Further study on synthesis of the cyclobakuchiols

Article abstract of DOI:10.1016/j.tet.2015.02.092

Abstract Two results are described. First, quinic acid was transformed into the monoacetate of 2-cyclohexene-1,4-diol. The Ni-catalyzed allylic substitution of the monoacetate with CH₂C(Me)MgBr/ZnCl₂/TMEDA followed by oxidation of th

Full text of DOI:10.1016/j.tet.2015.02.092

Tetrahedron 71 (2015) 2387e2392
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Further study on synthesis of the cyclobakuchiols
Hidehisa Kawashima, Masahiro Sakai, Yuki Kaneko, Yuichi Kobayashi *
Department of Bioengineering, Tokyo Institute of Technology, Box B-52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 January 2015
Received in revised form 25 February 2015
Accepted 27 February 2015
Available online 5 March 2015
Two results are described. First, quinic acid was transformed into the monoacetate of 2-cyclohexene-1,4-
diol. The Ni-catalyzed allylic substitution of the monoacetate with CH
lowed by oxidation of the resulting S 2-type product afforded the 4-(CH
cyclohexenone. BF $OEt -assisted 1,4-addition of the enone with (4-MeOC
nished the ketone, which is the key intermediate for the synthesis of cyclobakuchiols A and C. Second,
the allylic picolinate with CMe (OTES) and 4-MeOC groups at 3 and 4 positions of the cyclohexane
ring was synthesized through 1,4-addition of (4-MeOC Cu(MgBr)$MgBr to 4-(CMe (OTES))-2-
2
]C(Me)MgBr/ZnCl
]C(Me))-substituted 2-
Cu(MgBr)$MgBr fur-
2
/TMEDA fol-
N
2
3
2
6
H
4
)
2
2
2
6 4
H
Keywords:
Cyclobakuchiol
Quinic acid
Beta-pinene
Allylic substitution
Quaternary carbon
6
H
4
)
2
2
2
cyclohexenone. Allylic substitution of this picolinate followed by deprotection furnished cyclo-
bakuchiol C. Furthermore, the methyl ether of cyclobakuchiol C was transformed to cyclobakuchiol A.
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
methyl ether of 1 (Scheme 1). Furthermore, this ether was con-
verted into 2 through epoxidation. On the other hand, the addition
Cyclobakuchiols A and B (1, 3), isolated as a mixture from
Psoralea glandulosa L. in 1995, exhibit antipyretic and anti-in-
of the cyclohexane ester 7, derived from ent-5, to CH
2
¼CHSOPh
followed by elimination of the SOPh moiety furnished 3. Afterward,
we have continued synthetic study to develop another approach to
the intermediates and/or cyclobakuchiols in connection with bi-
ological investigation. Herein, we report alternative synthesis of
ketone 5 from quinic acid (8) and that of cyclobakuchiol C (2)
through the cyclohexenone 11, which is available from ent-4
(Scheme 2). Furthermore, conversion of a cyclobakuchiol C de-
rivative to cyclobakuchiol A (1) is presented as well.
1,2
flammatory properties. The structurally related cyclobakuchiol C
3
(
2) was isolated in 2007 from Psoralea coryllfolia, although its bi-
ological properties have not yet been revealed (Fig. 1). One of the
structural feature common to the cyclobakuchiols is a quaternary
carbon on the ring possessing vinyl and methyl groups. We recently
reported4 synthesis of cyclobakuchiols AeC (1e3), and elucidated
the absolute configuration for each by comparing their specific
rotations with those reported. Ketone 5, which is the intermediate
4
for the synthesis of 1 and 2, was synthesized from (þ)-
and subsequently transformed into allylic picolinate 6, which upon
allylic substitution5 with Me
Cu(MgBr)$MgBr /ZnI gave the
b-pinene (4)
2
2
2
Fig. 1. Cyclobakuchiols A, B, and C.
6 4
Scheme 1. The previous synthesis of cyclobakuchiols AeC. Ar: 4-(MeO)C H .
*
Corresponding author. Tel./fax: þ81 45 924 5789; e-mail address: ykobayas@
bio.titech.ac.jp (Y. Kobayashi).
http://dx.doi.org/10.1016/j.tet.2015.02.092
0
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

2388
H. Kawashima et al. / Tetrahedron 71 (2015) 2387e2392
enone 14 was obtained with >99% ee as determined by chiral HPLC
9
in yields compatible to those reported. DIBAL reduction of 14
10
afforded a diastereomeric mixture of 15 and 16. The products
were separated by chromatography on silica gel, and both were
subsequently transformed into monoacetate 9 by reactions in-
dicated in the scheme. The combined yield of 9 from enone 14
through 15 and 16 was 64%.
6
According to our procedure, monoacetate 9 was subjected to
Ni-catalyzed allylic substitution with CH
from CH ]C(Me)MgBr and ZnCl in the presence of TMEDA to
furnish the S 2 product 10 in 88% yield (Scheme 4). The high
2
]C(Me)ZnCl derived
2
2
11
N
regioselectivity (rs) and stereoselectivity (ss) were determined by
1
H NMR spectroscopy. Oxidation of 10 with NMO/TPAP (cat.) pro-
ceeded well to afford enone 17, which was somewhat volatile.
Consequently, without further purification, crude enone 17 was
subjected to a BF
MeOC Cu(MgBr)$MgBr
CuBr$Me S in a 2:1 ratio) to produce ketone 5 in 79% yield from 10
after chromatography. The total yield of 5 from quinic acid (8) was
3%.
3
$OEt
2
-assisted 1,4-addition reaction with (4-
6
H
4
)
2
2
(prepared from 4-MeOC MgBr and
6 4
H
2
3
6 4
Scheme 2. The present study. Ar: 4-(MeO)C H .
2
. Results and discussion
The key step in the previous synthesis of cannabidiol was the
nickel-catalyzed allylic substitution of monoacetate 9 with CH
C(Me)MgBr/ZnCl /TMEDA, which proceeds with rarely attainable
2-type selectivity giving 10 (Scheme 2). We envisioned that
oxidation of 10 and subsequent 1,4-addition of the resulting enone
with a 4-MeOC reagent would afford the key intermediate 5.
2
]
2
6
S
N
6 4
H
Monoacetate 9 has been synthesized from cyclohexa-1,3-diene
7
in a racemic form and in an optically active form by enzymatic
8
hydrolysis. In the latter hydrolysis, the use of the enzymes that are
somewhat uncommon in organic laboratories is inevitable to attain
high enantiomeric purity. We envisioned a method using enone 14,
9
which can be prepared from quinic acid (8) (Scheme 3). In practice,
Scheme 4. Synthesis of the ketone intermediate 5.
Previously, the (ꢀ)-isomer of
b-pinene (ent-4), the inexpensive
enantiomer, was transformed into enone 11. Although the ee was
4
12
somewhat low, conversion of 11 to cyclobakuchiols A and C would
provide an opportunity to synthesize a certain set of analogs as well
for biological investigation. Toward the end, the 1,4-addition of
3 2 6 4 2 2
BF $OEt -activated enone 11 with (4-MeOC H ) Cu(MgBr)$MgBr
afforded ketone 18, which was converted to ester 19 as a mixture of
the olefinic isomers in 72% yield from enone 11 (Scheme 5). This
ester was transformed to allylic picolinate 20 (ca. 3:2 mixture) in
8
6% yield. Without separation of the olefinic isomers, this picoli-
nate was subjected to ZnI -assisted allylic substitution with
Me Cu(MgBr)$MgBr (derived from MeMgBr and CuBr$Me S in the
:1 ratio) to afford 21 in 86% yield with high regio- and stereo-
2
2
2
2
2
1
13
selectivity, as determined by H NMR spectroscopy. Finally, the
TES and the Me protecting groups in 21 were removed by the re-
actions indicated in the scheme, thus furnishing 2 in 91% yield.
To synthesize cyclobakuchiol
dehydration of 2 with SOCl
A
(1), we first attempted
ꢁ
2
in pyridine at ꢀ10 C for 30 min
14
(Scheme 6). However, the product was a mixture of 1 and 22 in
a 1:1 ratio. By analogy of the substitution of phenol with PCl
5
to
15
chlorobenzene, X is likely chlorine. We then focused on de-
hydration of the methyl ether of 2 (i.e., 23) derived from 21 by
desilylation with PPTS in EtOH (Scheme 6). In practice, dehydration
with SOCl
exposure of 24 to PhSH and K
2
gave 24 cleanly in 89% yield over two steps. Finally,
CO in refluxing NMP furnished 1.
Scheme 3. Synthesis of the monoacetate.
2
3

H. Kawashima et al. / Tetrahedron 71 (2015) 2387e2392
2389
4
4
. Experimental
.1. General
The H NMR (300 or 400 MHz) and 13C NMR (75 or 100 MHz)
1
spectra were measured in CDCl
CHCl
¼7.26 ppm), and the center line of CDCl
¼77.1 ppm) as internal standards, respectively. Signal patterns are
indicated as br s (broad singlet), s (singlet), d (doublet), t (triplet), q
quartet), and m (multiplet). Coupling constants (J) are given in
Hertz (Hz). Chemical shifts of carbons are accompanied by minus
for C and CH ) and plus (for CH and CH ) signs of the attached
proton test (APT) experiments.
3
using SiMe
4
(d
¼0 ppm), residual
3
(d
3
triplet
(d
(
(
2
3
4.2. Synthesis of the key intermediate
4
.2.1. (3aR,7R,7aS)-7-Hydroxy-2,2-dimethyltetrahydrobenzo[d][1,3]
-(ꢀ)-quinic acid (8) (1.52 g,
dioxol-5(6H)-one (12). A suspension of
D
7.89 mmol), 2,2-dimethoxypropane (3.50 mL, 28.6 mmol), and p-
TsOH$H
2
O (151.7 mg, 0.80 mmol) in acetone (78 mL) was stirred for
1
h under reflux, and Et N (0.3 mL, 2.2 mmol) was added to the
3
mixture. The resulting mixture was concentrated and the residual
oil was purified by chromatography on silica gel (hexane/EtOAc) to
1
9
afford the corresponding lactone (1.64 g, 98%) as solids: ½
a
ꢂ
e36 (c
D
9
a
25
1
0
.80, CHCl
CDCl
1.33 (s, 3H), 1.52 (s, 3H), 2.21 (dd, J¼15, 3 Hz, 1H),
.29e2.45 (m, 2H), 2.63 (d, J¼12 Hz, 1H), 3.45 (s, 1H), 4.31 (dq, J¼6,
3
); lit.
½
a
ꢂ
ꢀ34.46 (c 1.625, CHCl
3
); H NMR (400 MHz,
5
86
3
) d
2
2
13
Hz, 1H), 4.45e4.53 (m, 1H), 4.72 (dd, J¼6, 2 Hz, 1H); C NMR
24.3, 27.0, 34.3, 38.1, 71.5, 71.6, 72.1, 75.9, 109.8,
(
1
100 MHz, CDCl
3
)
d
1
13
79.0. The H and C NMR spectra were consistent with those
9
a,9d
reported.
To an ice-cold solution of the above lactone (1.59 g, 7.42 mmol)
Scheme 5. Synthesis of cyclobakuchiol C.
in EtOH (60 mL) was added NaBH
4
(755 mg, 20.0 mmol) portion-
ꢁ
wise. The mixture was stirred at 0 C for 2.5 h and diluted with
acetone (6.0 mL, 81.4 mmol). The mixture was concentrated, and
the residue was dried for 2 days under reduced pressure for the
next reaction.
To an ice-cold solution of the above triol in phosphate buffer
(
pH 7, 50 mL) was added sodium periodate (1.87 g, 8.74 mmol) in
portions. After the addition, the mixture was stirred at room
temperature for 1 h and extracted with CH Cl repeatedly. The
combined extracts were dried over MgSO and concentrated. The
crude product was purified by chromatography on silica gel
2
2
4
1
9
(
hexane/EtOAc) to afford hydroxy ketone 12 (1.32 g, 96%): ½ ꢂ
a
D
9
b
1
þ135 (c 0.92, CHCl
3
); lit.
[
a
]
D
þ141.24 (c 0.89, CHCl
3
); H NMR
(
(
(
400 MHz, CDCl ) d 1.37 (s, 3H), 1.45 (s, 3H), 1.99 (br s, 1H), 2.47
3
dm, J¼18 Hz, 1H), 2.66 (d, J¼3 Hz, 1H), 2.71 (d, J¼3 Hz, 1H), 2.82
dd, J¼18, 4 Hz, 1H), 4.25 (br s, 1H), 4.32 (dt, J¼7, 2 Hz, 1H), 4.72 (dt,
13
J¼7, 3 Hz, 1H); C NMR (100 MHz, CDCl
3
) d 23.9, 26.4, 40.2, 41.6,
1
6
7.9, 72.2, 74.9, 108.8, 208.9. The H spectrum was consistent with
9
b
that reported.
4
.2.2. (3aR,7aS)-2,2-Dimethyltetrahydrobenzo[d][1,3]dioxol-5(6H)-
one (13). To an ice-cold solution of alcohol 12 (3.53 g, 19.1 mmol)
and Et N (8.0 mL, 57.4 mmol) in CH Cl (120 mL) was added a so-
lution of MsCl (1.80 mL, 23.0 mmol) in CH Cl (15 mL) over a period
of 10 min. The mixture was stirred at room temperature for 2 h and
diluted with satd NaHCO . The resulting mixture was extracted
with CH Cl twice. The combined extracts were washed with brine,
dried over MgSO , and concentrated to afford a residual oil, which
was purified by chromatography on silica gel (hexane/EtOAc) to
3
2
2
Scheme 6. Synthesis of cyclobakuchiol A.
2
2
3
3
. Conclusion
In conclusion, we developed a synthesis of the ketone in-
termediate 5 starting from quinic acid (8) and a transformation of
enone 11 to 2 and 1. These methods in combination with the pre-
vious synthesis of cyclobakuchiols AeC would provide analogs as
well for biological study of cyclobakuchiols.
2
2
4
1
9
give the corresponding enone (2.95 g, 92%): ½
a
ꢂ
þ138 (c 0.54,
D
9
c
1
CHCl
1.38 (s, 3H), 1.39 (s, 3H), 2.69 (dd, J¼18, 4 Hz, 1H), 2.93 (dm,
J¼18 Hz, 2H), 4.65e4.76 (m, 2H), 6.03 (d, J¼10 Hz, 1H), 6.45 (ddd,
3
); lit.
[a
]
D
þ147.5 (c 0.48, CHCl
3 3
); H NMR (400 MHz, CDCl )
d
13
J¼10, 3, 2 Hz, 1H); C NMR (100 MHz, CDCl
3
) d 26.9, 28.1, 39.1, 71.4,

2390
H. Kawashima et al. / Tetrahedron 71 (2015) 2387e2392
7
3.7, 110.2, 129.2, 146.2, 195.6. The 1H and 13C NMR spectra were
NaHCO
with Et
dried over MgSO
acetate, which was used for the next reaction without purification.
A solution of the above acetate and TBAF (1.0 M in THF, 2.0 mL,
2.0 mmol) in THF (10 mL) was stirred at room temperature for 1 h
and diluted with satd NH
with EtOAc three times. The combined extracts were washed with
brine, dried over MgSO , and concentrated. The residue was puri-
fied by chromatography on silica gel (hexane/EtOAc) to give mon-
3
. The resulting mixture was stirred for 30 min and extracted
O twice. The combined extracts were washed with brine,
, and concentrated to afford the corresponding
9
c
consistent with those reported.
2
A mixture of the above enone (2.50 g, 14.8 mmol) and 10% Pd/C
321 mg, 3.02 mmol) in EtOAc (150 mL) under hydrogen was stirred
4
(
at room temperature overnight and filtered through a pad of Celite.
The filtrate was concentrated and the residual oil was purified by
chromatography on silica gel (hexane/EtOAc) to give ketone 13
4
Cl. The resulting mixture was extracted
2
0
9b
(
2.41 g, 96%): ½
a
ꢂ
þ128 (c 0.97, CHCl
3
); lit.
[a
]
D
þ154.38 (c 0.78,
D
1
CHCl
3
); H NMR (400 MHz, CDCl
3
)
d
1.36 (s, 3H), 1.44 (s, 3H), 1.88
4
(
2
4
tm, J¼14 Hz, 1H), 2.03e2.15 (m, 1H), 2.25 (dm, J¼18 Hz, 1H),
2
0
.41e2.54 (m, 2H), 2.67 (dd, J¼18, 3 Hz, 1H), 4.54e4.60 (m, 1H),
oacetate 9 (172 mg, 81% from alcohol 15): [
a
]
D
þ87 (c 0.47, CHCl
3
);
.64e4.71 (m, 1H); 13C NMR (100 MHz, CDCl
)
d
24.1, 25.8, 26.2,
lit.
d
8b
½
a
ꢂ
25
D
þ70.0 (CHCl
) for 79% ee; H NMR (400 MHz, CDCl )
1
3
3
3
1
3
3.7, 42.2, 71.7, 73.1, 107.9, 210.1. The H spectrum was consistent
1.70e1.94 (m, 4H), 2.06 (s, 3H), 2.33 (br s, 1H), 4.14e4.23 (m, 1H),
9b
with that reported.
5.15e5.21 (m, 1H), 5.79 (ddd, J¼10, 4, 2 Hz, 1H), 5.97 (dd, J¼10, 4 Hz,
13
1
H); C NMR (100 MHz, CDCl
3
)
d
21.3 (þ), 25.0 (ꢀ), 28.2 (ꢀ), 65.4
1 13
4
.2.3. (S)-4-((tert-Butyldimethylsilyl)oxy)cyclohex-2-enone (14). To
a solution of ketone 13 (3.50 g, 20.6 mmol) and DBU (3.50 mL,
2.6 mmol) in benzene (120 mL) was added TBSCl (3.30 g,
1.8 mmol). The solution was stirred at room temperature for
0 min and heated to reflux. After 2 h, DBU (0.90 mL, 5.9 mmol) was
(þ), 67.3 (þ), 127.9 (þ), 134.9 (þ), 170.8 (ꢀ). The H NMR and
C
16
NMR spectra were consistent with those reported.
2
2
1
From 16: To an ice-cold solution of alcohol 16 (2.85 g,
12.5 mmol) in toluene (120 mL) were added diisopropyl azodi-
carboxylate (3.70 mL, 19.1 mmol), triphenylphosphine (4.90 g,
added again and the mixture was stirred further for 1.5 h under
reflux. The reaction mixture was washed sequentially with water,
18.7 mmol), and acetic acid (1.10 mL, 19.2 mmol). The mixture was
ꢁ
stirred at 0 C for 1.5 h and diluted with satd NaHCO
3
with vigorous
phosphate buffer (pH 4), satd NaHCO
3
, and brine. The organic layer
stirring. The layers were separated and the aqueous layer was
extracted with EtOAc twice. The combined extracts were washed
was dried over MgSO and concentrated to give a residue. Chro-
4
matography of the residue on silica gel (hexane/EtOAc) afforded
4
with brine, dried over MgSO , and concentrated to give a residue.
enone 14 (4.26 g, 91%): >99% ee by HPLC (Chiralcel OD-H, hexane/i-
Chromatography of the residue on silica gel (hexane/EtOAc) affor-
ded the corresponding acetate, which was used for the next
reaction.
A solution of the above acetate and TBAF (25.0 mL, 1.0 M in THF,
25.0 mmol) in THF (100 mL) was stirred at room temperature
ꢁ
PrOH¼99:1, 1 mL/min, 20 C, t
R
/min¼7.0 (S-isomer, major), 8.3 (R-
2
0
10b
20
D
isomer, minor)); ½
a
ꢂ
e97 (c 1.26, CHCl
3
); lit.
½
a
ꢂ
e102.0 (c 2.0,
D
1
CHCl
3
) for 98% ee; H NMR (400 MHz, CDCl
3
)
d
0.08 (s, 3H), 0.09 (s,
3
2
4
H), 0.88 (s, 9H), 1.96 (ddt, J¼9, 4, 13 Hz, 1H), 2.17 (ddq, J¼13, 1, 5 Hz,
H), 2.30 (ddd, J¼17, 13, 5 Hz, 1H), 2.53 (dt, J¼17, 4 Hz, 1H),
.45e4.52 (m, 1H), 5.88 (dm, J¼10 Hz, 1H), 6.79 (dt, J¼10, 2 Hz, 1H);
overnight and diluted with satd NH
extracted with EtOAc three times. The combined extracts were
washed with brine, dried over MgSO , and concentrated to give
a residue, which was purified by chromatography on silica gel
4
Cl. The resulting mixture was
13
C NMR (100 MHz, CDCl
3
)
d
ꢀ4.8 (þ), e4.6 (þ), 18.1 (ꢀ), 25.7 (þ),
4
1
3
2.9 (ꢀ), 35.5 (ꢀ), 67.0 (þ), 128.7 (þ), 153.8 (þ), 198.7 (ꢀ). The H
and C NMR spectra were consistent with those reported.9b,16
13
(hexane/EtOAc) to afford 9 (1.48 g, 76% from alcohol 16). The H
1
NMR spectrum was consistent with that obtained from alcohol 15.
4.2.4. (1R,4S)-4-((tert-Butyldimethylsilyl)oxy)cyclohex-2-enol (15)
and (1S,4S)-4-((tert-butyldimethylsilyl)oxy)cyclohex-2-enol (16). To
a solution of enone 14 (4.16 g, 18.4 mmol) in THF (100 mL) was
added DIBAL (1.07 M in hexane, 26.0 mL, 27.6 mmol) dropwise at
4.2.6. (1S,4S)-4-(Prop-1-en-2-yl)cyclohex-2-enol (10). To a solution
of ZnCl
THF (15 mL) was added CH
10.1 mmol). The mixture was stirred at room temperature for
10 min to produce CH ]C(Me)ZnCl for the reaction with mono-
acetate 9. To another ice-cold flask containing NiCl (PPh (1.00 g,
1.53 mmol) and THF (5 mL) was added CH ]C(Me)MgBr (0.82 M in
2
(1.67 g, 12.3 mmol) and TMEDA (1.92 mL, 12.9 mmol) in
2
]C(Me)MgBr (0.82 M in THF, 12.3 mL,
ꢁ
ꢁ
ꢀ
78 C, and the solution was allowed to warm to ꢀ40 C over 1 h
before addition of MeOH (22 mL, 552 mmol), H O (10 mL,
52 mmol), and NaF (23 g, 552 mmol). The resulting mixture was
2
2
5
2
3 2
)
stirred at room temperature overnight and filtered through a pad of
Celite. The filtrate was concentrated and the residual oil was puri-
fied by chromatography on silica gel (hexane/EtOAc) to afford cis
alcohol 15 (612 mg, 15%) and trans alcohol 16 (2.85 g, 68%) sepa-
2
THF, 5.61 mL, 4.60 mmol). The mixture was stirred at room tem-
ꢁ
perature for 10 min and cooled to 0 C. The solution of CH
2
]C(Me)
ZnCl, prepared above, was transferred to the mixture. The resulting
mixture was stirred at room temperature for 20 min, at which time
a solution of 9 (479 mg, 3.07 mmol) in THF (5þ5 mL) was injected.
The reaction was carried out at room temperature overnight, and
2
0
10a
rately. Cis alcohol 15: ½
a
ꢂ
e23 (c 0.67, EtOH); lit.
[
a
]
D
ꢀ30 (c 0.40,
D
1
EtOH); H NMR (400 MHz, CDCl ) d 0.068 (s, 3H), 0.071 (s, 3H), 0.89
3
(
1
s, 9H), 1.61e1.88 (m, 5H), 4.04e4.17 (m, 2H), 5.74 (dd, J¼10, 2 Hz,
13
H), 5.79 (dd, J¼10, 3 Hz,1H); C NMR (100 MHz, CDCl
3
)
d
ꢀ4.6 (þ),
quenched by addition of satd NH
extracted with Et O four times. The combined organic extracts
were washed with brine twice, dried over MgSO , and concentrated
4
Cl. The resulting mixture was
e4.5 (þ), 18.3 (ꢀ), 25.9 (þ), 28.3 (ꢀ), 28.6 (ꢀ), 64.9 (þ), 66.4 (þ),
2
1
13
1
30.7 (þ), 134.2 (þ). The H NMR and C NMR spectra were con-
4
7
b
20
D
sistent with those reported. Trans alcohol 16: ½
a
ꢂ
e99 (c 0.77,
to afford an oil, which was purified by chromatography on silica gel
1
CHCl
3
); lit.1
0a
[a
]
D
ꢀ96 (c 0.96, CHCl
3
) for 96% ee; H NMR
to give 10 (372 mg, 88%): >99% ee by HPLC (Chiralcel OD-H, hexane/
ꢁ
(400 MHz, CDCl
(
3
)
d
0.06 (s, 3H), 0.07 (s, 3H), 0.89 (s, 9H), 1.38e1.57
i-PrOH¼99/1, 1 mL/min, 25 C, t
R
/min¼18.5 (S-isomer, major), 19.3
2
1
1
m, 2H), 1.76 (br s, 1H), 1.95e2.02 (m, 1H), 2.07e2.14 (m, 1H), 4.25 (t,
(R-isomer, minor)); ½
a
ꢂ
e192 (c 0.554, CHCl
CDCl ) d 1.43e1.57 (m, 3H), 1.61 (br s, 1H), 1.72 (s, 3H), 1.86e1.97 (m,
3
); H NMR (400 MHz,
D
13
J¼6 Hz, 2H), 5.68 (d, J¼10 Hz, 1H), 5.74 (d, J¼10 Hz, 1H); C NMR
100 MHz, CDCl
ꢀ4.6 (þ), e4.5 (þ), 18.3 (ꢀ), 25.9 (þ), 30.9 (ꢀ),
1.1 (ꢀ), 66.6 (þ), 67.1 (þ), 131.8 (þ), 133.8 (þ). The H NMR and
3
(
3
3
)
d
1H), 1.99e2.13 (m, 1H), 2.74e2.81 (m, 1H), 4.19e4.26 (m, 1H),
1
13
C
4.69e4.71 (m, 1H), 4.75e4.78 (m, 1H), 5.69 (dddd, J¼10, 3, 1.5, 1 Hz,
17
13
NMR spectra were consistent with those published.
1H), 5.79 (ddt, J¼10, 1, 2 Hz, 1H); C NMR (100 MHz, CDCl
3
) d 20.9
(
þ), 25.6 (ꢀ), 31.4 (ꢀ), 43.0 (þ), 66.4 (þ), 110.7 (ꢀ), 131.1 (þ), 132.5
þ
4
.2.5. (1R,4S)-4-Hydroxycyclohex-2-en-1-yl acetate (9). From 15: A
solution of alcohol 15 (309 mg, 1.35 mmol) and acetic anhydride
0.65 mL, 6.88 mmol) in pyridine (0.85 mL, 10.6 mmol) was stirred
at room temperature for 3 h and diluted with Et O and satd
(þ), 147.9 (ꢀ); HRMS (EI) calcd for C
9
H14O [M ] 138.1045, found
1
13
138.1046. The H NMR and C NMR spectra were consistent with
6
(
those published. The regioselectivity (>98%) and the stereo-
selectivity (>98%) of 10 were determined by comparison of the H
1
2

H. Kawashima et al. / Tetrahedron 71 (2015) 2387e2392
2391
NMR data of the crude product with those reported for the
regioisomer and the stereoisomer (cis isomer of 10).
157.8 (ꢀ), 162.3 and 162.5 (ꢀ), 166.7 and 166.8 (ꢀ); HRMS (FAB)
6
18
þ
calcd for C26
H
42
O
4
SiNa [(MþNa) ] 469.2750, found 469.2753.
4
.2.7. (3S,4S)-3-(4-Methoxyphenyl)-4-(prop-1-en-2-yl)cyclohexa-
none (5). To a suspension of molecular sieves 4A (1.03 g) in CH Cl
10 mL) were added 4-methylmorpholine N-oxide (479 mg,
.09 mmol), tetrapropylammonium perruthenate (84.2 mg,
.240 mmol), and a solution of alcohol 10 (371 mg, 2.67 mmol) in
4.3.2. 2-((3S,4S)-3-(4-Methoxyphenyl)-4-(2-((triethylsilyl)oxy)
propan-2-yl)cyclohexylidene)ethyl picolinate (20). To a solution of
ester 19 (36.2 mg, 0.087 mmol) in THF (1 mL) was added DIBAL
2
2
(
4
0
CH
2
ꢁ
(0.18 mL, 1.04 M in hexane, 0.187 mmol) dropwise at ꢀ78 C, and
ꢁ
the solution was stirred at ꢀ78 C for 30 min before addition of H
2
O
2
Cl
2
(10 mL). The mixture was stirred at room temperature for
(0.10 mL, 5.56 mmol) and NaF (216 mg, 5.14 mmol). The resulting
mixture was stirred at room temperature for 30 min and filtered
through a pad of Celite. The filtrate was concentrated and the re-
sidual oil was purified by chromatography on silica gel (hexane/
EtOAc) to give the corresponding alcohol (33.3 mg,17.2 mmol, 94%):
h and filtered through a pad of Celite. The filtrate was concen-
trated to afford enone 17, which was passed through a pad of silica
gel for the next reaction.
2
To an ice-cold suspension of CuBr$Me S (830 mg, 4.04 mmol) in
ꢀ
1 1
THF (10 mL) was added 4-MeOC
8
6
H
4
MgBr (0.91 M in THF, 8.86 mL,
IR (neat) 3342, 1610, 1512, 1246, 1039, 741 cm
olefin mixture (300 MHz, CDCl 0.46e0.60 (m, 6H), 0.75e1.14 (m,
; H NMR of the
ꢁ
.06 mmol) dropwise. The mixture was stirred at 0 C for 30 min
3
) d
ꢁ
and cooled to ꢀ78 C. A solution of the above enone and BF
3
$OEt
2
15H), 1.20e3.71 (m, 9H), 3.783 and 3.786 (2s, 3H), 4.06 and 4.11 (2d,
J¼7 and 7 Hz, 2H), 5.28e5.35 and 5.37e5.45 (2m, 1H), 6.78e6.85
(m, 2H), 7.04e7.13 (m, 2H).
(
0.51 mL, 4.06 mmol) in THF (10 mL) was added to the mixture.
ꢁ
After the addition, the mixture was allowed to warm to ꢀ50 C over
h and diluted with satd NH Cl. The resulting mixture was
extracted with EtOAc three times. The combined organic layers
were washed with brine, dried over MgSO , and concentrated to
afford an oil. Chromatography of the residual oil on silica gel
hexane/EtOAc) afforded ketone 5 (516 mg, 79% from alcohol 10):
1
4
To an ice-cold solution of the above alcohol (212 mg,
0.524 mmol), picolinic acid (80.3 mg, 0.652 mmol), Et N (0.22 mL,
2
1.58 mmol), and DMAP (62.9 mg, 0.515 mmol) in CH Cl (6 mL) was
3
4
2
added 2-chloro-1-methylpyridinium iodide (272 mg, 1.07 mmol).
The mixture was stirred at room temperature overnight and diluted
(
1
H NMR (400 MHz, CDCl
.05e2.14 (m, 1H), 2.46e2.58 (m, 4H), 2.71 (dt, J¼3, 12 Hz, 1H), 2.93
dt, J¼6, 11 Hz, 1H), 3.78 (s, 3H) 4.63 (s, 1H), 4.65 (s, 1H), 6.82 (dm,
3
)
d
1.52 (s, 3H), 1.80e1.92 (m, 1H),
with satd NaHCO
three times. The combined extracts were washed with 1 N HCl and
brine, dried over MgSO , and concentrated to give a residue, which
3
. The resulting mixture was extracted with EtOAc
2
(
4
13
J¼9 Hz, 2H), 7.07 (dm, J¼9 Hz, 2H); C NMR (100 MHz, CDCl
3
)
d
19.6
was purified by chromatography on silica gel (hexane/EtOAc) to
furnish picolinate 20 (244 mg, 91%) as a mixture of the stereoiso-
(
1
þ), 31.8 (ꢀ), 41.3 (ꢀ), 47.5 (þ), 50.0 (ꢀ), 50.3 (þ), 55.2 (þ),112.7 (ꢀ),
1
ꢀ1 1
13.9 (þ), 128.2 (þ), 135.3 (ꢀ), 146.2 (ꢀ), 158.2 (ꢀ), 210.5 (ꢀ). The H
mers (ca. 3:2): IR (neat) 1718, 1512, 1246, 1038, 744 cm ; H NMR
of the olefin mixture (300 MHz, CDCl 0.45e0.57 (m, 6H),
.76e1.01 (m, 15H), 1.24e2.88 (m, 8H), 3.767 and 3.783 (2s, 3H),
and C NMR spectra were identical with that reported.4
13
3
) d
0
4
.3. Synthesis of cyclobakuchiol C
4.75 and 4.97 (2d, J¼7 and 7 Hz, 0.8H and 1.2H), 5.42 and 5.51 (2t,
J¼7 and 7 Hz, 0.4H and 0.6H), 6.79 and 6.81 (2d, J¼8.5 and 8.5 Hz,
2H), 7.07 and 7.11 (2d, J¼8.5 and 8.5 Hz, 2H), 7.43e7.51 (m, 1H),
4.3.1. Ethyl 2-((3S,4S)-3-(4-methoxyphenyl)-4-(2-((triethylsilyl)oxy)
13
propan-2-yl)cyclohexylidene)acetate (19). To an ice-cold suspension
of CuBr$Me S (169 mg, 0.824 mmol) in THF (3 mL) was added 4-
MeOC MgBr (1.87 mL, 0.87 M in THF, 1.63 mmol) dropwise.
The mixture was stirred at 0 C for 30 min and cooled to ꢀ78 C. A
solution of enone 11 (146 mg, 0.543 mmol) and BF $OEt (0.10 mL,
.810 mmol) in THF (2 mL) was added. The mixture was allowed to
7.80e7.88 (m, 1H), 8.09e8.18 (m, 1H), 8.74e8.80 (m, 1H); C NMR
2
(75 MHz, CDCl
3
)
d
6.8 (ꢀ), 7.2 (þ), 26.9 and 27.0 (þ), 27.1, 28.2, 28.3,
H
6 4
35.8, 38.8, 45.8 (for 3C, e), 31.3 and 31.5 (þ), 46.2 and 46.3 (þ), 53.2
and 53.3 (þ), 55.2 and 55.3 (þ), 62.3 (ꢀ), 76.1 and 76.2 (ꢀ), 113.65
and 113.73 (þ), 114.9 and 115.3 (þ), 125.2 (þ), 126.8 and 126.9 (þ),
128.6 (þ), 137.00 and 137.03 (þ), 139.6 and 139.8 (ꢀ), 145.9 and
ꢁ
ꢁ
3
2
0
ꢁ
warm to ꢀ40 C over 2 h and diluted with satd NH
was extracted with EtOAc three times. The combined organic layers
were washed with brine, dried over MgSO , and concentrated to
4
Cl. The product
146.1 (ꢀ), 148.4 (ꢀ), 149.90 and 149.93 (þ), 157.7 and 157.8 (ꢀ),
þ
167.0 (ꢀ); HRMS (FAB) calcd for C30
H
43
O
4
SiNa [(MþNa) ] 532.2859,
4
found 532.2850.
give crude ketone 18, which was passed through a short silica gel
column for the next reaction.
4.3.3. Triethyl((2-((1S,2S,4R)-2-(4-methoxyphenyl)-4-methyl-4-
To an ice-cold suspension of LiCl (94.2 mg, 2.22 mmol) in MeCN
vinylcyclohexyl)propan-2-yl)oxy)silane (21). To an ice-cold suspen-
(
2 mL) were added DBU (0.32 mL, 2.14 mmol) and triethyl phos-
2 2
sion of CuBr$Me S (44.2 mg, 0.215 mmol) and ZnI (70.7 mg,
ꢁ
phonoacetate (0.44 mL, 2.20 mmol). The mixture was stirred at 0 C
for 30 min, and the above ketone was added. The reaction was
carried out at room temperature overnight and quenched by ad-
dition of satd NH
EtOAc three times. The combined extracts were washed with brine,
dried over MgSO , and concentrated to give a residue, which was
0.221 mmol) in THF (1 mL) was added MeMgBr (0.41 mL, 1.06 M in
ꢁ
THF, 0.435 mmol) dropwise. The mixture was stirred at 0 C for
ꢁ
30 min and cooled to ꢀ40 C. A solution of picolinate 20 (73.0 mg,
4
Cl. The resulting mixture was extracted with
0.143 mmol) in THF (2 mL) was added to the mixture dropwise. The
ꢁ
resulting mixture was allowed to warm to 0 C over 3 h and diluted
4
with hexane and satd NH
separated and the aqueous layer was extracted with hexane twice.
The combined extracts were washed with aqueous Na and
brine successively, dried over MgSO , and concentrated. The crude
product was purified by chromatography on silica gel (hexane/
4
Cl with vigorous stirring. The layers were
purified by chromatography on silica gel (hexane/EtOAc) to afford
ester 19 (162 mg, 72% from enone 11) as a mixture of the stereo-
2 2 3
S O
ꢀ1
1
isomers (ca. 7:3): IR (neat) 1714, 1512, 1149, 1038, 741 cm
NMR of the olefin mixture (300 MHz, CDCl
0.52 (q, J¼8 Hz, 6H),
.91 (t, J¼8 Hz, 9H), 0.80, 1.00 and 1.01 (3s, 6H), 1.23 and 1.27 (2t,
J¼7 and 7 Hz, 3H), 1.29e1.48 (m, 1H), 1.74e1.91 (m, 1H), 2.06e2.45
m, 4H), 2.56e2.82 (m, 1H), 3.52e3.68 (m, 1H), 3.78 (s, 3H),
;
H
4
3
) d
2
2
0
EtOAc) to give olefin 21 (49.8 mg, 86%): ½
a
ꢂ
e3 (c 0.99, CHCl
3
); IR
0.48
D
ꢀ
1 1
3
(neat) 1512, 1248, 1041, 829 cm ; H NMR (300 MHz, CDCl ) d
(
(q, J¼8 Hz, 6H), 0.74 (s, 3H), 0.90 (t, J¼8 Hz, 9H), 0.94 (s, 6H),
1.24e1.46 (m, 4H), 1.58e1.82 (m, 2H), 1.94e2.04 (m, 1H), 2.62 (dt,
J¼3.5, 11.5 Hz, 1H), 3.78 (s, 3H), 5.02 (dd, J¼18, 1.5 Hz, 1H), 5.09 (dd,
J¼11, 1.5 Hz, 1H), 5.82 (dd, J¼18, 11 Hz, 1H), 6.79 (d, J¼8.5 Hz, 2H),
4
2
1
.05e4.19 (m, 2H), 5.53 and 5.65 (2s, 0.7H and 0.3H), 6.78e6.84 (m,
13
H), 7.03e7.14 (m, 2H); C NMR (75 MHz, CDCl
4.34 and 14.38 (þ), 25.6 (ꢀ), 26.9 and 27.5 (þ), 28.1 and 29.3 (ꢀ),
0.6 and 31.3 (þ), 36.6 and 38.7 (ꢀ), 44.8 and 45.7 (þ), 45.3 (ꢀ), 52.5
and 52.8 (þ), 55.2 and 55.3 (þ), 59.5 (ꢀ), 76.1 (ꢀ), 112.9 and 113.6
þ), 113.70 and 113.74 (þ), 128.5 and 128.6 (þ), 139.4 and 139.7 (ꢀ),
3
)
d
6.8 (ꢀ), 7.2 (þ),
1
3
3
7.05 (d, J¼8.5 Hz, 2H); C NMR (75 MHz, CDCl
3
)
d
6.9 (ꢀ), 7.3 (þ),
23.8 (ꢀ), 27.2 (þ), 31.3 (þ), 31.8 (þ), 37.5 (ꢀ), 38.0 (ꢀ), 41.9 (þ), 49.4
(ꢀ), 53.2 (þ), 55.3 (þ), 76.3 (ꢀ), 112.5 (ꢀ), 113.6 (þ), 128.6 (þ), 140.7
(

2392
H. Kawashima et al. / Tetrahedron 71 (2015) 2387e2392
(
ꢀ), 146.2 (þ), 157.6 (ꢀ); HRMS (FAB) calcd for C25
H
42
O
2
SiNa
H
2
O. The resulting mixture was extracted with EtOAc three times.
þ
[(MþNa) ] 425.2852, found 425.2841. The regioselectivity (99%)
The combined extracts were washed with brine, dried over MgSO
and concentrated. Chromatography of the crude product on silica
4
,
1
and the stereoselectivity (98%) were determined by H NMR
spectroscopy.
gel (hexane/EtOAc) furnished cyclobakuchiol A (1) (17.8 mg, 97%):
1
3
H NMR (300 MHz, CDCl ) d 0.98 (s, 3H), 1.48 (s, 3H), 1.33e1.72 (m,
4
0
.3.4. Cyclobakuchiol C (2). A solution of the TES ether 21 (62.2 mg,
.154 mmol) and PPTS (38.9 mg, 0.154 mmol) in EtOH (1.5 mL) was
4H), 1.77e1.86 (m, 2H), 2.21 (dt, J¼4, 11.5 Hz, 1H), 2.66 (dt, J¼3,
11.5 Hz, 1H), 4.49e4.56 (m, 2H), 4.86 (br s, 1H), 5.07 (dd, J¼18, 1 Hz,
1H), 5.13 (dd, J¼11, 1 Hz, 1H), 5.85 (dd, J¼18, 11 Hz, 1H), 6.71 (d,
stirred at room temperature for 22 h and diluted with satd NaHCO
The resulting mixture was extracted with EtOAc three times. The
combined extracts were washed with brine, dried over MgSO , and
concentrated to afford the corresponding alcohol, which was
passed through a short silica gel column for the next reaction.
3
.
13
J¼8.5 Hz, 2H), 6.99 (d, J¼8.5 Hz, 2H); C NMR (75 MHz, CDCl
3
)
4
d
19.7 (þ), 29.0 (ꢀ), 31.6 (þ), 37.5 (ꢀ), 37.8 (ꢀ), 42.7 (þ), 47.4 (ꢀ),
51.5 (þ), 111.2 (ꢀ), 112.7 (ꢀ), 115.0 (þ), 128.5 (þ), 138.3 (ꢀ), 146.3
1 13
(þ), 148.6 (ꢀ), 153.4 (ꢀ). The H and C NMR spectra were con-
4
To a suspension of the above alcohol and K
2
CO
3
(10.7 mg,
sistent with those reported.
0
0
.077 mmol) in NMP (1 mL) was added PhSH (0.020 mL,
.195 mmol). The mixture was stirred under reflux of NMP for 5 h,
Acknowledgements
cooled to room temperature, and diluted with H
mixture was extracted with EtOAc three times. The combined ex-
tracts were washed with brine, dried over MgSO , and concen-
trated. Chromatography of the residual oil on silica gel (hexane/
EtOAc) furnished cyclobakuchiol C (2) (38.6 mg, 91% from TES ether
2
O. The resulting
This study was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and Culture,
Japan (25116709).
4
2
2
4
26
D
1
2
1): ½
a
ꢂ
e42 (c 0.79, CHCl
3
); lit. ½
a
ꢂ
3
e45 (c 0.30, CHCl ); H NMR
D
(
3
300 MHz, CDCl ) d 0.96 (s, 3H), 1.15 (s, 6H), 1.18e1.54 (m, 3H),
Supplementary data
1
1
.66e1.87 (m, 4H), 2.67 (dt, J¼3, 11.5 Hz, 1H), 5.02 (dd, J¼18, 1 Hz,
H), 5.12 (dd, J¼11, 1 Hz, 1H), 5.78 (dd, J¼18, 11 Hz, 1H), 6.52 (d,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.02.092.
13
J¼8 Hz, 2H), 7.08 (br s, 2H), 7.77 (br s, 1H); C NMR (100 MHz,
CDCl
3
)
d
24.7 (þ), 25.5 (ꢀ), 29.4 (þ), 31.4 (þ), 37.4 (ꢀ), 37.6 (ꢀ), 41.4
(
(
þ), 48.3 (ꢀ), 53.1 (þ), 76.3 (ꢀ), 112.8 (ꢀ), 116.3 (þ), 129.1 (þ), 136.8
1
13
References and notes
ꢀ), 145.9 (þ), 155.4 (ꢀ). The H and C NMR spectra and the [
a]
D
4
value were consistent with those reported.
1. Backhouse, C. N.; Delporte, C. L.; Negrete, R. E.; Cassels, B. K.; Schneider, C.;
Breitmaier, E.; Feliciano, A. S. Phytochem. 1995, 40, 325e327.
4
.4. Synthesis of cyclobakuchiol A
.4.1. 1-Methoxy-4-((1S,2S,5R)-5-methyl-2-(prop-1-en-2-yl)-5-
2. Backhouse, C. N.; Delporte, C. L.; Negrete, R. E.; Erazo, S.; Zu n~ iga, A.; Pinto, A.;
Cassels, B. K. J. Ethnopharmacol. 2001, 78, 27e31.
3
4
. Yin, S.; Fan, C.-Q.; Yue, J.-M. J. Asian Nat. Prod. Res. 2007, 9, 29e33.
. Kawashima, H.; Kaneko, Y.; Sakai, M.; Kobayashi, Y. Chem.dEur. J. 2014, 20,
272e278.
4
vinylcyclohexyl)benzene (24). A solution of TES ether 21 (163.3 mg,
.406 mmol) and PPTS (122.9 mg, 0.489 mmol) in EtOH (4 mL) was
stirred at room temperature for 24 h and diluted with satd NaHCO
The resulting mixture was extracted with EtOAc three times. The
combined extracts were washed with brine, dried over MgSO , and
5
6
. Kaneko, Y.; Kiyotsuka, Y.; Acharya, H. P.; Kobayashi, Y. Chem. Commun. 2010, 46,
0
5482e5484.
3
.
. Kobayashi, Y.; Takeuchi, A.; Wang, Y.-G. Org. Lett. 2006, 8, 2699e2702.
7. (a) B €a ckvall, J.-E.; Bystr o€ m, S. E.; Nordberg, R. E. J. Org. Chem. 1984, 49,
4
619e4631; (b) Gatti, R. G. P.; Larsson, A. L. E.; B a€ ckvall, J.-E. J. Chem. Soc., Perkin
4
Trans. 1 1997, 577e583.
concentrated to afford crude alcohol 23, which was passed through
a short silica gel column for the next reaction.
8
. (a) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org.
Chem. 1991, 56, 2656e2665; (b) Harris, K. J.; Gu, Q.-M.; Shih, Y.-E.; Girdaukas,
G.; Sih, C. J. Tetrahedron Lett. 1991, 32, 3941e3944; (c) B
a€ ckvall, J.-E.; Gatti, R.;
To a suspension of the above alcohol in pyridine (4 mL) was
ꢁ
Schink, H. E. Synthesis 1993, 343e348; (d) L oꢀ pez-Pelegrín, J. A.; Janda, K. D.
added SOCl
2
(0.089 mL, 1.22 mmol) at ꢀ10 C. The mixture was
Chem.dEur. J. 2000, 6, 1917e1922; (e) Suzuki, H.; Yamazaki, N.; Kibayashi, C. J.
Org. Chem. 2001, 66, 1494e1496; (f) Hua, Z.; Yu, W.; Su, M.; Jin, Z. Org. Lett. 2005,
7, 1939e1942.
stirred at the same temperature for 30 min and diluted with satd
NaHCO . The resulting mixture was extracted with EtOAc three
times. The combined extracts were washed with brine, dried over
MgSO , and concentrated to give a residue, which was purified by
3
9. (a) Trost, B. M.; Romero, A. G. J. Org. Chem. 1986, 51, 2332e2342; (b) Audia, J. E.;
Boisvert, L.; Patten, A. D.; Villalobos, A.; Danishefsky, S. J. J. Org. Chem. 1989, 54,
4
3738e3740; (c) Barros, M. T.; Maycock, C. D.; Ventura, M. R. J. Org. Chem. 1997,
chromatography on silica gel (hexane/EtOAc) to afford olefin 24
62, 3984e3988; (d) Rohloff, J. C.; Kent, K. M.; Postich, M. J.; Becker, M. W.;
Chapman, H. H.; Kelly, D. E.; Lew, W.; Louie, M. S.; McGee, L. R.; Prisbe, E. J.;
Schultze, L. M.; Yu, R. H.; Zhang, L. J. Org. Chem. 1998, 63, 4545e4550; (e)
Schwardt, O.; Koliwer-Brandl, H.; Zimmerli, R.; Mesch, S.; Rossato, G.; Spreafico,
M.; Vedani, A.; Kelm, S.; Ernst, B. Bioorg. Med. Chem. 2010, 18, 7239e7251.
2
1
4
28
D
(
97.5 mg, 89% from TES ether 21): ½
a
ꢂ
þ2 (c 1.19, CHCl
3
); lit. ½
a
ꢂ
D
ꢀ
1 1
þ2.0 (c 0.76, CHCl
3
); IR (neat) 3074, 1512, 1248, 827 cm ; H NMR
300 MHz, CDCl ) d 0.98 (s, 3H), 1.48 (s, 3H), 1.33e1.75 (m, 4H),
3
(
1
0. (a) Bay oꢀ n, P.; Marjanet, G.; Toribio, G.; Alib eꢀ s, R.; de March, P.; Figueredo, M.;
1
1
1
.77e1.86 (m, 2H), 2.23 (dt, J¼4, 11.5 Hz, 1H), 2.68 (dt, J¼3, 11.5 Hz,
Font, J. J. Org. Chem. 2008, 73, 3486e3491; (b) O’Byrne, A.; Murray, C.; Keegan,
D.; Palacio, C.; Evans, P.; Morgan, B. S. Org. Biomol. Chem. 2010, 8, 539e545.
11. An attempted allylic substitution of 4-acetoxy-2-cyclohexen-1-one with
H), 3.76 (br s, 1H), 4.51 (br s, 1H), 4.54 (br s, 1H), 5.07 (dd, J¼18,
Hz,1H), 5.13 (dd, J¼11, 1 Hz,1H), 5.85 (dd, J¼18,11 Hz,1H), 6.79 (d,
13
J¼8.5 Hz, 2H), 7.04 (d, J¼8.5 Hz, 2H); C NMR (75 MHz, CHCl
3
)
CH2¼C(Me)ZnCl under similar conditions gave
a mixture of unidentified
products.
d
19.7 (þ), 29.0 (ꢀ), 31.6 (þ), 37.6 (ꢀ), 37.8 (ꢀ), 42.7 (þ), 47.5 (ꢀ),
1
2. Further racemization during the conversion of 11 to 18 was not observed.
5
1.4 (þ), 55.2 (þ), 111.2 (ꢀ), 112.6 (ꢀ), 113.5 (þ), 128.3 (þ), 138.1 (ꢀ),
13. Without ZnI , 21 was obtained with 75% regio- and 98% stereoselectivity in 78%
2
1
13
146.3 (þ), 148.6 (ꢀ), 157.6 (ꢀ). The H and C NMR spectra, IR
isolated yield. 3
4
14. 1H NMR (CDCl ): 22
d
7.03 (d, J¼8.5 Hz, 2H), 7.12 (d, J¼8.5 Hz, 2H); cf. 1
d 6.71
D
spectrum, and the [a] value were consistent with those reported.
(d, J¼8.5 Hz, 2H), 6.99 (d, J¼8.5 Hz, 2H).
1
5. Bunnett, J. F.; Zahlerz, R. E. Chem. Rev. 1951, 49, 273e412 (especially, page 293).
4
0
.4.2. Cyclobakuchiol A (1). To a suspension of olefin 24 (19.4 mg,
16. Arthurs, C. L.; Morris, G. A.; Piacenti, A.; Pritchard, R. G.; Stratford, I. J.; Tatic, T.;
Whitehead, R. C.; Williams, K. F.; Wind, N. S. Tetrahedron 2010, 66, 9049e9060.
.072 mmol) and K CO (3.7 mg, 0.027 mmol) in NMP (1 mL) was
2
3
1
7. Alib eꢀ s, R.; de March, P.; Figueredo, M.; Font, J.; Marjanet, G. Tetrahedron:
added PhSH (0.008 mL, 0.079 mmol). The mixture was stirred un-
Asymmetry 2004, 15, 1151e1155.
der reflux for 4 h, cooled to room temperature, and diluted with
18. Robertson, J.; Fowler, T. G. Org. Biomol. Chem. 2006, 4, 4307e4318.