Concise synthesis of (+)-β- and γ-apopicropodophyllins, and dehydrodesoxypodophyllotoxin

Article abstract of DOI:10.3390/molecules23113037

Herein, we present an expeditous synthesis of bioactive aryldihydronaphthalene lignans (+)-β- and γ-apopicropodophyllins, and arylnaphthalene lignan dehydrodesoxypodophyllotoxin. The key reaction is regiocontrolled oxidations of stereodivergent aryltetralin lactones, which were easily accessed from a nickel-catalyzed reductive cascade approach developed in our group.

Full text of DOI:10.3390/molecules23113037

molecules
Communication
Concise Synthesis of (+)-β- and
γ-Apopicropodophyllins,
and Dehydrodesoxypodophyllotoxin
Jian Xiao 1,2, Guangming Nan 1, Ya-Wen Wang 2 and Yu Peng 2,3,
*
1
University and College Key Lab of Natural Product Chemistry and Application in Xinjiang,
Yili Normal University, Yining 835000, China; xiaoj2012@lzu.edu.cn (J.X.);
nanguangming02@sohu.com (G.N.)
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China;
ywwang@swjtu.edu.cn
2
3
State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
*
Correspondence: pengyu@lzu.edu.cn
Academic Editors: David Barker and Derek J. McPhee
Received: 30 October 2018; Accepted: 17 November 2018; Published: 21 November 2018
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: Herein, we present an expeditous synthesis of bioactive aryldihydronaphthalene lignans
(+)- - and -apopicropodophyllins, and arylnaphthalene lignan dehydrodesoxypodophyllotoxin.
β
γ
The key reaction is regiocontrolled oxidations of stereodivergent aryltetralin lactones, which were
easily accessed from a nickel-catalyzed reductive cascade approach developed in our group.
Keywords: aryldihydronaphthalene lignan; arylnaphthalene lignan; oxidation; synthesis
1. Introduction
Lignans are a class of secondary metabolites in various plants, and most of them
have demonstrated interesting biological properties [
synthetic chemists [3,4
70,80-dihydronaphthalene (DHN) and 70-arylnaphthalene types are exemplified in Scheme 1a. Hong
and co-workers used organocatalytic domino Michael–Michael–aldol reactions to construct THN
1,2], thus attracting the attention of the
]. Some of 2,70-cyclolignans such as 7,8,80,70-tetrahydronaphthalene (THN),
skeleton of galbulin and realized its first enantioselective synthesis [
completed the first asymmetric synthesis of (
bond from in situ generated quinoid intermediate [
5
]. Barker and co-workers
0
−
)-cyclogalgravin based on a key construction of C2–C7
6
]. Notably, the other two structurally distinct class
of lignans could also be obtained from a common precursor in their syntheses. Ramana et al. proposed
a dehydrative cyclization of an aldehyde intermediate to build the DHN unit of sacidumlignan B,
whose subsequent aromatization led to the synthesis of sacidumlignan A [
7]. We were also involved in
this fascinating field and achieved the synthesis of these three molecules through Ueno–Stork radical
cyclization and Friedel–Crafts reaction [8,9]. However, almost all of the above syntheses applied
stepwise strategies (i.e., a sequence of C2–C70, C8–C80, then C1–C7 bonds formation in our previous
routes) for construction of the central core [10].
2. Results and Discussion
Recently, we completed a new synthesis of podophyllotoxin [11
as building block for the chemotherapeutic drugs etoposide and teniposide. The key reaction is
a Ni-catalyzed reductive tandem coupling [13 19] of dibromide that led to the simultaneous
construction of C8–C80 and C1–C7 bonds in THN framework of B (Scheme 1b). We envision that this
,12], an aryltetralin lignan used
–
A
Molecules 2018, 23, 3037; doi:10.3390/molecules23113037
www.mdpi.com/journal/molecules

Molecules 2018, 23, 3037
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aryltetralin lactone could serve as an advanced intermediate for the unified synthesis of the titled
arylnaphthalene, DHN and THN lignans
we disclosed the preliminary results.
C, by means of the regioselective late-stage oxidation. Herein,
Scheme 1.
(a) Several arylnaphthalene lignans and their DHN and THN derivatives; (b) Our
synthetic logic.
Starting from the commercially available 6-bromopiperonal and 3,4,5-trimethoxyphenyl bromide,
the chiral -bromo acetal was straightforwardly prepared as in gram-scale according to a known
route [11]. Under a fully intramolecular reductive nickel-catalysis ligated by ethyl crotonate (Scheme 2),
diastereodivergent (+)-deoxypicropodophyllin ( ) and (+)-isodeoxypodophyllotoxin ( ) were obtained
in 50% overall yield after a conversion of acetal moiety to the corresponding lactone. With aryltetralin
lactones and in hand, the designed regiocontrolled oxidation in central aliphatic ring could be
executed (vide infra).
β
1
2
3
2
3
Scheme 2. Reductive tandem cyclization for tetralin lactones.
0
0
0
First of all, the increase of an unsaturation degree at either C8–C8 or C7 –C8 location was pursued
in order to get (+)- -apopicropodophyllin ( ) and (+)- -apopicropodophyllin ( ) quickly. As shown
in Scheme 3, the introduction of a phenylselenyl group at C80 position of (+)-deoxypicropodophyllin
) was done by an initial enolization and subsequent quench with phenylselenyl bromide (PhSeBr)
at
78 ◦C. The generated products as two diastereoisomers (4a and 4b) were separated by column
β
5
γ
6
(2
−

Molecules 2018, 23, 3037
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chromatography on silica gel in 95% overall yield. The
α
-phenylselenide 4a is supposed to adopt a
pseudo-boat conformation, where the hydrogen atom at C8 is arranged cis to the -SePh. The requisite
syn-elimination of phenylselenoxide in situ generated from oxidation of 4a 20], eventually provided
(+)- -apopicropodophyllin ( ) with in vivo insecticidal activity against the fifth-instar larvae of
Brontispa longissima [21]. Its 1H NMR spectral data (Table S2) and optical rotation were in agreement
with the reported data by Toste and Meyers [22 23]. The structure was later unambiguously confirmed
by its single-crystal analysis (Figure 1) [24]. In contrast, the hydrogen atom at C70 is oriented at
cis-position of C80-PhSe in the favored half-chair conformer of
-phenylselenide 4b. Thus, a double
bond within C70–C80 was formed upon the subjection of 4b to m-CPBA, therefore affording to
(+)- -apopicropodophyllin (
) in 88% yield. As shown in Table S3, 1H NMR spectra of the synthetic
[
β
5
,
β
γ
6
6
was accord with the literature [25].
H
O
O
O
O
O
O
H
O
O
O
m-CPBA, NaHCO3
Se
O
O
O
H
CH2Cl2, 0 o
C
Ph
8'
8
(88%)
H
Se
H
Ar
OMe
OMe
(65%)
MeO
MeO
OMe
O
O
Ph
O
OMe
Ar = 3,4,5-trimethoxyphenyl
4a
5
(+)-β-Apopicropodophyllin ( )
H
O
LDA, PhSeBr
Syn-elimination
+
THF, −78 oC
H
H
O
O
MeO
OMe
O
O
O
H
O
O
O
OMe
(+)-Deoxypicropodophyllin (2)
O
SePh
m-CPBA, NaHCO3
Se
O
CH2Cl2, 0 o
C
H
Ph
8'
(88%)
7'
O
Ar
MeO
4b
OMe
MeO
OMe
H
O
OMe
OMe
(+)-γ-Apopicropodophyllin ( )
6
(30%)
Scheme 3. Regiodivergent oxidation of (+)-deoxypicropodophyllin (2).
Figure 1. X-ray crystal structure of (+)-β-apopicropodophyllin (5), selected H atoms have been omitted
for clarity.
Next, the potential aromatization within tetralin lactone was investigated. As shown in Scheme 4,
one-step conversion of (+)-isodeoxypodophyllotoxin ( ) to dehydrodesoxypodophyllotoxin ( ) was
3
7
realized in 56% yield promoted by a mixture of N-bromosuccinimide (NBS) and dibenzoyl peroxide
(BPO) in refluxing CCl4. The plausible mechanism of this tandem reaction would be radical
bromination [26] catalyzed by BPO occurs firstly, and a fast elimination of the resulting labile
benzylbromide followed by further oxidation, providing the central benzene ring in 7.
1H NMR
spectra data (Table S4) of synthetic dehydrodesoxypodophyllotoxin was consistent with previous
report [27].

Molecules 2018, 23, 3037
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Scheme 4. One-step conversion of tetralin to arylnaphthalene skeleton.
3. Materials and Methods
3.1. General Procedure
For product purification by flash column chromatography, SiliaFlash P60 (particle size: 40–63 µm
,
◦
pore size 60A) and petroleum ether (bp. 60–90 C) were used. All solvents were purified and
dried by standard techniques and distilled prior to use. All of experiments were conducted under
an argon or nitrogen atmosphere in oven-dried or flame-dried glassware with magnetic stirring,
unless otherwise specified. Organic extracts were dried over Na2SO4 or MgSO4, unless otherwise
noted. 1H and 13C-NMR spectra were taken on a Bruker AM-400, AM-600 and Varian mercury
300 MHz spectrometer with TMS as an internal standard and CDCl3 as solvent unless otherwise noted.
HRMS were determined on a Bruker Daltonics APEXII 47e FT-ICR spectrometer with ESI positive ion
mode. The X-ray diffraction studies were carried out on a Bruker SMART Apex CCD area detector
diffractometer equipped with graphite-monochromated Cu-K
measured on Kofler hot stage and are uncorrected.
α
radiation source. Melting points were
3.2. Synthesis of C9a-PhSe-Deoxypicropodophyllin (4a and 4b)
◦
A solution of
2
[
11] (100 mg, 0.25 mmol) in THF (8 mL) under argon was cooled to
−
78 C,
followed by the addition of freshly prepared LDA (0.5 mmol, 2.0 equiv). The stirred solution was
maintained at this temperature for 20 min, and a solution of PhSeBr (118 mg, 0.5 mm◦ol, 2.0 equiv)
in THF (3 mL) was then added. The resulting mixture was stirred for 20 min at
−
78 C, and then
quenched by water (1 mL). The mixture was extracted with EtOAc (2
organic layers were washed with water (2 8 mL) and brine (8 mL) respectively, dried over Na2SO4,
filtered and concentrated under reduced pressure. The crude product was purified by flash column
chromatography (petroleum ether/EtOAc = 4:1 petroleum ether/EtOAc =2:1) on silica gel to afford
4a (90 mg, 65% yield) as a white solid and 4b (42 mg, 30% yield) as a white solid. Characterization data
for 4a: Rf = 0.42 (petroleum ether/EtOAc = 1:1); 1H-NMR (400 MHz, CDCl3):
= 7.48 (d, J = 8.0 Hz,
×
30 mL). The combined
×
→
δ
1H), 7.47 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 7.2 Hz, 1H), 7.28 (t, J = 7.2 Hz, 2H), 6.68 (s, 1H), 6.61 (s, 2H), 6.56
(s, 1H), 5.88 (d, J = 1.2 Hz, 1H), 5.87 (d, J = 1.2 Hz, 1H), 4.49 (s, 1H), 4.10 (dd, J = 9.2, 7.6 Hz, 1H), 3.85
(s, 3H), 3.84 (s, 6H), 3.75 (dd, J = 5.2, 4.0 Hz, 1H), 3.48 (dd, J = 16.4, 8.4 Hz, 1H), 3.32–3.27 (m, 1H), 2.62
(d, J = 16.4 Hz, 1H) ppm; 13C-NMR (100 MHz, CDCl3):
δ = 176.7, 152.9 (2C), 147.2, 146.9, 137.7 (2C),
137.3, 134.6, 131.8, 129.9, 129.1 (2C), 126.1, 126.0, 109.3, 108.8, 106.8 (2C), 101.0, 73.3, 60.9, 56.2 (2C), 53.9,
51.3, 41.5, 35.0 ppm; HRMS (ESI): calcd. for C28H30NO7Se+ [M + NH4]+: 572.1182, found: 572.1186.
3.3. Synthesis of (+)-β-Apopicropodophyllin (5)
To a stirred solution of 4a (90 mg, 0.076 mmol) in CH2Cl2 (4 mL) was added m-CPBA (77%, 34.0 mg
0.15 mmol, 2.0 equiv) at 0 ◦C followed by the addition of NaHCO3 (12.6 mg, 0.15 mmol, 2.0 equiv).
After stirring for 15 min, the reaction mixture was extracted with CH2Cl2 (3 20 mL). The combined
organic layers were washed with saturated aqueous NaHCO3 (4 5 mL), water (5 mL) and brine (5 mL
respectively, then dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography (petroleum ether/EtOAc = 3:1 petroleum
,
×
×
)
→

Molecules 2018, 23, 3037
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ether/EtOAc = 1:1) on silica gel to afford (+)-
β
-apopicropodophyllin (
5
) (56 mg, 88% yield) as a
white solid. Rf = 0.37 (petroleum ether/EtOAc = 1:1); [α]2D0 = +92.04 (c = 1.00, CHCl3), [α]D23 = +65.1
(
c = 2.72, CHCl3)] [23]; m.p. 188–190 ◦C; 1H-NMR (300 MHz, CDCl3):
δ = 6.72 (s, 1H), 6.63 (s, 1H),
6.37 (s, 2H), 5.954 (s, 1H), 5.947 (s, 1H), 4.90 (d, J = 17.4 Hz, 1H), 4.82 (d, J = 17.4 Hz, 1H), 4.81 (s, 1H),
3.86 (dd, J = 22.2, 3.9 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 6H), 3.65 (dd, J = 22.2, 3.6 Hz, 1H) ppm; 13C-NMR
(100 MHz, CDCl3):
δ = 172.2, 157.2, 153.2 (2C), 147.3, 147.0, 138.3, 137.1, 129.7, 128.2, 123.8, 109.6, 107.7,
105.6 (2C), 101.3, 71.0, 60.8, 56.2 (2C), 42.8, 29.2 ppm.
This product (5 mg) was dissolved in EtOAc (1 mL) and hexane (2 mL). After three days, colorless
single crystals were obtained by slow evaporation of solvents at room temperature.
3.4. Synthesis of (+)-γ-Apopicropodophyllin (6)
To a stirred solution of 4b (42 mg, 0.16 mmol) in CH2Cl2 (3 mL) was added m-CPBA (77%, 72.0 mg
,
0.32 mmol, 2.0 equiv) at 0 ◦C followed by the addition of NaHCO3 (26.9 mg, 0.32 mmol, 2.0 equiv).
After stirring for 15 min, the reaction mixture was extracted with CH2Cl2 (3
organic layers were washed with saturated aqueous NaHCO3 (4 5 mL), water (5 mL) and brine (5 mL)
respectively, then dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography (petroleum ether/EtOAc = 3:1 petroleum
) (26 mg, 88% yield) as a white
×
20 mL). The combined
×
→
ether/EtOAc = 1:1) on silica gel to afford (+)-γ-apopicropodophyllin (6
solid. Rf = 0.23 (petroleum◦ether/EtOAc = 1:1); [α]2D0 = +27.03 (c = 1.00, CHCl3), [α]D19 = +25.0 (c = 1
,
CHCl3)] [28]; m.p. 206–208 C; 1H-NMR (300 MHz, CDCl3):
δ = 6.77 (s, 1H), 6.52 (brs, 3H), 5.97 (s, 2H),
4.70 (t, J = 8.7 Hz, 1H), 4.01 (t, J = 8.7 Hz, 1H), 3.92 (s, 3H), 3.83 (s, 6H), 3.39 (td, J = 15.9, 8.7 Hz, 1H), 2.94
(dd, J = 15.0, 6.9 Hz, 1H), 2.79 (dd, J = 15.6, 15.3 Hz, 1H) ppm; 13C-NMR (150 MHz, CDCl3): δ = 168.1
152.7, 148.7 (2C), 147.3, 146.8, 138.1, 130.7 (2C), 129.9, 129.6, 119.9, 109.5, 108.6, 101.6 (2C), 70.9, 61.0,
56.2 (2C), 35.8, 33.3 ppm.
,
3.5. Synthesis of Dehydrodesoxypodophyllotoxin (7)
An oven-dried 10 mL round-bottom flask was charged with NBS (17.8 mg, 0.1 mmol, 1.0 equiv)
and BPO (2.4 mg, 0.01 mmol, 0.1 equiv) at room temperature under argon, followed by the addition
of a solution of
82 ◦C. The reaction solvent was then evaporated in vacuo. The resulting residue was purified by
flash column chromatography (petroleum ether/EtOAc = 5:1 petroleum ether/EtOAc = 2:1) on
silica gel to afford dehydrodesoxypodophyllotoxin ( ) (22.2 mg, 56% yield) as a white solid. Rf = 0.45
(petroleum ether/EtOAc = 1:1); m.p. 271–273 ◦C; 1H-NMR (400 MHz, CDCl3):
= 7.70 (s, 1H), 7.21
(s, 1H), 7.12 (s, 1H), 6.55 (s, 2H), 6.09 (s, 2H), 5.38 (s, 2H), 3.97 (s, 3H), 3.84 (s, 6H) ppm; 13C-NMR
150 MHz, CDCl3): = 169.6, 153.0 (2C), 150.0, 148.7, 140.5, 139.8, 137.8, 134.6, 130.34, 130.30, 119.1,
3 (40.0 mg, 0.1 mmol) in CCl4 (3 mL). The reaction mixture was stirred for 2 h at
→
7
δ
(
δ
118.7, 107.3 (2C), 103.8, 103.6, 101.8, 68.0, 61.0, 56.1 (2C) ppm.
4. Conclusions
In summary,
-apopicropodophyllin (
). In phase I, their tetrahydronaphthalene (THN) backbone was constructed by a Ni-catalyzed
reductive cascade. In phase II, regioselective oxidation of stereodivergent tetralin lactone ( and
gave arylnaphthalene lignan 7 and its dihydronaphthalene (DHN) congeners (5 and 6) efficiently.
a
two-phase strategy was developed for the unified synthesis of
(+)-β
5
), (+)- -apopicropodophyllin ( ), and dehydrodesoxypodophyllotoxin
γ
6
(7
2
3)
Supplementary Materials: The following are available online. Copies of 1H-, 13C-NMR, and crystallographic
information files (CIFs) for 5.
Author Contributions: Y.P. conceived and designed the experiments; J.X. performed the experiments; J.X., G.N.,
Y.-W.W., and Y.P. analyzed the data; Y.-W.W. and Y.P. wrote the paper.
Funding: This work was supported by the Natural Science Foundation of China (nos. 21472075 and 21772078).
Conflicts of Interest: The authors declare no conflict of interest.

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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).