Synthesis of cyclobakuchiols A, B, and C by using conformation-controlled stereoselective reactions

Article abstract of DOI:10.1002/chem.201303538

Cyclohexanone with the pMeOC₆H₄ and CH ₂/C(Me) substituents at the C3 and C4-positions was prepared from (+)-β-pinene and converted to the allylic picolinate by a Masamune-Wittig reaction followed by reduction and esterification. Allylic substitution of this picolinate with Me₂CuMgBr×MgBr₂ in the presence of ZnI₂ proceeded with γ regio- and stereoselectively to afford the quaternary carbon center on the cyclohexane ring with the CH₂/CH and Me groups in axial and equatorial positions, respectively. This product was converted to cyclobakuchiol A by demethylation and to cyclobakuchiol C by epoxidation of the CH₂/C(Me) group. For the synthesis of cyclobakuchiol B, the enantiomer of the above cyclohexanone derived from (-)-β-pinene was converted to the cyclohexane-carboxylate, and the derived enolate was subjected to the reaction with CH₂/CHSOPh followed by sulfoxide elimination to afford the intermediate with the quaternary carbon center with MeOC(/O) and CH₂/CH groups in axial and equatorial positions. The MeOC(/O) group was transformed to the Me group to complete the synthesis of cyclobakuchiol B. Control is key! Synthesis of cyclobakuchiols A and C was stereoselectively accomplished by conformation-controlled substitution of allylic picolinate with Me₂CuMgBr×MgBr₂/ZnI ₂. On the other hand, cyclobakuchiol B was synthesized by stereoselective addition of the cyclohexanecarboxylate enolate to CH ₂/CHSOPh (see scheme). Copyright

Full text of DOI:10.1002/chem.201303538

DOI: 10.1002/chem.201303538
Full Paper
&
Stereocontrolled Synthesis
Synthesis of Cyclobakuchiols A, B, and C by Using Conformation-
Controlled Stereoselective Reactions
Hidehisa Kawashima, Yuki Kaneko, Masahiro Sakai, and Yuichi Kobayashi*[a]
Abstract: Cyclohexanone with the pMeOC6H4 and CH2= tion and to cyclobakuchiol C by epoxidation of the CH2=
C(Me) substituents at the C3 and C4-positions was prepared
from (+)-b-pinene and converted to the allylic picolinate by
a Masamune–Wittig reaction followed by reduction and
esterification. Allylic substitution of this picolinate with
Me2CuMgBr·MgBr2 in the presence of ZnI2 proceeded with g
regio- and stereoselectively to afford the quaternary carbon
center on the cyclohexane ring with the CH2=CH and Me
groups in axial and equatorial positions, respectively. This
product was converted to cyclobakuchiol A by demethyla-
C(Me) group. For the synthesis of cyclobakuchiol B, the
enantiomer of the above cyclohexanone derived from (À)-b-
pinene was converted to the cyclohexane-carboxylate, and
the derived enolate was subjected to the reaction with CH2=
CHSOPh followed by sulfoxide elimination to afford the in-
termediate with the quaternary carbon center with MeOC(=
O) and CH2=CH groups in axial and equatorial positions. The
MeOC(=O) group was transformed to the Me group to com-
plete the synthesis of cyclobakuchiol B.
Introduction
Cyclobakuchiols A and B are antipyretic and anti-inflammatory
compounds isolated as a mixture from Psoralea glandulosa L.[1]
Recently, cyclobakuchiol C was isolated from Psoralea coryllfo-
lia.[2] The structures with the relative stereochemistry have
been spectroscopically determined, and the suggested abso-
lute configuration is as depicted in Figure 1 on the basis of the
concomitant production of stereodefined bakuchiol (4) with an
S configuration and the probable cyclization of 4 to 1–3. The
biological potency of the mixture (1 and 2) is higher than that
of 4.[3] However, the potency of each cyclobakuchiol is unex-
plored, probably because of the difficulty in separating the
mixture[1,3] and the lack of a method for the synthesis of 1–3.
In this study, we report the synthesis of 1–3, in which the qua-
ternary carbon atoms are constructed in a stereoselective
manner. Furthermore, elucidation of the absolute configura-
tions of naturally occurring cyclobakuchiols A–C is presented
on the basis of specific rotation analysis.
Figure 1. Structures of cyclobakuchiols A–C and bakuchiol.
axial vinyl and equatorial alkyl groups. We supposed that the
cyclohexane I with Ar (pMeOC6H4) and R1 (Me2C(OH)or CH2=
C(Me)) in equatorial positions is the most stable conformer,
and that allylation of I with a methyl copper reagent would
produce II, in which the quaternary carbon center in 1 and 3 is
correctly furnished (Scheme 1). Furthermore, we realized that
the concept of the equatorial attack is applicable to a reaction
of enolate IV with a vinyl cation equivalent to afford V and
that conversion of the ester group (CO2R2) of V to Me would
produce 2. Practically, the synthesis of 1–3 by this approach
was quite successful, as described below. Furthermore, prepa-
ration of the key intermediate was improved so as to attain
high enantiomeric purity.
Recently, we reported the construction of a quaternary
carbon center on a cyclohexane ring by using SN2’ selective al-
lylic substitution with alkylcopper reagents.[4] The stereochem-
istry is controlled by the equatorial attack of reagents to the al-
lylic end (SN2’ position) in the thermodynamically stable chair
conformer, which creates a quaternary carbon center with the
[a] H. Kawashima, Y. Kaneko, M. Sakai, Prof. Dr. Y. Kobayashi
Department of Bioengineering
Tokyo Institute of Technology, B52
Results and Discussion
Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501 (Japan)
Fax: (+81)45-924-5789
First, the key intermediate I was designed as picolinate 10a, to
which we envisaged access through copper-assisted 1,4-addi-
tion of pMeOC6H4MgBr to enone 8 followed by a Wittig reac-
E-mail: ykobayas@bio.titech.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303538.
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Table 1. Pd-catalyzed enone formation.
Entry Pd(OAc)2 [mol%] DPPE [mol%] T [oC] t [h] Yield [%] ee [%]
1
2
3
4
5
5
10
5
5
5
5
10
5
5
5
80
80
80
80
50
10
18
40
3
51
73
72
66
62
81
–
n.d.[a]
38
3
0[b]
[a] n.d.=not determined. [b] Enol acetate 6 was recovered unchanged.
Scheme 1. Key reactions for construction of cyclobakuchiols.
zation of any advanced intermediate(s), enone 8 was convert-
ed to 10a through ketone 9a. Unfortunately, the intermediates
and 10a were oily compounds.
tion of the resulting ketone 9a (Scheme 2). In accordance with
the literature procedure,[5] the cyclobutane ring of nopinone
(1R)-5[6] was opened with Zn(OAc)2 and BF3·Et2O in Ac2O, and
Although the racemization was found to occur in the Pd-cat-
alyzed step, the low ee observed even at the beginning of the
reaction suggested that the BF3-assisted cyclobutane ring
opening of (1R)-5 is another likely step responsible for the rac-
+
emization through cation interchange between ring-CH-CMe2
and ring-C+-CHMe2. Because of the expected difficulty in im-
proving these steps, an altered synthesis shown in Scheme 3
was envisaged with the expectation that a similar cation inter-
change in the ring opening of 13 would be suppressed by
conformation of the ring-opening product, which is stabilized
by the pMeOC6H4 anchor. Furthermore, even when it was pro-
duced, the isomerization product, which is the diastereomer
with the two substituents in a cis relationship, was expected to
be removed by routine purification. Because the enone olefin
is furnished to the opposite side of the molecule, we convert-
ed (1S)-5[6] to enone 12 by bromination followed by dehydro-
bromination at 1408C with DBU or with Li2CO3/LiBr.[9] However,
the yields of 12 in both cases were only 30% over two steps,
whereas elimination of the sulfoxide, synthesized in 32% yield
from (1S)-5 (LDA, (PhS)2; MMPP= Magnesium Monoperoxyph-
thalate Hexahydrate), with K2CO3 in toluene at 1208C gave
a mixture of products.[10] We then attempted to follow the lit-
erature method by a-phenylselenenylation[11] using (PhSe)2,
MsOH, and SeO2 in CH2Cl2, wherein SeO2 is added in three
parts after every 15 h of reaction and isolation.[10a] However,
our attempt gave a mixture of products. Fortunately, the sub-
Scheme 2. Synthesis of the key picolinate: a) Zn(OAc)2, BF3·OEt2, Ac2O, 46%;
b) Pd(OAc)2, DPPE, Bu3Sn(OMe), CH2=CHCH2OCO2Et, MeCN, 808C, 10 h, 51%;
c) DIBAL; d) PCC; e) TESCl, imidazole, 60% (3 steps); f) pMeOC6H4MgBr
(3 equiv), CuBr·Me2S (1.5 equiv); g) (EtO)2P(O)CH2CO2Et, LiCl, DBU, 72%
(2 steps); h) 2-PyCO2H, [2-Cl-N-Me-Py]+ IÀ, DMAP, Et3N, 86% (2 steps).
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL=iBu2AlH; DMAP=4-(dime-
thylamino)pyridine; DPPE=ethylenebis(diphenylphosphine); PCC= pyridini-
um chlorochromate.
subsequent Pd-catalyzed olefination[7] of the resulting enol
acetate
6 with Pd(OAc)2, DPPE, Bu3Sn(OMe), and CH2= stitution of H2SO4 and MeOH for MsOH and CH2Cl2, respective-
CHCH2OCO2Et at 808C gave enone 7, which was transformed
to the TES (Et3Si) ether 8 in three steps. Although this method
is reported to be stereoselective on the basis of specific rota-
tion analysis, the ee of 8 synthesized herein was 72% as deter-
mined by sure chiral HPLC analysis. Reinvestigation of the Pd-
catalyzed step under various conditions is summarized in
Table 1. The enantiomeric purity of 7 was 81% ee when the re-
action was quenched before completion (3 h) (Table 1, entry 4),
whereas higher loading of the catalyst and a longer reaction
time resulted in 62–66% ee.[8] At a lower temperature (508C),
the reaction did not proceed. To recover high ee by recrystalli-
ly, accelerated the reaction substantially to afford 11 (diaste-
reomeric ratio (d.r.)>99:<1 by H NMR spectroscopy) in 90%
1
yield after only 5 h. Oxidation of 11 with H2O2 gave enone 12,
which upon reaction with pMeOC6H4MgBr/CuI furnished
ketone 13 in 83% yield from 11. Cyclobutane ring opening of
13 under the conditions used for (1R)-5 proceeded cleanly as
analyzed by TLC analysis. The product isolated was, however,
olefin 14b and not the AcO adduct 14a. The enol acetate 14b
was exposed to NaOMe in MeOH to afford 9b, which was
>99% ee by chiral HPLC analysis. Masamune–Wittig reaction
of 9b afforded ester 15 as a 1:1 olefin mixture, which was
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moiety, which makes the synthesis highly convenient. Finally,
demethylation of 16 with PhSH and K2CO3 afforded cyclobaku-
1
chiol A (1) in quantitative yield. The H and 13C NMR spectra of
1 thus synthesized were consistent with those previously re-
ported.[1]
Next, the synthesis of cyclobakuchiol C (3) was undertaken
by starting from 16, which upon epoxidation with mCPBA fol-
lowed by hydride reduction with LiAlH4 produced 18 in 66%
yield (Scheme 4). Finally, demethylation with PhSH/K2CO3 pro-
1
duced 3 as solids in 88% yield. The H and 13C NMR spectra of
3 were consistent with those reported for gummy 3.[2]
To establish access to cyclobakuchiol B (2) through enolate
capture by a vinyl cation equivalent (Scheme 1, approach to 2),
we applied the method developed for the synthesis of ketone
Scheme 3. Synthesis of cyclobakuchiol A: a) (PhSe)2 (0.6 equiv), SeO2
(1.2 equiv), H2SO4 (0.9 equiv), MeOH, RT, 5 h, 90%; b) 7% H2O2, pyridine;
c) pMeOC6H4MgBr (2.5 equiv), CuI (0.6 equiv), 83% (2 steps); d) Zn(OAc)2,
BF3·OEt2, Ac2O. e) NaH, MeOH, 91% (2 steps); f) (EtO)2P(O)CH2CO2Et, LiCl,
DBU, 81%; g) DIBAL. h) 2-PyCO2H, [2-Cl-N-Me-Py]+IÀ, DMAP, Et3N, 100%
(2 steps); i) Me2CuMgBr·MgBr2 (1.5 equiv), ZnI2 (1.7 equiv), THF, À788C, 1 h,
92%; j) PhSH, K2CO3, NMP, 2208C, 99%. NMP=N-methylpyrrolidone.
transformed to the key picolinate 10b by DIBAL (iBu2AlH) re-
duction followed by esterification with PyCO2H.
Without separation, the olefin mixture 10b was subjected to
allylic substitution with Me2CuMgBr·MgBr2 in the presence of
ZnI2 to afford 16 in 92% yield. To determine the regio- and ste-
reoselectivity, we synthesized regioisomer 17 in 98% yield with
97% regioselectivity (r.s.) by allylic substitution of 10b with
Me2CuMgBr·MgBr2 in the absence of ZnI2 [Eq. (1)] and the dia-
stereoisomer of 16 (i.e., 25) by the method delineated in
1
Scheme 5. With the H NMR spectra of the isomers in hand, we
calculated the regio- and diastereoselectivity of the allylation
to give 16 to be 97% r.s. and 98% d.r. We emphasize that the
stereochemistry is controlled by the conformation of the cyclo-
hexane ring and is little affected by the geometry of the allylic
Scheme 5. Synthesis of cyclobakuchiol B: a) (PhSe)2 (0.6 equiv), SeO2
(1.2 equiv), H2SO4 (0.9 equiv), MeOH, 89%; b) H2O2, pyridine;
c) pMeOC6H4MgBr (2.5 equiv), CuI (0.6 equiv), 85% (2 steps); d) Zn(OAc)2,
BF3·OEt2, Ac2O; e) NaH, MeOH, 93% (2 steps); f) TsCH2NC, tBuOK, THF;
g) KOH, PrOH; h) CH2N2, 88% (3 steps); i) LDA, THF, À788C then 21a,
À1058C; j) NaHCO3, xylene, reflux, 85% (2 steps); k) LiAlH4, THF; l) TsCl, Et3N,
DMAP, 91% (2 steps); m) NaBH4, DMF, 808C, 12 h, 82%; n) PhSH, K2CO3, NMP,
2208C, 93%. LDA=lithium diisopropylamide.
Scheme 4. Synthesis of cyclobakuchiol C: a) mCPBA, NaHCO3; b) LiAlH4, THF,
66% (2 steps); c) PhSH, K2CO3, NMP, 2208C, 88%. mCPBA=3-chloroperoxy-
benzoic acid.
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9b from (1S)-5 to (1R)-5, which afforded ent-9b with >99% ee
by chiral HPLC analysis (Scheme 5). A methoxycarbonyl moiety
was installed on the carbonyl carbon atom of ent-9b by reduc-
tive cyanation[12] with TsCH2NC and tBuOK followed by hydroly-
sis of the resulting nitrile 19 (diastereomeric mixture) and
esterification. The methyl ester 20, which was isolated in 88%
yield, was a single diastereomer, and downward stereochemis-
try (equatorial in the chair conformation) was tentatively as-
signed to the CO2Me group, although the stereochemistry was
indecisive to the next reaction.
trogen) resulted in a higher d.r. of 92% without a delay in the
reaction (entry 6). This protocol was successful in reacting 20
with 21a, and subsequent elimination of PhSOH afforded
olefin 23 with 96% d.r. in 85% yield (two steps). The methyl
ester group in 23 was then converted to the methyl group in
three steps. Finally, demethylation of 25 furnished 2 in 93%
1
yield. The H and 13C NMR spectra of 2 synthesized were con-
sistent with those reported previously.[1]
Amongst the different methods[13–18] for introducing a vinyl
group to the a-position of carbonyl compounds, we chose
two of them on the basis of operational simplicity: 1) aldol re-
action with MeCHO followed by the elimination of H2O and
2) addition to CH2=CHSOPh (21a) followed by elimination of
PhSOH. The former method was examined by using an ester
with the Me2C(OTES) substituent in place of CH2=C(Me), which
gave the corresponding product with 90% d.r. in 61% yield in
three steps. To achieve higher d.r. and yield, we changed the
focus of our investigation to the latter method, although this
method has not been extensively explored.[14] An enolate
anion was prepared from 20 with LDA as a 1:1 E/Z mixture
[Eq. (2)], which was determined by 1H NMR spectroscopy of
the derived TMS enol ether 26,[19] and was subjected to reac-
tion with CH2=CHSOPh (21a) at À788C in THF. The reaction
completed in 30 min to afford the adduct 22, which upon ther-
molysis produced ester 23, but with 86% d.r., as determined
Although a comparison of the specific rotation is one way to
establish the absolute configuration of natural cyclobakuchiol-
s A–C, specific rotations have been reported for few of the
compounds: cyclobakuchiol C[2] ([a]D20 =À15.3 (c=0.38 in
MeOH)) and the two methyl ethers of cyclobakuchiols (report-
ed as isomers A and B)[20] derived from bakuchiol (4) with an S
configuration by acid-catalyzed cyclization ([a]D = +3.1 (c=
0.16) and À30.6 (c=0.18) in EtOH for isomers A and B, respec-
tively). On the basis of [a]2D8 =À18 (c=0.30 in MeOH) obtained
for synthetic 3, cyclobakuchiol C is definitely suggested to pos-
sess the same absolute configuration as that of 3. Regarding
cyclobakuchiols A and B, 16 and 25 (the methyl ethers of
1 and 2) showed [a]D26 = +3.2 (c=0.76) and [a]2D8 =À32 (c=
0.58) in EtOH. The latter [a]D value strongly indicates that
isomer B should be 25, and that isomer A should thus be 16.
Consequently, naturally occurring cyclobakuchiols A and B
were definitely assigned as 1 and 2.
1
by H NMR spectroscopy. To optimize the reaction conditions,
we studied a model reaction by using esters 27 (R=Me) and
21a (Ar=Ph) under the conditions used for 20, whereas we
did not examine the other methods, such as GaCl3-mediated
addition of a thioester TMS ether to TMS acetylene that pro-
ceeds with somewhat low 75% d.r.[15b] In practice, the addition
of ester 27 to 21a proceeded with a level of d.r. (86–87%) sim-
ilar to that of the real case (Table 2, entry 1). However, no im-
provement was provided by larger esters 27 (R=Et, tBu) or by
2-pyridyl sulfoxide 21b (Ar=2-pyridyl) (entries 2–5). In con-
trast, a lower reaction temperature of À1058C (MeOH/liquid ni-
Conclusion
The synthesis of 1–3 was stereoselectively accomplished by
taking advantage of the conformation-controlled reactions,
specifically, allylic substitution of picolinate 10b with
Me2CuMgBr·MgBr2/ZnI2 and the addition of the enolate derived
from ester 20 to CH2=CHSOPh (21a). The high stereoselectivity
observed in the allylic substitution and the enolate capture by
the vinyl sulfoxide was independent of the olefin stereochem-
istry of allylic picolinate 10b and the enolate derived from
ester 20, respectively. In addition, we developed a method for
the synthesis of enone 12 and its enantiomer ent-12 with high
enantiomeric purity. With 1–3 in hand for the first time, the ab-
solute configurations of naturally occurring cyclobakuchiols A–
C were established as 1–3 by [a]D analysis. Research concern-
ing biological studies of each cyclobakuchiol is ready to start.
Table 2. Model study.[a,b]
Entry
R
Ar
T [8C]
d.r. 28
d.r. 29
1
2
3
4
5
6
Me
Me
Et
Et
tBu
Me
Ph
2-Py
Ph
2-Py
Ph
Ph
À78
À78
86
84
84
84
72
92
87
n.d.
n.d.
n.d.
73
À78
À78
À78
Experimental Section
À105[d]
n.d.
General methods
[a] LDA (3 equiv), CH2=CHSOAr (2 equiv). [b] Diastereomeric ratio of 27:
R=Me, 7:3; R=Et, 8:2; R=tBu, 7:3. [c] Determined by 1H NMR spectros-
copy. [d] MeOH/N2 (liq.).
The 1H (300 or 400 MHz) and 13C NMR (75 or 100 MHz) spectro-
scopic data were recorded in CDCl3 by using Me4Si (d=0 ppm)
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and the centerline of the triplet (d=77.1 ppm), respectively, as in-
ternal standards. Signal patterns are indicated as brs (broad sin-
glet), s (singlet), d (doublet), t (triplet), q (quartet), and m (multip-
let). Coupling constants (J) are given in Hertz (Hz). Chemical shifts
of carbon atoms are accompanied by minus (for C and CH2) and
plus (for CH and CH3) signs of the attached proton test (APT) ex-
periments. HRMS was performed with a double-focusing mass
spectrometer with an ionization mode of positive FAB or EI as indi-
cated for each compound. The solvents that were distilled prior to
use are THF (from Na/benzophenone), Et2O (from Na/benzophe-
none), and CH2Cl2 (from CaH2). After the reactions were completed,
the organic extracts were concentrated by using an evaporator,
and then the residues were purified by chromatography on silica
gel (Kanto, spherical silica gel 60N. [Cu(acac)2] was purchased from
TCI, Japan, and used without purification, whereas CuBr·Me2S was
prepared as described previously.[21]
J=9, 6 Hz, 1H), 5.95 (d, J=9 Hz, 1H), 7.52 ppm (dd, J=9, 6 Hz,
1H); the 1H NMR spectrum was consistent with that reported.[10]
pMeOC6H4MgBr (8.0 mL, 0.90m in THF, 7.20 mmol) was added
dropwise to a suspension of CuI (328 mg, 1.72 mmol) in THF (8 mL)
at À788C and the solution was stirred at À788C for 30 min. A solu-
tion of the above enone 12 in THF (8 mL) was added dropwise.
The mixture was allowed to warm to À508C over 2 h and saturat-
ed NH4Cl was added. The resulting mixture was extracted with
EtOAc three times. The combined organic layers were washed with
brine, dried over MgSO4, and concentrated to afford a residual oil,
which was purified by chromatography on silica gel (hexane/
EtOAc) to give ketone 13 (581 mg, 83% from 11). [a]2D4 =À45.3 (c=
1.13 in CHCl3); IR (neat): n˜ =1708, 1513, 1250, 1035, 826 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=0.98 (s, 3H), 1.39 (s, 3H), 1.89 (d, J=
11 Hz, 1H), 2.38 (t with fine couplings, J=5 Hz, 1H), 2.55 (dt, J=11,
6 Hz, 1H), 2.62 (t, J=5 Hz, 1H), 2.67 (dd, J=19, 7 Hz, 1H), 2.78 (dd,
J=19, 9 Hz, 1H), 3.38 (t, J=8 Hz, 1H), 3.80 (s, 3H), 6.87 (d with fine
couplings, J=9 Hz, 2H), 7.17 ppm (d with fine couplings, J=9 Hz,
2H); 13C NMR (100 MHz, CDCl3): d=22.0 (+), 22.8 (À), 26.1 (+), 36.6
(+), 41.1 (À), 41.9 (À), 46.8 (+), 55.3 (+), 57.2 (+), 114.1 (+), 127.8
(+), 136.5 (À), 158.1 (À), 213.4 ppm (À); HRMS (FAB): m/z: calcd for
C16H20O2+: 244.1463 [M+]; found: 244.1464.
Synthetic methods
(1S,5R)-6,6-Dimethylbicyclo[3.1.1]heptan-2-one
((1S)-5):
RuCl3·nH2O (51 mg) was added to a suspension of (+)-b-pinene
(1.03 g, 7.54 mmol) and NaIO4 (6.70 g, 31.3 mmol) in CCl4 (10 mL),
MeCN (10 mL), and H2O (15 mL), and the mixture was stirred at RT
for 2 h and then diluted with H2O. The resulting mixture was ex-
tracted with CH2Cl2 three times. The combined extracts were dried
over MgSO4 and concentrated to afford a residual oil, which was
purified by chromatography on silica gel (hexane/EtOAc) to afford
ketone (1S)-5 (952 mg, 91%). [a]2D3 =À39.8 (c=1.131 in MeOH);
1H NMR (400 MHz, CDCl3): d=0.86 (s, 3H), 1.33 (s, 3H), 1.59 (d, J=
10 Hz, 1H), 1.90–2.10 (m, 2H), 2.21–2.27 (m, 1H), 2.34 (ddd, J=19,
9, 2 Hz, 1H), 2.49–2.64 ppm (m, 3H); 13C NMR (100 MHz, CDCl3): d=
21.4 (À), 22.1 (+), 25.3 (À), 25.9 (+), 32.8 (À), 40.4 (+), 41.2 (À),
(3S,4S)-3-(4-Methoxyphenyl)-4-(prop-1-en-2-yl)cyclohexanone
(9b): BF3·OEt2 (0.25 mL, 1.99 mmol) was added to an ice-cold mix-
ture of ketone 13 (909 mg, 3.72 mmol) and Zn(OAc)2 (722 mg,
3.93 mmol) in Ac2O (10 mL). The mixture was stirred at RT over-
night and diluted with H2O. The resulting mixture was extracted
with EtOAc three times. The combined extracts were washed with
saturated NaHCO3 and brine, dried over MgSO4, and concentrated
to afford acetate 14b, which was used for the next reaction with-
out further purification.
NaH (80 mg, 60% in mineral oil, 2.01 mmol) was added to a solu-
tion of the above acetate in MeOH (10 mL) at RT. The mixture was
stirred for 30 min and then diluted with saturated NH4Cl. The re-
sulting mixture was extracted with EtOAc three times. The com-
bined organic layers were washed with brine, dried over MgSO4,
and concentrated to afford a residual oil, which was purified by
chromatography on silica gel (hexane/EtOAc) to give ketone 9b
(825 mg, 91% from 13). >99% ee by chiral HPLC analysis (see the
Supporting Information); [a]2D3 = +55 (c=0.65 in CHCl3); m.p. 118–
1
58.0 (+), 215.0 ppm (À); the H NMR spectrum was consistent with
that reported.[22]
(1S,3R,5S)-6,6-Dimethyl-3-(phenylselanyl)bicyclo[3.1.1]heptan-2-
one (11): H2SO4 (0.20 mL, 18m, 3.60 mmol) was added to an ice-
cold solution of ketone (1S)-5 (570 mg, 4.12 mmol), (PhSe)2
(708 mg, 2.27 mmol), and SeO2 (549 mg, 4.95 mmol) in MeOH
(8 mL). The mixture was stirred at RT for 5 h and diluted with satu-
rated NaHCO3. The resulting mixture was extracted with EtOAc
three times. The combined extracts were washed with brine, dried
over MgSO4, and concentrated to afford a residual oil, which was
purified by chromatography on silica gel (hexane/EtOAc) to afford
selenide 11 (1.09 g, 90%). [a]2D4 = +32.4 (c=0.888 in CHCl3);
1H NMR (400 MHz, CDCl3): d=0.84 (s, 3H), 1.35 (s, 3H), 1.87 (d, J=
11 Hz, 1H), 2.17–2.28 (m, 2H), 2.49–2.63 (m, 2H), 2.70 (t, J=5 Hz,
1H), 3.86 (dd, J=9, 2 Hz, 1H), 7.28–7.34 (m, 3H), 7.63–7.70 ppm
(m, 2H); 13C NMR (100 MHz, CDCl3): d=22.1 (+), 25.7 (À), 25.9 (+),
31.6 (À), 40.3 (+), 40.8 (+), 42.2 (À), 57.7 (+), 128.3 (+), 129.2 (+),
130.5 (À), 134.7 (+), 210.1 ppm (À); the 1H NMR spectrum was
consistent with that reported.[10]
119 8C; IR (neat): n˜ =1700, 1517, 1254, 1030 cmÀ1
;
1H NMR
(400 MHz, CDCl3): d=1.52 (s, 3H), 1.86 (ddt, J=13, 6, 12 Hz, 1H),
2.05–2.14 (m, 1H), 2.45–2.59 (m, 4H), 2.71 (dt, J=3, 12 Hz, 1H),
2.93 (dt, J=6 and 11 Hz, 1H), 3.78 (s, 3H), 4.63 (s, 1H), 4.65 (s, 1H),
6.82 (d with fine couplings, J=9 Hz, 2H), 7.07 ppm (d with fine
couplings, J=9 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=19.6 (+),
31.9 (À), 41.3 (À), 47.5 (À), 50.0 (À), 50.3 (+), 55.2 (+), 112.7 (À),
113.9 (+), 129.2 (+), 135.3 (À), 146.2 (À), 158.2 (À), 210.4 ppm (À);
HRMS (FAB): m/z: calcd for C16H20O2+: 244.1463 [M+]; found:
244.1464.
Ethyl 2-[(3S,4S)-3-(4-methoxyphenyl)-4-(prop-1-en-2-yl)cyclohex-
ylidene]acetate (15): DBU (1.80 mL, 12.1 mmol) and triethyl phos-
phonoacetate (2.51 mL, 12.5 mmol) were added to a suspension of
LiCl (556 mg, 13.1 mmol) in MeCN (6 mL) at 08C. The mixture was
stirred at 08C for 30 min, and then ketone 9b (725 mg, 2.97 mmol)
was added. The reaction was carried out at RT overnight and
quenched by addition of saturated NH4Cl. The resulting mixture
was extracted with EtOAc three times. The combined extracts were
washed with brine, dried over MgSO4, and concentrated to give
a residue, which was purified by chromatography on silica gel
(hexane/EtOAc) to afford the ester 15 (756 mg, 81%) as a mixture
(1S,4S,5S)-4-(4-Methoxyphenyl)-6,6-dimethylbicyclo-
[3.1.1]heptan-2-one (13): 7% H2O2 (2.09 mL, 4.24 mmol) was
added to an ice-cold solution of selenide 11 (841 mg, 2.87 mmol)
and pyridine (0.46 mL, 5.70 mmol) in CH2Cl2 (6 mL). The mixture
was stirred at RT overnight and diluted with saturated NaHSO3. The
resulting mixture was extracted with CH2Cl2 three times. The com-
bined extracts were washed with saturated CuSO4 and brine, dried
over MgSO4, and concentrated to afford enone 12, which was used
for the next reaction without further purification. Enone 12:
1H NMR (400 MHz, CDCl3): d=1.04 (s, 3H), 1.52 (s, 3H), 2.14 (d, J=
8 Hz, 1H), 2.60 (q, J=6 Hz, 1H), 2.72 (dt, J=2, 6 Hz, 1H), 2.85 (dt,
1
of the stereoisomers (1:1 by H NMR spectroscopy). IR (neat): n˜ =
1
1713, 1648, 1513, 1249, 1151 cmÀ1; H NMR (400 MHz, CDCl3): d=
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1.26, 1.29 (2 t, J=7, 7 Hz, 3H), 1.48 (s, 3H), 1.52–1.67 (m, 1H), 1.91–
2.07 (m, 2H), 2.28–2.43 (m, 2H), 2.47–2.57 (m, 1H), 2.59–2.69 (m,
1H), 3.770, 3.774 (2s, 1.5, 1.5H), 3.93–4.01 (m, 1H), 4.13, 4.17 (2 q,
J=7, 7 Hz, 2H), 4.56, 4.58 (2s with fine couplings, 2H), 5.65, 5.68
(2s, 0.5, 0.5H), 6.79, 6.81 (2 d with fine couplings, J=9, 9 Hz, 2H),
7.07, 7.09 ppm (2 d with fine couplings, J=9, 9 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=14.29, 14.30 (+), 19.55, 19.58 (+), 29.2, 33.0,
33.8, 37.4, 38.3, 46.5 (for 3C, À), 47.9, 48.8 (+), 51.1, 51.3 (+), 55.0
(+), 59.5, 59.6 (À), 111.8, 111.9 (À), 113.5, 113.7 (+), 113.7, 113.8 (+),
128.1, 128.2 (+), 136.3, 136.6 (À), 147.0, 147.1 (À), 157.8, 158.0 (À),
160.9, 161.2 (À), 166.5, 166.7 ppm (À); HRMS (FAB): m/z: calcd for
C20H26O3+: 314.1882 [M+]; found: 314.1881.
sulting mixture was stirred at 08C for 30 min and cooled to À788C.
A solution of picolinate 10b (E/Z=1:1, 471 mg, 1.25 mmol) in THF
(15 mL) was added to the mixture dropwise. The resulting mixture
was stirred at À788C for 1 h and quenched by addition of saturat-
ed NH4Cl with vigorous stirring. The layers were separated and the
aqueous layer was extracted with EtOAc twice. The combined ex-
tracts were washed with brine, dried over MgSO4, and concentrat-
ed to give a residue, which was purified by chromatography on
silica gel (hexane/EtOAc) to afford olefin 16 (310 mg, 92%): 97%
regioselectivity, 98% stereoselectivity. [a]2D8 = +2.0 (c=0.76 in
CHCl3), [a]2D6 = +3.2 (c=0.76 in EtOH); lit.[20] [a]RDT = +3.1 (c=0.16
in EtOH); IR (neat): n˜ =1643, 1612, 1512, 1247 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=0.98 (s, 3H), 1.48 (s, 3H), 1.35–1.72 (m, 4H),
1.77–1.86 (m, 2H), 2.23 (dt, J=4, 12 Hz, 1H), 2.68 (dt, J=3, 12 Hz,
1H), 3.76 (s, 3H), 4.51 (s with fine coupling, 1H), 4.53 (brs, 1H),
5.07 (dd, J=18, 1 Hz, 1H), 5.13 (dd, J=11, 1 Hz, 1H), 5.85 (dd, J=
18, 11 Hz, 1H), 6.79 (d, J=9 Hz, 2H), 7.04 ppm (d, J=9 Hz, 2H);
13C NMR (100 MHz, CHCl3): d=19.7 (+), 29.1 (À), 31.6 (+), 37.6 (À),
37.8 (À), 42.8 (+), 47.6 (À), 51.5 (+), 55.2 (+), 111.2 (À), 112.6 (À),
113.6 (+), 128.3 (+), 138.1 (À), 146.3 (+), 148.6 (À), 157.6 ppm (À);
HRMS (FAB): m/z: calcd for C19H26O+: 270.1984 [M+]; found:
270.1984; the 1H NMR spectrum was consistent with that report-
ed.[20]
2-[(3S,4S)-3-(4-Methoxyphenyl)-4-{2-[(triethylsilyl)oxy]propan-2-
yl}cyclohexylidene]ethyl picolinate (10b): DIBAL (5.1 mL, 1.02m in
hexane, 5.20 mmol) was added dropwise to a solution of ester 15
(646 mg, 2.05 mmol) in THF (20 mL) at À788C, and the solution
was stirred at À788C for 30 min before the addition of H2O (2 mL,
111 mmol) and NaF (6.03 g, 144 mmol). The resulting mixture was
stirred at RT for 30 min and filtered through a pad of Celite. The fil-
trate was concentrated in vacuo to afford a residual oil, which was
purified by chromatography on silica gel (hexane/EtOAc) to afford
the alcohol (557 mg, 100%) as a mixture of the stereoisomers (1:1
by H NMR spectroscopy). H NMR (400 MHz, CDCl3): d=1.41–1.60
(m, 1H), 1.479 and 1.481 (2s, 1.5 and 1.5H), 1.82–2.02 (m, 2H),
2.14–2.29 (m, 1H), 2.30–2.39 (m, 1H), 2.40–2.64 (m, 2H), 2.70–2.82
(m, 1H), 3.770, 3.774 (2s, 1.5, 1.5H), 4.08–4.23 (m, 2H), 4.52–4.60
(m, 2H), 5.39–5.48 (m, 1H), 6.806, 6.812 (2 d with fine couplings,
J=7, 8 Hz, 2H), 7.06, 7.07 ppm (2 d with fine couplings, J=7, 8 Hz,
2H); 13C NMR (100 MHz, CDCl3): d=19.67, 19.70 (+), 28.4 (À), 33.3,
33.8 (À), 36.4, 37.7 (À), 45.9 (À), 48.0, 48.6 (+), 51.6, 51.8 (+), 55.1,
55.2 (+), 58.5, 58.6 (À), 111.56, 111.61 (À), 113.62, 113.65 (+),
121.33 (+), 128.22, 128.25 (+), 137.1, 137.2 (À), 142.4, 142.7 (À),
147.6, 147.7 (À), 157.8, 157.9 ppm (À).
1
1
Cyclobakuchiol A (1): PhSH (0.03 mL, 0.29 mmol) was added to
a suspension of olefin 16 (51 mg, 0.188 mmol) and K2CO3 (20 mg,
0.148 mmol) in NMP (3.5 mL). The reaction was carried out at
2208C overnight and quenched by addition of 1n HCl. The result-
ing mixture was extracted with EtOAc three times. The combined
extracts were dried over MgSO4 and concentrated to give a residue,
which was purified by chromatography on silica gel (hexane/
EtOAc) to afford cyclobakuchiol A (1) (48 mg, 99%) as a solid:
[a]2D1 =0 (c=0.40 in CHCl3); m.p. 66–698C; IR (nujol): n˜ =3260,
1
1512, 1456, 1238, 827 cmÀ1; H NMR (400 MHz, CDCl3): d=0.98 (s,
3H), 1.34–1.45 (m, 2H), 1.48 (s, 3H), 1.50–1.71 (m, 2H), 1.76–1.85
(m, 2H), 2.21 (dt, J=4, 12 Hz, 1H), 2.67 (dt, J=3, 12 Hz, 1H), 4.48–
4.56 (m, 2H), 4.67 (brs, 1H), 5.07 (dd, J=18, 1 Hz, 1H), 5.13 (dd, J=
11, 1 Hz, 1H), 5.85 (dd, J=18, 11 Hz, 1H), 6.71 (d with fine cou-
plings, J=8 Hz, 2H), 6.99 ppm (d with fine couplings, J=8 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=19.7 (+), 29.0 (À), 31.6 (+), 37.6 (À),
37.8 (À), 42.8 (+), 47.5 (À), 51.5 (+), 111.2 (À), 112.6 (À), 115.1 (+),
128.6 (+), 138.3 (À), 146.3 (+), 148.6 (À), 153.4 ppm (À); HRMS
(FAB): m/z: calcd for C18H22O+: 256.1827 [M+]; found: 256.1824; the
1H and 13C NMR spectra were consistent with those reported.[1]
2-Chloro-1-methylpyridinium iodide (836 mg, 3.27 mmol) was
added to an ice-cold solution of the above alcohol (438 mg,
1.61 mmol), picolinic acid (275 mg, 2.23 mmol), Et3N (0.66 mL,
4.76 mmol), and DMAP (208 mg, 1.70 mmol) in CH2Cl2 (10 mL). The
mixture was stirred at RT overnight and diluted with saturated
NaHCO3. The resulting mixture was extracted with EtOAc three
times. The combined extracts were washed with 1n HCl and brine,
dried over MgSO4, and concentrated to give a residue, which was
purified by chromatography on silica gel (hexane/EtOAc) to picoli-
nate 10b (607 mg, 100% from 15) as a mixture of the stereoiso-
1
mers (1:1 by H NMR spectroscopy). IR (neat): n˜ =1738, 1718, 1512,
1-Methoxy-4-[(1S,2S)-2-(prop-1-en-2-yl)-5-propylidenecyclohex-
yl]benzene (17): MeMgBr (0.44 mL, 0.99m in THF, 0.43 mmol) was
added slowly to an ice-cold suspension of CuBr·Me2S (40 mg,
0.20 mmol) in THF (1 mL). The resulting mixture was stirred at 08C
for 30 min and cooled to À408C. A solution of picolinate 10b (E/
Z=1:1, 50 mg, 0.13 mmol) in THF (1 mL) was added to the mixture
dropwise. The resulting mixture was allowed to warm to À108C
over 1 h and diluted with saturated NH4Cl with vigorous stirring.
The layers were separated and the aqueous layer was extracted
with EtOAc twice. The combined extracts were washed with brine,
dried over MgSO4, and concentrated to give a residue, which was
purified by chromatography on silica gel (hexane/EtOAc) to afford
olefin 17 as a 1:1 mixture of the E and Z isomers (35 mg, 98%).
97% regioselectivity; [a]D20 =À58 (c=0.63 in CHCl3); IR (neat): n˜ =
1
1246, 1126 cmÀ1; H NMR (400 MHz, CDCl3): d=1.48 (s, 3H), 1.46–
1.68 (m, 1H), 1.83–2.07 (m, 2H), 2.19–2.31 (m, 1H), 2.33–2.65 (m,
3H), 2.83–2.94 (m, 1H), 3.77, 3.78 (2s, 1.5, 1.5H), 4.55 (d with fine
couplings, J=10 Hz, 2H), 4.87–5.05 (m, 2H), 5.49–5.58 (m, 1H),
6.80, 6.81 (2d with fine couplings, J=9, 9 Hz, 2H), 7.06, 7.09 (2d
with fine couplings, J=9, 9 Hz, 2H), 7.43–7.51 (m, 1H), 7.84 (ddt,
J=3, 2, 8 Hz, 1H), 8.15 (t with fine couplings, J=8 Hz, 1H), 8.72–
8.84 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=19.6, 19.7 (+),
28.6, 33.1, 33.6, 36.4, 38.0, 45.8 (for 3C, À), 47.8, 48.4 (+), 51.6 (+),
55.12, 55.14 (+), 62.08, 62.13 (À), 111.60, 111.65 (À), 113.61, 113.64
(+), 116.0, 116.1 (+), 125.15, 125.17 (+), 127.10, 126.82 (+), 128.21,
128.28 (+), 136.95, 136.98 (+), 136.95, 137.00 (À), 145.4, 145.6 (À),
147.5, 147.6 (À), 148.37, 148.39 (À), 149.87, 149.90 (+), 157.8, 157.9
(À), 165.2, 165.3 ppm (À); HRMS (FAB): m/z: calcd for C24H27NO3 +
H+: 378.2069 [M+H+]; found: 378.2064.
3070, 1513, 1247, 1039, 826 cmÀ1 1H NMR (400 MHz, CDCl3): d=
;
0.94 and 0.97 (2t, J=8, 8 Hz, 1.5, 1.5H), 1.45–1.47 (m, 1H), 1.48 (s,
3H), 1.79–1.94 (m, 2H), 1.94–2.11 (m, 2H), 2.11–2.23 (m, 1H), 2.23–
2.37 (m, 1H), 2.37–2.56 (m, 2H), 2.71 (dd, J=11, 2 Hz, 1H), 3.77,
3.78 (2s, 1.5, 1.5H), 4.52 (brs, 1H), 4.55 (brs, 1H), 5.14, 5.18 (2t, J=
7, 7 Hz, 0.5, 0.5H), 6.79, 6.81 (2d, J=8, 8 Hz, 1, 1H), 7.06, 7.08 ppm
1-Methoxy-4-[(1S,2S,5R)-2-(prop-1-en-2-yl)-5-vinylcyclohexyl]-
benzene (16): MeMgBr (3.80 mL, 0.99m in THF, 3.76 mmol) was
added slowly to an ice-cold suspension of CuBr·Me2S (389 mg,
1.89 mmol) and ZnI2 (664 mg, 2.08 mmol) in THF (10 mL). The re-
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(2d, J=8, 8 Hz, 1, 1H); 13C NMR (100 MHz, CDCl3): d=14.9 (+), 19.8
(+), 20.5, 20.6 (À), 28.1 (À), 33.5, 34.2 (À), 36.5, 37.7 (À), 46.1 (À),
48.2, 48.9 (À), 51.96, 52.01 (+), 55.20 (+), 111.4 (À), 113.59, 113.63
(+), 124.25, 124.34 (+), 128.31, 128.34 (+), 137.6, 137.7 (À), 137.8
(À), 148.14, 148.17 (À), 157.75, 157.82 ppm (À); HRMS (FAB): m/z:
calcd for C19H26O+Na+: 293.1881 [M+Na+]; found: 293.1888.
[10] a) M. Watanabe, B. Z. Awen, M. Kato, J. Org. Chem. 1993, 58, 3923–
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[12] O. H. Oldenziel, D. van Leusen, A. M. van Leusen, J. Org. Chem. 1977, 42,
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[13] Aldol with MeCHO followed by elimination: a) Y. Hayashi, S. Orikasa, K.
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Acknowledgements
[14] Addition to vinyl sulfoxide followed by elimination: a) R. H. van
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This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Science, Sports, and Cul-
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[15] Addition to TMS acetylene/GaCl3: a) M. Yamaguchi, T. Tsukagoshi, M. Ari-
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Keywords: allylic substitution
copper · magnesium · synthesis design
·
asymmetric synthesis
·
[16] Addition to PhSeCH2CHO followed by elimination: a) D. L. J. Clive, C. G.
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[20] A. S. C. P. Rao, U. R. Nayak, S. Dev, Tetrahedron 1974, 30, 1107–1114.
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Received: September 7, 2013
Published online on November 22, 2013
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