Chromatography-free “two-pots” asymmetric total synthesis of (+)-sesamin and (+)-aschantin

Article abstract of DOI:10.1016/j.tet.2020.131483

A gram-scale chromatography-free asymmetric total synthesis of both homo- and heterobiaryl furofuran lignans containing at least one methylenedioxy phenyl unit such as (+)-sesamin and (+)-aschantin is accomplished in “two-pots” from easily accessible enantiopure lactone involving four steps in high overall yields. Steps- and pot economy are the key advantages of the protocol. Additionally, the bromo-functionality of the intermediates is useful for late stage functionalization.

Full text of DOI:10.1016/j.tet.2020.131483

Tetrahedron 76 (2020) 131483
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chromatography-free “two-pots” asymmetric total synthesis of
(þ)-sesamin and (þ)-aschantin
,
Saumen Hajra*, Sujay Garai 1 2, Biswajit Sen 2
Centre of Biomedical Research, Sanjay Gandhi Post Graduate Institute of Medical Sciences Campus, Raebareli Road, Lucknow, 226014, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A gram-scale chromatography-free asymmetric total synthesis of both homo- and heterobiaryl furofuran
lignans containing at least one methylenedioxy phenyl unit such as (þ)-sesamin and (þ)-aschantin is
accomplished in “two-pots” from easily accessible enantiopure lactone involving four steps in high
overall yields. Steps- and pot economy are the key advantages of the protocol. Additionally, the bromo-
functionality of the intermediates is useful for late stage functionalization.
Received 2 July 2020
Received in revised form
3 August 2020
Accepted 5 August 2020
Available online 17 August 2020
© 2020 Elsevier Ltd. All rights reserved.
Keywords:
Chromatography-free
Pot-economy
Asymmetric synthesis
Sesamin
Aschantin
1. Introduction
The variation of aryl units and their stereochemical orientation led
to the structural as well as biological diversity [2]. Among all the
In 21st century, the modern science and industry are empha-
sizing on two principal issues e “green” and “efficiency” (practi-
cability) for the synthesis of a target compound. These are
characterized in terms of different economic factors such as atom
economy, redox economy, step economy and pot economy. The
minimization of number of reaction steps to a target compound
(step economy) reduces the length, cost, effort, separation
methods, development- and execution time. Similarly, the carrying
out several reactions in one-pot or reactor omitting work up pro-
cedure and/or without isolating or purifying the intermediate
compounds (pot economy) reduces the amount of solvent, waste,
time, labor and the cost. Thus, both the step- and pot-economy are
very important issues in synthesizing a target molecule in terms of
‘greenness’ and practicability [1].
oxyarenes, 3,4-methylenedioxy arene is more abundant than
others and is also known to have strong impact in bioactivities, for
example, (þ)-sesamin 1 and (þ)-aschantin 2 (Scheme 1). (þ)-Ses-
amin
1 is a symmetrical furofuran lignan having two 3,4-
methylenedioxy arene units and a major constituent of sesame
seeds. It exhibits anticancer, anti-inflammatory, antihypertensive,
antioxidant and estrogen receptor modulator properties [3]. On the
other hand, (þ)-aschantin 2, an unsymmetrical furofuran lignan
having two different arene units, exhibits various bioactivities like
inhibition of inducible NO synthetase, antiplasmodial activity,
Ca2þ-antagonistic activity, platelet activating factor-antagonistic
activity, chemo-preventative or therapeutic activity mediated via
inhibition of mTOR kinase etc. [4] Thus because of widespread
biological properties, several efforts are made for the racemic as
well as non-racemic synthesis of both symmetrical and unsym-
metrical furofuran lignans such as (þ)-sesamin 1 and (þ)-aschantin
2, respectively [5,6]. But in terms of step- and pot-economy all the
reported protocols are inefficient and reveal a lack of greenness.
Herein, we report gram-scale unified asymmetric total synthesis of
(þ)-sesamin 1 and (þ)-aschantin 2 accomplished in two-pots and
free from any chromatography in whole process.
Furofuran lignans are important and the largest subclass of non-
butyrolactone lignans isolated from various vascular plants. These
lignans are known to exhibit a broad range of biological properties.
* Corresponding author.
E-mail
addresses:
saumen.hajra@cbmr.res.in,
saumen.hajra@gmail.com
(S. Hajra).
Both (þ)-sesamin 1 and (þ)-aschantin 2 are exo-exo furofuran
lignans having the same stereochemistry and a common 3,4-
methylenedioxy arene unit. So we realized that both could be
1
Present address: Curadev Pharma Pvt. Ltd., B-87, Sector 83, Noida, Uttar Pra-
desh, 201305, India.
2
S.G. and B. S. contributed equally to this work.
https://doi.org/10.1016/j.tet.2020.131483
0040-4020/© 2020 Elsevier Ltd. All rights reserved.

2
S. Hajra et al. / Tetrahedron 76 (2020) 131483
purification (Scheme 3). LiHMDS mediated aldol reaction of the
lactone 3 with the 6-bromopipernal 4a in THF at ꢀ78 ꢁC produced
the aldol product 7 as a 1:1 mixture of diastereomers, determined
by 1H NMR analysis of the crude mixture. After workup, the crude
lactone alcohol 7 was fully reduced with in situ prepared CaBH4
(from CaCl2 and NaBH4) in THF. Again after workup, the crude
mono-O-TBS protected tetraol 8 was treated with 50% aqueous HCl
in THF at rt. The desilylation and subsequent dehydrative cycliza-
tion gave exclusively dibromo sesamin 9 as a white solid. The
consumption of starting compound and the formation of inter-
mediate product of each step was monitored by TLC and MS anal-
ysis. The overall yield for the three step synthesis of
dibromosesamin 9 from lactone 3 without purification of inter-
mediate compounds was found to be very high (72%).
The stereoselective formation of thermodynamically stable exo-
exo furofuran lignan from a mixture of diastereomeric tetraol could
be rationalized from the generation of a common quinoid inter-
mediate 10.
Debromination of compound
9 can provide the natural
(þ)-sesamin 1 and additionally the bromo-functionality can be
utilized for the late functionalization to synthesize the analogues of
sesamin. So we put our effort for the debromination of 7 (Table 1).
Metal halogen exchange protocol using n-BuLi, Mg and Turbo
Grignard reagent (i-
PrMgCl.LiCl) gave either poor yield of desired product 1 along
with decomposition/intractable mixture or no reaction (entries
1e5). Pd-catalyzed hydrogenation using i-PrOH and molecular
hydrogen (H2) were also not successful (entries 6 and 7). Interest-
ingly, Pd(OAc)2 catalyzed transfer hydrogenation using sodium
formate gave the desired desbromo product, sesamin 1 in 43% yield
(entry 9). To our delight, changing the catalyst to Pd2(dba)3 afforded
the smooth reaction with excellent yield (96%; entry 10).
Scheme 1. Important bioactive furofuran lignans and their proposed synthetic
precursor.
synthesized from the enantiopure lactone 3 using a same sequence
of reactions such as aldol reaction varying aldehyde, reduction and
cyclization (Scheme 1). Recently, we have developed an organo-
catalytic one-pot protocol for highly diastereo- and enantiose-
lective synthesis of the lactone 3, where electronic and steric factor
of ortho-bromo-group played an important role in the reactivity
and selectivity and it was further utilized in building the complex
lignan [7]. Here, we presumed that the bromo-functionality may
help in solidification/precipitation of intermediate compounds and
would be useful for the late stage functionalization too.
2. Results and discussion
We commenced the synthesis of (þ)-sesamin 1 from the
enantiopure lactone 3, which was obtained in gram scale with high
diastereoselectivity (dr 10:1) and excellent enantioselectivity
(>99%) in two steps by following our developed protocol from 6-
bromopiperonal 4a and methyl 4-oxobutanoate 5 (Scheme 2)
[7c]. We planned to execute the one-pot base mediated aldol re-
action of lactone 3 with 6-bromopiperonal 4a, reduction followed
by deprotection-cyclization using same solvent. For this purpose,
we initially validated each step using THF as solvent and carried
forward the crude product for the subsequent steps without
Scheme 3. Optimization of sequential one-pot synthesis of dibromosesamin 9 from
Scheme 2. Synthesis of enantiopure lactone 3 [7c].
lactone 3.

S. Hajra et al. / Tetrahedron 76 (2020) 131483
3
Table 1
chromatography-free “two-pots” gram-scale asymmetric total
synthesis of (þ)-sesamin using only one workup at debromination
step. NMR and optical rotation of the synthesized (þ)-sesamin 1 are
in well agreement with the literature [6f].
Optimization of debromination reaction.a
The similar protocol can be utilized for the synthesis of other
exo-exo furofuran lignans varying the aldehyde in aldol step.
Accordingly, “two-pots” asymmetric total synthesis of hetero-biaryl
furofuran lignan, (þ)-aschantin 2 was commenced from 2 g of
lactone 3 and 3,4,5-trimethoxy benzaldehyde 4b (Scheme 5).
Gratifyingly, without any complication we achieved the
chromatography-free “two-pots” asymmetric total synthesis of
(þ)-aschantin 2 with excellent selectivity in high overall yield
(0.93 g, 50%).
entry reagent/s
solvent time (h) temp (ꢁC) yieldb (%)
Spectral and optical rotation data of synthesized (þ)-aschantin 2
1
2
3
4
5
6
7
8
9
n-BuLi
THF
THF
THF
THF
1
4
ꢀ78
25
60
25
60
70
25
25
80
80
20
are also in good agreement with the literature [6c].
Mg (I2 cat.)
Mg (I2 cat.)
iPrMgCl.LiCl
iPrMgCl.LiCl
Pd(OAc)2/K2CO3
Pd(OH)2/H2
Pd/C/H2
NR
<10
NR
NR
NR
NR
15
12
2
12
12
6
12
12
12
Additionally, to demonstrate the late stage functionalization of
bromo-functionality of aryl unit, the dibromo sesamin 9 was sub-
jected to the Suzuki coupling reaction with phenyl boronic acid
using Pd2(dba)3 as a catalyst (Scheme 6). It underwent smooth
coupling reaction and afforded the diphenyl substituted sesamin 12
in good yield.
THF
iPrOH
EtOAc
EtOH
Pd(OAc)2/PPh3/HCO2Na DMF
Pd2(dba)3/HCO2Na DMF
43
96
10
a
All the reactions were performed under N2 atmosphere with 50 mg scale.
Concentration of the reaction was maintained 0.1 M.
3. Conclusion
b
Isolated yield. NR ¼ no reaction (starting material recovered).
In summary, we have demonstrated a pot- and step-economy
general protocol for the asymmetric synthesis of both homo- and
hetero-biaryl furofuran lignans, in particular, containing at least
one methylenedioxy arene unit. A highly efficient “two-pots” gram-
scale asymmetric total synthesis of (þ)-sesamin and (þ)-aschantin
have been showcased, which involve only one work up and free
from any chromatographic purification. Thus the developed pro-
tocol reduces the amounts of solvent use, waste, time, labor and the
cost. Additionally, the synthesized furofuran core containing bro-
moarene unit can be easily functionalized in late stage to other
analogues.
After standardization of each step we focused on the scalability
and pot-economy. For this purpose, we made our effort to carry out
the first three steps aldol, reduction and desilylative-cyclization in
“one-pot” (pot economy) using same THF without workup and
purification of intermediate compounds (Scheme 4). After the
LiHMDS mediated aldol reaction of TBS-lactone 3 (2 g, 4.65 mmol)
and 6-bromopiperonal 4a, the reaction was treated with the stoi-
chiometric amount of AcOH to destroy the excess Li-reagent. It was
then reacted with in situ prepared CaBH4 in THF. The complete
reduction to 8 was monitored by MS analysis. After completion, it
was quenched with solid NH4Cl and stirred. The solid residue was
filtered off and the filtrate containing tetraol 8 (THF solution) was
treated with 50% aqueous HCl. After stirring for 24 h at rt, it pro-
duced white precipitate. On filtration, it gave sufficiently pure
dibromo sesamin 9. This was used for the debromination without
any purification. Pd2(dba)3/HCO2Na mediated debromination of 9
afforded the targeted (þ)-sesamin 1 (1.06 g, 64%) after purification
by crystallization from diethyl ether. We thus accomplished the
4. Experimental section
4.1. General methods
All the reactions were carried out under an atmosphere of argon
using oven-dried glassware. Commercially available reagents were
Scheme 4. Gram Scale chromatography free synthesis of (þ)-sesamin.
Scheme 5. Gram Scale chromatography free synthesis of (þ)-aschantin.

4
S. Hajra et al. / Tetrahedron 76 (2020) 131483
solvent was evaporated out under vacuum to afford the title
compound 8 as a colourless gummy liquid (0.16 g). HRMS (ESI-
TOF): m/z (M þ Na)þ calcd for C26
H
Br81BrO8SiNaþ 685.0267;
79
34
found 685.0229.
Step 3: Synthesis of compound 9: To the THF (1 mL) solution of
compound 8 was added 50% aqueous HCl (4 mL) at 0 ꢁC. The
reaction mixture was then allowed to stir at room temperature
for 48 h. The whole mixture was diluted with H2O (20 mL) and
the aqueous layer was extracted with EtOAc (3 ꢂ 25 mL). The
combined organic layer was washed with brine and dried over
Na2SO4. Solvent evaporation under vacuum gave the crude
product which was purified by column chromatography (Hex-
anes/EtOAc 9:1) and afforded compound 9 as a white solid
Scheme 6. Synthesis of sesamin analogue.
(0.086 g, 72% over three steps). Rf 0.6 (Hexanes/EtOAc 9:1);
20
[
a
]
¼ ꢀ12 (c ¼ 0.97 CHCl3); mp 188e190 ꢁC; 1H NMR
D
(400 MHz, CDCl3)
d
6.99 (s, 2H), 6.95 (s, 2H), 5.98 (d, J ¼ 1.2 Hz,
purchased and used without further purification. Solvents were
dried and distilled following standard literature procedure. Flash
column chromatography was performed using silica gel (230e400
mesh) when required. Analytical TLC was performed on
aluminium-backed plates coated with silica gel 60 with F254 indi-
cator and compounds were visualized by irradiation of UV light.
The 1H NMR spectra were recorded with 400 MHz and 800 MHz
and 13C NMR spectra recorded with 100 MHz and 200 MHz using
2H), 5.96 (d, J ¼ 1.2 Hz, 2H), 5.09 (d, J ¼ 2.8 Hz, 2H), 4.48 (pseudo
t (dd), J ¼ 8.4 Hz 2H), 4.18 (dd, J ¼ 9.2, 4.8 Hz, 2H), 2.94 (m, 2H).;
13C NMR (100 MHz, CDCl3)
d 147.61, 147.49, 134.74, 112.76, 111.81,
106.81, 101.74, 84.50, 73.50, 54.21.; HRMS (ESI-TOF) m/z
79
79
(M
C
þ
Na)þ calcd for C20 Br2O6Naþ/C20 Br81BrO6Naþ/
H H
16 16
81
H
Br2O6Naþ 532.9206, 534.9186 and 536.9165; found
20 16
532.9202, 534.9188 and 536.9164, respectively.
CDCl3 or DMSO‑d6. 1H NMR chemicals shift are expressed in ppm(
d)
relative to
chemical shift are expressed in ppm(
CDCl3 and
d
¼ 7.27 for CDCl3 and
d
¼ 2.50 for DMSO‑d6. 13C NMR
4.3. Synthesis of (þ)-sesamin 1
d
) relative to
d
¼ 77.00 for
d
¼ 39.51 for DMSO‑d6 resonance. HRMS and Electron
To an oven dried two-necked RB was added compound 9 (0.08 g,
0.157 mmol) in DMF (0.8 mL). HCO2Na (0.053 g, 0.78 mmol) was
added to that solution. Argon was flushed for 10 times into this
mixture. Pd2dba3 (0.0072 g, 0.0078 mmol) was added then and
argon was flushed for additional 3 times. The mixture was heated to
80 ꢁC for 12 h. After completion of the reaction, water (25 mL) was
added to that. The aqueous part was extracted with EtOAc
(3 ꢂ 35 mL). The combined organic layer was washed with brine,
dried over Na2SO4. Solvent evaporation under vacuum gave the
spray ionization (ESI) mass spectrometry (MS) experiment were
performed on Agilent Technologies 6530 Accurate-Mass Q-TOF LC/
MS. Optical rotation value was measured on a Digipol 781 M6U
Automatic Polarimeter. Enantiomeric excess (ee) was measured by
HPLC analysis with chiral stationary phase. The melting points
(mps) were determined using a STUART SMP30 melting point
apparatus and are uncorrected.
O-TBS lactone 3 was prepared in grams scale following our
earlier protocol [7c].
crude product which was purified by column chromatography
27
(0.053 g 96%). Rf 0.35 (Hexanes/EtOAc 9:1); [
a
]
D
¼ þ68 (c ¼ 0.5
4.2. Synthesis of (1S,3aR,4S,6aR)-1,4-bis(6-bromobenzo[d][1,3]
dioxol-5-yl)tetrahydro-1H,3H-furo[3,4-c]furan 9
CHCl3)
[
lit [6f]. þ68.9 in CHCl3]; mp 124e126 ꢁC [lit[8].
122e123 ꢁC]; 1H NMR (400 MHz, CDCl3)
d 6.86 (s, 2H), 6.81 (d, AB
type, J ¼ 8.5 Hz, 2H), 6.78 (d, AB type, J ¼ 8.5 Hz, 2H), 5.96 (s, 4H),
4.72 (d, J ¼ 3.4 Hz, 2H), 4.24 (pseudo t, J ¼ 7.6 Hz, 2H), 3.88 (dd,
Step 1: Synthesis of compound 7: To an oven dried two-necked
RB was added TBS-lactone 3 (0.1 g, 0.23 mmol) in THF (2 mL). It
was cooled to ꢀ78 ꢁC. LiHMDS (0.28 mL, 0.28 mmol, 1 M in THF)
was added to it and stirred for 45 min. 6-bromopiperonal 4a
(0.073 g, 0.32 mmol) in THF (1 mL) was added to the reaction
mixture and stirred for additional 6 h at the same temperature.
After complete consumption of the TBS Lactone 3, the reaction
mixture was quenched by 1M AcOH solution in THF. The tem-
perature of the mixture was then raised to room temperature. It
was diluted with H2O (20 mL). The aqueous part was extracted
with EtOAc (3 ꢂ 35 mL). The combined organic layer was
washed with brine (10 mL) and was dried over Na2SO4. The
solvent was evaporated under vacuum to afford the crude
compound as a gummy yellow liquid. It was triturated before
using for the Step 2 without further purification (0.18 g crude
J ¼ 9.3, 3.1 Hz, 2H), 3.06 (s, 2H).; 13C NMR (100 MHz, CDCl3)
d 147.93,
147.08, 134.98, 119.36, 108.17, 106.48, 101.06, 85.77, 71.68, 54.29;
HRMS (ESI-TOF) m/z (M þ Na)þ calcd for C20H18O6Naþ 377.0980;
found 377.1001.
4.4. Synthesis of 5-bromo-6-((1S,3aR,4S,6aR)-4-(3,4,5-
trimethoxyphenyl)tetrahydro-1H,3H-furo[3,4-c]furan-1-yl)benzo[d]
[1,3]dioxole 11
Step 1: To an oven dried two-necked RB was added TBS-lactone
3 (0.1 g, 0.23 mmol) in THF (2 mL). It was cooled to ꢀ78 ꢁC.
LiHMDS (0.28 mL, 0.28 mmol, 1 M in THF) was added to it and
stirred for 45 m. 3, 4, 5-trimethoxybenzaldehyde 4b (0.063 g,
0.32 mmol) in THF (1 mL) was added to the reaction mixture and
stirred for additional 6 h at the same temperature. After
completion of the reaction the reaction was quenched by 1M
AcOH solution in THF. The temperature of the mixture was then
raised to room temperature. It was diluted with H2O (20 mL).
The aqueous part was extracted with EtOAc (3 ꢂ 35 mL). The
combined organic layer was washed with brine (10 mL) and was
dried over Na2SO4. The solvent was evaporated under vacuum to
afford the crude aldol product as a gummy yellow liquid. It was
weight). HRMS (ESI-TOF) m/z (M
þ
Na)þ calcd for
79
C H
26 30
Br81BrO8SiNaþ 680.9954; found 680.9932.
Step 2: Synthesis of compound 8: To the THF (1 mL) solution of
crude 7 was added to in situ generated CaBH4 (CaCl2 0.153 g,
1.38 mmol; NaBH4 0.105 g, 2.76 mmol) in THF/MeOH (1:1; 2 mL)
ꢁ
at 0 C. It was allowed to stir at room temperature for 6 h. The
completion of the reaction was monitored by mass spectroscopy
analysis. The reaction was quenched with solid NH4Cl and then
filtered through celite pad. The filtrate was collected. The
triturated before using for the Step
2 without further

S. Hajra et al. / Tetrahedron 76 (2020) 131483
5
purification (0.176 g crude weight). HRMS (ESI-TOF): m/z
and stirred for 45 min. 6-bromopiperonal 4a (1.12 g, 4.88 mmol) in
THF (5 mL) was added to the reaction mixture and stirred for
additional 6 h at the same temperature. After complete consump-
tion of the TBS Lactone, it was allowed to warm to 0 ꢁC and then the
reaction mixture was quenched by 1M AcOH solution in THF. To this
reaction mixture was added to in situ generated CaBH4 (CaCl2 3.1 g,
27.9 mmol; NaBH4 2.12 g, 55.8 mmol) in THF/MeOH (1:1, 15 mL) at
0 ꢁC. It was allowed to stir at room temperature for 6 h. At this stage,
the mass spectroscopy analysis showed the complete conversion to
tri-ol. The reaction was quenched with solid NH4Cl and then
filtered through celite pad. The filtrate was collected and the vol-
ume was reduced to 5 mL under vacuum. It was then cooled to 0 ꢁC.
50% aqueous HCl (20 mL) was added to it. The reaction mixture was
then allowed to stir at room temperature for 48 h. The whole
mixture was diluted with H2O (50 mL) and cooled to 10 ꢁC. The
white precipitate formed was filtered out and dried to get the
compound 9 as a white solid (1.6 g, 66%). It was taken directly for
the next reaction without further purification.
79
(M þ Na)þ calcd for C28
H
37
BrO9SiNaþ 649.1267; found 649.1215.
Step 2: To the THF (1 mL) solution of the above aldol compound
was added to in situ generated CaBH4 (CaCl2 0.153 g, 1.38 mꢁmol;
NaBH4 0.105 g, 2.76 mmol) in THF/MeOH (1:1; 2 mL) at 0 C. It
was allowed to stir at room temperature for 6 h. At this stage, the
mass spectroscopy analysis showed the complete conversion to
tri-ol. The reaction was quenched with solid NH4Cl and then
filtered through celite pad. The filtrate was collected. The sol-
vent was evaporated out under vacuum to afford the O-TBS-
tetraol as a colourless gummy liquid (0.16 g). HRMS (ESI-TOF):
79
m/z (M þ Na)þ calcd for C28
H
BrO9SiNaþ 651.1601; found
41
651.1525.
Step 3. Synthesis of compound 11: To the THF (1 mL) solution of
the above crude tetraol was added 50% aqueous HCl (2 mL) at
0
ꢁC and then raised it to room temperature. The reaction was
stirred for an additional 48 h. The whole mixture was diluted
with H2O (20 mL) and the aqueous layer was extracted with
EtOAc (3 ꢂ 35 mL). The combined organic layer was washed
with brine, dried over Na2SO4. Solvent evaporation under vac-
uum gave the crude product which was purified by column
chromatography (Hexanes/EtOAc 8:2) and afforded the com-
Second-Pot: To an oven dried two-necked RB was added com-
pound 9 (1.6 g, 3.12 mmol) in DMF (14 mL). HCO2Na (1.06 g,
15.6 mmol) was added to that solution. Argon was flushed for 10
times into this mixture. Pd2dba3 (0.142 g, 0.156 mmol) was added
then and argon was flushed for additional 3 times. The mixture was
heated to 80 ꢁC for 12 h. After completion of the reaction, it was
cooled to room temperature and then diluted with EtOAc (250 mL).
The mixture was then filtered over a celite bed. The filtrate was
collected. The solvent was evaporated out under vacuum. The crude
obtained was crystallized from diethylether to afford the (þ)-ses-
pound 11 as a yellowish solid (0.069 g. 62% over three steps). Rf
20
0.4 (Hexanes/EtOAc 4:1); [
a
]
D
¼ þ17 (c ¼ 0.51 CHCl3); mp
153e155 ꢁC; 1H NMR (400 MHz, CDCl3)
d 7.01 (s,1H), 6.96 (s,1H),
6.58 (s, 2H), 5.98 (d, J ¼ 3.5 Hz, 2H), 5.10 (d, J ¼ 3.8 Hz, 1H), 4.67
(d, J ¼ 6.0 Hz, 1H), 4.50 (pseudo t (dd), J ¼ 8.5 Hz, 1H), 4.28 (dd,
J ¼ 9.2, 6.6 Hz, 1H), 4.11 (dd, J ¼ 9.3, 5.7 Hz, 1H), 4.03 (dd, J ¼ 9.3,
3.9 Hz, 1H), 3.88 (s, 6H), 3.84 (s, 3H), 3.11e2.92 (m, 2H).; 13C
amin as a white solid (1.06 g, 96%). Rf 0.35 (Hexaness/EtOAc 9:1);
27
[a
]
¼ þ68 (c ¼ 0.5 CHCl3) [lit [6f]. þ68.9 in CHCl3]; mp 124e126 ꢁC
NMR (100 MHz, CDCl3)
112.9, 111.9, 106.6, 102.8, 101.8, 85.6, 85.5, 74.1, 71.7, 60.8, 56.1,
54.6, 54.; HRMS (ESI-TOF): m/z (M
Na)þ calcd for
BrO7Naþ 479.0700 and 481.0680; found
d 153.4, 147.6, 147.5, 137.4, 136.5, 134.8,
D
[ lit [8]. 122e123 ꢁC]; 1H NMR (400 MHz, CDCl3)
d 6.86 (s, 2H), 6.81
þ
(d, AB type, J ¼ 8.5 Hz, 2H), 6.78 (d, AB type, J ¼ 8.5 Hz, 2H), 5.96 (s,
4H), 4.72 (d, J ¼ 3.4 Hz, 2H), 4.24 (pseudo t (dd), J ¼ 7.6 Hz, 2H), 3.88
(dd, J ¼ 9.3, 3.1 Hz, 2H), 3.06 (s, 2H).; 13C NMR (100 MHz, CDCl3)
79
81
C
H H
BrO7Naþ/C22
22 23 23
479.0695 and 481.0682, respectively.
d
147.93, 147.08, 134.98, 119.36, 108.17, 106.48, 101.06, 85.77, 71.68,
54.29; HRMS (ESI-TOF): m/z [(M þ Na)þ calcd for C20H18O6Naþ
4.5. Synthesis of (þ)-aschantin 2
377.1001; found 377.0984.
To an oven dried two-necked RB were added compound 11
(0.06 g, 0.12 mmol) and HCO2Na (0.041 g, 0.6 mmol) in DMF
(0.6 mL). Argon was flushed for 10 times into this mixture. Pd2dba3
(0.005 g, 0.044 mmol) was added then and argon was flushed for
additional 3 times. The mixture was heated to 80 ꢁC for 12 h. After
completion of the reaction, water (20 mL) was added to that. The
aqueous part was extracted with EtOAc (3 ꢂ 35 mL). The combined
organic layer was washed with brine and dried over Na2SO4. Sol-
vent evaporation under vacuum gave the crude product which was
purified by column chromatography (Hexanes/EtOAc 8:2) and gave
4.7. Gram-scale chromatography-free ‘two-pot’ total synthesis of
(þ)-aschantin 2
First-Pot: To an oven dried two-necked RB was added TBS-
lactone 3 (2 g, 4.65 mmol) in THF (30 mL). It was cooled
to ꢀ78 ꢁC. LiHMDS (5.58 mL, 5.58 mmol,1 M in THF) was added to it
and stirred for 45 m. 3, 4, 5-trimethoxybenzaldehyde 5b (0.957 g,
4.88 mmol) in THF (5 mL) was added to the reaction mixture and
stirred for additional 6 h at the same temperature. After completion
of the reaction it was allowed to warm at 0 ꢁC and then the reaction
mixture was quenched by 1M AcOH solution in THF. To this reaction
mixture was added to in situ generated CaBH4 (CaCl2 3.1 g,
27.9 mmol; NaBH4 2.12 g, 55.8 mmol) in THF/MeOH (1:1; 15 mL) at
0 ꢁC. It was allowed to stir at room temperature for 6 h. At this stage,
the mass spectroscopy analysis showed the complete conversion to
tri-ol. The reaction was quenched with solid NH4Cl and then
filtered through celite pad. Filtrate was collected and volume was
reduced to 5 mL and keep at 0 ꢁC and then 50% aqueous HCl (20 mL)
was added to that and transferred it to room temperature and
stirred for an additional 48 h. After completion of the reaction the
whole mixture was diluted with H2O (50 mL) and then cooled to
10 ꢁC. The precipitate formed was filtered out to get the crude
compound as a yellowish white solid. It was used for the next re-
action without further purification (1.27 g. 57%).
aschantin 2 as a colourless solid (0.53 g, 91%). Rf 0.25 (Hexanes/
27
EtOAc 4:1); [
a]
¼ þ64.1 (c ¼ 0.32 CHCl3) [ lit [6c]. þ65 in CHCl3];
D
mp 122e124 ꢁC [ lit [6c]. 122 ꢁC]; 1H NMR (400 MHz, CDCl3)
d 6.86
(s, 1H), 6.82 (d, J ¼ 8 Hz, 1H), 6.79 (d, J ¼ 8 Hz, 1H), 6.58 (s, 2H), 5.96
(s, 2H), 4.75e4.70 (m, 2H), 4.28 (td, J ¼ 9.5, 6.0 Hz, 2H), 3.93e3.90
(m, 2H), 3.88 (s, 6H), 3.85 (s, 3H), 3.08 (q, J ¼ 5.0, 4.1 Hz, 2H).; 13C
NMR (100 MHz, CDCl3) d 153.4,147.6,147.5,137.4,136.5,134.8,112.9,
111.9, 106.6, 102.8, 101.8, 85.6, 85.5, 74.1, 71.7, 60.8, 56.1, 54.6, 54.;
HRMS (ESI-TOF): m/z (M þ H)þ calcd for C22H25O7þ 401.1600; found
401.1593.
4.6. Gram-scale chromatography-free ‘two-pots’ total synthesis of
(þ)-sesamin 1
First-Pot: To an oven dried two-necked RB was added TBS-
lactone 3 (2 g, 4.65 mmol) in THF (30 mL). It was cooled
to ꢀ78 ꢁC. LiHMDS (5.58 mL, 5.58 mmol, 1 M in THF) was added to it
Second-Pot: To an oven dried two-necked RB were added
compound 11 (1.27 g, 2.65 mmol) and HCO2Na (0.54 g 7.95 mmol)
in DMF (5 mL). Argon was flushed for 10 times into this mixture.

6
S. Hajra et al. / Tetrahedron 76 (2020) 131483
Pd2dba3 (0.12 g 0.132 mmol) was added then and argon was flushed
for additional 3 times. The mixture was heated to 80 ꢁC for 12 h.
After completion of the reaction, it was cooled to room temperature
and then diluted with EtOAc (250 mL). The mixture was then
filtered over a celite bed. The filtrate was collected. The solvent was
evaporated out under vacuum. The crude obtained was crystalized
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131483.
References
from diethylether/hexaness to afford the title compound as a white
27
solid (0.93 g, 91%). Rf 0.25 (Hexanes/EtOAc 4:1); [
a
]
¼ þ64.1
D
[1] (a) C. Vaxelaire, P. Winter, M. Christmann, Angew. Chem. Int. Ed. 50 (2011)
3605e3607;
(b) Y. Hayashi, Chem. Sci. 7 (2016) 866e880.
[2] a) R.D. Harworth, J. Chem. Soc. (1942) 448e456;
(c ¼ 0.32 CHCl3) [lit [6c]. þ65 in CHCl3] mp 122e124 ꢁC [ lit [6c].
122 ꢁC]; 1H NMR (400 MHz, CDCl3)
d
6.86 (s, 1H), 6.82 (d, J ¼ 8 Hz,
1H), 6.79 (d, J ¼ 8 Hz, 1H), 6.58 (s, 2H), 5.96 (s, 2H), 4.75e4.70 (m,
2H), 4.28 (td, J ¼ 9.5, 6.0 Hz, 2H), 3.93e3.90 (m, 2H), 3.88 (s, 6H),
3.85 (s, 3H), 3.08 (q, J ¼ 5.0, 4.1 Hz, 2H).; 13C NMR (100 MHz, CDCl3)
b) D.C. Ayres, J.D. Loike, Cambridge University Press, Cambridge, 1990;
c) Q. Song, N.H. Fischer, Rev. Soc. Quim. Mex. 43 (1999) 211e218;
d) M. Saleem, J.H. Kim, M.S. Ali, Y.S. Lee, Nat. Prod. Rep. 22 (2005) 696e716;
e) V. Habauzit, M.N. Horcajada, Phytochemistry Rev. 7 (2008) 313e344;
f) W.R. Cunha, M.L.A.E. Silva, R.C.S. Veneziani, S. Ricardo, J. Kenupp, Phytochem.
Glob. Perspect. Role Nutr. Health (2012);
d
153.4, 147.6, 147.5, 137.4, 136.5, 134.8, 112.9, 111.9, 106.6, 102.8,
101.8, 85.6, 85.5, 74.1, 71.7, 60.8, 56.1, 54.6, 54.; HRMS (ESI-TOF): m/z
[(M þ H)þ calcd for C22H25Oþ7 401.1600; found 401.1604.
g) J. Zhang, J. Chen, Z. Liang, C. Zhao, Chem. Biodivers. 11 (2014) 1e54.
[3] a) E. Okuyama, K. Suzumura, M. Yamazaki, Chem. Pharm. Bull. 43 (1995)
2200e2204;
4.8. Synthesis of (1S,3aR,4S,6aR)-1,4-bis(6-phenylbenzo[d][1,3]
dioxol-5-yl)tetrahydro-1H,3H-furo[3,4-c]furan 12
b) K. Hashimoto, T. Yanagisawa, Y. Okui, Y. Ikeya, M. Maruno, T. Fujita, Planta
Med. 60 (1994) 124e127;
c) M. Takasaki, T. Konoshima, I. Yasuda, T. Hamano, H. Tokuda, Biol. Pharm. Bull.
20 (1997) 776e780;
To a 10 mL oven dried double neck RB flask was added com-
pound 9 (0.05 g, 0.098 mmol) in 1,4- dioxane: H2O (9:1) (2.0 mL)
under argon. Pd2dba3 (0.018 g, 0.019 mmol), K3PO4 (0.084 g,
0.392 mmol), tricyclohexylphosphine (0.011g, 0.039 mmol) and
phenylboronic acid (0.028 g, 0.235 mmol) were subsequently
added. The reaction mixture was then degassed with argon
following freeze-pump-thaw technique. It was then heated to
100 ꢁC on a preheated oil-bath for 8 h. Upon completion of the
reaction, water (20 mL) was added and the organic mixture was
extracted with EtOAc (3 ꢂ 50 mL). The combined organic extracts
were washed with water (20 mL), washed with brine, dried over
Na2SO4 and concentrated in vacuo. The crude product obtained was
purified by column chromatography to afford the title compound
(yield 0.041 g; 82%) as a white solid. mp 178e180 ꢁC. Rf 0.25
d) Y.M. Chiung, H. Hayashi, H. Matsumoto, T. Otani, K. Yoshida, M.Y. Huang,
R.X. Chen, J.R. Liu, M.J. Nakayama, Antibiot 47 (1994) 487e491;
e) W.D. MacRae, G. Towers, Phytochemistry 23 (1984) 1207e1220;
f) S. Iwakami, Y. Ebizuka, U. Sankawa, Heterocycles 30 (1990) 795e798;
g) S. Iwakami, J.B. Wu, Y. Ebizuka, U. Sankawa, Chem. Pharm. Bull. 40 (1992)
1196e1198;
i) K. Ichikawa, T. Kinoshita, S. Nishibe, U. Sankawa, Chem. Pharm. Bull. 34 (1986)
3514e3517.
[4] a) Y.Y. Chao, I.S. Chen, J.L. Yeh, J.J. Chen, Y.C. Ko, J.S. Cheng, C.P. Liu, Y.K. Lo, W. Su,
K.J. Chou, Eur. J. Pharmacol. 443 (2002) 31e38;
b) Y.Y. Chao, C.R. Jan, Y.C. Ko, J.J. Chen, B.P. Jiann, Lu, W.C. Chen, W. Su, I.S. Chen,
Life Sci. 70 (2002) 3109e3121;
c) Y.Y. Chao, W. Su, C.R. Jan, Y.C. Ko, J.J. Chen, J.S. Cheng, C.P. Liu, Y.K. Lo,
K.J. Chou, K.C. Lee, Arch. Toxicol. 75 (2002) 695e702;
d) J.S. Kim, J.Y. Kim, H.J. Lee, H.J. Lim, Y. Lee da, H. Kim do, J.H. Ryu, Phytother
Res. 24 (2010) 748e753;
e) R. Ortet, S. Prado, E.L. Regalado, F.A. Valeriote, J. Media, J. Mendiola,
O.P. Thomas, J. Ethnopharmacol. 138 (2011) 637e640;
f) C.J. Lee, J.H. Jang, J.Y. Lee, M.H. Lee, Y. Li, H.W. Ryu, K.I. Choi, Z. Dong, H. S Lee,
S.R. Oh, Carcinogenesis 36 (2015) 1223e1234;
g) S.S. Kwon, J.H. Kim, H.U. Jeong, Y.Y. Cho, S.R. Oh, H.S. Lee, Molecules 21 (2016)
554.
(Hexanes/EtOAc 7:1); 1H NMR (400 MHz, CDCl3)
d 7.41e7.32 (m,
6H), 7.23 (d, J ¼ 7.2 Hz, 4H), 6.90 (s, 2H), 6.68 (s, 2H), 5.96 (s, 4H),
4.73 (d, J ¼ 3.4 Hz, 2H), 3.70 (dd, J ¼ 9.2, 6.6 Hz, 2H), 3.14 (dd, J ¼ 9.2,
4.0 Hz, 2H), 2.77 (d, J ¼ 3.2 Hz, 2H). 13C NMR (100 MHz, CDCl3)
[5] For the racemic synthesis of Sesamin and Aschantin: a) M. Beroza,
M.S. Schechter, J. Am. Chem. Soc. 78 (1956) 1242e1247;
b) K. Orito, K. Yorita, H. Suginome, Tetrahedron Lett. 32 (1991) 5999e6002;
c) H. Suginome, K. Orito, K. Yorita, M. Ishikawa, N. Shimoyama, T. Sasaki, J. Org.
Chem. 60 (1995) 3052e3064;
d
147.1, 146.4, 140.8, 134.8, 133.0, 129.4, 128.4, 127.2, 110.3, 105.8,
101.1, 82.7, 72.0, 55.0. HRMS (ESI-TOF): m/z (M þ Na)þ calcd for
C
22H22O9Naþ 529.1627; found 529.1619.
d) K.K. Rana, C. Guin, S.C. Roy, Tetrahedron Lett. 41 (2000) 9337e9338;
e) S.C. Roy, K.K. Rana, C. Guin, J. Org. Chem. 67 (2002) 3242e3248.
[6] For the asymmetric synthesis of Sesamin and Aschantin: a) S. Takano,
T. Ohkawa, S. Tamori, S. Satoh, K. Ogasawara, J. Chem. Soc., Chem. Commun.
(1988) 189e191;
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
b) K. Samizu, K. Ogasawara, Chem. Lett. (1995) 543e544;
c) D. Enders, V. Lausberg, G.D. Signore, O.M. Berner, Synthesis
4 (2002)
515e522;
d) N.A. Swain, R.C.D. Brown, G. Bruton, J. Org. Chem. 69 (2004) 122e129;
e) J.C. Kim, K.H. Kim, J.C. Jung, O.S. Park, Tetrahedron Asymmetry 17 (2006)
3e6;
Acknowledgements
f) M. Inai, R. Ishikawa, N. Yoshida, N. Shirakawa, Y. Akao, Y. Kawabe, T. Asakawa,
M. Egi, Y. Hamashima, T. Kan, Synthesis 47 (2015) 3513e3521.
[7] a) S. Hajra, A.K. Giri, J. Org. Chem. 73 (2008) 3935e3937;
b) S. Hajra, A.K. Giri, S. Hazra, J. Org. Chem. 74 (2009) 7978e7981;
c) S. Hajra, S. Garai, S. Hazra, Org. Lett. 19 (2017) 6530e6533.
[8] R.W. Doskotch, F.S. El-Feraly, Can. J. Chem. 47 (1969) 1139e1142.
This research was supported by Council of Scientific and In-
dustrial Research (Govt. of India), New Delhi (02(0184)/14/EMR-II).
SG thanks UGC, New Delhi and B. S. thanks DST-INSPIRE for their
research fellowship, respectively.