Concise Total Synthesis of (±)-Deguelin and (±)-Tephrosin Using a Vinyl Iodide as a Key Building Block

Article abstract of DOI:10.1021/acs.jnatprod.7b00794

A concise and protecting-group-free total synthesis of the antiproliferative natural product (±)-deguelin (2) was accomplished in four steps and 62% overall yield from commercially available precursors. The key transformation employed a vinyl iodide as the pivotal building block to construct the 4-acylchromene substructure present in deguelin. Subsequent Cu₂O-mediated α-hydroxylation of deguelin (2) afforded tephrosin (3) in 90% yield.

Full text of DOI:10.1021/acs.jnatprod.7b00794

Note
pubs.acs.org/jnp
Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX
Concise Total Synthesis of ( )-Deguelin and ( )-Tephrosin Using a
Vinyl Iodide as a Key Building Block
Shengtao Xu,# Guangyu Wang,# Feijie Xu, Wenlong Li, Aijun Lin, Hequan Yao, and Jinyi Xu*
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia
Xiang, Nanjing 210009, People’s Republic of China
S
* Supporting Information
ABSTRACT: A concise and protecting-group-free total
synthesis of the antiproliferative natural product ( )-deguelin
(2) was accomplished in four steps and 62% overall yield from
commercially available precursors. The key transformation
employed a vinyl iodide as the pivotal building block to
construct the 4-acylchromene substructure present in deguelin.
Subsequent Cu2O-mediated α-hydroxylation of deguelin (2)
afforded tephrosin (3) in 90% yield.
otenoids, members of a class of compounds isolated from
rotenone (1) in four steps with 22% overall yield.9 Although
RDerris and Lonchocarpus species, exhibit significant the semisynthesis of deguelin (2) starting from relatively
pesticidal and antiproliferative properties.1 A cis-fused
inexpensive rotenone (1) facilitated the biological studies of
deguelin and its simple analogues, extensive structure−activity
relationship (SAR) studies of deguelin (2) for the development
of potential antitumor agents were abandoned due to the
lengthy and inefficient total synthesis.10 Thus, it is essential to
develop a concise and efficient synthetic route to deguelin (2)
to accelerate the development of therapeutic lead compounds.
Tephrosin (3) is another rotenoid and, along with deguelin,
is mainly isolated from plants of the genus Derris.11 The
anticancer activity and mechanism of action of deguelin (2)
have been studied extensively, but biological studies on
tephrosin (3) are rarely reported partly due to its limited
availability. A few recent studies showed that tephrosin (3)
inhibited mouse skin tumor promotion, invasion of cancer cells,
and nuclear factor-κB (NF-κB) activity.12 Nevertheless, the
mechanism of its anticancer activity has not been defined.
Although tephrosin (3) is the 12a-hydroxy analogue of deguelin
(2), the direct α-C−H hydroxylation of the α-substituted
carbonyl in deguelin to obtain α-substituted tephrosin is quite
challenging. There has only been one reported de novo total
synthesis of tephrosin (3).13
tetrahydrochromeno[3,4-b]chromene core is often found in
rotenoid natural products, such as rotenone (1), deguelin (2),
and tephrosin (3) (Figure 1).2 In particular, deguelin (2)
displayed potent antiproliferative activity in several in vitro and
in vivo studies and attracted considerable attention from
biologists and chemists.3 In recent years, the antitumor activity
of deguelin (2) and its mechanism of action have been
extensively studied. It was reported that deguelin (2) exhibited
potent apoptotic and antiangiogenic activities against various
human cancer cells, such as lung, prostate, head and neck, and
stomach cancer cells.4 The antitumor activity of deguelin (2)
has been associated with cell-cycle arrest and induction of
apoptosis mediated mainly through mitogen-activated protein
kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt
signal transduction cascades.5 Recent studies showed that
deguelin (2) binds to the ATP-binding pocket of heat shock
protein 90 (Hsp90), causing the destabilization of various client
Hsp90 proteins, such as CDK4, Akt, MEK, and hypoxia-
inducible factor 1α (HIF-1α), and ultimately suppressed tumor
growth.6 The significant antiproliferative activity and specific
mechanism of action of deguelin make it a compelling lead
compound for therapeutic lead optimization and development.
Since its isolation from Tephrosia vogelii by Hanriot in 1907,
several total syntheses of racemic deguelin (2) have already
been reported.7 Recently, an enantioselective synthesis of
deguelin (2) was reported, and the biological evaluation of both
enantiomers showed that the unnatural (+)-deguelin was
slightly more potent than its enantiomer in some cancer cell
lines.8 However, for biological studies, deguelin (2) and its
analogues are still usually prepared from the natural product
Our group is dedicated to the structure modification and
SAR study of natural products, and a concise and efficient total
synthesis of deguelin (2), tephrosin (3), and their structurally
diverse analogues would be beneficial.
Among the several total syntheses reported for deguelin (2),7
the construction of the tetrahydrochromeno[3,4-b]chromene
skeleton of deguelin (2) via 4-acylchromene 5 (Scheme 1)
Received: September 18, 2017
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.7b00794
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Journal of Natural Products
Note
Figure 1. Structures of rotenone (1), deguelin (2), and tephrosin (3).
Scheme 1. Reported Approaches to the Synthesis of ( )-Deguelin (2) via 4-Acylchromene (5)
Scheme 2. Retrosynthetic Analysis for the Synthesis of Deguelin (2) and Tephrosin (3)
proved to be a relatively efficient strategy.7c,d As shown in
Scheme 1, Kim and Nayak completed a formal synthesis of
deguelin (2) in eight steps by constructing the 4-acylchromene
moiety via an intramolecular alkyne−carbonyl metathesis in the
presence of In(OTf)3.7d Pastine and Sames reported a concise
total synthesis of deguelin (2) with a linear sequence of six
steps in 68% yield through a hydroarylation of an alkynone
intermediate using a platinum catalyst.7c However, the use of a
noble metal catalyst and/or multiple steps limits the broad
application of these synthetic methods. Thus, a search for a
more concise transition-metal-free method to establish the
complex 4-acylchromene functionality was undertaken.
Considering that vinyl halides have been extensively used in
organic synthesis, such as in Sonogashira couplings, Nozaki−
Hiyama−Kishi reactions, and Kumada couplings,14 the addition
of the vinyl anion derived from vinyl iodide 7 to benzaldehyde
8 could generate the bis-chromene 9 (Scheme 2). Indeed, some
examples of vinyl iodides being used in the total syntheses of
natural products for the preparation of unsaturated ketones
have been disclosed.15 With this key strategy in mind, the
retrosyntheses of deguelin (2) and tephrosin (3) were designed
as shown in Scheme 2. The direct α-C−H hydroxylation of
deguelin (2) would afford tephrosin (3), and deguelin (2)
could be generated through the cyclization of bis-chromene 9.
In previous reports, the phenolic group of 2,2-dimethylchro-
mene is often protected as the O-methyl ether, and the
subsequent demethylation step was inefficient due to selectivity
problems arising from the presence of two other methoxy
groups in intermediates such as 5.7c,d,8 In the proposed scheme,
it is anticipated that the o-hydroxy-4-acylchromene 9 could be
cyclized directly. Bis-chromene 9 could be assembled by the
coupling of intermediates 7 and 8, and the common building
block 8 is commercially available. Vinyl iodide 7 could be
synthesized via the oxidation of a hydrazone by iodine in the
presence of a base.
B
DOI: 10.1021/acs.jnatprod.7b00794
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Journal of Natural Products
Note
Scheme 3. Total Syntheses of ( )-Deguelin (2) and ( )-Tephrosin (3)
As shown in Scheme 3, the synthesis of deguelin (2) started
from the preparation of the key vinyl iodide building block 7,
which was carried out by the conversion of chromanone 10 into
the hydrazone by heating with N2H4·H2O in refluxing MeOH.
Oxidation of the hydrazone by iodine in the presence of base
gave the vinyl iodide in 85% yield.16 Initially, vinyl iodide 7 was
obtained in only 21% yield over two steps. The mechanism
proposed by Barton suggests that the hydrazone is oxidized by
iodine to the diazo compound first. Nucleophilic attack on the
iodine and subsequent loss of nitrogen afford an iodocarboca-
tion. Elimination of HI finally affords the vinyl iodide.17 Thus, a
variety of conditions (solvent, base, molar ratio, and temper-
ature) were screened to increase the yield of 7. The reaction
proceeded smoothly in anhydrous tetrahydrofuran (THF) with
tetraethylamine (TEA) as a base and provided 7 in 85% yield.
Next the assembly of 4-acylchromene 9 from 7 and
commercially available benzaldehyde 8 was investigated. n-
BuLi-induced metal−halogen exchange generated a vinylic
anion that adds to benzaldehyde 8 to link the two chromene
moieties.18 The resulting crude product was oxidized by 2-
Iodoxybenzoic acid (IBX) to afford ketone 9 in 80% yield.
Intermediate 9 was transformed into deguelin (2) in 92% yield
by a base-catalyzed intramolecular oxo-Michael addition. Thus,
deguelin (2) was prepared in four linear steps in 62% overall
yield.
Having established a robust route to deguelin, the synthesis
of tephrosin (3) from deguelin (2) was attempted. As a 12a-
hydroxy analogue of deguelin, tephrosin can be obtained by
oxidation of the deguelin enolate.19 In recent years, α-C−H
hydroxylation of α-substituted carbonyl compounds to obtain
α-hydroxy carbonyl compounds has received considerable
attention, and transition-metal catalysis with molecular O2 for
selective C−H hydroxylation of carbonyl compounds has been
widely applied.20 Schoenebeck and co-workers developed an
efficient method using a metal oxide (Cu2O) and the base
hppH (1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine)
for C−H hydroxylation.21 Following optimization of the
reaction conditions, the reaction of deguelin with O2 using a
catalytic amount of Cu2O in the presence of hppH proceeded
smoothly to afford tephrosin (3) in 90% yield. The
spectroscopic data for the synthesized deguelin (2) and
tephrosin (3) matched those reported for the natural products
(Supporting Information).9b
In summary, short, efficient, protecting-group-free total
syntheses were developed for ( )-deguelin (2) and ( )-teph-
rosin (3) in four steps with 62% overall yield and five steps with
54% overall yield, respectively. The synthesis employed a vinyl
iodide to concisely construct the 4-acylchromene skeleton of
the rotenoids. Importantly, the small number of steps and the
high overall yield make it a potentially viable option for both
the scalable preparation of deguelin (2) and tephrosin (3) as
well as the synthesis of their analogues to facilitate further
medicinal chemistry studies.
EXPERIMENTAL SECTION
■
General Experimental Procedures. 1H NMR and 13C NMR
spectra were obtained using a Bruker AV-300 or AV-500 spectrometer
(Bruker Company, Germany) in the indicated solvents (CDCl3 or
DMSO-d6 with tetramethylsilane as the internal standard). The values
of the chemical shifts are expressed in δ values (ppm), and the
coupling constants (J) are reported in Hz. ESIMS and HRESIMS data
were collected on a Finnigan MAT 95 spectrometer (Finnigan,
Germany). Flash column chromatography was carried out on 200−
300 mesh silica gel purchased from Qingdao Haiyang Chemical Co.
Ltd. (Qingdao, People’s Republic of China). Reactions were
monitored by thin-layer chromatography on 0.25 mm silica gel plates
(GF254) and visualized under UV light.
4-Iodo-6,7-dimethoxy-2H-chromene (7). Compound 10 (500
mg, 2.4 mmol, 1.0 equiv), freshly distilled hydrazine hydrate (98%, 720
mg, 14.4 mol, 6.0 equiv), and triethylamine (0.5 mL, 3.6 mmol, 1.5
equiv) were heated in refluxing MeOH (25 mL) for 2.5 h. After
completion of the nucleophilic addition, the mixture was poured onto
H2O and extracted with EtOAc (50 mL). The combined organic phase
was washed with brine (20 mL) and H2O (20 mL) and dried over
anhydrous MgSO4. After evaporation of the solvent, the crude
hydrazone was obtained and used without further purification.
Triethylamine (3 mL, 22.5 mmol, 9.3 equiv) in THF (24 mL) was
added via cannula over 2 min to a stirred solution of iodine (1.71 g,
6.75 mmol, 2.8 equiv) in THF (20 mL) at 0 °C. A solution of
hydrazone in THF (10 mL) was added via cannula over 5 min. The
mixture was kept at room temperature for 2 h, and the suspension was
C
DOI: 10.1021/acs.jnatprod.7b00794
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Journal of Natural Products
Note
filtered through sintered glass. The solid phase was washed with
EtOAc (5 × 3 mL), and the combined organic layers were washed
with saturated aqueous Na2S2O3 (2 × 20 mL). The organic phase was
concentrated in vacuo. Purification of the crude product by flash
column chromatography (silica gel, 1:20 EtOAc/petroleum ether)
= 10.1 Hz, H-5′), 4.63 (1H, dd, J = 12.1, 2.4 Hz, H-6), 4.58−4.56 (1H,
m, H-6a), 4.49 (1H, dd, J = 12.1, 1.1 Hz, H-6), 4.42 (1H, s, OH-12a),
3.81 (3H, s, H-3′), 3.73 (3H, s, H-2′), 1.45 (3H, s, H-8′), 1.39 (3H, s,
H-7′); 13C NMR (75 MHz, CDCl3) δ 191.40 (C-12), 160.79 (C-9),
156.70 (C-7a), 151.22 (C-4a), 148.48 (C-3), 144.05 (C-2), 128.85 (C-
5′), 128.58 (C-11), 115.45 (C-4′), 111.91 (C-10), 111.18 (C-11a),
109.59 (C-1), 109.17 (C-8), 108.74 (C-1a), 101.19 (C-4), 78.03 (C-
6′), 76.34 (C-6a), 67.51 (C-12a), 63.91 (C-6), 56.46 (C-2′), 55.90 (C-
3′), 28.58 (C-8′), 28.35 (C-7′); HRESIMS m/z 433.1273 [M + Na]+
(calcd for C23H22NaO7, 433.1258).
1
yielded 7 as a yellow solid (647 mg, 85%): H NMR (300 MHz,
CDCl3) δ 6.74 (1H, s), 6.30 (1H, s), 6.28 (1H, t, J = 4.1 Hz), 4.58
(2H, d, J = 4.1 Hz), 3.81 (3H, s), 3.78 (3H, s); 13C NMR (75 MHz,
CDCl3) δ 150.71, 148.16, 143.79, 129.29, 115.53, 114.67, 100.25,
92.95, 67.58, 56.60, 56.14; HRESIMS m/z 316.9671 [M − H]− (calcd
for C11H10IO3, 316.9680).
(6,7-Dimethoxy-2H-chromen-4-yl)(5-hydroxy-2,2-dimethyl-
2H-chromen-6-yl)methanone (9). n-BuLi (0.744 mL, 1.86 mmol,
2.5 mol/L, 3.0 equiv) was added to freshly distilled THF (20 mL) at
−78 °C. Compound 7 (200 mg, 0.62 mmol, 1.0 equiv) was added, and
the reaction mixture was stirred until the temperature reached 25 °C,
at which point 8 (128 mg, 0.62 mmol, 1.0 equiv) was added. After
stirring for 1 h, the reaction was quenched with saturated NH4Cl, and
the product was extracted with EtOAc (30 mL), washed with brine,
dried over anhydrous MgSO4, and evaporated under reduced pressure.
The crude product was added to a well-stirred solution of IBX (212
mg, 0.75 mmol, 1.2 equiv) in dry DMSO (20 mL) at room
temperature. After stirring for 20 min, a solution of 10% saturated
aqueous NaHCO3 (10 mL) was added. The product was extracted
with EtOAc (20 mL), the organic layer was washed with brine and
dried over anhydrous MgSO4, and the solvent was removed under
reduced pressure to afford the crude product. Purification by flash
column chromatography (silica gel, 1:10 EtOAc/petroleum ether)
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.7b00794.
Additional information (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*Tel (J.-Y. Xu): +86 025-83271299. Fax: +86 025-83302827. E-
mail: jinyixu@china.com.
ORCID
Aijun Lin: 0000-0001-5786-4537
Jinyi Xu: 0000-0002-1961-0402
1
yielded 9 as a yellow solid (198 mg, 80%): H NMR (300 MHz,
DMSO-d6) δ 12.56 (1H, s), 7.11 (1H, d, J = 8.8 Hz), 6.97 (1H, s),
6.62 (1H, d, J = 10.1 Hz), 6.51 (1H, d, J = 9.9 Hz), 6.35 (1H, d, J = 8.8
Hz), 5.86−5.80 (1H, m), 5.78 (1H, d, J = 10.1 Hz), 4.59 (2H, m), 3.79
(3H, s), 3.62 (3H, s), 1.41 (6H, s); 13C NMR (75 MHz, CDCl3) δ
197.28, 159.71, 159.31, 146.54, 145.67, 144.21, 133.95, 127.54, 123.50,
121.42, 121.27, 117.95, 115.36, 114.63, 111.78, 108.46, 108.11, 77.48,
65.09, 61.34, 56.25, 29.30, 28.10; HRESIMS m/z 395.1498 [M + H]+
(calcd for C23H23O6, 395.1489).
Author Contributions
#S. Xu and G. Wang contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the National Natural Science
Foundation of China (Nos. 81373280, 81673306), the Project
Program of State Key Laboratory of Natural Medicines, China
Pharmaceutical University (No. SKLNMKF201710), and the
China Postdoctoral Science Foundation (Nos. 2015M581903,
2017T100424).
Deguelin (2). Compound 9 (50 mg, 0.126 mmol) was dissolved in
a saturated solution of KOAc in EtOH (0.5 mL), and the mixture was
stirred at rt for 1 h. EtOAc and H2O were added to the reaction
mixture. The layers were separated, and the aqueous layer was
extracted with EtOAc (2 × 20 mL). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, and concentrated
under reduced pressure. The crude residue was filtered through silica
gel (petroleum ether/EtOAc, 4:1) to yield ( )-deguelin (2) as a white
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■
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DOI: 10.1021/acs.jnatprod.7b00794
J. Nat. Prod. XXXX, XXX, XXX−XXX