Concise synthesis and confirmation of the absolute configurations of naturally occurring bioactive 2,7′-cyclolignans

Article abstract of DOI:10.1016/j.tetlet.2021.152827

A concise asymmetric synthesis of naturally occurring bioactive 2,7′-cyclolignans, namely 4,4′-dihydroxy-3′,5,5′-trimethoxy-2,7′-cyclolignan and 4,4′-dihydroxy-3,3′,5-trimethoxy-2,7′-cyclolignan, possessing the uncommon 8,8′-syn dimethyl stereochemistry and unsymmetrical C-6 units with 7′,8′-anti-orientation is described using a substrate-controlled stereoselective Friedel-Crafts cyclization as the key step. The products were obtained in good yields with high stereoselectivity. The absolute configurations of natural 4,4′-dihydroxy-3′,5,5′-trimethoxy-2,7′-cyclolignan and those of natural 4,4′-dihydroxy-3,3′,5-trimethoxy-2,7′-cyclolignan were assigned as (7′S,8S,8′S) and (7′R,8R,8′R), respectively, based on the experimental circular dichroism (CD) spectra of the corresponding synthesized compounds.

Full text of DOI:10.1016/j.tetlet.2021.152827

Tetrahedron Letters 66 (2021) 152827
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise synthesis and confirmation of the absolute configurations
of naturally occurring bioactive 2,70-cyclolignans
⇑
Nannaphat Chumsri, Chutima Kuhakarn, Pawaret Leowanawat, Vichai Reutrakul, Darunee Soorukram
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
A concise asymmetric synthesis of naturally occurring bioactive 2,70-cyclolignans, namely 4,40-dihy-
droxy-30,5,50-trimethoxy-2,70-cyclolignan and 4,40-dihydroxy-3,30,5-trimethoxy-2,70-cyclolignan, pos-
sessing the uncommon 8,80-syn dimethyl stereochemistry and unsymmetrical C-6 units with 70,80-anti-
orientation is described using a substrate-controlled stereoselective Friedel-Crafts cyclization as the
key step. The products were obtained in good yields with high stereoselectivity. The absolute configura-
tions of natural 4,40-dihydroxy-30,5,50-trimethoxy-2,70-cyclolignan and those of natural 4,40-dihydroxy-
3,30,5-trimethoxy-2,70-cyclolignan were assigned as (70S,8S,80S) and (70R,8R,80R), respectively, based on
the experimental circular dichroism (CD) spectra of the corresponding synthesized compounds.
Ó 2021 Elsevier Ltd. All rights reserved.
Article history:
Received 13 November 2020
Revised 23 December 2020
Accepted 5 January 2021
Available online 23 January 2021
Keywords:
Lignans
Podophyllotoxin
2,70-Cyclolignan
1-Arylnaphthalene
Asymmetric synthesis
Introduction
biological profiles of 1–3, we were inspired to develop a concise
asymmetric approach to access 1 and 2 and their derivatives. The
Podophyllotoxin and related aryltetralin cyclolignans are
important natural products which have received widespread atten-
tion in the pharmaceutical industry due to their remarkable biolog-
ical activities including antiviral, antitumor, anti-oxidant,
antimicrobial and anti-malarial properties [1–3]. Aiming at
improving the bioactivities, water solubility, and decreasing the
toxicity of these natural compounds, current research on the isola-
tion [4–8], synthesis [9–15], and structureꢀactivity relationship
(SAR) studies of podophyllotoxin derivatives and related arylte-
tralin cyclolignans attracts much attention and is an active area
in chemistry and biology.
goals of the present work were not only to facilitate the biological
activity screening of 1 and 2 and their derivatives, but also to con-
firm the reported absolute configurations which are crucial for SAR
studies. Structurally, 1 and 2 share a rare 8,80-syn dimethyl stereo-
chemistry and unsymmetrical C-6 units (the two aromatic rings)
with 70,80-anti orientation. The atropdiastereomers were not
reported for both 1 and 2 suggesting free rotation around the
10,70 bond. Although there are numerous reports regarding the syn-
thesis of 2,70-cyclolignans [17–22], the asymmetric synthesis of 1
and 2 has not been reported.
As outlined in Scheme 1, the synthesis of 1 and the enantiomer
of 2 (ent-2) was planned through key substrates 1,4-diarylbutane
derivatives 4a and 4b, respectively. Upon treatment of 4a and 4b
with a mild acid, an oxocarbenium ion I should be readily formed
which subsequently undergoes a substrate-controlled stereoselec-
tive Friedel-Crafts cyclization to provide 1 and ent-2, respectively.
The stereoselectivity of the cyclization is proposed to be governed
by the inherent stereochemistry of the methyl groups. 1,4-
Diarylbutanes 4a and 4b could be readily prepared from alkene
(2S,3R)-5 after oxidative cleavage of the double bond to yield the
respective aldehyde, followed by reaction with an aryllithium.
Alkene (2S,3R)-5 could be obtained from aryl ketone (2R,3R)-6 after
reduction of the carbonyl group followed by deoxygenation.
Finally, the synthesis of aryl ketone (2R,3R)-6 was planned to start
from Weinreb amide (2R,3R)-7 containing the 2,3-anti-dimethyl
moieties required for 1 and ent-2.
4,40-Dihydroxy-30,5,50-trimethoxy-2,70-cyclolignan (1) and 4,40-
dihydroxy-3,30,5-trimethoxy-2,70-cyclolignan (2) are naturally
occurring 2,70-cyclolignans isolated from an ethanol extract of
the barks of Machilus robusta [5] and Macchilus wangchianan [6],
respectively (Fig. 1). It was reported that 1 reduced DL-galac-
tosamine (GalN)-induced hepatocyte (WBF344 cells) damage and
2 inhibited the release of b-glucuronidase in rat polymorphonu-
clear leukocytes (PMNs) induced by platelet-activating factor
(PAF). SG-1 (3), a fully methylated derivative of 1 obtained via a
semi-synthesis, was identified as a potent HIV-1 non-nucleoside
reverse transcriptase inhibitor [16]. In light of the interesting
⇑
Corresponding author.
E-mail address: darunee.soo@mahidol.ac.th (D. Soorukram).
https://doi.org/10.1016/j.tetlet.2021.152827
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

N. Chumsri, C. Kuhakarn, P. Leowanawat et al.
Tetrahedron Letters 66 (2021) 152827
Fig. 1. The structures of podophyllotoxin, 1, 2, ent-2, and SG-1 (3).
Scheme 1. Retrosynthetic analysis of 1 and ent-2.
Oxidative cleavage of the double bond of (2S,3R)-10a using OsO4
(5 mol%) and NMO (3 equiv.) in a mixture of water and CH2Cl2 at
room temperature for 14 h (overnight) followed by treatment with
NaIO4 (2 equiv.) afforded the corresponding aldehyde. Without
chromatographic purification, the obtained aldehyde was treated
with [4-(benzyloxy)-3,5-dimethoxyphenyl]lithium to give alcohol
11a in 58% yield as a mixture of diastereomers (dr = 91:5:4).
Friedel-Crafts cyclization of 11a mediated by BF.3OEt2 (3 equiv.)
in dry CH2Cl2 provided the desired product 12a in 90% yield with
high diastereoselectivity (dr = 90:10). The relative stereochemistry
Results and discussion
The synthesis of 1 started from Weinreb amide (2R,3R)-7
(dr = 93:7, 99% ee) [23,24] which upon treatment with [4-(benzy-
loxy)-3-methoxyphenyl]lithium [freshly generated via lithium/
bromine exchange of 1-(benzyloxy)-4-bromo-2-methoxybenzene
(1.2 equiv.) using n-BuLi (1.6 M in hexanes) (1.2 equiv.) at
ꢀ78 °C for 10 min] gave aryl ketone (2R,3R)-8a (60% yield,
dr = 92:8, 1H NMR analysis) (Scheme 2). Subsequent reduction of
the carbonyl group of (2R,3R)-8a using NaBH4 (4 equiv.) in MeOH
at ꢀ78 °C gave the corresponding alcohol 9a in 91% yield as a mix-
ture of diastereomers (dr = 85:9:6). Deoxygenation of 9a using tri-
ethylsilane (Et3SiH) (5 equiv.) and boron trifluoride diethyl
etherate (BF.3OEt2) (3 equiv.) in dry CH2Cl2 at ꢀ20 °C rapidly took
place within approximately 3 min to provide the desired alkene
(2S,3R)-10a in a nearly quantitative yield (99% yield, dr = 93:7).
at the 70,80-position was determined by the coupling constant
3
0
0
between H-70 and H-80 ( J7 ,8 = 6.8 Hz) suggesting an anti relation-
ship between H-70 and H-80. Additionally, the stereochemistry of
12a was confirmed on the basis of NOESY experiments (see the
ESI). Finally, debenzylation of 12a was conducted [H2, Pd/C (2
equiv.), dry EtOAc, rt, 30 min] to afford 1 in nearly quantitative
2

N. Chumsri, C. Kuhakarn, P. Leowanawat et al.
Tetrahedron Letters 66 (2021) 152827
Scheme 2. Synthesis of 1 and ent-2.
yield (99% yield, dr = 94:6) which, after a single recrystallization
(CH2Cl2:hexanes), gave 1 with an improved diastereomeric ratio
(dr = 96:4). It should be noted that under standard hydrogenolysis
conditions [H2, Pd(OH)2/C, dry EtOAc, rt, overnight], 11a can be
converted to 1 with comparable efficiency (99% yield, dr = 91:9)
(Scheme 3). Using a similar synthetic pathway for 1, ent-2
(dr = 92:8) could be synthesized in a highly stereoselective manner
starting from the respective precursor (Scheme 2). To our delight,
ent-2 with dr = 98:2 was obtained after recrystallization (CH2Cl2:
hexanes).
At this stage, the substrate-controlled stereoselective Friedel-
Crafts cyclization of 11a and 11b leading to 12a and 12b with high
stereoselectivity should be discussed. As depicted in Scheme 4,
upon treatment of 11 with BF3. OEt2, an oxonium ion intermediate
I was generated and rapidly underwent cyclization through a more
favorable transition state III (II vs. III) leading to cyclized
intermediate IV. Deprotonation and re-aromatization of IV then
provided 12.
The synthesized compounds 1 (dr = 96:4) and ent-2 (dr = 98:2)
displayed similar spectroscopic data with those of the natural
Scheme 3. Hydrogenolysis of (2S,3S)-11a leading to 1.
3

N. Chumsri, C. Kuhakarn, P. Leowanawat et al.
Tetrahedron Letters 66 (2021) 152827
Scheme 4. Proposed mechanism for the substrate-controlled stereoselective Friedel-Crafts cyclization.
Fig. 2. The conformers of 1 and ent-2.
compounds previously reported in the literature (see the ESI).
Conclusion
A concise asymmetric synthesis of 2,70-cyclolignans, namely
Compound 1 favorably existed in conformer A (trans diaxial rela-
tionship between H-70 and H-80) according to the observed large
3
0
0
vicinal coupling constant between H-70 and H-80 ( J7 ,8 = 7.0 Hz;
180° dihedral angle). In contrast, ent-2 which more preferably
adopted conformer C (trans diequatorial relationship between H-
(70S,8S,80S)-4,40-dihydroxy-30,5,50-trimethoxy-2,70-cyclolignan (1)
and (70S,8S,80S)-4,40-dihydroxy-3,30,5-trimethoxy-2,70-cyclolignan
(ent-2) was described. Starting from a readily available chiral
Weinreb amide precursor, the synthesis of compounds 1 and ent-
2 bearing three contiguous stereocenters can be achieved with
high stereoselectivity in 28% overall yield after eight synthetic
transformations. The present work provides important information
on the stereochemistry of bioactive 2,70-cyclolignans which should
be useful for further SAR study. Additionally, the developed syn-
thetic approach should also be useful for the asymmetric synthesis
of various bioactive 2,70-cyclolignans especially those containing
the 8,80-syn dimethyl stereochemistry and unsymmetrical C-6
units.
70 and H-80; 60° dihedral angle) showed a small vicinal coupling
3
0
0
constant between H-70 and H-80 ( J7 ,8 = 2.3 Hz). NOESY experi-
ments were employed to further confirm the relative stereochem-
istry and preferred conformation assigned (Fig. 2). The
experimental circular dichroism (CD) spectrum of synthesized 1
was in close agreement with that of natural 1; a first negative Cot-
ton effect (CE) at 287 nm and a second positive CE near 272 nm
(see the ESI). By comparison of the specific rotation values [synthe-
25
20
sized 1, [
a]
+82.2 (c 0.1, CHCl3), and natural 1, [
a
]
+97 (c 0.1,
D
D
CHCl3)], the experimental CD spectra, and a review by Loike and
Ayres [25] stating that 70S-aryltetralins displayed a first negative
CE near 290 nm and a second positive CE near 270 nm while the
70R-configuration showed an opposite pattern, the absolute configu-
rations of synthesized 1 could be confirmed as (70S,8S,80S) and were
the same as those assigned for natural 1. In contrast, the experimen-
tal CD spectrum of ent-2 showed a first negative CE near 289 nm and
a second positive CE at 275 nm which is opposite to that reported for
natural 2. By comparison of the specific rotation values [ent-2,
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
25
20
[a]
+96.0 (c 0.03, CHCl3), and natural 2, [
a
]
ꢀ13 (c 0.03, CHCl3)]
Acknowledgements
D
D
and the patterns of the CD spectra, the absolute configurations of
synthesized ent-2 were thus concluded as (70S,8S,80S) which is the
enantiomer of natural 2 for which the enantiomeric purity was
implied to be 13.5% ee.
The authors acknowledge financial support from the Thailand
Research Fund (RSA6180025 and IRN58W0005), the Center of
Excellence for Innovation in Chemistry (PERCH-CIC), Ministry of
4

N. Chumsri, C. Kuhakarn, P. Leowanawat et al.
Tetrahedron Letters 66 (2021) 152827
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