.3 (C(1)); 151.1 (C(6)); 144.4, 142.7 (C(3), C(1’)); 124.5
(C(2)); 114.3 (C(2’); 75.5 (C(7)); 60.5 (MeCH2O); 47.0 (C(5)); 43.1 (C(4)); 23.1 (MeꢁC(5)); 14.4
(MeCH2O). ESI-MS: 321.0 ([M þ H]þ). HR-ESI-MS: 343.0165 (C12H17INaOþ2 , [M þ Na]þ; calc.
343.1063).
Negishi Reaction: General Procedure. A dried flask was charged with ZnCl2 (1.3 equiv.), and heated
by a hot gun under vacuum until the ZnCl2 was melted. Then the flask was filled with Ar gas and cooled
to r.t. Anh. THF (10 ml) was added into the flask to dissolve the anh. ZnCl2. Another dried flask was
charged with the appropriate bromoarene (1.1 mmol, 1.1 equiv.) and THF (10 ml) under Ar, and then
cooled to ꢁ 788 for 0.5 h. A soln. of (1.6m BuLi 1.2 equiv.) in THF was added dropwise to the
bromoarene soln. at ꢁ 788 over 15 min, and stirring was continued for 30 min. Then the ZnCl2 soln. was
added dropwise to the organolithium soln. at ꢁ 788 over 15 min, and the resulting soln. was stirred at r.t
for 1 h. Meanwhile, a mixture of [Pd(OAc)2] (0.05 equiv.), PPh3 (0.10 equiv.), and THF (5 ml) was
stirred at r.t. for ca. 30 min until the brown soln. was formed, and this soln. was added to the organozinc
soln., followed by a soln. of the iodoalkadienoate 11 (1.0 mmol, 1.0 equiv.). The mixed soln. was stirred
for one 1 h at r.t., then quenched with H2O (20 ml), and extracted with AcOEt (20 ml ꢂ 4). The extract
was dried (Na2SO4) and concentrated and the crude product purified by CC (petroleum ether/AcOEt
6 :1 to 100 :1): 12a (90.1%), 12b (52.3%), 12c (58.7%), 12d (53.7%), 12e (48.3%), or 12f (71.3%).
Colorless oils.
Data of Ethyl (2E,6E)-7-{4-{[(tert-Butyl)diphenyl-silyl]oxy}phenyl}-5-ethenyl-5-methylhepta-2,6-
1
dienoate (12a) as an Example. H-NMR: 7.72 – 7.34 (m, 10 H, Ph2Si); 7.10 (d, J ¼ 8.7, 2 H, C6H4); 6.89
(dt, J(2,3) ¼ 15.6, J(3,4) ¼ 7.5, HꢁC(3)); 6.70 (d, J ¼ 8.7, 2 H, C6H4); 6.21 (d, J(6,7) ¼ 16.5, HꢁC(7)); 5.98
(d, J(6,7) ¼ 16.5, HꢁC(6)); 5.88 – 5.79 (m, HꢁC(2), HꢁC(1’)); 5.07 – 4.98 (m, CH2(2’)); 4.16 (q, J ¼ 7.5,
t
MeCH2O); 2.36 (d, J(3,4) ¼ 7.5, CH2(4)); 1.26 (t, J ¼ 7.5, MeCH2O); 1.16 (s, MeꢁC(5)); 1.09 (s, Bu).
13C-NMR: 166.2 (C¼O); 144.9; 143.9; 140.8; 139.1; 129.2; 128.9; 127.0; 126.3; 125.5; 125.5; 125.4; 125.4;
125.3; 124.1; 122.8; 113.5 (C(2’)), 60.2 (MeCH2O), 43.6 (C(4)); 42.8 (C(5)); 29.6 (Me3C); 25.6 (Me3C);
23.5 (MeꢁC(5)); 14.2 (MeCH2O). ESI-MS: 525.6 ([M þ H]þ). HR-ESI-MS: 547.2639 (C34H40NaO3Siþ,
[M þ Na]þ; calc. 547.2647).
Selective 1,2-Addition Reaction of 12 with MeMgI: General Procedure. To a soln. of (3.0m MeMgI
1.2 ml, 3.0 equiv.) was added dropwise a soln. of ester 12 (0.12 mmol, 1.0 equiv.) in THF (5 ml) at r.t., and
the mixture was stirred for 1 h. The reaction was quenched with H2O (5 ml), the mixture extracted with
AcOEt (3 ꢂ 10 ml), dried (Na2SO4), and concentrated, and the crude product purified by CC
(petroleum ether/AcOE): 13a (88.0%), 13b (48.3%), 13c (68.4%), 13d (72.0%), or 13f (80%). Colorless
oils.
(3E,7E)-8-{4-{[(tert-Butyl)diphenylsilyl]oxy}phenyl}-6-ethenyl-2,6-dimethylocta-3,7-dien-2-ol
(13a): 1H-NMR: 7.72 – 7.33 (m, 10 H, Ph2Si); 7.09 (d, J ¼ 8.7, 2 H, C6H4); 6.69 (d, J ¼ 8.7, 2 H, C6H4); 6.18
(d, J(7,8) ¼ 16.5, HꢁC(8)); 6.00 (d, J(7,8) ¼ 16.5, HꢁC(7)); 5.83 (dd, J(1’,2’) ¼ 17.4, 10.5, HꢁC(1’));
5.60 – 5.56 (m, HꢁC(3), HꢁC(4)); 5.08 – 4.98 (m, CH2(2’)); 2.17 (d, J(4,5) ¼ 5.7, CH2(5)); 1.5 – 1.4 (br.,
OH); 1.27 (s, 2 MeꢁC(2)); 1.12 (s, MeꢁC(6)); 1.09 (s, tBu). 13C-NMR: 154.8; 145.5; 141.1; 135.5; 135.3;
132.9; 130.7; 129.9; 127.8; 127.0; 126.9; 123.0; 119.7; 112.2 (C(2’)); 70.8 (C(2)); 43.9 (C(5)); 42.5 (C(6));

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Helvetica Chimica Acta – Vol. 93 (2010)
29.9; 29.8; 26.5; 23.4; 19.5. ESI-MS: 533.3 ([M þ Na]þ). HR-ESI-MS: 533.2846 (C34H42NaO2Siþ, [M þ
Na]þ; calc. 533.2859).
(3E,7E)-6-Ethenyl-8-(4-methoxyphenyl)-2,6-dimethylocta-3,7-dien-2-ol (13b): 1H-NMR: 7.30 (d, J ¼
8.4, 2 H, C6H4); 6.84 (d, J ¼ 8.4, 2 H, C6H4), 6.27 (d, J(7,8) ¼ 15.9, HꢁC(8)); 6.07 (d, J(7,8) ¼ 15.9,
HꢁC(7)); 5.88 (dd, J(1’,2’) ¼ 10.2, 17.4, HꢁC(1’)); 5.63 – 5.59 (m, HꢁC(3), HꢁC(4)); 5.07 – 4.98 (m,
CH2(2’)); 3.81 (s, MeO); 2.22 (d, J(4,5) ¼ 5.7, CH2(5)); 1.5 – 1.4 (br., OH); 1.30 (s, 2 MeꢁC(2)); 1.17 (s,
MeꢁC(6)). 13C-NMR: 158.8; 145.6; 141.1; 135.4; 130.5; 127.2; 126.8; 123.0; 113.9; 112.1 (C(2’)), 70.7
(C(2)); 55.3 (MeO); 43.9 (C(5)); 42.6 (C(6)); 29.9 (2 MeꢁC(2)); 23.4 (MeꢁC(6)). EI-MS: 286 (Mþ).
HR-EI-MS: 286.1933 (C19H26Oþ2 , Mþ; calc. 286.1930).
(3E,7E)-6-Ethenyl-2,6-dimethyl-8-phenylocta-3,7-dien-2-ol (13c): 1H-NMR (CDCl3) 7.31 – 7.28 (m, 5
arom. H), 6.32 (d, J(7,8) ¼ 16.2, HꢁC(8)); 6.20 (d, J(7,8) ¼ 16.2, HꢁC(7)); 5.88 (dd, J(1’,2’) ¼ 10.8, 17.4,
HꢁC(1’)); 5.63 – 5.59 (m, HꢁC(3), HꢁC(4)); 5.07 – 4.98 (m, CH2(2’)); 2.22 (d, J(4,5) ¼ 5.7, CH2(5));
1.5 – 1.4 (br., OH); 1.30 (s, 2 MeꢁC(2)); 1.17 (s, MeꢁC(6)). 13C-NMR: 145.4; 141.2; 137.7; 137.5; 128.5;
127.5; 127.0; 126.1; 122.9; 112.4 (C(2’)); 70.8 (C(2)); 43.8 (C(5)); 42.7 (C(6)); 29.9 (2 MeꢁC(2)); 23.4
(MeꢁC(6)). EI-MS: 256 (Mþ). HR-EI-MS: 256.1827 (C18H24O2þ, Mþ; calc. 256.1821).
1
(3E,7E)-6-Ethenyl-2,6-dimethyl-8-(4-methylphenyl)octa-3,7-dien-2-ol (13d): H-NMR (CDCl3) 7.25
(d, J ¼ 8.1, 2 arom. H); 7.10 (d, J ¼ 8.1, 2 arom. H); 6.28 (d, J(7,8) ¼ 16.5, HꢁC(8)); 6.14 (d, J(7,8) ¼ 16.5,
HꢁC(7)); 5.88 (dd, J(1’,2’) ¼ 10.8, 17.7, HꢁC(1’)); 5.68 – 5.54 (m, HꢁC(3), HꢁC(4)); 5.06 – 4.98 (m,
CH2(2’)); 2.32 (s, MeC6H4); 2.22 (d, J(4,5) ¼ 6.0, CH2(5)); 1.5 – 1.4 (br., OH); 1.29 (s, 2 MeꢁC(2)); 1.17 (s,
MeꢁC(6)). 13C-NMR: 145.5; 141.1; 136.7; 136.4; 134.9; 129.2; 127.3; 126.0; 123.0; 112.2 (C(10)); 70.8
(C(2)); 43.9 (C(5)); 42.6 (C(6)); 29.9 (2 MeꢁC(2)); 23.5 (MeꢁC(6)); 21.1 (MeC6H4). EI-MS: 270 (Mþ).
HR-EI-MS: 270.1983 (C19H26Oþ, Mþ; calc. 270.1984).
(3E,7E)-6-Ethenyl-2,6-dimethyl-8-[4-(trifluoromethyl)phenyl]octa-3,7-dien-2-ol (13e): 1H-NMR:
7.55 (d, J ¼ 8.0, 2 arom. H); 7.44 (d, J ¼ 8.0, 2 arom. H); 6.36 (d, J(7,8) ¼ 16.5, HꢁC(8)); 6.30 (d,
J(7,8) ¼ 16.5, HꢁC(7)); 5.88 (dd, J(1’,2’) ¼ 10.5, 17.7, HꢁC(1’)); 5.69 – 5.59 (m, HꢁC(3), HꢁC(4)); 5.09
(d, J(1’,2’) ¼ 10.5, HcisꢁC(2’)); 5.03 (d, J(1’,2’) ¼ 17.7, HtransꢁC(2’)); 2.22 (d, J(4,5) ¼ 6.0, CH2(5)); 1.45 (br.
s, OH); 1.30 (s, 2 MeꢁC(2)); 1.20 (s, MeꢁC(6)). 13C-NMR: 144.8; 141.5; 141.2; 140.2; 126.4; 126.2; 125.5;
125.4; 125.4; 122.6; 112.8 (C(2’)); 70.8 (C(2)); 43.7 (C(5)); 42.9 (C(6)); 29.9 (2 MeꢁC(2)); 23.3
(MeꢁC(6)). EI-MS: 324 (Mþ). HR-EI-MS: 324.1705 (C19H23F3Oþ, Mþ; calc. 324.1701).
(3E,7E)-6-Ethenyl-2,6-dimethyl-8-(naphthalen-2-yl)octa-3,7-dien-2-ol (13f): 1H-NMR: 7.80 – 7.30
(m, 7 arom. H); 6.48 (d, J(7,8) ¼ 16.2, HꢁC(8)); 6.33 (d, J(7,8) ¼ 16.2, HꢁC(7)); 5.88 (dd, J(1’,2’) ¼
10.5, 17.7, HꢁC(1’)); 5.69 – 5.59 (m, HꢁC(3), HꢁC(4)); 5.09 (d, J(1’,2’) ¼ 10.5, HcisꢁC(2’)); 5.05 (d,
J(1’,2’) ¼ 17.7, HtransꢁC(2’)); 2.24 (d, J(4,5) ¼ 5.7, CH2(5)); 1.40 – 1.50 (br. s, OH); 1.30 (s, 2 MeꢁC(2));
1.20 (s, MeꢁC(6)). 13C-NMR: 145.3; 141.3; 137.9; 135.1; 133.7; 132.8; 128.1; 127.8; 127.6; 126.2; 125.7;
125.6; 123.6; 122.9; 112.5 (C(2’)); 70.8 (C(2)); 43.9 (C(5)); 42.8 (C(6)); 29.9 (2 MeꢁC(2)); 23.3
(MeꢁC(6)). EI-MS: 306 (Mþ). HR-EI-MS: 306.1984 (C22H26Oþ, Mþ; calc. 306.1984).
(ꢀ)-D3-2-Hydroxybakuchiol (¼4-[(1E,5E)-3-Ethenyl-7-hydroxy-3,7-dimethylocta-1,5-dien-1-yl]phe-
nol; 14). To a soln. of 13a (0.117 g, 0.23 mmol) in THF (5 ml) was added dropwise a soln. of Bu4NF ·
3 H2O (0.218 g, 0.69 mmol) in THF (5 ml) at r.t., and then the resulting soln. was stirred for 1 h. The
soln. was quenched with H2O (10 ml) and extracted with AcOEt (20 ml ꢂ 3), the extract dried (Na2SO4)
and concentrated, and the crude product purified by CC (petroleum ether/AcOEt 6 :1, Rf 0.18): 0.049 g
1
(77.8%) of 14. Colorless oil. Spectral data: consistent with [28]. H-NMR: 7.23 (d, J ¼ 8.4, 2 arom. H);
6.76 (d, J ¼ 8.4, 2 arom. H); 6.24 (d, J(7,8) ¼ 16.5, HꢁC(8)); 6.04 (d, J(7,8) ¼ 16.5, HꢁC(7)); 5.87 (dd,
J(1’,2’) ¼ 10.5, 17.7, HꢁC(1’)); 5.63 – 5.59 (m, HꢁC(3), HꢁC(4)); 5.50 – 5.40 (br. s, OHC6H4); 5.04 (d,
J(1’,2’) ¼ 10.5, HcisꢁC(2’)); 5.00 (d, J(1’,2’) ¼ 17.7, HtransꢁC(2’)); 2.21 (d, J(4,5) ¼ 5.7, CH2(5)); 1.60 – 1.55
(br. s, 1 OH); 1.30 (s, 2 MeꢁC(2)); 1.16 (s, MeꢁC(6)). 13C-NMR ((D6)DMSO): 157.1; 146.2; 142.7;
134.4; 128.6; 127.6; 127.0; 121.6; 115.8; 112.3 (C(2’)); 69.3 (C(2)); 44.0 (C(5)); 42.7 (C(6)); 30.6
(2 MeꢁC(2)); 23.6 (MeꢁC(6)). ESI-MS : 295.0 ([M þ Na]þ). HR-ESI-MS: 295.1668 (C18H24NaO2þ,
[M þ Na]þ; calc. 295.1672).

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Received June 25, 2009