Asymmetric Total Synthesis of PD-116740

Article abstract of DOI:10.1021/acs.orglett.0c03990

A new approach was developed to achieve the asymmetric total synthesis of (+)-PD-116740, an angucyclinone from the actinomycete isolate (WP 4669). A sequence of asymmetric dihydroxylation followed by oxidative cyclization was applied to stereoselectively construct the core trans-9,10-dihydrophenanthrene-9,10-diol B-C-D ring. A new Cu salt Cu(OH)OTf·NMI2 was found to be the best oxidant to induce the oxidative coupling and phenol oxidation.

Full text of DOI:10.1021/acs.orglett.0c03990

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Asymmetric Total Synthesis of PD-116740
Chaoying Zheng, Tao Xie, Haibing He,* and Shuanhu Gao*
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ABSTRACT: A new approach was developed to achieve the asymmetric total synthesis of (+)-PD-116740, an angucyclinone from
the actinomycete isolate (WP 4669). A sequence of asymmetric dihydroxylation followed by oxidative cyclization was applied to
stereoselectively construct the core trans-9,10-dihydrophenanthrene-9,10-diol B−C−D ring. A new Cu salt Cu(OH)OTf·NMI2 was
found to be the best oxidant to induce the oxidative coupling and phenol oxidation.
n 1985, Hokanson and co-workers reported the discovery of
The intriguing structures and promising biological activities
of these polyketides have led many groups to develop
syntheses, including the Larsen,7 Hauser,8 Suzuki,9 and Shi10
groups. In 2008, Suzuki and co-workers took advantage of a
strategy of chirality transfer from axial to central and SmI2-
mediated Pinacol cyclization to build the trans-9,10-dihydro-
phenanthrene-9,10-diol, which was used in the first total
synthesis and absolute structure assignment of 1 (Scheme
1A).9 This strategy was also successfully used in the
asymmetric synthesis of TAN-1085 (4) and FD-594 aglycon
(5) by the same group.11 Shi and co-workers developed a Pd-
catalyzed atroposelective C−H olefination to construct the
axially chiral biaryls, which was used in the total synthesis of
TAN-1085 (4) (Scheme 1B).10 Recently, we developed a new
strategy involving an asymmetric dihydroxylation and a Cu-
mediated oxidative phenol coupling reaction to build the trans-
dihydrophenanthrenediol fragment which was used in the total
synthesis of FD-594 (Scheme 1C).12 As a further application of
this strategy, we reinvestigated the Cu-promoted oxidative
cyclization and achieved the asymmetric total synthesis of
(+)-PD-116740.
I
PD-116740 (1) from fermentation broth of the actino-
mycete isolate (WP 4669) (Figure 1).1 It belongs to a big
Figure 1. trans-9,10-Dihydrophenanthrene-9,10-diol-containing natu-
ral products.
Taking advantage of the convergent approach, we first
planned to prepare A/B and D ring fragments (Scheme 2).
Commercially available naphthalene-1,5-diol was selected as
the starting material, which could be transformed into quinone
12 and 12′ through a known procedure on a large scale
(Scheme 2A).13 Reduction of quinone by sodium hydrosulfite
family of angucycline polycyclic aromatic polyketides,2 and
exhibits activities against HCT-8 human adenocarcinoma (IC50
= 3.3 μm) and LI210 lymphocytic leukemia (IC50 = 2.1 μm).
PD-116740 contains a highly oxygenated angular tetracyclic
skeleton including a trans-9,10-dihydrophenanthrene-9,10-diol
fragment (B−C−D ring), which is distinguished with the most
commonly occurring fully aromatized angucycline antibiotics.
The same biosynthetic pathway3 leads to the formation of
biogenetically and structurally related polycyclic polyketides
including PM070747 (2)4 TAN-1084 (3)5 and TAN-1085
(4). The structural unit of trans-dihydrophenanthrene-diol also
exists in the xanthone-type natural product FD-594 aglycon
(5).6
Received: December 1, 2020
Published: January 5, 2021
https://dx.doi.org/10.1021/acs.orglett.0c03990
© 2021 American Chemical Society
Org. Lett. 2021, 23, 469−473
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12′ was converted to 16′ in 53% total yield over four steps on
a decagram scale. Compounds 16 and 16′ containing an A−B
ring with different protecting groups might facilitate the
selective deprotection and preparation of derivatives.
Scheme 1. Strategies for the Construction of the trans-9,10-
Dihydrophenanthrene-9,10-diol Framework
The preparation of the D ring fragment commenced with
the known benzyl alcohol 17 (Scheme 2B).15 TBS protection
of the diol provided 18 in 76% yield. Lithium/bromide
exchange with n-BuLi gave the anion species, which interacted
with dimethyl formamide (DMF) to introduce the aldehyde
group. After selective deprotection of phenol-TBS group under
basic conditions, 19 was generated in 70% over two steps. The
aldehyde was then converted into alkyne with dimethyl 1-
diazoacetonylphosphonate (Ohira−Bestmann reagent)16 to
afford 20. The terminal alkyne was then subjected to Cu-
catalyzed vinyl boration conditions17 to give compound 21 in
75% yield as another coupling fragment.
With both A/B and D rings in hand, a Pd-catalyzed Suzuki−
Miyama reaction18 was utilized for the coupling of two
fragments (Scheme 3). Treatment of 16 or 16′ and 21 with
Pd(dppf)Cl2·DCM in the presence of K2CO3 in t-BuOH and
Scheme 3. Total Synthesis of PD-116740
Scheme 2. Preparation of A/B and D Ring Fragments
gave hydroquinone, and the less sterically hindered phenol
group was protected as the benzyl ether to form the phenol 14
in 91% yield over two steps. After selective bromination at the
ortho-position14 (74%) and MOM protection (96%) of the
last phenol group, fragment 16 was achieved as the precursor
of the coupling reaction. Using the same procedure, quinone
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Table 1. Optimization Conditions of Cu-Mediated Oxidative Coupling
a
b
c
d
1
Reaction scale: 19 mg. Reaction volume: 1 mL. Determined by H NMR analysis using CH2Br2 as an internal standard. Isolated yield.
water produced the desired coupling product 22 and 22′ in
83% and 75% yield, respectively. Asymmetric dihydroxylation
of the disubstituted alkene with osmium tetroxide and chiral
ligand (DHQ)2PHAL provided chiral diol 2319 in excellent
yield of 97% as well as the excellent enantioselectivity of 98%
ee (determined by HPLC, see details in the Supporting
Information). Another diol 23′ was also afforded with good
yield and enantioselectivity (93%, 93% ee). The three hydroxyl
groups were then protected by the TES group, and the phenol-
TES ether was selectively removed under basic conditions to
furnish 24 and 24′ in good yield. It has been proven that the
introduction of the bulky TES silyl groups on the diol helps to
induce the following oxidative coupling and prevents the
oxidative cleavage reaction. Then removal of the benzyl group
gave the oxidative coupling precursor 25 and 25′.
ligands, and the reaction atmosphere. For the specific
substrates 25 and 25′, we preferred a double oxidation: (1)
oxidative cyclization to form a C2−C3 aryl−aryl bond and (2)
further oxidation of the phenol B ring to quinone. Therefore, it
is necessary to screen the reaction conditions with respect to
the copper(II) salt and ligands.
Using bisphenol 25 as a model substrate, which was
subjected to cyclization reaction under the air atmosphere in
the room temperature (Table 1). We first tested the oxidative
cyclization with stoichiometric amounts of copper(II) salts
(2.0 equiv) using TMEDA (2.0 equiv) as a ligand in
acetonitrile (entries 1 and 2), which produced a mixture of
cyclized products including MOM-protected product 27, the
desired over oxidized product 28, and MOM-protected over
oxidized product 29.24 We reasoned that the Cu-mediated
oxidative cyclization occurred and generated cyclized product,
which could be further oxidized to quinone 28 under aerobic
conditions. The generation of 27 and 29 might be caused by
an intermolecular and intramolecular migration process of the
MOM group from 28. Koga’s reagent25 Cu(OH)Cl·TMEDA
was investigated from stoichiometric to catalytic (entries 3−6,
Table 1), and 28 was obtained in a good yield and ratio in the
presence of 0.5 equiv Cu salt (entry 5). To improve the
reactivity of the oxidant, we prepared other copper catalysts by
changing the anion coordinates and ligands (entries 7−10).26
We found that using Cu(OH)OTf·NMI2 as an oxidant formed
28 as a single product in 48% yield (entry 10). We envisioned
that the N-methylimidazole (NMI)27 acts as a suitable ligand
We next turned our attention to construct the trans-9,10-
dihydrophenanthrene-9,10-diol unit through an oxidative
cyclization reaction. The Cu-mediated oxidative coupling has
been extensively used in the total synthesis of polyketides and
peptides.20 For instance, Tatsuta and co-workers completed
the first total synthesis of TMC-66 by using Cu(OH)Cl·
(NMI)2-mediated oxidative coupling,21 and the same copper
salt was also used by Ready and co-workers to forge the core
skeleton of kigamicins.22 Baran and co-workers used [Cu-
(MeCN)4][PF6] as the catalyst and TMEDA as a ligand to
synthesize arylomycins and analogues.23 During our previous
synthetic studies of FD-594, we found that the oxidative
coupling reaction was highly dependent on the anionic effects,
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Letter
to accelerate the formation of the intermediate 26 (Scheme 3)
and following cyclization/oxidation. Finally, after screening the
reaction solvents (entries 11−17), it was found that the
isolated yield of the reaction was increased to 71% when DMF
was used as a solvent (entry 17).
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21971068, 21772044), the “National Young Top-Notch
Talent Support Program”, Program of Shanghai Academic/
Technology Research Leader (18XD1401500), Program of
Shanghai Science and Technology Committee
(18JC1411303), “Shuguang Program” supported by Shanghai
Education Development Foundation (Grant No. 19SG21), the
Program for Changjiang Scholars and Innovative Research
Team in University, and “the Fundamental Research Funds for
the Central Universities” for generous financial support.
Cu(OH)OTf·NMI2-mediated oxidative cyclization was also
tested using bisphenol 25′ and provided the desired product
28′ in a comparative yield. To finish the total synthesis, global
removal of the silyl protecting groups in compound 28
1
produced PD-116740 (1) in 63% yield. H and 13C NMR
spectra and high-resolution mass spectrometry data for this
synthetic compound were fully consistent with those of the
natural product (Scheme 3).1,9
In conclusion, the asymmetric total synthesis of PD-116740
was accomplished through a convergent approach in 13 steps.
This achievement disclosed that the asymmetric dihydrox-
ylation followed by oxidative cyclization is a reliable method to
stereoselectively construct the trans-9,10-dihydrophenan-
threne-9,10-diol fragment. In addition, Cu(OH)OTf·NMI2
was found to be the best oxidant to induce the oxidative
cyclization and phenol oxidation.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03990.
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23′, 24, 24′, 25, 25′, 27, 28, 28′, and 28+29 (ZIP)
AUTHOR INFORMATION
Corresponding Authors
■
́
́
̃
iga, P.; Benedit, G.;
(4) Perez, M.; Schleissner, C.; Rodríguez, P.; Zun
Haibing He − Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development, East
China Normal University, Shanghai 200062, China;
Email: hbhe@chem.ecnu.edu.cn
Shuanhu Gao − Shanghai Key Laboratory of Green Chemistry
and Chemical Processes, School of Chemistry and Molecular
Engineering and Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development, East
China Normal University, Shanghai 200062, China;
orcid.org/0000-0001-6919-4577; Email: shgao@
chem.ecnu.edu.cn
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Authors
Chaoying Zheng − Shanghai Key Laboratory of Green
Chemistry and Chemical Processes, School of Chemistry and
Molecular Engineering, East China Normal University,
Shanghai 200062, China
Tao Xie − Shanghai Key Laboratory of Green Chemistry and
Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, China
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03990
Notes
The authors declare no competing financial interest.
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