A stereoselective approach to bioactive secolignans: Synthesis of peperomin C and its analogues

Article abstract of DOI:10.1016/j.tet.2014.07.101

A stereoselective approach to secolignans is described. The key synthetic strategy involves an asymmetric aldol reaction to control the creation of the stereogenic center at the β-carbon of the target secolignans. In the present work, peperomin C and its analogues, i.e., 2,6-didehydropeperomin C and 2-epi-peperomin C were successfully synthesized in good yields with high stereoselectivities.

Full text of DOI:10.1016/j.tet.2014.07.101

Tetrahedron 70 (2014) 7577e7583
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A stereoselective approach to bioactive secolignans: synthesis of
peperomin C and its analogues
*
Darunee Soorukram , Jaray Panmuang, Patoomratana Tuchinda, Chutima Kuhakarn,
Vichai Reutrakul, Manat Pohmakotr
Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Rama VI Road,
Bangkok 10400, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 April 2014
Received in revised form 16 July 2014
Accepted 29 July 2014
Available online 4 August 2014
A stereoselective approach to secolignans is described. The key synthetic strategy involves an asym-
metric aldol reaction to control the creation of the stereogenic center at the b-carbon of the target se-
colignans. In the present work, peperomin C and its analogues, i.e., 2,6-didehydropeperomin C and 2-epi-
peperomin C were successfully synthesized in good yields with high stereoselectivities.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Secolignans
Peperomins
Asymmetric aldol reaction
1. Introduction
Secolignan is a subclass of lignans1 found in various plants that
have widely been used in Chinese folk medicine. Among those,
secolignans, namely peperomins A, B, C, D, and E (Fig. 1) are the
well-known representatives.2 Peperomin-type secolignans show
a broad range of potent biological activities. For example, peper-
omins AeD, the
found to exhibit antitumor,2d anti-HIV-1,2e and anti-angiogenic2f
activities. Peperomin E and 2,6-didehydropeperomin B, the
methylene- -butyrolactone derivatives, show inhibitory effects on
the growth of cancer cell lines2c and anti-inflammatory activity.2l In
addition, among a variety of peperomins, those containing an
a-methyl-g-butyrolactone derivatives, have been
a
-
g
a
-
methylene moiety, such as peperomin E and secolignan 1, exhibit
inhibitory activity against the liver tumor cell.2d To date, a variety of
bioactive peperomin-type secolignans, varying in the aromatic
groups at C-5, the
eCH2O-sugar), and relative orientation of the substituents at the
and -positions, have been reported. These include secolignans 2
and 3 bearing a rare 2,3-cis configuration.3
a-substituents (e.g., eCH2OH, eCH2OR, and
a
-
b
Due to their broad range of biological activities, peperomin-type
secolignans have received considerable attention for further de-
velopment as potential chemotherapeutic agents.4 Having taken
the importance of structureeactivity relationship (SAR) study into
Fig. 1. Selected representatives of peperomin-type secolignans.
account, we therefore aim toward the investigation on the de-
velopment of a stereoselective methodology that would allow
a practical synthesis of naturally occurring secolignans and their
derivatives.5 Herein, we wish to report our synthetic approach
* Corresponding author. Tel.: þ66 2201 5148; fax: þ66 2354 7151; e-mail ad-
dress: darunee.soo@mahidol.ac.th (D. Soorukram).
http://dx.doi.org/10.1016/j.tet.2014.07.101
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

7578
D. Soorukram et al. / Tetrahedron 70 (2014) 7577e7583
leading to the stereoselective synthesis of 2,3-trans, 2,3-cis, and
methylene peperomin-type secolignans.
a
-
Our synthesis began with the synthesis of compound 8.7 Based
on the procedure reported by Evans,8 compound 8 was treated with
4-(benzyloxy)-3,5-dimethoxybenzaldehyde (Ar1CHO)9 in the
€
presence of dibutylboron triflate (Bu2BOTf) (1.1 equiv) and Hunig’s
2. Results and discussion
base (i-Pr2NEt) (1.2 equiv) in dry CH2Cl2 at ꢀ78 ꢁC for 6 h (Scheme
2). Diastereoselective alkylation of the boron enolate derived from
compound 8 with aldehyde, Ar1CHO, proceeded with high dia-
stereoselectivity (>99% dr, 400 MHz 1H NMR analysis). The desired
Evans’ syn product 910 was obtained in 88% yield as a single di-
astereomer as determined by 1H and 13C NMR analyses after
chromatographic purification (see Supplementary data). Next, the
conversion of the Evans’ syn product 9 into a chiral ketone 11 was
investigated. Thus, reductive cleavage of compound 9 upon treat-
Our synthetic approach is outlined in Scheme 1. We planned to
use a chiral oxazolidinone auxiliary (Evans chiral auxiliary)6 in an
asymmetric aldol reaction as a key step to synthesize and control
the creation of the stereocenter at an
tone of type 4. The chiral intermediate 4 can be converted into 2,3-
trans, 2,3-cis as well as -methylene secolignans via a chiral
butyrolactone 5 (Scheme 1). Here we report on stereoselective
synthesis of peperomin and its analogues, 2,6-
a-carbon of a chiral aryl ke-
a
g-
C
11
ment with LiBH4 in THF at 0 ꢁC for 1 h gave diol 10 (93% yield) and
didehydropeperomin C (6) and 2-epi-peperomin C (7) (Scheme 2).
the recovered oxazolidinone auxiliary (87% yield). Selective pro-
tection of a primary alcohol moiety of diol 10 was achieved in high
yield and selectivity by treatment of the diol 10 with tert-butyldi-
methylsilyl chloride (TBSCl) in the presence of 4-N,N-dimethyla-
minopyridine (DMAP) and Et3N in anhydrous CH2Cl2 at room
temperature for 3 h.12 The corresponding mono-TBS-protected al-
cohol was obtained in 92% yield. Subsequent benzylic oxidation
using MnO2 provided the desired chiral ketone 11 in 84% yield.
Having successfully been prepared, the chiral ketone 11 was
employed as a key substrate for further manipulation directed the
synthesis of peperomin C and its analogues 6 and 7. Thus, treatment
of ketone 11 with [4-(benzyloxy)-3,5-dimethoxyphenyl]lithium
(12) in THF at ꢀ78 ꢁC for 1 h gave the corresponding diaryl alcohol
13 (78% yield). Subsequent reductive deoxygenation of the diaryl
alcohol 13 was accomplished by treatment of 13 with Et3SiH and
BF3$Et2O in anhydrous CH2Cl2 at ꢀ20 ꢁC for 5 min followed by
removal of the TBS ether by using TBAF providing the required al-
cohol 14 (84% yield, two steps). Conversion of the alcohol 14 to
chiral g-butyrolactone 16 was achieved by a two-step reaction in-
volving oxidative cleavage of the terminal alkene moiety of 14
followed by successive oxidation. After examining optimal condi-
tions, it was found that treatment of 14 with OsO4 (5 mol %), N-
Scheme 1. Synthetic plan to synthesize chiral aryl ketone 4 as a key synthetic in-
termediate leading to secolignans.
Scheme 2. A stereoselective synthesis of peperomin C and its analogues 6 and 7.

D. Soorukram et al. / Tetrahedron 70 (2014) 7577e7583
7579
methylmorpholine-N-oxide (NMO) (3 equiv) then NaIO4 (2 equiv)
followed by oxidation of the resulting lactol by using pyridinium
secolignans containing two symmetrical aromatic rings at C-5, such
as peperomin C, were obtained in high stereoselectivity. Moreover,
chlorochromate (PCC) in CH2Cl2 provided
89% yield. Debenzylation of 15 followed by methylation of the
resulting phenol product afforded -butyrolactone 16 in 92% yield.
g
-butyrolactone 15 in
its analogues bearing an a-methylene moiety and 2,3-cis stereo-
chemistry, i.e., 2,6-didehydropeperomin C and 2-epi-peperomin C,
respectively, were also readily synthesized in good yields and
stereoselectivities. The present approach should be found useful for
the SAR study of peperomin-type secolignans since naturally oc-
g
The synthesized g-butyrolactone 16 shows a specific optical rota-
tion value of [
reported in the literature {[
a
]
22 ꢀ13.5 (c 1.0, CHCl3), which is consistent with that
D
25
a
]
ꢀ13.0 (c 1.0, CHCl3)}.13
curring secolignans and their derivatives, varying in the
stituents and the relative orientation of the - and -substituents of
-butyrolactone ring, could be readily prepared according to our
a-sub-
D
For the synthesis of peperomin C,
g-butyrolactone 16 was
a
b
treated with LDA (1 equiv) in THF at ꢀ78 ꢁC followed by trapping
with methyl iodide at ꢀ78 ꢁC for 1 h. Peperomin C, together with 2-
epi-peperomin C (7), was obtained in 37% yield as an 83:17 mixture
of diastereomers as determined by 1H NMR analysis. Comparable
results were obtained when LiHMDS was used as a base in place of
LDA. Attempts to separate peperomin C and 7 by means of chro-
matographic methods were unsuccessful. Fortunately, up to 97:3
diastereomeric ratio of peperomin C (15% yield) with 99% ee as
determined by HPLC analysis (Daicel Chiral OD-H column; i-PrOH/
hexane)14 could be obtained after recrystallization from EtOAc/
hexanes. The synthesized peperomin C shows a specific optical
g
reported methodology.
4. Experimental section
4.1. General
The 1H NMR spectra were recorded on a Bruker DPX-300
(300 MHz) or a Bruker-400 (400 MHz) spectrometer in CDCl3 us-
ing tetramethylsilane (TMS) as an internal standard. The 13C NMR
spectra were recorded on a Bruker DPX-300 (75 MHz) or a Bruker-
400 (100 MHz) spectrometer in CDCl3. The chemical shifts are re-
rotation value of [
a]
24 þ27.3 (c 0.68, CHCl3) {lit.2a
[a
]
27 þ42.7 (c 0.06,
D
D
CHCl3)}. Its 1H and 13C NMR data are in agreement with those re-
ported for the natural compound (see Supplementary data).
ported as d-values in parts per million (ppm) relative to the deu-
terated solvent peak; CDCl3 (dH: 7.27, dC: 77.0) or TMS (dH: 0.00). The
IR spectra were recorded on a Perkin Elmer Spectrum GX FT-IR
spectrometer. The mass spectra were recorded by using a Thermo
Finnigan Polaris Q mass spectrometer. The high-resolution mass
spectra were recorded on an HR-TOF-MS Micromass model VQ-
TOF2 mass spectrometer. Melting points were recorded on
a Buchi M-565 melting Point Apparatus and uncorrected. HPLC was
performed with Agilent 1100 Series HPLC Value System using i-
PrOH/hexanes as mobile phase. Tetrahydrofuran (THF) was distilled
from sodiumebenzophenone ketyl. Dichloromethane (CH2Cl2) and
pentane were distilled over calcium hydride and stored over acti-
Starting from g-butyrolactone 16, a 2,6-didehydropeperomin C
(6) can be readily synthesized. Eschenmoser methylenation of 16
was carried out according to the previously reported procedure by
Danishefsky.15 Thus, the
g-butyrolactone 16 was treated with
LiHMDS (1.5 equiv) in THF at ꢀ78 ꢁC for 1 h followed by trapping
with the Eschenmoser salt (2 equiv) and the resulting was main-
tained at ꢀ78 ꢁC (2 h) and at room temperature (16 h). Without
purification, the corresponding adduct was subsequently treated
with m-chloroperbenzoic acid (m-CPBA) in the presence of
NaHCO3. The desired 2,6-didehydropeperomin C (6) was obtained
in 45% yield after chromatographic purification.
ꢀ
vated molecular sieves (4 A). Methanol (MeOH) was distilled over
Finally, the conversion of 2,6-didehydropeperomin C (6) into 2-
epi-peperomin C (7) should be straightforward through a simple
catalytic hydrogenation. It is expected that the bulkiness of the b-
diarylmethyl group of 6 would direct the hydrogenation process to
take place from the opposite site in order to avoid the steric in-
teraction leading to 2-epi-peperomin C (7) with a 2,3-cis stereo-
Mg powder. Column chromatography was performed by using
Merck silica gel 60 (Art 7734). Other common solvents [CH2Cl2,
hexanes, ethyl acetate (EtOAc), MeOH, and acetone] were distilled
before use.
4.2. (R)-4-Benzyl-3-(pent-4-enoyl)oxazolidin-2-one (8)
chemistry as
a
major diastereomer. Therefore, catalytic
hydrogenation of 6 (H2, Pd/C, EtOH)16 provided 7 in 91% yield with
good diastereoselectivity (dr¼90:10) as determined by 1H NMR
analysis. Similar results were obtained when pyridine was used as
a co-solvent for hydrogenation (H2, Pd/C) in dry benzene;17 7 was
obtained in 99% yield (dr¼90:10). Compound 7 (12% yield; 99% ee)
with the diastereomeric ratio up to 95:5 as determined by HPLC
analysis (Daicel Chiral OD-H column; i-PrOH/hexane)14 could be
obtained after recrystallization from EtOAc/hexanes. The 2,3-cis
stereochemistry of 7 was confirmed from NOE experiments as
depicted in Fig. 2 (see Supplementary data). Irradiation of H-3
resulted in an NOE enhancement for H-2. Additionally, upon irra-
diation of eCH3-6, an NOE enhancement was observed for H-5.
Compound (8) was synthesized according to the literature
procedure7 and obtained (492 mg, 95% yield) as a colorless liquid;
23
23
Rf (20% EtOAc/hexanes) 0.33; [
a
]
ꢀ61.7 (c 0.8, CHCl3) {lit.7d
[a]
D
ꢀ55 (c 0.8, CHCl3)}; IR (neat): nmax 1777, 1702, 1384, 1211, 916 cmꢀD1
;
1H NMR (300 MHz, CDCl3):
d 7.40e7.20 (m, 5H, ArH), 5.90 (ddt,
J¼17.1, 10.3, 6.6 Hz, 1H, CH), 5.13 (dd, J¼17.1, 1.4 Hz, 1H, CHH), 5.06
(dd, J¼10.3, 1.1 Hz, 1H, CHH), 4.77e4.64 (m, 1H, CH), 4.27e4.17 (m,
2H, CH2O), 3.32 (dd, J¼13.4, 3.1 Hz, 1H, CHH), 3.20e2.96 (m, 2H,
CH2), 2.79 (dd, J¼13.4, 9.6 Hz, 1H, CHH), 2.55e2.42 (m, 2H, CH2). 13
C
NMR (75 MHz, CDCl3): d 172.5 (CO),153.4 (CO),136.6 (CH),135.2 (C),
129.4 (2ꢂCH),128.9 (2ꢂCH),127.3 (CH),115.7 (CH2), 66.1 (CH2), 55.1
(CH), 37.8 (CH2), 34.7 (CH2), 28.1 (CH2); m/z (EI) 260 [(MþH)þ, 25],
259 (Mþ, 100), 231 (17), 178 (28), 117 (29), 91 (44), 55 (50); HRMS
(ESI-TOF): MNaþ, found 282.1101. C15H17NO3Na requires 282.1106.
4.3. (R)-4-Benzyl-3-{(R)-2-{(R)-[4-(benzyloxy)-3,5-
dimethoxyphenyl](hydroxy)methyl}pent-4-enoyl}oxazolidin-
2-one (9)
Fig. 2. The key NOE correlations of 2-epi-peperomin C (7).
To a solution of compound 8 (457 mg, 1.76 mmol) in dry CH2Cl2
(4.5 mL) cooled at ꢀ78 ꢁC was added a solution of Bu2BOTf (1 M in
CH2Cl2, 1.94 mL, 1.94 mmol) dropwise over 10 min. The resulting
solution was allowed to stir at ꢀ78 ꢁC for 30 min, and then i-Pr2NEt
(0.36 mL, 2.6 mmol) was slowly added. After stirring at ꢀ78 ꢁC for
45 min, a solution of 4-(benzyloxy)-3,5-dimethoxybenzaldehyde
3. Conclusions
In conclusion, we have reported a stereoselective approach to
synthesize peperomin-type secolignans. Based on this approach,

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D. Soorukram et al. / Tetrahedron 70 (2014) 7577e7583
(528 mg, 1.94 mmol) in dry CH2Cl2 (1.7 mL) was added dropwise
over 10 min, then the resulting reaction mixture was allowed to stir
at ꢀ78 ꢁC for 6 h and quenched with phosphate buffer (pH 7, 4 mL)
at ꢀ78 ꢁC. The cooling bath was replaced by an ice-bath then MeOH
(6 mL) was added followed by the addition of a solution mixture of
MeOH and 30% aqueous H2O2 solution [2:1 (v/v), 6 mL]. After
stirring at 0 ꢁC for 1 h, the reaction mixture was diluted with CH2Cl2
(50 mL), and then the solvents were removed in vacuo. The
resulting residue was dissolved in EtOAc and H2O and extracted
with EtOAc (3ꢂ30 mL). The combined organic phase was washed
with a saturated aqueous NaHCO3 solution, brine, and dried over
anhydrous Na2SO4. Purification by column chromatography [SiO2,
reaction mixture was quenched with H2O (5 mL) and extracted
with EtOAc (3ꢂ30 mL). The combined organic phase was washed
with brine (30 mL) and dried over anhydrous Na2SO4. Evaporation
of the solvent and purification by column chromatography [SiO2,
20% EtOAc/hexanes] gave the corresponding mono-TBS protected
alcohol (370 mg, 92% yield) as a colorless liquid; Rf (20% EtOAc/
hexanes) 0.40; [
a
]
22 þ14.4 (c 1.0, CHCl3); IR (neat): nmax 3486, 1592,
D
1504, 1463, 1328, 1252, 1232, 1130, cmꢀ1
;
1H NMR (400 MHz,
CDCl3):
d
7.39 (d, J¼7.1 Hz, 2H, ArH), 7.27e7.16 (m, 3H, ArH), 6.48 (s,
2H, ArH), 5.66e5.54 (m, 1H, CH), 4.97e4.90 (m, 2H, CHH), 4.92 (s,
2H, CH2O), 4.90e4.86 (m, 1H, CH), 3.73 (s, 6H, 2ꢂOCH3), 3.70 (d,
J¼2.6 Hz, 1H, OH), 3.67 (d, J¼4.0 Hz, 2H, CH2), 2.14e1.94 (m, 2H,
CH2), 1.83e1.75 (m, 1H, CH), 0.85 [s, 9H, Si(CH3)3], 0.01 (s, 3H,
20% EtOAc/hexanes] gave syn-aldol product 9 (820 mg, 88% yield)
22
as a pale yellow viscous oil; Rf (40% EtOAc/hexanes) 0.31; [
a
]
SiCH3), 0.00 (s, 3H, SiCH3). 13C NMR (100 MHz, CDCl3):
d 153.2
D
ꢀ69.9 (c 1.0, CHCl3); IR (CHCl3): nmax 3528, 1778, 1690, 1594, 1500,
(2ꢂC), 138.6 (C), 137.9 (C), 137.1 (CH), 135.6 (C), 128.5 (2ꢂCH), 128.0
(2ꢂCH), 127.7 (CH), 116.4 (CH2), 103.1 (2ꢂCH), 76.6 (CH), 74.9 (CH2),
64.5 (CH2), 56.1 (2ꢂCH3), 46.2 (CH), 29.0 (CH2), 25.8 (3ꢂCH3), 18.1
(C), ꢀ5.5 (CH3), ꢀ5.6 (CH3); m/z (EI) 472 (Mþ, 46), 367 (100), 323
(24), 231 (30), 211 (94), 91 (51); HRMS (ESI-TOF): MNaþ, found
495.2535. C27H40O5SiNa requires 495.2543.
1463, 1385, 1130 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
7.49e7.44 (m,
2H, ArH), 7.34e7.23 (m, 6H, ArH), 7.19e7.14 (m, 2H, ArH), 6.62 (s, 2H,
ArH), 5.95e5.80 (m, 1H, CH), 5.12 (dd, J¼17.1, 1.2 Hz, 1H, CHH), 5.05
(d, J¼10.1 Hz, 1H, CHH), 4.98 (s, 2H, CH2O), 4.88 (d, J¼6.2 Hz, 1H,
CH), 4.51 (ddd, J¼10.1, 6.2, 4.1 Hz, 1H, CH), 4.39e4.32 (m, 1H, CH),
3.99 (dd, J¼9.0, 2.4 Hz, 1H, CHH), 3.82 (s, 6H, 2ꢂOCH3), 3.79 (dd,
J¼8.5, 8.5 Hz, 1H, CHH), 3.19 (dd, J¼13.4, 3.2 Hz, 1H, CHH),
2.73e2.53 (m, 4H, CHH, CH2 and OH). 13C NMR (100 MHz, CDCl3):
To a solution of mono-TBS protected alcohol (1.73 g, 3.66 mmol)
in dry n-pentane (40 mL) was added MnO2 (9.56 g, 110 mmol) at
room temperature. The resulting brown suspension was stirred at
room temperature, and the progress of the reaction was monitored
by TLC. After the complete consumption of the starting material
(12 h), the reaction mixture was filtered through Celite pad, and the
residue was eluted with EtOAc (250 mL). Compound 11 (1.44 g, 84%
yield) was obtained as a yellow oil; Rf (20% EtOAc/hexanes) 0.52;
d
174.4 (CO), 153.4 (2ꢂC), 153.1 (CO), 137.7 (C), 137.0 (C), 136.2 (C),
135.2 (CH), 135.1 (C), 129.3 (2ꢂCH), 128.9 (2ꢂCH), 128.4 (2ꢂCH),
128.1 (2ꢂCH), 127.8 (CH), 127.4 (CH), 117.3 (CH2), 103.2 (2ꢂCH), 75.0
(CH), 74.9 (CH2), 65.9 (CH2), 56.1 (2ꢂCH3), 55.6 (CH), 49.3 (CH), 38.0
(CH2), 32.4 (CH2); m/z (EI) 531 (Mþ, 13), 336 (23), 263 (27), 181 (23),
91 (100); HRMS (ESI-TOF): MNaþ, found 554.2147. C31H33NO7Na
requires 554.2155.
[a
]
22 þ2.3 (c 1.0, CHCl3); IR (neat): nmax 1674, 1584, 1502, 1463, 1415,
D
1323, 1129, 837 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
7.50e7.45 (m,
2H, ArH), 7.37e7.26 (m, 3H, ArH), 7.22 (s, 2H, ArH), 5.75 (ddt, J¼17.1,
10.1, 7.0 Hz, 1H, CH), 5.15 (s, 2H, CH2O), 5.05 (dd, J¼17.1, 1.5 Hz, 1H,
CHH), 4.99 (d, J¼10.1 Hz, 1H, CHH), 3.92e3.84 (m, 1H, CHH), 3.88 (s,
6H, 2ꢂOCH3), 3.79e3.66 (m, 2H, CHH and CH), 2.48 (ddd, J¼14.1,
7.0, 7.0 Hz, 1H, CHH), 2.31 (ddd, J¼14.1, 7.0, 7.0 Hz, 1H, CHH), 0.8 [s,
9H, SiC(CH3)3], 0.0 (s, 3H, SiCH3), ꢀ0.6 (s, 3H, SiCH3); 13C NMR
4.4. (1R,2S)-2-Allyl-1-[4-(benzyloxy)-3,5-dimethoxyphenyl]
propane-1,3-diol (10)
To a solution of syn-aldol adduct 9 (539 mg, 1.0 mmol) in dry
THF (3 mL) cooled at 0 ꢁC were added dry MeOH (90
mL, 2.2 mmol)
and a solution of LiBH4 (51 mg, 2.3 mmol) in dry THF (3.5 mL) under
an argon atmosphere. The reaction mixture was stirred at 0 ꢁC for
1 h, then quenched with an aqueous NaOH solution (1 M, 3 mL) and
extracted with EtOAc (3ꢂ30 mL). The combined organic phase was
washed with brine (30 mL) and dried over anhydrous Na2SO4.
Evaporation of the solvent and purification by column chroma-
tography [SiO2, 100% Et2O] gave the diol 10 (336 mg, 93% yield) as
(100 MHz, CDCl3):
d
201.8 (CO), 153.2 (2ꢂC), 141.3 (C), 137.4 (C),
135.4 (CH), 133.4 (C), 128.4 (2ꢂCH), 128.1 (2ꢂCH), 127.9 (CH), 116.8
(CH2),106.0 (2ꢂCH), 74.9 (CH2), 64.9 (CH2), 56.2 (2ꢂCH3), 48.6 (CH),
33.4 (CH2), 25.7 (3ꢂCH3), 18.1 (C), ꢀ5.6 (2ꢂCH3); m/z (EI) 471
[(MþH)þ, 3], 413 (100), 281 (17), 91 (17). HRMS (ESI-TOF): MNaþ,
found 493.2381. C27H38O5SiNa requires 493.2386.
a colorless liquid; Rf (100% Et2O) 0.25; [
a
]
22 þ15.0 (c 1.0, CHCl3); IR
4.6. (S)-1,1-Bis[4-(benzyloxy)-3,5-dimethoxyphenyl]-2-{[(tert-
butyldimethylsilyl)oxy]methyl}pent-4-en-1-ol (13)
D
(neat): nmax 3407, 1639, 1592, 1504, 1456, 1419, 1328, 1234, 1127,
1028 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
7.41 (d, J¼6.7 Hz, 2H, ArH),
7.29e7.17 (m, 3H, ArH), 6.46 (s, 2H, ArH), 5.66 (ddt, J¼17.0, 10.0,
7.1 Hz, 1H, CH), 5.00e4.89 (m, 2H, CHH), 4.92 (s, 2H, CH2O), 4.81 (d,
J¼4.1 Hz, 1H, CH), 3.72 (s, 6H, 2ꢂOCH3), 3.65e3.52 (m, 2H, CH2),
2.08e1.95 (m, 2H, CH2), 1.90e1.81 (m, 1H, CH). 13C NMR (100 MHz,
A flame-dried round bottom flask equipped with a magnetic
stirring bar, an argon inlet, and a rubber septum was charged with
2-(benzyloxy)-5-bromo-1,3-dimethoxybenzene
(142
mg,
0.44 mmol) and dry THF (0.5 mL). The solution was cooled to
ꢀ78 ꢁC, and then a solution of n-BuLi (1.85 M in hexanes, 0.24 mL,
0.44 mmol) was added dropwise, and the stirring was continued for
10 min to provide aryllithium 12. A solution of compound 11
(106 mg, 0.23 mmol) in dry THF (0.5 mL) was then added dropwise.
The resulting yellow solution was allowed to stir at ꢀ78 ꢁC for 1 h,
then quenched with a saturated aqueous NH4Cl solution (5 mL) and
extracted with EtOAc (3ꢂ30 mL). The combined organic phase was
washed with brine (30 mL) and dried over anhydrous Na2SO4.
Evaporation and purification by column chromatography [SiO2, 20%
CDCl3):
d
153.2 (2ꢂC), 138.3 (C),137.7 (C), 137.0 (CH),135.7 (C),128.4
(2ꢂCH), 128.0 (2ꢂCH), 127.8 (CH), 116.4 (CH2), 103.1 (2ꢂCH), 76.1
(CH), 74.9 (CH2), 63.7 (CH2), 56.0 (2ꢂCH3), 46.2 (CH), 29.8 (CH2); m/
z (EI) 358 (Mþ, 36), 341 (20), 273 (19), 267 (29), 249 (34), 156 (100),
124 (17), 91 (40); HRMS (ESI-TOF): MNaþ, found 381.1678.
C
21H26O5Na requires 381.1678.
4.5. (S)-1-[4-(Benzyloxy)-3,5-dimethoxyphenyl]-2-{[(tert-bu-
tyldimethylsilyl)oxy]methyl}pent-4-en-1-one (11)
EtOAc/hexanes] gave 13 (125 mg, 78% yield) as a yellow oil; Rf (20%
23
To a mixture of diol 10 (307 mg, 0.85 mmol) and DMAP (10 mg,
0.085 mmol) in dry CH2Cl2 (3 mL), Et3N (0.36 mL, 2.55 mmol) was
added. The resulting reaction mixture was then treated with a so-
lution of TBSCl (384 mg, 2.55 mmol) in dry CH2Cl2 (3 mL) at room
temperature. The progress of the reaction was monitored by TLC.
After the complete consumption of the starting material (3 h), the
EtOAc/hexanes) 0.31; [
a
]
ꢀ22.6 (c 1.0, CHCl3); IR (CHCl3): nmax
D
3420, 1591, 1505, 1464, 1416, 1321, 1132, 838 cmꢀ1
(400 MHz, CDCl3): 7.52e7.45 (m, 4H, ArH), 7.37e7.25 (m, 6H, ArH),
6.81 (s, 2H, ArH), 6.80 (s, 2H, ArH), 5.88e5.77 (m, 1H, CH), 5.22 (s,
1H, OH), 5.08 (brs, 1H, CHH), 5.05 (d, J¼3.6 Hz, 1H, CHH), 5.00 (s, 2H,
CH2O), 4.99 (s, 2H, CH2O), 3.83 (s, 6H, 2ꢂOCH3), 3.82 (s, 6H,
;
1H NMR
d

D. Soorukram et al. / Tetrahedron 70 (2014) 7577e7583
7581
2ꢂOCH3), 3.77 (dd, J¼10.0, 2.0 Hz, 1H, CHH), 3.67 (d, J¼10.0 Hz, 1H,
CHH), 2.56e2.44 (m,1H, CHH), 2.39 (dd, J¼10.0, 1.3 Hz,1H, CH), 2.24
(dd, J¼13.9, 5.7 Hz, 1H, CHH), 0.91 [s, 9H, SiC(CH3)3], 0.01 (s, 3H,
(100); HRMS (ESI-TOF): MNaþ, found 607.2668. C36H40O7Na re-
quires 607.2672.
SiCH3), ꢀ0.05 (s, 3H, SiCH3); 13C NMR (100 MHz, CDCl3):
d
153.1
4.8. (3R)-3-{Bis[40-(benzyloxy)-30,50-dimethoxyphenyl]
methyl}butyrolactone (15)
(2ꢂC), 153.0 (2ꢂC), 143.5 (C), 141.7 (C), 137.9 (C), 137.8 (C), 137.2
(CH), 135.5 (C), 135.4 (C), 128.3 (4ꢂCH), 128.0 (4ꢂCH), 127.7 (CH),
127.6 (CH), 116.4 (CH2), 102.9 (2ꢂCH), 102.8 (2ꢂCH), 81.3 (C), 74.9
(CH2), 74.8 (CH2), 62.1 (CH2), 56.2 (2ꢂCH3), 56.1 (2ꢂCH3), 46.1 (CH),
30.0 (CH2), 25.7 (3ꢂCH3), 18.0 (C), ꢀ5.95 (CH3), ꢀ5.99 (CH3); m/z
(EI) 714 (Mþ, 1), 551 (14), 515 (46), 473 (51), 461 (100), 370 (33), 91
(45); HRMS (ESI-TOF): MNaþ, found 737.3482. C42H54O8SiNa re-
quires 737.3486.
To a solution mixture of 14 (190 mg, 0.32 mmol) and NMO
(113 mg, 0.96 mmol) in CH2Cl2 (13 mL) were added a solution of
OsO4 (2.5% in t-BuOH, 0.16 mL, 0.016 mmol) and H2O (0.16 mL,
8.9 mmol) consecutively at room temperature. The resulting yellow
solution was stirred at room temperature, and the progress of the
reaction was monitored by TLC. After the complete consumption of
the starting material (9 h), NaIO4 (137 mg, 0.64 mmol) was added to
the reaction mixture at room temperature. After stirring for 30 min,
the reaction mixture was quenched with a saturated aqueous
Na2S2O3 solution (15 mL) and extracted with CH2Cl2 (3ꢂ30 mL).
The combined organic phase was washed with brine (30 mL) and
dried over anhydrous Na2SO4. After removal of the solvent, the
obtained crude product was dissolved in dry CH2Cl2 (13 mL), and
PCC (104 mg, 0.48 mmol) was added at room temperature. After
stirring for 4 h, the reaction mixture was diluted and extracted with
EtOAc (3ꢂ30 mL). The combined organic phase was washed with
brine (30 mL) and dried over anhydrous Na2SO4. Evaporation and
purification by column chromatography [SiO2, 50% EtOAc/hexanes]
gave 15 (167 mg, 89% yield) as a pale yellow oil; Rf (50% EtOAc/
4.7. (R)-2-{Bis[4-(benzyloxy)-3,5-dimethoxyphenyl]methyl}
pent-4-en-1-ol (14)
To a solution of 13 (788 mg, 1.1 mmol) in dry CH2Cl2 (18 mL)
cooled at ꢀ20 ꢁC under an argon atmosphere was added Et3SiH
(0.88 mL, 5.5 mmol) followed by the addition of BF3$OEt2 (0.4 mL,
3.3 mmol). After the complete consumption of the starting ma-
terial (5 min), the reaction mixture was quenched with a saturated
aqueous NaHCO3 solution (10 mL) and extracted with CH2Cl2
(3ꢂ30 mL). The combined organic phase was washed with brine
(30 mL) and dried over anhydrous Na2SO4. Evaporation and pu-
rification by column chromatography [SiO2, 20% EtOAc/hexanes]
gave the corresponding product (696 mg, 91% yield) as a yellow
hexanes) 0.38; [
a]
22 ꢀ6.4 (c 1.0, CHCl3); IR (CHCl3): nmax 1774, 1591,
D
24
oil; Rf (20% EtOAc/hexanes) 0.40; [
a
]
D
ꢀ14.1 (c 1.0, CHCl3); IR
1505, 1463, 1133 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
7.46 (d,
(neat): nmax 1589, 1506, 1456, 1417, 1326, 1241, 1130, 836 cmꢀ1
;
1H
J¼7.1 Hz, 4H, ArH), 7.37e7.24 (m, 6H, ArH), 6.44 (s, 4H, ArH), 4.98 (s,
4H, 2ꢂCH2), 4.26 (dd, J¼9.4, 7.2 Hz,1H, CHH), 3.99 (dd, J¼9.4, 6.8 Hz,
1H, CHH), 3.81 (s, 12H, 4ꢂOCH3), 3.65 (d, J¼11.6 Hz, 1H, CH),
3.36e3.23 (m, 1H, CH), 2.58 (dd, J¼17.8, 8.3 Hz, 1H, CHH), 2.29 (dd,
NMR (400 MHz, CDCl3):
d¼7.49e7.44 (m, 4H, ArH), 7.30e7.24 (m,
6H, ArH), 6.52 (s, 2H, ArH), 6.50 (s, 2H, ArH), 5.78 (ddt, J¼17.2, 10.0,
7.1 Hz, 1H, CH), 5.03e4.90 (m, 6H, CHH and 2ꢂCH2), 3.82 (s, 6H,
2ꢂOCH3), 3.80 (s, 6H, 2ꢂOCH3), 3.73 (d, J¼10.9 Hz, 1H, CH), 3.53
(dd, J¼9.8, 2.8 Hz, 1H, CHH), 3.33 (dd, J¼9.8, 4.0 Hz, 1H, CHH),
2.25e2.15 (m, 1H, CH), 2.15e2.02 (m, 2H, CH2), 0.9 [s, 9H, Si(CH3)3],
ꢀ0.05 (s, 3H, SiCH3), ꢀ0.08 (s, 3H, SiCH3); 13C NMR (100 MHz,
J¼17.8, 7.7 Hz, 1H, CHH); 13C NMR (100 MHz, CDCl3):
d 176.5 (CO),
153.8 (2ꢂC), 153.7 (2ꢂC), 137.7 (2ꢂC), 137.3 (2ꢂC), 136.2 (C), 136.1
(C), 128.4 (4ꢂCH), 128.1 (4ꢂCH), 127.8 (2ꢂCH), 104.9 (2ꢂCH), 104.8
(2ꢂCH), 74.9 (2ꢂCH2), 72.0 (CH2), 56.3 (4ꢂCH3), 55.6 (CH), 40.3
(CH), 34.1 (CH2); m/z (EI) 584 (Mþ, 23), 493 (100), 461 (31), 403 (17),
371 (29), 334 (26), 317 (77), 181 (20), 91 (98); HRMS (ESI-TOF):
MNaþ, found 607.2301. C35H36O8Na requires 607.2308.
CDCl3):
d
¼153.4 (2ꢂC), 153.3 (2ꢂC), 139.7 (C), 139.5 (C), 137.9
(2ꢂC), 137.0 (CH), 135.6 (C), 135.5 (C), 128.4 (4ꢂCH), 128.1 (4ꢂCH),
127.7 (2ꢂCH), 116.2 (CH2), 105.6 (2ꢂCH), 105.4 (2ꢂCH), 75.0 (CH2),
74.9 (CH2), 61.2 (CH2), 56.3 (2ꢂCH3), 56.2 (2ꢂCH3), 53.3 (CH), 44.5
(CH), 33.0 (CH2), 25.9 (3ꢂCH3), 18.3 (C), ꢀ5.5 (CH3), ꢀ5.6 (CH3); m/
z (EI) 698 (Mþ, 11), 641 (9), 475 (100), 433 (49), 421 (31), 384 (44),
91 (40); HRMS (ESI-TOF): MNaþ, found 721.3537. C42H54O7SiNa
requires 721.3537.
4.9. (3R)-3-[Bis(30,40,50-trimethoxyphenyl)methyl]butyr-
olactone (16)5b
Compound 15 (175 mg, 0.3 mmol) and PdCl2 (106 mg, 0.6 mmol)
were dissolved in dry MeOH (6 mL) under an argon atmosphere.
The argon inlet was replaced by a hydrogen gas balloon, and the
reaction mixture was stirred at room temperature. After the com-
plete consumption of the starting material (2 h), the reaction
mixture was filtered through Celite pad, and the residue was then
washed with EtOAc (150 mL). After removal of the solvent, the
obtained crude product was dissolved in acetone (0.25 mL) then
(MeO)2SO2 (0.11 mL, 1.2 mmol) and anhydrous K2CO3 (124 mg,
0.9 mmol) were added. The reaction mixture was heated to reflux
for 1 h then it was cooled to room temperature and extracted with
EtOAc (3ꢂ30 mL). The combined organic phase was washed with
brine and dried over anhydrous Na2SO4. Evaporation and purifi-
cation by column chromatography [SiO2, 50% EtOAc/hexanes] gave
To a solution of the above-mentioned compound (346 mg,
0.5 mmol) in dry THF (1 mL) cooled at 0 ꢁC was added dropwise
a solution of TBAF (1 M in THF, 2.6 mL, 2.6 mmol). The reaction
mixture was stirred and slowly warmed up to room temperature
overnight. The reaction mixture was quenched with H2O (15 mL)
and extracted with EtOAc (3ꢂ30 mL). The combined organic phase
was washed with brine (30 mL) and dried over anhydrous Na2SO4.
Evaporation and purification by column chromatography [SiO2, 40%
EtOAc/hexanes] gave 14 (269 mg, 92% yield) as a yellow oil; Rf (40%
EtOAc/hexanes) 0.38; [
a
]
D
22 ꢀ27.2 (c 1.0, CHCl3); IR (neat): nmax 3522,
1590, 1506, 1456, 1418, 1326, 1241, 1128, 747 cmꢀ1
;
1H NMR
(400 MHz, CDCl3):
d
7.46 (brd, J¼7.5 Hz, 4H, ArH), 7.36e7.23 (m, 6H,
ArH), 6.52 (s, 4H, ArH), 5.90e5.77 (m, 1H, CH), 5.05 (s, 1H, CHH),
5.01 (d, J¼8.6 Hz, 1H, CHH), 4.98 (s, 2H, CH2), 4.96 (s, 2H, CH2), 3.80
(s, 6H, 2ꢂOCH3), 3.79 (s, 6H, 2ꢂOCH3), 3.72 (d, J¼11.2 Hz, 1H, CH),
3.61 (dd, J¼11.0, 3.6 Hz, 1H, CHH), 3.48 (dd, J¼11.0, 4.6 Hz, 1H, CHH),
2.38e2.27 (m, 1H, CH), 2.22e2.12 (m, 1H, CHH), 2.11e2.01 (m, 1H,
a white solid of 16 in 92% yield (119 mg); Rf (50% EtOAc/hexanes)
22
0.13; [
a
[
]
ꢀ13.5 (c 1.0, CHCl3); mp 168e170 ꢁC (EtOAc/hexanes)
D
25
[lit.5b
a
]
ꢀ13.0 (c 1.0, CHCl3); mp 168e169 ꢁC]; 1H NMR
D
(400 MHz, CDCl3):
d
6.47 (d, J¼1.2 Hz, 4H, ArH), 4.30 (dd, J¼9.5,
CHH); 13C NMR (100 MHz, CDCl3):
d
153.5 (2ꢂC), 153.4 (2ꢂC), 139.1
7.2 Hz, 1H, CHH), 4.00 (dd, J¼9.5, 6.6 Hz, 1H, CHH), 3.86 (s, 12H,
4ꢂOCH3), 3.82 (s, 6H, 2ꢂOCH3), 3.66 (d, J¼11.7 Hz, 1H, CH),
3.38e3.28 (m, 1H, CH), 2.61 (dd, J¼17.8, 8.3 Hz, 1H, CHH), 2.30 (dd,
(C), 139.0 (C), 137.8 (2ꢂC), 136.7 (CH), 135.6 (C), 135.5 (C), 128.3
(4ꢂCH), 128.0 (4ꢂCH), 127.7 (2ꢂCH), 116.6 (CH2), 105.4 (2ꢂCH),
105.1 (2ꢂCH), 74.9 (2ꢂCH2), 62.6 (CH2), 56.2 (2ꢂCH3), 56.1
(2ꢂCH3), 53.7 (CH), 44.3 (CH), 33.9 (CH2); m/z (EI) 584 (Mþ, 20), 493
(49), 475 (19), 402 (19), 334 (33), 317 (28), 285 (13), 243 (18), 91
J¼17.8, 7.5 Hz, 1H, CHH); 13C NMR (100 MHz, CDCl3):
d 176.4 (CO),
153.6 (2ꢂC), 153.5 (2ꢂC), 137.6 (2ꢂC), 137.2 (2ꢂC), 104.7 (2ꢂCH),
104.6 (2ꢂCH), 72.0 (CH2), 60.8 (2ꢂCH3), 56.2 (4ꢂCH3), 55.7 (CH),

7582
D. Soorukram et al. / Tetrahedron 70 (2014) 7577e7583
40.2 (CH), 34.0 (CH2). 1H and 13C NMR data of 16 are identical with
those reported in the literature.
42.7 (CH); m/z (EI) 444 (Mþ, 2), 347 (100), 318 (8); HRMS (ESI-TOF):
MNaþ, found 467.1682. C24H28O8Na requires 467.1682.
4.12. 2-epi-Peperomin C (7)
4.10. Peperomin C
Compound 6 (27 mg, 0.06 mmol) and Pd/C (2 mg) were dis-
solved in a mixture of dry benzene and pyridine (1:1 v/v, 1 mL)
under an argon atmosphere. The argon inlet was replaced by
a balloon filled with hydrogen gas, and the reaction mixture was
stirred at room temperature. After the complete consumption of
the starting material (20 min), the reaction mixture was filtered
through Celite pad, and the residue was then washed with MeOH.
Compound 7 was obtained as a white solid in 99% yield (26.5 mg,
90:10 dr). Recrystallization from EtOAc/hexanes gave compound 7
To a solution of i-Pr2NH (50 mL, 0.33 mmol) in dry THF (0.5 mL)
cooled at ꢀ78 ꢁC under an argon atmosphere was added dropwise
n-BuLi (1.71 M in hexanes, 0.16 mL, 0.27 mmol). After stirring at
ꢀ78 ꢁC for 30 min, a solution of 16 (133 mg, 0.3 mmol) in dry THF
(0.5 mL) was added dropwise, then the resulting reaction mixture
was allowed to stir at ꢀ78 ꢁC for 1 h. MeI (20
mL, 0.33 mmol) was
then added to the reaction mixture at ꢀ78 ꢁC and the stirring was
continued for 1 h. The reaction mixture was quenched with a sat-
urated aqueous NH4Cl solution and extracted with EtOAc
(3ꢂ30 mL). The combined organic phase was washed with brine
and dried over anhydrous Na2SO4. After removal of the solvent, the
crude product was purified by column chromatography [SiO2, 50%
EtOAc/hexanes] to provide peperomin C as a white solid (50 mg,
37% yield, 83:17 dr). Recrystallization from EtOAc/hexanes gave
peperomin C with 99% ee and 97:3 dr; Rf (50% EtOAc/hexanes) 0.16;
with 99% ee and 95:5 dr; Rf (40% EtOAc/hexanes) 0.16; [
a
]
26 ꢀ67.7 (c
D
0.46, CHCl3); mp 170e171 ꢁC (EtOAc/hexanes); IR (CHCl3): nmax
1767, 1591, 1506, 1463, 1421, 1329, 1132 cmꢀ1
;
1H NMR (400 MHz,
CDCl3): 6.52 (s, 2H, ArH), 6.43 (s, 2H, ArH), 4.06e4.00 (m, 1H,
d
CHH), 4.00e3.93 (m, 1H, CHH), 3.86 (s, 6H, 2ꢂOCH3), 3.84 (s, 6H,
2ꢂOCH3), 3.83 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.74 (d, J¼12.0 Hz,
1H, CH), 3.47e3.34 (m, 1H, CH), 2.73 (dq, J¼7.7, 7.6 Hz, 1H, CH), 1.14
24
D
25
[
[
a
a
]
]
þ27.3 (c 0.68, CHCl3) {lit.5b
[
a]
þ43.3 (c 0.06, CHCl3), lit.2a
D
(d, J¼7.6 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3):
d 180.0 (CO),
27
D
þ42.7 (c 0.06, CHCl3)}; mp 149e150 ꢁC (EtOAc/hexanes)
153.6 (2ꢂC), 153.2 (2ꢂC), 137.4 (2ꢂC), 137.1 (2ꢂC), 104.4 (2ꢂCH),
104.2 (2ꢂCH), 70.5 (CH2), 60.9 (CH3), 60.8 (CH3), 56.3 (2ꢂCH3), 56.2
(2ꢂCH3), 50.8 (CH), 43.2 (CH), 37.5 (CH), 10.5 (CH3); m/z (EI) 446
(Mþ, 1), 346 (100); HRMS (ESI-TOF): MNaþ, found 469.1833.
[lit.2a mp 158e160 ꢁC (MeOH)]; 1H NMR (400 MHz, CDCl3):
d 6.49
(s, 2H, ArH), 6.48 (s, 2H, ArH), 4.31 (dd, J¼9.6, 7.6 Hz, 1H, CHH), 3.86
(s, 6H, 2ꢂOCH3), 3.85 (s, 6H, 2ꢂOCH3), 3.86e3.83 (m,1H, CHH), 3.82
(s, 6H, 2ꢂOCH3), 3.65 (d, J¼11.4 Hz, 1H, CH), 2.99e2.88 (m, 1H, CH),
2.43e2.33 (m, 1H, CH), 0.94 (d, J¼7.2 Hz, 3H, CH3); 13C NMR
C24H30O8Na requires 469.1838.
(100 MHz, CDCl3):
d
179.8 (CO), 153.6 (2ꢂC), 153.5 (2ꢂC), 137.5
Acknowledgements
(2ꢂC), 137.1 (2ꢂC), 104.8 (2ꢂCH), 104.7 (2ꢂCH), 70.4 (CH2), 60.9
(CH3), 60.8 (CH3), 56.6 (CH), 56.3 (4ꢂCH3), 47.4 (CH), 40.3 (CH), 15.8
(CH3).
The authors acknowledge financial supports from the Thailand
Research Fund (MRG5580046), the Office of the Higher Education
Commission and Mahidol University under the National Research
Universities Initiative, Mahidol University, and the Center of Ex-
cellence for Innovation in Chemistry (PERCH-CIC).
4.11. 2,6-Didehydropeperomin C (6)
To a solution of hexamethyldisilazane (0.1 mL, 0.48 mmol) in dry
THF (0.5 mL) cooled at ꢀ78 ꢁC under an argon atmosphere was
added dropwise n-BuLi (1.71 M in hexanes, 0.23 mL, 0.4 mmol).
After stirring at ꢀ78 ꢁC for 30 min, a solution of 16 (97 mg,
0.22 mmol) in dry THF (0.5 mL) was added dropwise, then the
resulting reaction mixture was allowed to stir at ꢀ78 ꢁC for 1 h.
Eschenmoser’s salt (122 mg, 0.66 mmol) was then added to the
reaction mixture at ꢀ78 ꢁC. After stirring at ꢀ78 ꢁC for 30 min, the
reaction mixture was allowed to warm up to room temperature and
stirred for 16 h. The reaction mixture was diluted with Et2O (10 mL)
then quenched with a saturated aqueous NaHCO3 solution (10 mL)
and extracted with CH2Cl2 (3ꢂ30 mL). The combined organic phase
was washed with brine and dried over anhydrous Na2SO4. After
removal of solvent, the crude mixture was dissolved in CH2Cl2
(3 mL), and a saturated aqueous NaHCO3 solution (1.4 mL) and m-
CPBA (76 mg, 0.44 mmol) were added. The reaction mixture was
stirred at room temperature for 1 h then extracted with CH2Cl2
(3ꢂ30 mL). The combined organic phase was washed with brine
and dried over anhydrous Na2SO4. Evaporation and purification by
column chromatography [SiO2, 50% EtOAc/hexanes] gave 6 (44 mg,
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.07.101.
References and notes
1. Moss, G. P. Pure Appl. Chem. 2000, 72, 1493e1523.
2. (a) Chen, C.-M.; Jan, F.-Y.; Chen, M.-T.; Lee, T.-J. Heterocycles 1989, 29, 411e414;
(b) Govindachari, T. R.; Krishna Kumari, G. N.; Partho, P. D. Phytochemistry 1998,
49, 2129e2131; (c) Xu, S.; Li, N.; Ning, M.-M.; Zhou, C.-H.; Yang, Q.-R.; Wang,
M.-W. J. Nat. Prod. 2006, 69, 247e250; (d) Wu, J.-L.; Li, N.; Hasegawa, T.; Sakai,
J.-I.; Mitsui, T.; Ogura, H.; Kataoka, T.; Oka, S.; Kiuchi, M.; Tomida, A.; Turuo, T.;
Li, M.; Tang, W.; Ando, M. J. Nat. Prod. 2006, 69, 790e794; (e) Zhang, G.-L.; Li, N.;
Wang, Y.-H.; Zheng, Y.-T.; Zhang, Z.; Wang, M.-W. J. Nat. Prod. 2007, 70,
662e664; (f) Lin, M.-G.; Yu, D.-H.; Wang, Q.-W.; Lu, Q.; Zhu, W.-J.; Bai, F.; Li, G.-
X.; Wang, X.-W.; Yang, Y.-F.; Qin, X.-M.; Fang, C.; Chen, H.-Z.; Yang, G.-H. Chem.
Biodivers. 2011, 8, 862e871; (g) Cheng, M.-J.; Lee, S.-J.; Chang, Y.-Y.; Wu, S.-H.;
Tsai, I.-L.; Jayaprakasan, B.; Chen, I.-S. Phytochemistry 2003, 63, 603e608; (h)
Monache, F. D.; Compagnone, R. S. Phytochemistry 1996, 43, 1097e1098; (i)
Feng, B.-M.; Qin, H.-H.; Wang, H.-G.; Shi, L.-Y.; Yu, D.-Y.; Ji, B.-Q.; Zhao, Q.;
Wang, Y.-Q. J. Nat. Med. 2012, 66, 562e565; (j) Kavitha, J.; Gopalaiah, K.; Ra-
jasekhar, D.; Subbaraju, G. V. J. Nat. Prod. 2003, 66, 1113e1115; (k) Feng, W.-S.;
Chen, H.; Zheng, X.-K.; Wang, Y.-Z.; Gao, L.; Li, H.-W. J. Asian Nat. Prod. Res. 2009,
11, 658e662; (l) Tsutsui, C.; Yamada, Y.; Ando, M.; Toyama, D.; Wu, J.-L.; Wang,
L.; Taketani, S.; Kataoka, T. Bioorg. Med. Chem. Lett. 2009, 19, 4084e4087; (m)
Kataoka, T. J. Antibiot. 2009, 62, 655e667.
3. (a) Felippe, L. G.; Batista, J. M., Jr.; Baldoqui, D. C.; Nascimento, I. R.; Kato, M. J.;
Bolzani, V. S.; Furlan, M. Phytochem. Lett. 2011, 4, 245e249; (b) Felippe, L. G.;
Batista, J. M., Jr.; Baldoqui, D. C.; Nascimento, I. R.; Kato, M. J.; He, Y.; Nafie, L. A.;
Furlan, M. Org. Biomol. Chem. 2012, 10, 4208e4210; (c) See also Refs. 2d and 2f.
4. (a) Chou, S. -Y.; Wang, S. -S.; Tsai, H. -J.; Chen, S. -F.; Ku, H. U.S. Patent
5,981,577A, 1999. (b) Wang, X.-Z.; Liang, J.-Y.; Wen, H.-M.; Shan, C.-X.; Liu, R. J.
Pharm. Biomed. Anal. 2014, 94, 1e11; (c) Wang, X.-Z.; Liang, J.-Y.; Wen, H.-M.;
Shan, C.-X.; Liu, R. J. Chromatogr., B 2014, 944, 82e89; (d) See also Refs. 2 and 3.
5. (a) Cruz-Almanza, R.; Higareda, F. P. Heterocycles 1992, 34, 2323e2330; (b) Sibi,
M. P.; Johnson, M. D.; Punniyamurthy, T. Can. J. Chem. 2001, 79, 1546e1555; (c)
45% yield) as a white solid; Rf (50% EtOAc/hexanes) 0.28; [
a
]
25 ꢀ7.8
D
(c 0.77, CHCl3); mp 166e167 ꢁC (EtOAc/hexanes); IR (CHCl3): nmax
1761, 1592, 1506, 1464, 1421, 1329, 1242, 1132, 1004 cmꢀ1; 1H NMR
(400 MHz, CDCl3):
d
¼6.49 (s, 2H, ArH), 6.48 (s, 2H, ArH), 6.16 (d,
J¼2.1 Hz, 1H, CHH), 4.87 (d, J¼2.1 Hz, 1H, CHH), 4.34 (dd, J¼9.6,
7.7 Hz, 1H, CHH), 4.03 (dd, J¼9.6, 4.4 Hz, 1H, CHH), 3.86 (s, 6H,
2ꢂOCH3), 3.85 (s, 6H, 2ꢂOCH3), 3.83 (s, 6H, 2ꢂOCH3), 3.90e3.80
(m, 1H, CH), 3.74 (d, J¼11.5 Hz, CH); 13C NMR (100 MHz, CDCl3):
d
¼170.8 (CO),153.6 (2ꢂC), 153.3 (2ꢂC), 137.3 (C), 137.2 (C), 137.0 (C),
136.8 (C), 135.8 (C), 124.9 (CH2), 105.3 (2ꢂCH), 104.9 (2ꢂCH), 69.7
(CH2), 60.9 (CH3), 60.8 (CH3), 56.3 (2ꢂCH3), 56.2 (2ꢂCH3), 55.8 (CH),

D. Soorukram et al. / Tetrahedron 70 (2014) 7577e7583
7583
ꢁ
Morita, M.; Yamauchi, S. Biosci. Biotechnol. Biochem. 2009, 73, 2445e2451; (d)
Morita, M.; Nichiwaki, H.; Shingai, Y.; Fujimoto, A.; Masuda, T.; Yamauchi, S.
Biosci. Biotechnol. Biochem. 2011, 75, 939e943.
Angew. Chem., Int. Ed. 1998, 37, 2995e2998; (d) Kerherve, J.; Botuha, C.; Dubois,
J. Org. Biomol. Chem. 2009, 7, 2214e2222; (e) Peng, L. F.; Stanton, B. Z.; Maloof,
N.; Wang, X.; Schreiber, S. L. Bioorg. Med. Chem. Lett. 2009, 19, 6319e6325.
8. (a) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem. Soc. 1981, 103,
3099e3111; (b) Yamauchi, S.; Okazaki, M.; Akiyama, K.; Sugahara, T.; Kishida,
T.; Kashiwagi, T. Org. Biomol. Chem. 2005, 3, 1670e1675.
6. (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127e2129; (b)
Evans, D. A.; Nelson, J. V.; Taber, T. R. In Topics in Stereochemistry; Allinger, N. L.,
Eliel, E. L., Wilen, S. H., Eds.; Wiley: New York, NY, 1982; Vol. 13, pp 1e115; (c)
Evans, D. A.; Vogel, E.; Nelson, J. V. J. Am. Chem. Soc. 1979, 101, 6120e6123; (d)
Heathcock, C. H. In Asymmetric Synthesis. Stereodifferentiation Addition Re-
actions, Part B; Morrison, J. D., Ed.; Academic Press, Inc.: Orlando, Florida, 1984;
Vol. 3, pp 111e212; (e) Heathcock, C. H. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 2, pp 181e238;
(f) Kim, B. M.; Williams, S. F.; Masamune, S. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 2, pp 239e275;
(g) Paterson, I. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, UK, 1991; Vol. 2, pp 301e319; (h) Gennari, C. In Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK,
1991; Vol. 2, pp 629e660; (i) Mukaiyama, T. Org. React. 1982, 28, 203e331; (j)
Mukaiyama, T.; Kobayashi, S. Org. React. 1994, 46, 1e103; (k) Cowden, C. J.;
Paterson, I. Org. React. 1997, 51, 1e200; (l) Carreira, E. M. In Comprehensive
Asymmetric Catalysis IeIII; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, Germany, 1999; Vol. 3, pp 997e1065; (m) Carreira, E. M.;
Fettes, A.; Martl, C. Org. React. 2006, 67, 1e216; (n) Heravi, M. M.; Zadsirjan, V.
Tetrahedron: Asymmetry 2013, 24, 1149e1188 and references cited therein.
7. (a) Evans, D. A.; Mathre, D. J. J. Org. Chem. 1985, 50, 1830e1835; (b) Gage, J. R.;
Evans, D. A. Org. Synth. 1990, 68, 83e91; (c) Kamenecka, T. M.; Danishefsky, S. J.
9. 4-(Benzyloxy)-3,5-dimethoxybenzaldehyde was used in the present work since
its corresponding products would readily be transformed into a variety of
peperomin-type secolignans varying in the substituents on aromatic groups at
C-5 via debenzylation.
10. (a) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920e1923; (b)
Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J.; Bartroli, J.
Pure Appl. Chem. 1981, 53, 1109e1127; (c) Arya, P.; Qin, H. Tetrahedron 2000, 56,
917e947; (d) See also Ref. 6.
11. (a) Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61, 4192e4193; (b) Arm-
strong, A.; Barsanti, P. A.; Blench, T. J.; Ogilvie, R. Tetrahedron 2003, 59, 367e375.
12. Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 20, 99e102.
13. The reported optical rotation value for 16 with 98% de, see, Ref. 5b.
14. Racemic compounds were synthesized and used for the resolution of the en-
antiomer and diastereomer peaks. See Supplementary data.
15. (a) Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew. Chem., Int. Ed.
Engl. 1971, 10, 330e331; (b) Dudley, G. B.; Tan, D. S.; Kim, G.; Tanski, J. M.;
Danishefsky, S. J. Tetrahedron Lett. 2001, 42, 6789e6791.
16. Kennedy, J. W. J.; Hall, D. G. J. Org. Chem. 2004, 69, 4412e4428.
17. Horne, D. A.; Fugmann, B.; Yakushijin, K.; Buchi, G. J. Org. Chem. 1993, 58, 62e64.
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