Theoretical and experimental study of the absolute configuration of helical structure of (2R,3S)-Rubiginone A2 analog

Article abstract of DOI:10.1016/j.tet.2012.11.050

A novel analogue of (2R,3S)-Rubiginone A₂ was synthesized as a chiral helical model compound via an eight-step procedure (2.7% overall yield). Quantum methods, such as density functional theory (DFT) at different basis sets of 6-311+(d), 6-311+

Full text of DOI:10.1016/j.tet.2012.11.050

Tetrahedron 69 (2013) 1189e1194
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Theoretical and experimental study of the absolute configuration
of helical structure of (2R,3S)-Rubiginone A2 analog
,
c
,
,
b
,
,
a,b,
Bei-Dou Zhou a 1, Jie Ren a 1, Xin-Chun Liu c , Hua-Jie Zhu
*
*
a State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academic of Sciences, 132# Lanhei Rd., Kunming 650204, PR China
b College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002, PR China
c Graduate University of CAS, Beijing 100049, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2012
Received in revised form 4 November 2012
Accepted 13 November 2012
Available online 20 November 2012
A novel analogue of (2R,3S)-Rubiginone A2 was synthesized as a chiral helical model compound via an
eight-step procedure (2.7% overall yield). Quantum methods, such as density functional theory (DFT) at
different basis sets of 6-311þ(d), 6-311þþG(2d,p), were used to compute its optical rotation and elec-
tronic circular dichroism at the B3LYP/6-311þþG(2d,p) level in the gas phase and in solution using PCM
model, respectively. UV corrections were performed in electronic circular dichroism (ECD) simulations to
match the experimental ECD well. The suitable computational methods, e.g., B3LYP/6-311þþG(2d,p)//
B3LYP/6-311þþG(2d,p) in the gas phase using zero-point energy in Boltzmann statistics, were found
and suggested for optical rotation and circular dichroism computations that can be used for absolute
configuration determination of chiral helical compounds.
Keywords:
(2R,3S)-Rubiginone A2 analogue synthesis
Absolute configuration
DFT
Ó 2012 Elsevier Ltd. All rights reserved.
Optical rotation
Electronic circular dichroism
1. Introduction
form two major helical conformations (2A and 2B) and exist in
solution. The two conformations can exchange quickly due to the low
Determination of absolute configuration has been always a big
challenge in stereochemistry. Theoretical methods, such as quantum
tools used in calculations of specific optical rotation (OR) and elec-
tronic circular dichroism (ECD) have been used in the determination
of absolute configurations, and a great number of chiral compounds
have been well investigated via the methods.1 However, it has rarely
been well utilized in examining absolute configurations of chiral he-
lical structures, which are an important type of compounds. For ex-
transition state barrier and they cannot be detectable at room tem-
perature, this looks like that the two major conformations of cyclo-
hexane in solution. They have different relative energy. Therefore, the
two helical conformers have different contributions to the whole OR
and ECD both in theory and experiment.
2. Results and discussion
2
ample, (2R,3S)-Rubiginone A2 (1) and its novel analog 2 can form
helical conformations due to repulsive interaction between the two
carbonyl O atoms in solution. Nevertheless, helical structures gener-
ally exhibit remarkable bioactivities,2 which have attracted the many
researchers’ synthesis interests.3 Thus, it is of great importance to
systematically investigate the correlation of structures and their OR
andECD.Intheliterature,(2R,3S)-1was first reported withinteresting
antitumor activity. But for an economical and easy study, its novel
analog 2 was synthesized as a model molecule in the relationship
investigation. Since the repulsive force exists between the two O
atoms, the two O atoms cannot locate in the same plane. One O atom
must be back and another should be front of the paper. Thus, they
2.1. Synthesis of (2R,3S)-2
Absolute configurations of chiral centers may have partial ra-
cemization under some reaction conditions in totally synthetic
procedure. Although chiral catalysts have been widely employed to
construct chiral centers, it was also reported that the same ligand
might lead different configuration formation when different sub-
strates were used.4 Thus, the best way is to use chiral building
blocks whose chiral centers can be preserved during the trans-
formation. Based on this consideration, the commercially available
(2R,5R)-(þ)-dihydrocarvone 3 was employed as the enantiopure
starting material (Fig. 1) for the synthesis of (2R,3S)-2.
In an early synthetic scheme, we tried to synthesize (R)-6-
methylcyclohex-2-enone 4 from 2-cyclohexen-1-one with assis-
tance of chiral auxiliary reagent. In practice, 4 was synthesized from
(2R,5R)-(þ)-dihydrocarvone 3 directly. Ozonolysis of 3 in methanol
* Correspondingauthors. Tel./fax:þ86 312 5994812/8715216179; e-mail addresses:
zhuhuajie@hotmail.com, hjzhu@mail.kib.ac.cn (H.-J. Zhu).
1
These authors contributed equally to this work.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.050

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B.-D. Zhou et al. / Tetrahedron 69 (2013) 1189e1194
1
Repulsive
2
3
O
O
O
O
O
O
12
3a
10
7
O
O
9
8
11
6
OH
OH
OH
OH
4
6a
5a
5
OMeO
Rubiginone A2, 1
O
O
O
(2R,3S)-2
2A
2B
Fig. 1. The synthetic route to (2R,3S)-2.
and subsequent treatment with Cu(OAc)2/FeSO4 resulted in cyclic
The NOE between H-2 and H-3 was not observed and this exhibited
the two protons are trans-position. Since C-2 has R configuration,
therefore, it has an S configuration on C-OH (C-3). Thus, the obtained
product had (2R,3S) configuration. If it has (2R,3R) absolute config-
uration, its OR should be negative based on the OR of ꢀ106 in
chloroform for (2R,3R)-SNA-8073-B, which has the same planar
structure as (2R,3S)-Rubiginone A2 except for stereochemistry.12
a,b
-unsaturated enone 4 in 42% yield.5 In the step, ozone should be
kept in appropriate flow and flushed away at ꢀ78 ꢁC at the end of
oxidation. a
-Iodination of enone 4 gave iodoenone 5 in 67%yield.6 As
the catalyst, 1.5 N pyridine was enough. Palladium-catalyzed cross
coupling under Negishi conditions afforded ketodienes 6 in 68%
yield.7 ZnBr2 was very useful in the step. Grignard reagent did not
attack carbonyl group after reactionwith ZnBr2, so carbonyl group in
5 was unnecessary to be protected. However, it was very critical to
dry the ZnBr2 because of its humidity. Starting from ketodienes 6,
Luche reduction (NaBH4/CeCl3) afforded enol 7 in 62% yield.8 Its
absolute configuration was assigned after final product 2 was ob-
tained and used in ROESY experiments. The methoxymethyloxy
(OMOM) derivative 8 was obtained from enol 7 in 77% by reaction
with methyl chloromethyl ether (MOMCl) and diisopropylethyl-
amine (DIPEA).9 What is more, it can endure basic reagent and ox-
idant in the following reaction. So it is suitable toprotect the hydroxy
in enol 7. Treatment of methoxymethyloxy derivative 8 with 2-
bromonaphthalene-1,4-dione at 80 ꢁC in toluene afforded the
cycloadduct, which was immediately subjected tothe aromatization
reaction with K2CO3 in MeOH to provide dione 9 in a yield of 40%.
Subsequent photooxygenation of dione 9 afforded the trione 10 in
85% yield.10 In the photo-oxidation reaction, ethyl acetate was used
as a solvent. Chloroform or dichloromethane may afford haloge-
nated by-product, and benzene is a toxic solvent. Hydrolysis of tri-
one 10 in the presence of aqueous hydrochloric acid (3 N) in alcohol
afforded 2 in 88% yield.11 2.7% of overall yield was achieved via the
eightsteps reaction. The purityof thefinal productwas examinedvia
HPLCusing mixtureof waterand acetonitrile (35/65)at the flow-rate
of 1 mL/min. The pure product was then used in ROESYexperiments.
OR of (2R,3S)-2 was measured in two solvents (½a D
ꢂ
20, þ75 (c 0.5,
chloroform) or þ82 (c 0.5, methanol)), and its ECD spectra were de-
termined in methanol. The effect of methanol on its ECD used here is
investigated. The ECD is illustrated in Fig. 2. To confirm that the loss of
MOM group from 10 to 2 under strong acidic condition did not result
in the configuration change of C-3, the OR and ECD of 10 were mea-
sured.TherecordedORof10 was þ235(c1.0, chloroform). Inaddition,
the recorded ECD of 10 in methanol seemed the same as that of 2
(Fig. 2, superimposed CDs). Both ECDs had the positive Cotton effects
at about 210, 269, and 331 nm, respectively, and a negative Cotton
effect at 230 nm. These results indicated that both 2 and 10 had the
sameabsoluteconfigurationsonC-2andC-3,namely(2R,3S).Itmeant
that the configurations of C-3 and C-2 were kept unchanged in the
conversion of 10 to 2 under the condition of refluxing in 3 N HCl.
2.2. OR computational methods
The conformational searches were performed by using
MMFF94S force field. Totally ten free conformations were found
(Fig. 3). The ten conformations were then optimized at the B3LYP/6-
31G(d), B3LYP/6-31þG(d,p), and B3LYP/6-311þþG(2d,p) levels in
the gas phase, respectively.13 Only the geometries obtained at the
B3LYP/6-311þþG(2d,p) level were illustrated in Fig. 3. Their

B.-D. Zhou et al. / Tetrahedron 69 (2013) 1189e1194
1191
D
D
D
C
C
B
C
C
A
10
10
5
4
2
5
0
0
0
-5
-5
Exp. for 10 (pink)
Exp. for 2 (blue)
-2
-10
-10
Exp. for 2
Exp. for 10
-4
200
300
400
200
300
400
200
300
400
Wavelength (nm)
Wavelength (nm)
Wavelength (nm)
Fig. 2. The recorded ECDs for (2R,3S)-2 (A), (2R,3S)-10 (B) measured in MeOH and their superimpose ECD (C). Effect of MeOH on ECD was considered here.
effect of chloroform on OR values, all ten conformations were fur-
ther optimized at the B3LYP/6-311þG(d) level by using PCM model.
The OR data were computed at the B3LYP/6-311þþG(2d,p) level in
the gas phase ([a] g) and in chloroform ([a]Dl), respectively. All of
D
the ORs for (2R,3S)-2 are summarized in Table 1.
Table 1
The OR values using four quantum methods
Optimization in the gas phase
Optimization in solution
e
f
g
h
i
j
[a
]
[
a
]
D
[
a
]
D
[a
]
[
a
]
Dg
[a]
Dl
DE
z-p
Gibbs
Dsp
Method 1a þ57.3 þ55.1
Method 2b þ40.6 þ97.5
Method 3c þ37.0 þ91.4
þ111.9
þ129.9
þ202.3
d
ꢀ20.2
ꢀ21.5
ꢀ25.6
d
d
d
d
d
d
d
Method 4d
d
d
þ19.8
ꢀ9.0
a
B3LYP/6-311þþG(2d,p)//B3LYP/6-31G(d).
b
c
d
e
f
B3LYP/6-311þþG(2d,p)//B3LYP/6-31þG(d,p).
B3LYP/6-311þþG(2d,p)//B3LYP/6-311þþG(2d,p).
B3LYP/6-311þþG(2d,p)//PCM/B3LYP/6-311þG(d).
Using total energy in OR in computations.
Using zero-point energy.
g
h
i
Using free energy.
Using SPE.
Performed in the gas phase.
j
Performed in CHCl3.
The OR data predicted in the gas phase had correct positive sign.
Most of the predicted OR values were from þ41 to þ129. The closest
predicted OR value was þ91.4 by using the ZPE in method 3. Un-
fortunately, the ORs obtained by using the SPE in chloroform were
negative (from ꢀ20.2 to ꢀ25.6) in all three methods. It seems that the
use of SPE corrections in chloroform is not suitable for OR predictions
forthe chiralhelical structures. Atthe same time, itwasfoundthatthe
method 4, PCM/B3LYP/6-311þþG(2d,p)//PCM/B3LYP/6-311þG(d),
could not provide correct OR predictions for the helical chiral com-
pound, for example, the predicted OR was ꢀ9.0. Based on the results,
the best method for the OR prediction on helical structures should be
methods 1, 2, and 3 in the gas phase by using ZPE.
2.3. ECD computational methods
Fig. 3. The ten conformations obtained at the B3LYP/6-311þþG(2d,p) level and their
Encouraged by the close predictions with method 3 in the gas
phase, the ECDs for (2R,3S)-2 were computed at the B3LYP/6-
311þþG(2d,p) level by using the conformations obtained at the
B3LYP/6-311þþG(2d,p) level.14 The TEE data were used in ECD
simulations. Unexpectedly, it seemed that the predicted ECD curve
of 2 had different configuration from the expected (2R,3S) (see the
superimposed plot in Fig. 4b). Actually, the synthesized 2 should
have the absolute configuration of (2R,3S). Therefore, the method
used herein may not be suitable for predictions on the absolute
configuration of helical structures.
relative Gibbs free energy data (kcal/mol).
relative Gibbs free energy (GFE) data were also summarized below
the structures, respectively. The optical rotations were then calcu-
lated for the ten conformers at the B3LYP/6-311þþG(2d,p) level in
the gas phase. Total electronic energy (TEE) were used in OR
computations ([
([ Gibbs). Zero-point energy corrections were also used in OR
prediction ([
the B3LYP/aug-cc-pVDZ level in chloroform by using PCM model
was used in OR computations ([ sp). To further investigate the
a] E). GFE data were also used in OR calculations
D
a
]
D
a] z-p). Then, the single point energy (SPE) obtained at
D
Alternatively, GFE and ZPE (vibrational corrections) were used in
ECD simulations again (Fig. 5). In both cases, the simulations were
a
]
D

1192
B.-D. Zhou et al. / Tetrahedron 69 (2013) 1189e1194
could predict the relatively correct OR values by using TEE and ZPE
data. Thismethod canpredict ECD well, especiallyusingGFEafter UV
corrections. However, using SPE to predict OR magnitudes may lead
wrong conclusion. Wrong ECD prediction may happen if using TEE.
3. Experimental section
3.1. General methods
Experiments,whichrequired aninertatmospherewerecarriedout
under argon. Melting points were obtained on a micro melting point
apparatus and are uncorrected. 1H and 13C NMR spectra were de-
termined in CDCl3 at 400 MHz for 1H and 100 MHz for 13C or 500 MHz
for 1H and 125 MHz for 13C. IR spectra were recorded with KBr pellets.
Optical rotations were determined on a polarimeter. High resolution
mass (HRMS) data were recorded via a positive ion electrospray or
electron impact mass spectrometry using a time-of-flight analyzer.
Silica gel (200e300 mesh) was used for flash column chroma-
tography. Tetrahydrofuran and toluene were dried over sodium
metal under argon. Other reagents and solvents were used directly
if not otherwise specifics.
Fig. 4. Comparison of the experimental ECD with the computed ECD using total
electronic energy in simulations.
3.2. Synthetic details and characterization
Fig. 5. The simulated ECD for (2R,3S)-2 using zero-point energy and Gibbs free energy
without UV corrections (A) and with UV corrections (B).
3.2.1. (R)-6-Methylcyclohex-2-enone (4). To a solution of (2R,5R)-
(þ)-dihydrocarvone 3 (2.0 g,13.6 mmol) in methanol(40 mL), cooled
at ꢀ78 ꢁC, was introduced a steam of ozone till a blue color persisted.
Thenthe solutionwas flushed with oxygen till the colordisappeared.
The reaction mixture was then allowed to warm to ꢀ20 ꢁC, and
copper (II) acetate monohydrate (3.3 g, 16.5 mmol, 1.2 equiv) was
added. FeSO4$7H2O (4.6 g, 16.5 mmol, 1.2 equiv) was added 10 min
later. The greensolutionwas maintained at ꢀ20 ꢁC for 3 h and then at
room temperature for 3 h. After the addition of water (80 mL), the
solutionwas extracted with ether (5ꢃ25 mL). The combined organic
layers werethenwashed with an aqueous saturated Na2CO3 solution
(5ꢃ12 mL) and brine (3ꢃ10 mL), and finally dried over anhydrous
Na2SO4. After filtration the solvent was removed by rotatory evap-
oration and the crude product was purified by flash column chro-
matography with acetone/petroleum ether (1:40 v/v) to give
compound 4 as a light yellow oil (0.62 g, 42%). Rf¼0.38 (1:10, ethyl
close to the experimental results. Red-shifts were observed in the
simulated ECDs. For example, the positive Cotton effects at 210,
269, and 331 nm in experiments moved to 212, 294, and near
340 nm in simulations with ZPE, and 216, 288, and 338 nm with
GFE, respectively. After UV correction, the simulated ECD was closer
to the experimental ECD (Fig. 5B). The results revealed that more
reasonable predictions on ECD of chiral helical structures could be
obtained by using GFE in its ECD simulations.
Finally, the B3LYP/6-31þG(d,p)-optimized in the gas phase and
the B3LYP/6-311þG(d)-optimized geometries in chloroform were
employed further in ECD computations at the B3LYP/6-
311þþG(2d,p) level, respectively. The simulated ECD spectra were
illustrated in Fig. 6. It was found that both of the simulated ECDs did
not match the experimental results well. Large red-shifts were
found, especially when the B3LYP/6-31þG(d,p)-optimized geome-
tries were used in ECD computations (Fig. 6(A)), even if the UV
corrections were performed, the differences are still large and they
were not illustrated here.
acetate/petroleum ether); ½a D20
ꢂ
þ103 (c 1.0, CH2Cl2); IR (KBr) nmax
1.13 (3H, d,
3070, 2960, 2873,1729 cmꢀ1; 1H NMR (CDCl3, 500 MHz)
d
J¼6.8 Hz, CH3), 1.69e1.79 (1H, m, H-5), 2.04e2.08 (1H, m, H-5),
2.36e2.42 (3H, m, 2 H-4 and H-6), 5.98 (1H, td, J2,3¼10 Hz,
4J2,4¼1.9 Hz, H-2), 6.92 (1H, m, J2,3¼10 Hz, J3,4¼3.8 Hz, H-3). 13C NMR
A
B
(CDCl3, 125 MHz)
d 15.0, 25.5, 30.8, 41.6, 129.3, 149.7, 202.4; HRMS
6
4
(ESI) m/z calcd for C7H10ONa [MþNa]þ 133.0624, found 133.0635.
4
2
0
2
0
3.2.2. (R)-2-Iodo-6-methylcyclohex-2-enone (5). To an ice-cold so-
lution of enone 4 (1.0 g, 9.1 mmol) in CH2Cl2 (25 mL) and pyridine
(2 mL) was added solid I2 (3.0 g, 11.8 mmol) gradually. Upon com-
pletion, the mixture was stirred 3 h at room temperature. Then it
was diluted with Et2O and H2O. The organic layer was separated,
and the aqueous layer was extracted with Et2O twice. The com-
bined organic layers were washed with an aqueous saturated
Na2S2O3 solution, 2 M HCl (4ꢃ12 mL), brine (3ꢃ10 mL), and then
dried (Na2SO4). The solution was concentrated and the crude
product was purified by flash column chromatography with ethyl
acetate/petroleum ether (1:40, v/v) to give compound 5 as a yellow
viscous oil (1.44 g, 67%). Rf¼0.46 (1:10 ethyl acetate/petroleum
-2
-4
-2
-4
200
Exp ECD;
300
400
200
300
400
Wavelength (nm)
Wavelength(nm)
Calcd using TEE;
Calcd using ZPE.
Calcd using GFE;
Fig. 6. The computed ECD spectra at the B3LYP/6-311þþG(2d,p) level using B3LYP/6-
31þG(d,p)-optimized geometries in the gas phase (A) and B3LYP/6-311þG(d)-
optimized conformers in CHCl3 using PCM model (B).
ether); ½a 2D0
þ54.3 (c 1.0, ethyl acetate); IR (KBr) nmax 2928, 1725,
ꢂ
2.4. Conclusion
1687, 513 cmꢀ1; 1H NMR (CDCl3, 500 MHz)
d
1.21 (3H, d, J¼6.8 Hz,
Based on the comparison of the three methods, it was found that
the method of B3LYP/6-311þþG(2d,p)//B3LYP/6-311þþG(2d,p)
CH3), 1.78e1.88 (1H, m, H-5), 2.10e2.15 (1H, m, H-5), 2.45e2.63
(3H, m, 2 H-4 and H-6), 7.70e7.73 (1H, m, H-3); 13C NMR (CDCl3,

B.-D. Zhou et al. / Tetrahedron 69 (2013) 1189e1194
1193
125 MHz)
d
15.9, 29.5, 30.6, 41.5, 103.7, 158.5, 195.0; HRMS (EI) m/z
96.4, 111.2, 132.2, 138.5; HRMS (EI) m/z calcd for C11H18O2 [M]þ
182.1307, found 182.1302.
calcd for C7H9IO [M]þ 235.9698, found 235.9704.
3.2.3. (R)-6-Methyl-2-vinylcyclohex-2-enone (6). ZnBr2 was heated
at150ꢁC invacuum forhalfanhour. Thedried ZnBr2 (3.6g,15.8 mmol,
2.2 equiv) was dissolved in distilled THF (15 mL) under argon. The
solution was cooled to ꢀ30 ꢁC, then vinylmagnesium bromide
(15.8 mL, 2.2 equiv 1.0 M in THF) was added and the reaction tem-
perature was raised to room temperature about 15 min. In other flask,
a mixture of enone 5 (1.7 g, 7.2 mmol) and tetrakis (triphenylphos-
phine) palladium (0.35 mol %) was dissolved in distilled THF (8 mL)
under argon. The mixture of Grignard solution and ZnBr2 was added
to it at room temperature. Upon completion, an aqueous saturated
NH4Cl solution was added to quench the reaction at 0 ꢁC. Ether
(40 mL) was added to the mixture, and the organic layer was washed
with an aqueous saturated NH4Cl solution (3ꢃ10 mL), brine
(3ꢃ10 mL), and then dried (Na2SO4). The crude product was purified
by flash column chromatography with acetone/petroleum ether
(1:50 v/v) to give compound 6 as a light yellow oil (0.66 g, 68%).
3.2.6. (3R,4S)-4-(Methoxymethoxy)-3-methyl-1,2,3,4-tetrahydro-
tetraphene-7,12-dione (9). A solution of 2-bromonaphthalene-1,4-
dione (0.16 g, 0.66 mmol) and diene 8 (0.10 g, 0.55 mmol) in freshly
distilled toluene (8 mL) was stirred under argon at 80 ꢁC for 12 h
followed at 100 ꢁC for 2 h. After the solvent was removed invacuo, the
crude DielseAlder adduct was dissolved in MeOH (10 mL), treated
with solid K2CO3 (0.23 g, 1.7 mmol), and stirred at 64 ꢁC for 1 h. The
solvent was removed invacuo, treated with water, and extracted with
CHCl3. The organic layer was washed with brine, dried (Na2SO4),
concentrated, and purified by flash column chromatography with
ethyl acetate/petroleum ether (1:30, v/v) to give compound 9 as
a yellow solid (74 mg, 40%). Rf¼0.53 (1:10 ethyl acetate/petroleum
ether); ½a 2D0
ꢂ
þ79.5(c 1.0, ethyl acetate); mp: 175e177 ꢁC; IR (KBr) nmax
3071, 2927, 2854,1707,1671,1588,1306,1272,1037, 717cmꢀ1;1HNMR
(CDCl3, 400 MHz)
d
1.11 (3H, d, J¼6.8 Hz, CH3),1.85e1.86 (1H, m, H-2),
1.92e1.96 (1H, m, H-2), 2.11e2.15 (1H, m, H-3), 3.31e3.38 (1H, m, H-
1), 3.42(3H, s, CH3O), 3.58e3.65(1H, m, H-1), 4.65 (1H, d, J¼3.3 Hz, H-
4), 4.75e4.83 (2H, dd, J¼6.9 and 25.6 Hz), 7.73e7.85 (3H, m),
Rf¼0.58 (1:10 ethyl acetate/petroleum ether); ½a D20
ꢂ
þ48.0 (c 1.0,
CH2Cl2); IR (KBr) nmax 2925, 2854, 1630, 1549, 588 cmꢀ1
;
1H NMR
(CDCl3, 500 MHz)
d
1.15 (3H, d, J¼6.8 Hz, CH3),1.69e1.79 (1H, m, H-5),
8.23e8.27 (3H, m); 13C NMR (CDCl3, 100 MHz)
d 15.9, 25.4, 28.0, 31.7,
2.04e2.10 (1H, m, H-5), 2.38e2.48 (3H, m, 2H-4 and H-6), 5.14 (1H, d,
J¼11.3 Hz, H-20),5.64(1H, d,J¼17.6 Hz, H-20),6.51e6.56(1H,dd, J¼11.3
and 17.7 Hz, H-10), 6.97 (1H, t, J¼4.5 Hz, H-3); 13C NMR (CDCl3,
56.0, 60.7, 95.8, 125.4, 126.7, 127.5, 131.3, 132.7, 133.6, 134.4, 134.8,
135.3, 135.4, 141.9, 144.3, 183.9, 185.7; HRMS (EI) m/z calcd for
C
21H20O4 [M]þ 336.1362, found 336.1357.
125 MHz) d 16.6, 27.0, 32.1, 43.4,117.0,130.8,133.0,145.8,151.2; HRMS
(EI) m/z calcd for C9H12O [M]þ 136.0888, found 136.0877.
3.2.7. (2R,3S)-10. Following the procedure for photooxygenation,
a solution of dione 9 (36 mg, 0.11 mmol) in ethyl acetate (10 mL) was
irradiated witha150Whalogenlamp underanatmosphereofoxygen
for 48 h. Solvent was removed in vacuo and then the residue was
purified by flash column chromatography with ethyl acetate/petro-
leum ether (1:10 v/v) to give compound 10 as a yellow solid (32 mg,
85%). Rf¼0.38 (1:3 ethyl acetate/petroleum ether); mp: 181e183 ꢁC;
3.2.4. (1S,6R)-6-Methyl-2-vinylcyclohex-2-enol (7). To an ice-cold
solution of enone 6 (0.55 g, 4.0 mmol) and CeCl3$7H2O (15 mg,
0.04 mmol) in 12 mL of MeOH solid NaBH4 (167 mg, 4.4 mmol) were
added in small portions over 10 min. After the mixture was stirred at
room temperature for 5 min, Et2O and H2O were added to it. The or-
ganic layer was separated, and the aqueous layer was extracted with
Et2O three times. The combined organic layers were washed with
brine and dried over anhydrous Na2SO4. The crude product was pu-
rified by flash column chromatography with ethyl acetate/petroleum
ether (1:30, v/v) to give compound 7 as a light yellow oil (0.35 g, 62%).
½
a 2D0
ꢂ
þ215 (c 1.0, ethyl acetate), or þ235 (c 1.0, chloroform); IR (KBr)
nmax 3072, 2927, 1777, 1706, 1675, 1640, 1591, 1324, 1281, 1031,
713 cmꢀ1 1H NMR (CDCl3, 400 MHz)
;
d
1.28 (3H, d, J¼6.7 Hz, CH3),
2.58e2.63 (1H, m), 2.71e2.77 (1H, dd, J¼9.4 and 17.4 Hz), 3.00e3.07
(1H, dd, J¼7.7 and 17.4 Hz), 3.39 (3H, s, CH3O), 4.55 (1H, d, J¼6.9 Hz),
4.61 (2H, d, J¼8.1 Hz), 7.74 (1H, d, J¼7.9 Hz), 7.79e7.83 (2H, m), 8.20
(1H, d, J¼8.3Hz), 8.26(1H, d,J¼8.6Hz), 8.39(1H, d,J¼7.9 Hz); 13CNMR
Rf¼0.39 (1:10 ethyl acetate/petroleum ether); ½a D20
þ138 (c 1.0, ethyl
ꢂ
acetate); IR (KBr) nmax 3426, 3073, 3028, 2926, 1640, 1629 cmꢀ1; 1H
NMR (CDCl3, 400 MHz)
d
1.10 (3H, d, J¼6.8 Hz, CH3),1.43e1.53 (4H, m),
(CDCl3, 100 MHz) d 17.1, 33.8, 42.0, 55.6, 75.3, 94.5, 126.9, 127.4, 129.1,
2.15e2.21 (2H, m), 4.25 (1H, s, H-1), 5.03 (1H, d, J¼10.9 Hz, H-20), 5.39
132.6, 133.8, 134.5, 134.9, 136.6, 148.2, 182.2, 198.9, 204.3; HRMS (EI)
(1H, d, J¼17.6 Hz, H-20), 5.85 (1H, t, J¼4.1 Hz, H-3) 6.27e6.34 (1H, dd,
m/z calcd for C21H18O5 [M]þ 350.1154, found 350.1153.
J¼10.9 and 17.7 Hz, H-10); 13C NMR (CDCl3,100 MHz)
d 17.4, 23.9, 26.5,
34.0, 66.3, 111.2, 132.3, 137.9, 138.2; HRMS (EI) m/z calcd for C9H14
O
3.2.8. (2R,3S)-2. A solution of trione 10 (30 mg, 0.1 mmol) in 4 mL
of alcohol was added 3 N HCl solution, then it was refluxed until
reactant disappeared (TLC monitoring). Solvent was removed in
vacuo and then residue was purified by flash column chromatog-
raphy to afford compound 2 as a yellow solid (23 mg, 88%). Rf¼0.10
(1:3 ethyl acetate/petroleum ether). Its purity was checked by HPLC
[M]þ 138.1045, found 138.1041.
3.2.5. (5R,6S)-6-(Methoxymethoxy)-5-methyl-1-vinylcyclohex-1-ene
(8). To a solution of the enol 7 (0.33 g, 2.4 mmol) and a catalytic
amount of DMAP in 10 mL of CH2Cl2, were added 0.83 mL
(4.8 mmol) of DIPEA and 0.55 mL (7.2 mmol) of MOMCl. The mix-
ture was stirred at room temperature for 4 h. A cold aqueous sat-
urated NaHCO3 solution was added to quench the reaction. Then, it
was diluted with Et2O and H2O. The organic layer was separated,
and the aqueous layer was extracted with Et2O three times. The
combined organic layers were washed with brine and dried over
anhydrous Na2SO4. The crude product was purified by flash column
chromatography with ethyl acetate/petroleum ether (1:50, v/v) to
give compound 8 as a light yellow oil (0.33 g, 77%). Rf¼0.55 (1:30
as 98%. Mp: 172e174 ꢁC; ½a D20
þ75.3 (c 0.5, chloroform); IR (KBr)
ꢂ
nmax 3678, 3440, 3073, 2925, 1699, 1673, 1640, 1591, 1326, 1285,
714 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d
1.23 (3H, d, J¼6.9 Hz, CH3),
2.13 (1H, d, J¼3.0 Hz, OH), 2.55e2.63 (1H, m), 2.79e2.85 (1H, dd,
J¼8.6 and 16.8 Hz), 2.94e3.00 (1H, dd, J¼6.8 and 16.8 Hz), 4.83 (1H,
s), 7.77 (1H, d, J¼8.1 Hz), 7.79e7.81 (2H, m), 8.18 (1H, d, J¼6.8 Hz),
8.25 (1H, d, J¼8.8 Hz), 8.39 (1H, d, J¼8.0 Hz); 13C NMR (CDCl3,
100 MHz)
d 16.6, 35.1, 42.5, 71.8, 127.2, 127.6, 130.2, 132.0, 132.7,
134.1, 134.8, 135.1, 135.2, 135.6, 135.9, 150.1, 182.5, 183.7, 198.8;
ethyl acetate/petroleum ether); ½a D20
ꢂ
þ94.3 (c 1.0, ethyl acetate); IR
HRMS (EI) m/z calcd for C19H14O4 [M]þ 306.0892, found 306.0894.
(KBr) nmax 2925, 1639, 1629, 1037 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d
1.08 (3H, d, J¼6.1 Hz, CH3), 1.26e1.69 (3H, m), 2.18e2.31 (2H, m),
3.36 (3H, s, CH3O), 4.21 (1H, s, H-6), 4.70e4.76 (2H, dd, J¼6.8 and
17.5 Hz), 4.99 (1H, d, J¼11.1 Hz, H-20), 5.44 (1H, d, J¼17.6 Hz, H-20),
5.91 (1H, t, J¼3.8 Hz, H-2), 6.31e6.38 (1H, dd, J¼11.1 and 17.6 Hz, H-
Acknowledgements
H.J.Z. thanks the financial support from NSFC (30873141), 973
Program (2009CB522300), and Hebei University. The Super-
10); 13C NMR (CDCl3, 100 MHz)
d
18.2, 24.2, 26.1, 34.0, 55.6, 71.8,

1194
B.-D. Zhou et al. / Tetrahedron 69 (2013) 1189e1194
4. (a) White, J. D.; Shaw, S. Org. Lett. 2011, 13, 2488e2491; (b) Bai, B.; Shen, L.; Ren,
J.; Zhu, H. J. Adv. Synth. Catal. 2012, 354, 354e358.
Computational-Centers in CAS (in KIB and in QDIO) are appreciated
for the computation supports.
5. For straightforward synthesis of (R)-6-methylcyclohex-2-enone, see: (a)
ꢀ
Solladie, G.; Hutt, J. J. Org. Chem. 1987, 52, 3560e3566; (b) Schreiber, S. L.
J. Am. Chem. Soc. 1980, 102, 6163e6165.
6. (a) Scott, T. L.; Soderberg, B. C. G. Tetrahedron 2003, 59, 6323e6332; (b) Negishi,
Supplementary data
ꢁ
E.-I.; Tan, Z.; Liou, S.-Y.; Liao, B. Q. Tetrahedron 2000, 56, 10197e10207.
NMR spectra for all compounds, computed OR, ECD for (2R,3S)-2
and ECD for (2R,3S)-10. This material is available free of charge.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.11.050.
ꢀ
7. Barriault, L.; Thomas, J. D. O.; Clement, R. J. Org. Chem. 2003, 68, 2317e2323.
ꢂ
8. Carreno, M. C.; Urbano, A.; Vitta, C. D. J. Org. Chem. 1998, 63, 8320e8330.
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