Calixanthomycin A: Asymmetric Total Synthesis and Structural Determination

Article abstract of DOI:10.1021/acs.orglett.1c00193

We report the first asymmetric total synthesis and structural determination of calixanthomycin A. Taking advantage of a modular strategy, a concise approach was developed to assemble the hexacyclic skeleton with both enantiomers of the lactone A ring. Stereoselective glycosylation coupled the angular hexacyclic framework with a monosaccharide fragment to produce calixanthomycin A and its stereoisomers. This enable us to determine and assign the absolute configuration of C-25 (25S) and monosaccharide (derivative of l-glucose).

Full text of DOI:10.1021/acs.orglett.1c00193

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Calixanthomycin A: Asymmetric Total Synthesis and Structural
Determination
Kuanwei Chen, Tao Xie, Yanfang Shen, Haibing He, Xiaoli Zhao,* and Shuanhu Gao*
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ABSTRACT: We report the first asymmetric total synthesis and
structural determination of calixanthomycin A. Taking advantage of
a modular strategy, a concise approach was developed to assemble
the hexacyclic skeleton with both enantiomers of the lactone A
ring. Stereoselective glycosylation coupled the angular hexacyclic
framework with a monosaccharide fragment to produce calix-
anthomycin A and its stereoisomers. This enable us to determine
and assign the absolute configuration of C-25 (25S) and
monosaccharide (derivative of L-glucose).
alixanthomycin A (1) belongs to the family of polycyclic
C
xanthone-type natural products1 that was isolated from
cultures of S. albus BAC-AB1692/916/170 by Brady and co-
workers in 2014.2 Biological studies revealed that this molecule
shows potent antiproliferative activity against HCT-116 cells
(IC50 = 0.43 nM). Calixanthomycin A contains a highly
oxygenated angular hexacyclic skeleton that includes a lactone
A ring, a xanthone D−E−F ring, and a β-linked mono-
saccharide. The structure of 1 was proposed according to
spectroscopic investigations, and the absolute configuration of
the lactone and monosaccharide remained unestablished.2
Interestingly, a biogenetically related polycyclic xanthone IB-
00208 (2) was discovered by Romero and co-workers from the
culture broth of Actinomadura sp. in 2003.3 IB-00208 exhibits
highly cytotoxic activities against several human tumor cell
lines and potent antibiotic activities against several Gram-
positive bacteria.3 The structural differences between calix-
anthomycin A and IB-00208 mainly rely on the oxidation state
of C−D ring and position of methoxy groups around the F
ring.
The challenging structural features and biological potentials
of polycyclic xanthones (Figure 1), such as FD-594 (3),4
kibdelone C (4),5 kigamicin A (5),6 and arixanthomycins A−C
(6−8),7 have attracted considerable attention from the
synthetic community, including the groups of Kelly,8 Suzuki,9
Porco,10 Ready,11 Martin,12 and us.13 We are interested in the
biological functions and mechanism studies of this family of
natural products, which prompted us to initiate a research
program to explore its chemical synthesis.13 In this work, we
report a modular synthetic route for the asymmetric total
synthesis calixanthomycin A and its stereoisomers, which
enable us to determine and assign the relative stereochemistry
and absolute configuration of this natural molecule.
Figure 1. Structures of polycyclic xanthones.
Received: January 18, 2021
Published: February 19, 2021
We envisioned that a modular strategy could enable a
flexible and efficient approach to prepare the stereoisomers of
https://dx.doi.org/10.1021/acs.orglett.1c00193
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1769−1774
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natural products and, therefore, to determine its stereo-
chemistry (Scheme 1). Fragment coupling of 9 (two
Scheme 2. Preparation of Two Enantiomers of the A−B
Ring
Scheme 1. Synthetic Plan
enantiomers of isochromanone A−B ring) and 10 (xanthone
D−E−F ring) followed by the oxidative cyclization might
furnish the angular hexacyclic framework, which could be
connected with the monosaccharide 11a or 11b (G ring)
through a late-stage glycosylation. A series of reliable reactions
were designed to prepare 9 and 10 by coupling the easily
available fragments 12−16.
Our synthesis started from the scalable preparation of two
enantiomers of the isochromanone A−B ring (Scheme 2). A
known symmetric 1,3-dibromo-2,5-dimethoxybenzene 14 was
selected as the starting material.14 Treatment of 14 with n-BuLi
gave the corresponding aromatic anion, which interacted with
S-propylene oxide 13a in the presence of Lewis acid (BF3·
Et2O) to form chiral alcohol 17a in 77% yield. Reaction of
alcohol 17a with methoxymethyl chloride (MOMCl) in the
presence of ZnBr2 in dichloromethane generated the
benzopyran ring 18a in perfect yield through an oxa-Pictet−
Spengler cyclization.15 Oxidation of the isochroman ring was
carried out with CrO3 under basic conditions (3,5-dimethyl
pyrazole) to provide lactone 19a in 55% yield,12,16 and its
structure and absolute configuration were confirmed by X-ray
diffraction analysis. Then replacement of the methyl protecting
groups of 19a with MOM ether through a two-step sequence
gave 20a. Pd-catalyzed Sonogashira coupling of 20a with
ethynyltriisopropylsilane 12 followed by desilylation produced
the terminal alkyne 21a in 80% yield over two steps. Using the
same transformations starting from 14 and R-propylene oxide
13b, another enantiomer isochromanone 21b was achieved
and its absolute configuration was determined by X-ray
diffraction analysis of 20b.
Scheme 3. Preparation of D−E−F Ring and Two
Enantiomers of Monosaccharide
The D−E−F xanthone ring was efficiently prepared from
two highly functionalized benzene rings 15 (D ring) and 16 (F
ring) (see details in the Supporting Information). Coupling of
15 and 16 under the basic conditions through a SNAr reaction
gave product 22, which was oxidized to carboxylic acid 23 in
mixture, which helped to selectively remove the benzyl
protecting group and yielded 24 as the coupling precursor.
Two enantiomers of monosaccharide 11a and 11b were
synthesized according to a modified procedure from D- and L-
glucose via a seven-step sequence, respectively (see details in
the Supporting Information).18
With all of the coupling fragments 21, 24, and 11 in hand,
we began to prepare the angular hexacyclic core framework
(Scheme 4A). A second palladium-catalyzed Sonogashira
good yield (Scheme 3). Following the methodology developed
17
́
by Aube, 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) was
added to a solution of freshly prepared acyl chloride, which
promoted an intramolecular Friedel−Crafts acylation to form
the xanthone framework. We also developed a one-pot
operation by adding trifluoroacetic acid (TFA) to the reaction
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Scheme 4. Total Synthesis and Structural Determination of Calixanthomycin A
cross-coupling of fragments 21a and 24 produced the desired
coupling product 25a in 80% yield. Pd/C-catalyzed hydro-
genation of 25a followed by selective removal of the MOM
group on C3-phenol mediated by a carbonyl group on C-1
yielded the desired biphenol 26a in 84% yield over two steps.
Next, we investigated the Cu-mediated oxidative phenol
coupling reactions,19 which have been used in our previous
synthetic studies of FD-59413a and PD-116740.19f Reaction of
biphenol 26a with 0.5 equiv of Cu(OH)Br·NMI2 in
acetonitrile at 75 °C under an air atmosphere generated the
cyclized hexacyclic skeleton 27a in 80% yield. After protection
of free phenol groups of 27a with benzyl groups, two
atropisomers 28a′ and 28a′′ were obtained as a mixture of
inseparable compounds with a ratio of 1:1. We reasoned that
the introduction of benzyl groups prevented the free rotation
of biaryl C4−C5 bond and generated a axial chirality. Using
the same transformations, hexacyclic framework 28b (a
mixture of inseparable compounds with a ratio of 1:1) was
prepared from fragments R-21b and 24.
We then turned our attention to couple the hexacyclic
skeleton with the monosaccharide fragment (Scheme 4B,C).
The phenolic MOM group on C-22 of 28a/29a was selectively
removed under acidic conditions to produce the glycosyl
acceptor. Using p-trifluoromethanesulfonic anhydride (Tf2O)
as an activator,20 11a was converted to the glycosyl tosylate
species which interacted with acceptor in the presence of
KHMDS to generate the desired β-linked glycoside 29a and
29b in 60% and 55% yield over two steps. Removal of three
benzyl groups through the palladium-catalyzed hydrogenation
(H2, 5 MPa) afforded target 30a and 30b that could be used to
identify and compare with the reported natural calixanthomy-
cin A (1). We found that the 1H and 13C NMR spectra of our
synthetic sample of 30a were in agreement with those of the
natural product (see details in the Supporting Information).2
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Authors
In contrast, those of synthetic 30b and the natural product are
significantly different. However, compound 30a ([α]20D = −62,
c = 0.01 in CHCl3) holds an opposite optical rotation to the
Kuanwei Chen − Shanghai Key Laboratory of Green
Chemistry and Chemical Processes, School of Chemistry and
Molecular Engineering, East China Normal University,
Shanghai 200062, China
natural calixanthomycin A ([α]20 = +68), which revealed
D
(−)-30a to be the enantiomer of natural calixanthomycin A.
To further confirm this proposal, we prepare the (+)-1 using
28b and 11b through the same three-step transformations
Tao Xie − Shanghai Key Laboratory of Green Chemistry and
Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, China
1
(Scheme 4D). The H and 13C NMR spectra, high-resolution
mass spectrum, and optical rotation of synthetic 1 ([α]20
=
D
+51, c = 0.009 in CHCl3) were consistent with the
corresponding data of the natural product.2 We thus determine
and assign the absolute configuration of C-25 to be the S-
configuration, which shares the same configuration of lactone
with FD-594 (3) and monosaccharide to be the derivative of L-
glucose. The calixanthomycin A aglycon 31 was also achieved
by removal of protecting groups from 27b (Scheme 4E).
In conclusion, we have achieved the first asymmetric total
synthesis and structural determination of the polycyclic
xanthone calixanthomycin A in LLS 15 steps. The modular
strategy enabled us to prepare the stereoisomers of natural
products efficiently to determine the stereochemistry and
absolute configuration of calixanthomycin A. The existence of
the derivative of L-glucose in calixanthomycin A, instead of the
D-derivative, might give hints to better understand the
biosynthetic pathway of this family of natural molecules. We
plan to carry out the structure−activity relationship (SAR)
studies of synthetic samples regarding to their anticancer
activities, which will be reported in due course.
Yanfang Shen − Shanghai Key Laboratory of Green Chemistry
and Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, China
Haibing He − Shanghai Engineering Research Center of
Molecular Therapeutics and New Drug Development, East
China Normal University, Shanghai 200062, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00193
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21971068, 21772044), Program of Shanghai Academic/
Technology Research Leader (18XD1401500), Program of
Shanghai Science and Technology Committee
(18JC1411303), “Shuguang Program (19SG21)”, and “the
Fundamental Research Funds for the Central Universities” for
generous financial support.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00193.
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Corresponding Authors
Xiaoli Zhao − Shanghai Key Laboratory of Green Chemistry
and Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai
200062, China; orcid.org/0000-0002-4458-6432;
Email: xlzhao@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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