Asymmetric Total Synthesis of the Complex Polycyclic Xanthone FD-594

Article abstract of DOI:10.1002/anie.201915787

A highly convergent approach was developed to achieve the first asymmetric and scalable total synthesis of FD-594, a complex polycyclic xanthone natural product from Streptomyces sp. TA-0256, in a longest linear sequence (LLS) of 20 steps. The trans-9,10-

Full text of DOI:10.1002/anie.201915787

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Accepted Article
Title: Asymmetric Total Synthesis of FD-594
Authors: Tao Xie, Chaoying Zheng, Kuanwei Chen, Haibing He, and
Shuanhu Gao
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COMMUNICATION
Asymmetric Total Synthesis of FD-594
[
a]
[a]
[a]
[b]
[a,b]
Tao Xie , Chaoying Zheng , Kuanwei Chen , Haibing He , Shuanhu Gao*
Abstract: A highly convergent approach was developed to achieve
the first asymmetric and scalable total synthesis of FD-594, a
complex polycyclic xanthone natural product from Streptomyces sp.
TA-0256, in (LLS) 20 steps. The trans-9,10-dihydrophenanthrene-
9
,10-diol fragment (B-C-D ring) was generated through a new
strategy involving an asymmetric dihydroxylation, followed by Cu-
mediated oxidative cyclization. Late-stage stereoselective
glycosylation assembled the angular hexacyclic framework with a β-
linked 2,6-dideoxy trisaccharide fragment.
FD-594 (1), a complex polycyclic xanthone-type natural
product,[1] was isolated from Streptomyces sp. TA-0256 by
Kakinuma and co-workers in 1998 (Figure 1). [2] It was reported
that FD-594 inhibits growth of P388 and HeLa tumor cells with
an IC50 of 0.25 and 0.10 g/mL.[2] It also exhibits moderate
activity against some Gram-positive bacteria, such as
staphylococcus aureus 209P-J (IC50=0.10 g/mL). FD-594
contains a challenging structure featured by a highly oxygenated
angular hexacyclic framework that includes an isochromanone
moiety (A-B ring), a trans-9,10-dihydrophenanthrene-9,10-diol
fragment (B-C-D ring), a xanthone scaffold (D-E-F ring) and a β-
linked trisaccharide unit comprising D-oleandrose and D-olivose.
The biogenetically related polycyclic xanthone MS0901809 (2),
discovered in the same Streptomyces species as FD-594, differs
from it only in the way in which the E and F rings are
connected.[3] FD-594 differs from other polycyclic xanthones
such as kigamicin A (3) [4] and kibdelone C (4) [5] primarily in
oxidation state and functional groups on the C and F rings. The
intriguing structures and biological activities of polycyclic
Figure 1. Polycyclic xanthone natural products.
previous work, we constructed tetrahydroxanthones using photo-
[
17]
induced C–O bond formation,
and synthesized dimeric
18]
1
xanthone ascherxanthone A [ as well as polycyclic xanthone
xanthones have led many groups to develop syntheses,
[
6]
[7]
[8]
[9]
kibdelone
asymmetric dihydroxylation followed by oxidative cyclization to
form the trans-9,10-dihydrophenanthrene-9,10-diol core
C a new strategy of
(4).[19] Herein, we report
including Kelly,
Porco,
Ready,
and Martin.
A
breakthrough toward the synthesis of FD-594 came in 2009
when Suzuki and coworkers prepared the corresponding
aglycone. [10] They used a creative strategy to shift chirality from
(Scheme 1B, III). We propose that II may serve as an
advanced intermediate to prepare both FD-594 and
biogenetically related kigamicins, when followed by selective
dehydroxylation of the C-6 hydroxyl group.
axial to central in order to build the B-C-D ring of trans-9,10-
[
11]
dihydrophenanthrene-9,10-diol (Scheme 1A).
group also used this strategy in their total syntheses of TAN-
085, [12] PD-116740[13] and pradimicinone. [14] Recently, Bennett
The same
1
and coworkers reported the stereoselective formation of the β-
linked trisaccharide unit through a reagent-controlled strategy in
which the dideoxy-sugar donors are activated using p-
toluenesulfonyl chloride. [15]
We aimed to achieve the first total synthesis of FD-594 (1) as
part of our on-going interest in the total synthesis of bioactive
polycyclic natural products and their medicinal chemistry.[16] In
[
a]
T. Xie, C. Zheng, K. Chen, Prof. Dr. S. Gao
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, School of Chemistry and Molecular Engineering
East China Normal University
3663 North Zhongshan Road, Shanghai 200062, China
E-mail: shgao@chem.ecnu.edu.cn
[
b]
Dr. H. He, Prof. Dr. S. Gao
Shanghai Engineering Research Center of Molecular Therapeutics
and New Drug Development, East China Normal University
3663 North Zhongshan Road, Shanghai 200062, China
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Synthetic plan.
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We envisioned the overall synthetic efficiency to
synthesizing FD-594 lies on a right ring forming sequence and
terminal alkyne 19, which underwent Cu-catalyzed vinyl boration
in the presence of DPEphos to stereospecifically generate 10 in
87% yield on a decagram scale.
stereo-controlled bond forming transformations.
A
highly
convergent approach was proposed (Scheme 2), in which late-
stage glycosylation would couple the angular hexacyclic
framework 5 with the trisaccharide scaffold 6, formed through
selective -linking of the 2-deoxy-sugars 7 and 8. The hexacyclic
core structure 5 would be generated through an asymmetric
dihydroxylation of the product formed through Suzuki–Miyaura
coupling of fragments 10 (isochromanone A-B ring) and 11
The xanthone fragment (D-E-F ring) was efficiently
prepared from two highly substituted benzene rings 20 and 21
(see details in Supporting Information). Site-selective lithiation of
21 followed by intermolecular addition of 20 and Dess-Martin
oxidation gave diaromatic ketone 23 (Scheme 2B). HF promoted
deprotection of the SEM group followed by C-O bond formation
N
via an S Ar procedure under the basic condition gave 24
(
xanthone D-E-F ring). The dihydroxylation product would then
bearing the xanthone framework in 62% yield over three steps
on a large scale. Replacing the methoxymethyl ether with the
methoxy-2,2,2-trichloroethyl (MOTCE) ether on F ring afforded
substrate 25 in high yield over 2 steps, which facilitates the
selective deprotection step required in the following
glycosylation.
undergo oxidative cyclization to furnish the trans-9,10-
dihydrophenanthrene-9,10-diol fragment (B-C-D ring).
Scheme 2. Retrosynthetic analysis of FD-594.
Our synthesis started from the scalable preparation of two
fragments 10 and 11 for the cross-coupling reaction (Scheme 3).
We constructed the chiral isochromanone A-B ring through Pt-
catalyzed enantioselective diboration followed by Pd-catalyzed
cross-coupling, recently developed by Morken and coworkers [20]
(
3
Scheme 3A). Treating pentene 12 with Pt(dba) in the presence
of chiral phosphonite ligand L1 and bis(pinacolato)diboron gave
the desired pinacol boronate 13 in 88% yield on a >15-g scale,
[
20]
and this boronate was selectively cross-coupled with 1-
bromo-3,5-dimethoxybenzene 14 using Pd(OAc) and RuPhos.
2
The resulting product was oxidized to produce alcohol 15 in 70%
yield with enantioselective excess (ee) of 91%. The
isochromanone ring was installed through acid-mediated
cyclization with trimethoxymethane and Jones oxidation reagent.
The structure and absolute configuration of 17 was confirmed by
X-ray diffraction analysis. Simple recrystallization of 17
increased ee to >99%. Removal of methyl groups and selective
activation of the phenol group generated triflate 18 in good yield
over two steps. Pd-catalyzed Sonogashira coupling of 18 with
ethynyltrimethylsilane followed by desilylation afforded the
Scheme 3. Preparation of fragments 10 and 25.
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Scheme 4. Total synthesis of FD-594 aglycon and FD-594.
FD-594 contains
a
unique trisaccharide fragment
dihydroxylation of the coupling product between 10 and 24
were also investigated (see details in Supporting Information).
The large TBS group was added to protect the diol as the
corresponding silyl ether. Acidic condition and hydrogenation
were used to selectively deprotect the phenols on C-13 and C-
15, producing phenol 28 in 95% yield over 2 steps. Cu-
mediated oxidative phenol coupling reactions are widely used
to form aryl–aryl bonds,[25] which have proven to be a reliable
methodology in the synthesis of TMC 66 by Tatsuta et al.,[25c]
and kigamicins by Ready and Ma.[4d] To investigate the
reactivity of oxidative cyclization, we also prepared 28a and
28b bearing free hydroxyl groups and saturated methylene on
C-6 and C-7. We studied the reaction conditions including
different Cu-oxidants and solvents (see Table S1 in Supporting
comprising the β-linked 2,6-dideoxy sugars D-oleandrose and
D-olivose. Stereoselective glycosylation with 2,6-dideoxy
sugars is challenging because the C-2 atom lacks a group that
can participate in formation of the β-glycosidic bond. [21] We
adopted the reagent-controlled strategy developed by Bennett
and coworkers in which the dideoxy-sugar donors are activated
using p-toluenesulfonyl chloride in the presence of 2,4,6-tri-tert-
butylpyrimidine (TTBP). [15, 22] This generates a reactive α-
glycosyl tosylate species that interacts with acceptors via an
2 process that shows excellent β-selectivity.[
22, 23]
S
N
Following
the reliable glycosylation as described by Bennett and
[15, 22]
coworkers,
we prepared the β-linked trisaccharide
fragments on
Information).
a
gram scale (see details in Supporting
Information). We found reaction of compound 28 with
o
With all of the coupling fragments in hand, we set about
preparing the angular hexacyclic core framework (Scheme 4).
The palladium-catalyzed Suzuki–Miyaura cross-coupling of
fragments 10 and 25 produced the desired coupling product 26
in 92% yield. Sharpless asymmetric dihydroxylation of the C6-
C7 olefin was attempted by treating 26 with osmium tetroxide
Cu(OH)Br•NMI
2
in acetonitrile at 75 C under an N
2
atmosphere
smoothly generated the cyclized hexacyclic core 30 in 90%
crude yield after 75 min. This high yield depended on using
acetonitrile as the solvent. Using DMF as solvent lead to a low
2
conversion rate and Cu(OH)Cl•NMI did not react efficiently
under these conditions, even after prolonged incubation. The
same reaction condition lead the decomposition of substrate
28a. Alternatively, substrate 28b underwent the oxidative
cyclization in a low reaction rate, this result revealed that two
4 2
) and chiral ligand (DHQ)
PHAL in dichloromethane.[24]
(
OsO
This afforded 27 bearing the desired chiral diol at C-6 and C-7
in 96% yield as single diastereomer. Asymmetric
a
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COMMUNICATION
bulky TBS protecting groups brought C-15a and C-15b closer
together and thereby facilitated subsequent oxidative coupling.
Generating the rings in this sequence ensures a scalable
approach and maximal synthetic efficiency. We are currently
exploring the medicinal chemistry of FD-594 and its analogues,
and applying the synthetic strategy to the total synthesis of
kigamicins, which will be reported in due course.
When we performed oxidative phenol coupling under an O
2
atmosphere, it was found the intermolecular coupling of
cyclized product 30 occurred to form the 10,10’-para-dimer 31,
which could be achieved in 50% yield after prolonging the
reaction time to 2.5 h. Global removal of protecting groups from
3
0, by means of Zn/AcOH and acidic condition, gave the FD-
Acknowledgements
594 aglycon 32, whose analytical data were in good agreement
with those reported by Suzuki.[2, 10] This convergent, 17-step
strategy can generate over 300 mg of FD-594 aglycon from 14
with overall yield of 20%.
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), the
Program for Changjiang Scholars and Innovative Research
Team in University and “the Fundamental Research Funds for
the Central Universities” for generous financial support. We
thank Professor Peng Xu (SIOC) for meaningful discussion
about the glycosylation reactions.
We then turned our attention to assembling the hexacyclic
carbon skeleton and trisaccharide fragment. To do so, three
free phenol groups were masked as benzyl ethers, and the
phenolic MOTCE group on C-12 was selectively removed using
zinc/acetic acid to give the glycosyl acceptor 33 as shown in
Scheme 4B. We first selected 1-hydroxyl sugar 34a and 1-O-
acetate 34b as model substrates to explore the reactivity and
stereoselectivity of this glycosidation under three types of
conventional reaction conditions. Treatment of glycosyl acetate
Keywords: xanthone • FD-594 • oxidative cyclization • total
synthesis • glycosylation
3
4b with TMSI generated glycosyl iodide, which should interact
with 33,[
21, 26]
but this led to recovery of the starting material and
only trace amounts of glycoside product. Mitsunobu
glycosylation of 33 with 1-hydroxyl sugar 34a in the presence of
PPh and DEAD produced glycoside product 35 in 30% yield,
3
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then attempted to activate the sugar donor using p-
toluenesulfonyl chloride as described by Bennett’s group. [15, 22]
Compound 34a was transformed into the corresponding α-
glycosyl tosylate species, which reacted with acceptor 33 in the
presence of KHMDS to afford the desired β-linked glycoside 35
as the major product in 61% yield (dr = 7:1). The same reaction
conditions were used to couple trisaccharide 36 with 33,
furnishing the β-linked glycoside 37 in 55% yield and
stereoselectivity of :=2.2:1. To improve the stereoselectivity,
we optimized the reaction conditions of glycosylation by
changing the sulfonylating agents, additives and base (see
Table S2 in Supporting Information). We found that using p-
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[
2
trifluoromethanesulfonic anhydride (Tf O) as an activator gave
the desired β-linked glycoside 37 as a single diastereomer in 48%
yield (brsm yield: 73%). We reasoned that the hemiacetal of 36
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[
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2
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In conclusion, we have achieved the first asymmetric total
synthesis of the complex polycyclic xanthone FD-594, isolated
from Streptomyces sp. TA-0256, in LLS 20 steps using a
convergent approach. The chiral isochromanone A-B ring is
constructed using Pt-catalyzed enantioselective diboration
followed by Pd-catalyzed cross-coupling. The trans-9,10-
dihydrophenanthrene-9,10-diol fragment (B-C-D ring) is
2
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[
prepared by
a
new strategy involving an asymmetric
1
dihydroxylation followed by Cu-mediated oxidative cyclization.
Late-stage stereoselective glycosylation assembles the angular
hexacyclic framework with a 2,6-dideoxy trisaccharide fragment.
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COMMUNICATION
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Angewandte Chemie International Edition
10.1002/anie.201915787
COMMUNICATION
Natural Product Synthesis
Tao Xie, Chaoying Zheng, Kuanwei Chen,
Haibing He, Shuanhu Gao*
__________ Page – Page
Asymmetric Total Synthesis of FD-594
The first asymmetric total synthesis of FD-594, a complex polycyclic xanthone from
Streptomyces sp. TA-0256, was described herein.
This article is protected by copyright. All rights reserved.