Total Synthesis and Structural Revision of Chaetoviridins A

Article abstract of DOI:10.1021/acs.orglett.7b02053

The first synthesis of the proposed structures of chaetoviridins A 1-4 has been achieved in 10 steps by controlling the syn- or anti-aldol side chain. The angular lactone has been regioselectively introduced by condensation of a chiral dioxin-4-one to cazisochromene. Comparison of the NMR and circular dichroism data of the synthesized and reported natural products led to the complete reassignment and renaming of the chaetoviridins.

Full text of DOI:10.1021/acs.orglett.7b02053

Letter
pubs.acs.org/OrgLett
Total Synthesis and Structural Revision of Chaetoviridins A
Mehdi Makrerougras, Romain Coffinier, Samuel Oger, Arnaud Chevalier, Cyrille Sabot,*
and Xavier Franck*
Normandie Univ, CNRS, UNIROUEN, INSA Rouen, COBRA (UMR 6014 & FR 3038), 76000 Rouen, France
S
* Supporting Information
ABSTRACT: The first synthesis of the proposed structures of chaetoviridins A 1−4 has been achieved in 10 steps by controlling
the syn- or anti-aldol side chain. The angular lactone has been regioselectively introduced by condensation of a chiral dioxin-4-
one to cazisochromene. Comparison of the NMR and circular dichroism data of the synthesized and reported natural products
led to the complete reassignment and renaming of the chaetoviridins.
zaphilones are bioactive secondary metabolites isolated
from various fungi; they present an extremely large
in natural products.3 Chaetoviridins A have been reported to
have wide biological activities, such as inhibitors of caspase 3 and
cholesteryl ester transfer protein (CETP), and have antimalarial,
antimycobacterial, antifungal, and cytotoxic activity.1 However,
structural variations associated with a panel of biological activities
make it difficult to draw any sort of structure−activity
relationship.
A
structural diversity as well as wide biological activity spectrum.1
Azaphilones are characterized by an oxabicyclic scaffold that
bears an oxygenated quaternary center at the C-7 position
(Figure 1). This 7-hydroxyl can be of (R) or (S) absolute
Chaetoviridins A,4−9 isolated from diverse Chaetomium
species, have an angular lactone structure, a branched pentenyl
side chain at position 3, and a chlorine atom at position 5 (Figure
2). On the lactone ring can be found a syn or anti aldol side chain
such as in chaetoviridin A 14,5,7,9 and 4′- or 5′-epimers 2 and 3.7
(7R)- or (7S)-Epimers can also be found naturally such as in 5′-
Figure 1. General structure of azaphilones.
configuration such as in (−) or (+) mitorubrin, respectively,2a
with (7S)-isomers being the most common among the
azaphilones. However, the 7-hydroxyl can be part of an angular
or linear furanone ring such as in trichoflectin2b or
rubropunctatin,2c respectively. The pyranoquinone cycle can
also be reduced to a dihydropyranic ring such as in
epicocconone.2d In addition to that, many reduced or rearranged
skeletons exist, enhancing the structural diversity and biological
activity spectrum of this family.
Azaphilones and more particularly chaetoviridins A are in the
limelight of numerous researches in particular regarding the
identification of gene cluster responsible for their biosynthesis
and genome mining approaches providing new access to diversity
Figure 2. Proposed structures of chaetoviridin A and epimers.
Received: July 5, 2017
© XXXX American Chemical Society
A
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epi-chaetoviridin A 37 (7S) or in 7,5′-bis-epi-chaetoviridin A 48
(7R) as well as in dehydrated (7R)- or (7S)-chaetoviridin E 5.5,8
Another epimer of chaetoviridin A has been described, being the
C-11 epimer 6; this compound was also named chaetoviridin E.6
As a consequence, two “chaetoviridin E” exist with different
structures (5, 6).
Scheme 1. Synthesis of Cazisochromene 14
The isolation and structural elucidation of chaetoviridin A 1
was achieved by Natori in 1990, who established the
configuration of the aldol as syn, based on NMR studies.4 This
configuration was adopted in subsequent studies, in particular for
the structural determination of other epimers.5,7,9 However,
without this being ever mentioned, Collado and Pupo reported
in 2011 X-ray data of 1 showing an anti (4′R,5′R) aldol chain.7
This absolute configuration was, however, already assigned to the
1
4′-epi-chaetoviridin A 2, which exhibited a H and 13C NMR
spectrum different from that of 1. Accordingly, following
suspected structural misassignment(s), we undertook the total
synthesis of chaetoviridin A and its epimers in order to
unambiguously attribute their structure. Besides, while ester-
functionalized azaphilones have already been synthesized,1 no
linear or angular lactone-bearing natural azaphilone has ever
been synthesized.10−24
The retrosynthetic analysis of chaetoviridin A 1 with syn aldol
side chain highlights two main fragments: the bicyclic oxygenated
fragment 14, a recently identified intermediate in the biosyn-
thesis of azaphilones, named cazisochromene,2b,c and a chiral
dioxin-4-one 21 bearing the syn aldol chain (Figure 3). Due to the
possibility of either 7R or 7S configuration in chaetoviridin A and
to remove any structural ambiguity, synthesis of both C7-epimers
was undertaken.
chiral syn aldol moiety of the natural product. N-Propionyl (S)-
benzyl thiazolidin-2-thione 15 reacted under standard con-
ditions28 with acetaldehyde to give the syn Evans aldol 16 in 80%
yield. The chiral auxiliary was smoothly removed by
methanolysis to give the corresponding methyl ester 17 in a
moderate 55% yield. Claisen condensation of the lithium enolate
of t-BuOAc with methyl ester 17 gave the β-ketoester 18 (91%
yield), and protection of the secondary hydroxyl as an acetate
gave the β-ketoester 19a in 88% yield. The formation of the
dioxinone skeleton 20 was performed in 75% yield by adding
H2SO4 to a mixture of 19a, Ac2O, and acetone.29 To avoid β-
elimination of acetate 20 occurring under standard deacetylating
conditions (MeOH in the presence of K2CO3 or other bases),
enzymatic hydrolysis with Candida cylindracea30 was performed,
giving clean deacetylation of the dioxinone 20, albeit with a slow
reaction rate. The so-obtained free hydroxyl group was then
reprotected as a TBS-ether giving (4S,5R)-dioxinone 21 with
70% yield for the last two steps (Scheme 2).
Figure 3. Retrosynthetic analysis.
Scheme 2. Synthesis of Dioxinone (4S,5R)-21
The synthesis of the key intermediate cazisochromene 14
started with chlorination of methyl atratate 7 before protecting
the phenol groups as methoxymethyl ethers (Scheme 1).
Benzylic deprotonation of 8 followed by addition of CO2 yielded
the carboxylic acid 9, which was activated as pentafluorophenol
ester 10. Addition of the lithiated anion of trimethylsilyl methyl
phosphonate onto 10 gave the β-ketoester 11 following Cossy′s
procedure.27a It should be noted at this stage that use of other
carboxylic acid derivatives (acid chlorides, Weinreb amides,
acylbenzotriazoles, etc.) and methylphosphonate as the
nucleophile did not yield the desired β-ketoester 11 with
acceptable yields.27b−d Then treating 11 with freshly prepared
chiral aldehyde 13 in the presence of potassium carbonate
performed the Horner−Wadsworth−Emmons (HWE) reaction
and lactonization to 12, installing the pentenyl side chain with
37% yield for the last two steps and without epimerization
(Figure S1). Lactone 12 was reduced to the lactol by 1 equiv of
DIBAL-H and oxidatively dearomatized in the presence of IBX,
TFA, and water25,26 to yield cazisochromene 14 as a ∼1:1
mixture of inseparable C7-epimers but with controlled 11S
absolute configuration.
With the two key intermediates 14 and 21 in hand, we
undertook their condensation according to our previous
studies.25,26 Dioxinone 21 and cazisochromene 14 were heated
in toluene for 30 min before adding Et3N. Under these
conditions, the intermediate β-ketoester 22 was formed and
gratifyingly condensed regioselectively at position 8, installing
the angular lactone of the natural product. It is worth noting that
opposite regioselectivity was observed when preparing analogues
The second fragment, identified as dioxinone 21, was prepared
via a diastereoselective titanium-based aldolization, installing the
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of the nonchlorinated dihydropyranic azaphilone epicocconone,
thus demonstrating the importance of the chlorine atom in the
regio-outcome of the process.26 The silylated crude product 23
was directly treated by HF/pyridine to give the (7S,4′S,5′R)-
chaetoviridin A 24 with 17% yield and its 7-epimer (7R,4′S,5′R)-
chaetoviridin A 25 with 20% yield over two steps (Scheme 3).
Scheme 4. Synthesis of anti Chaetoviridins A 29−32
Scheme 3. Synthesis of (7S,4′S,5′R,11S)-Chaetoviridin A 24
and (7R,4′S,5′R,11S)-Chaetoviridin A 25
chains. Starting from (S,S)-dioxinone 28, (7S,4′S,5′S)-chaetovir-
idin A 29 and (7R,4′S,5′S)-chaetoviridin A 30 were obtained
with 14 and 15% yield, respectively. The other set of anti
chaetoviridins A was prepared starting from (R,R)-dioxinone 28;
accordingly, (7S,4′R,5′R)-chaetoviridin A 31 and (7R,4′R,5′R)-
chaetoviridin A 32 were obtained with 11 and 14% yield,
respectively. For the four compounds 29−32, the absolute
configuration at C-7 was attributable, thanks to the circular
dichroism, as for 24 and 25 (Figure S2).
Analysis of the NMR data of 31 revealed, as expected, that they
perfectly matched the reported data of natural chaetoviridin A 1;
therefore confirming that the natural product has structure 31.
This also confirms that the anti structure of reported natural 4′-
epi-chaetoviridin 2 has to be corrected to syn such as in 24.
In addition, NMR data of (7S,4′S,5′S)-chaetoviridin A 29
perfectly match the reported data for the natural product 5′-epi-
chaetoviridin A 3, validating the anti structure of the natural
product; however, natural compound 3 should be renamed 4′,5′-
bis-epi-chaetoviridin A.
Significantly, no trace of retro-aldolization, β-elimination, or
epimerization products was observed, and so despite the basic
conditions. Note that for simplification of the discussion
throughout the Letter, the 11S stereochemical information will
not be specifically mentioned, unless necessary, as it is common
to all the chaetoviridins prepared here.
At this stage, the UV CD spectra of 24 and 25 were recorded
and a negative Cotton effect (Δε371 −24.3) allowed assigning the
(7S) configuration for 24, whereas 25 showed a positive Cotton
effect (Δε364 +19.7), establishing the (7R) configuration (Figure
S2).8
Surprisingly, by comparing the 1H and 13C NMR spectra of the
synthetic (7S,4′S,5′R)-chaetoviridin A 24 with literature data of
chaetoviridin A 1, important differences were observed in
particular at δH 4.30 vs 3.89 ppm (H5′) and 1.06 vs 1.18 ppm (4′-
CH3) and at δC 9.9 vs 13.5 ppm (4′-CH3), 19.4 vs 21.4 ppm
(C6′), 67.4 vs 70.9 ppm (C5′), and 165.3 vs 162.7 ppm (C8).4,5,7
Concerning the reported 7′,5′-bis-epi-chaetoviridin A 4, our
NMR data were found to be identical to (7R,4′S,5′S)-
chaetoviridin A 30; this is in accord with the reported structure8
and further confirms the presence of the unusual epimeric (7R)
center in this azaphilone; however natural compound 4 should be
renamed as 7,4′,5′-tris-epi-chaetoviridin A.
1
However, it turned out that H and 13C NMR data of 24 were
identical to those reported by Borges et al. for the 4′-epi-
chaetoviridin 2, which has been described bearing an anti-aldol
side chain.7 In our synthesis, the syn-stereocontrolled con-
struction of the aldol moiety unambiguously fixes the syn
relationship between H4′ and H5′ in 24. Accordingly, the
reported 4′-epi-chaetoviridin A 2, described with an anti aldol
side chain, has to be corrected to syn such as in (7S,4′S,5′R)-
chaetoviridin A 24.
To further confirm the misassignment of the aldol side chain of
the chaetoviridins A, we undertook the preparation of
chaetoviridin A epimers bearing anti aldol moieties. To this
end, we synthesized the two enantiomers of the dioxinones 28
bearing the anti aldol side chain (Scheme 4). Their synthesis
started with the anti-methylation of both enantiomers of methyl
3-hydroxybutanoate 26 to give the anti aldols 27.31 Then, each
enantiomer was individually converted to the (R,R)- or (S,S)-
dioxinone 28 in five steps, following the procedure developed for
the conversion of 17 to the syn dioxinone 21 (Scheme 2). Each
anti-dioxinone was then reacted with cazisochromene 14 under
thermal basic conditions, and the crude mixtures were desilylated
with HF/pyridine to yield the chaetoviridins with anti aldol side
For the 11-epimer of chaetoviridin A,6 named chaetoviridin E
6, we propose to revise its name to 11-epi-chaetoviridin A and its
structure to the anti aldol side chain and (7S,4′R,5′R,11R)
absolute configuration. Consequently, only one chaetoviridin E
will remain, possessing the β-eliminated side-chain such as in 5.
In conclusion, we have synthesized the natural product
chaetoviridin A along with three related natural epimers in ten
steps by preparing their biogenetic precursor cazisochromene.
The synthesis of this fragment involved two key steps, the
lactonisation/HWE one-pot process to build the 3-vinyl-
isocoumarine core, and an oxidative dearomatization to obtain
the pyranoquinone scaffold. The condensation of a function-
alized chiral acylketene to cazisochromene allowed the tricyclic
skeleton of chaetoviridins A to be built regioselectively. Detailed
analysis of NMR and circular dichroism data allowed us to
unambiguously revise the structure of all the chaetoviridins A. Of
note, easy separation of C7-epimers at the last step of the
C
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AUTHOR INFORMATION
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*E-mail: cyrille.sabot@univ-rouen.fr.
*E-mail: xavier.franck@insa-rouen.fr.
ORCID
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Xavier Franck: 0000-0002-5615-7504
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
The authors gratefully acknowledge the Fondation pour le
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chaetoviridin A. We are grateful to Dr. Laure Guilhaudis (Rouen
University) for her help in acquisition of CD spectra, to Emilie
Petit (INSA de Rouen) for chiral HPLC analyses, to Patricia
Martel (University of Rouen) for IR analyses, and to Albert
Marcual (CNRS) for HRMS analyses. We thank Dr. Hao Gao
(Jinan University, China) for kindly providing us with NMR
spectra of 7,4′,5′-tris-epi-chaetoviridin A (formerly 7,5′-bis-epi-
chaetoviridin A). We also thank Pr. Peter Karuso (Macquarie
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