Efficient and Divergent Total Synthesis of (-)-Epicoccin G and (-)-Rostratin A Enabled by Double C(sp3)-H Activation

Article abstract of DOI:10.1021/jacs.9b09359

Dithiodiketopiperazines are complex polycyclic natural products possessing a variety of interesting biological activities. Despite their interest, relatively few total syntheses have been completed. We herein report the enantioselective, scalable, and divergent total synthesis of two symmetrical pentacyclic dithiodiketopiperazines, (-)-epicoccin G and (-)-rostratin A. A common intermediate was synthesized on a multigram scale from inexpensive, commercially available starting materials using an enantioselective organocatalytic epoxidation and a double C(sp³)-H activation as key steps, with the latter allowing the efficient simultaneous construction of the two five-membered rings. In addition to the cis,cis-fused target (-)-epiccocin G, the more challenging (-)-rostratin A, possessing two trans ring junctions, was obtained for the first time on a 500 mg scale through the optimization of each step and validation on multigram quantities. Both natural products were synthesized with high overall yields (13-20%). This study should facilitate access to this fascinating and yet understudied family of biologically active natural products.

Full text of DOI:10.1021/jacs.9b09359

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Communication
Efficient and Divergent Total Synthesis of (–)-Epicoccin G
and (–)-Rostratin A Enabled by Double C(sp3)–H Activation
Pierre Thesmar, and Olivier Baudoin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b09359 • Publication Date (Web): 26 Sep 2019
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Efficient and Divergent Total Synthesis of (–)-Epicoccin G and (–)-Rostratin A
Enabled by Double C(sp )–H Activation
3
Pierre Thesmar and Olivier Baudoin*
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University of Basel, Department of Chemistry, St. Johanns-Ring 19, CH-4056 Basel, Switzerland.
Supporting Information Placeholder
ABSTRACT: Dithiodiketopiperazines are complex
polycyclic natural products possessing a variety of
interesting biological activities. Despite their interest,
relatively few total syntheses have been completed. We
herein report the enantioselective, scalable and divergent
total synthesis of two symmetrical pentacyclic
after, the groups of Reisman and Tokuyama disclosed
the synthesis of the dihydrooxepine-containing 7-5-6-5-
7 DTPs acetylaranotin (4) and acetylapoaranotin.
Interestingly, all of these total syntheses proceed with
the initial construction of the AB/DE bicyclic systems
and assembly of the central DKP ring (C) at a later
stage.
7
,8
9
dithiodiketopiperazines, (–)-epicoccin
G
and (–)-
rostratin A. A common intermediate was synthesized on
multigram scale from inexpensive, commercially
available starting materials using an enantioselective
3
organocatalytic epoxidation and a double C(sp )–H
activation as key steps, with the latter allowing the
efficient simultaneous construction of the two five-
membered rings. In addition to the cis,cis-fused target (–
)-epiccocin G, the more challenging (–)-rostratin A
possessing two trans ring junctions was obtained for the
first time on a 500 mg scale through the optimization of
each step and validation on multigram quantities. Both
natural products were synthesized with high overall
yields (13-20%). This study should facilitate the access
to this fascinating and yet understudied family of
biologically active natural products.
Figure
1.
Examples
of
naturally
occurring
dithiodiketopiperazines with a pentacyclic framework
Dithiodiketopiperazines
abundant class of natural products exhibiting a great
diversity of biological properties. In particular, (–)-
epicoccin G (1), isolated from the fungus Epicoccum
nigrum, was shown to possess in vitro anti-HIV-1 and
antiplasmodial activities, and (–)-rostratin A (2),
(DTPs)
constitute
an
In recent years, C–H activation has gained increasing
importance in total synthesis, offering step-economical
access to key intermediates or allowing late-stage
1
10
introduction of key functional groups. In this context,
2
we and others developed an array of methods based on
3
0
3
Pd -catalyzed C(sp )–H activation for the construction
isolated from the marine-derived fungus Exserohilum
rostratum, was shown to be cytotoxic against HCT-116
11
of various carbo- and heterocyclic systems, and
demonstrated their applicability in natural product
4
cancer cells (Figure 1). These interesting bioactivities,
12
synthesis. Herein, we report a new strategy based on
combined with
a
challenging sulfurated fused
double C–H activation for the concise and divergent
enantioselective synthesis of (–)-epiccocin G (1) and (–
pentacyclic framework, have attracted the attention of
synthetic chemists in recent years. However, despite a
significant number of synthetic studies, only three
research groups have reported total syntheses of DTPs
based on such a pentacyclic framework, and hence these
molecules remain major synthetic challenges. On the
one hand, Nicolaou and co-workers reported the
pioneering synthesis of several 6-5-6-5-6 DTPs,
)-rostratin A (2), which are synthesized for the second
5
and first time, respectively. Structurally, these molecules
differ from the oxidation degree at C5/C5’, the nature of
the sulfur substituents at C2/C2’, and last but not least
the presence of cis (1) or trans (2) A-B/D-E ring
junctions.
Our retrosynthetic analysis is depicted in Figure 2.
Target compounds 1-2 were thought to arise from the
3
,6
including epicoccin G (1) and haematocin (3). Shortly
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common intermediate 5 through manipulation of the C4-
Page 2 of 7
excellent yield and enantioselectivity (e.r. 97:3) for keto-
epoxide 11. The triflation of 11 was performed via
formation of the lithium enolate and reaction with
phenyl triflimide to give alkenyl triflate 8, which was
sensitive and rapidly engaged in the next step. The
epoxide was opened via nucleophilic substitution by an
excess of L-alanine tert-butyl ester in trifluoroethanol at
65 °C. The ring-opening occurred with complete
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C5/C4’-C5’ double bonds and late-stage introduction of
the sulfur atoms at C2/C2’ as advised in earlier
3,6-8
studies.
For the synthesis of 2, we anticipated that the
control of the contra-thermodynamic trans ring junctions
would be a significant challenge. Indeed, the cis,cis 6-5-
6
-5-6 pentacyclic system was calculated to be more
–1
stable than the trans,trans system by 5 kcal mol by
DFT (Figure S1), and no such trans-fused pentacyclic
DTP natural product has been synthesized to date, to the
best of our knowledge. Then, a twofold application of
16
regioselectivity, consistent to a related example. Of
note, 50-60% of the initially engaged L-alanine tert-
butyl ester could be easily recovered. The secondary
alcohol was then acetylated to give compound 12 as a
97:3 diastereoisomeric mixture matching the
enantiomeric purity of epoxide 8, as expected from the
stereospecificity of the epoxide opening. Cleavage of the
tert-butyl ester under mildly acidic conditions furnished
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our C(sp )–H activation transform to the C3–C4 and
C3’–C4’ bonds in 5 would lead to the ditriflate precursor
3
6
.
The intramolecular C(sp )–H alkenylation of
13
14
cyclohexenyl bromides
and triflates
has been
3
reported, but such a double C(sp )–H alkenylation
reaction is unprecedented. Diketopiperazine formation
15
aminoacid 7, which was isolated as
a
single
by cyclodimerization would allow building intermediate
diastereoisomer after recrystallization (79% overall yield
from epoxide 8). Cyclodimerization of 7 mediated by
6
from monomeric amino acid 7. The latter would arise
from the regioselective and stereospecific opening of
BOP-Cl and collidine furnished the C -symmetric
2
enantiomerically pure epoxide 8 with L-alanine tert-
diketopiperazine 6 in high yield on a decagram scale.
Then bis-triflate 6 was submitted to the key double
16
butyl ester. Finally, epoxide 8 would be obtained from
3
cyclohexenone 9 by using List’s organocatalytic
C(sp )–H alkenylation reaction. Reaction conditions
1
7
enantioselective epoxidation. This retrosynthetic plan
were optimized, starting with standard conditions that
proved successful in previous complex settings (see the
5
,6
differs from most previous approaches by constructing
1
2b,c
simultaneously rings B and D from A-C-E precursor 6
Supporting Information for details).
In particular,
5
d,g
instead of constructing ring C last, while minimizing
non-strategic functional group manipulations. This
should result in a significant overall step-economy for
the synthesis of targets 1-2.
using the well-defined Pd(PCy ) complex (4 mol%),
3
2
supplemented with free tricyclohexylphosphine (20
mol%) was found to be key to avoid premature catalyst
decomposition leading to unproductive mixtures
including 5, unreacted 6, the mono-C–H alkenylation
product and proto-detriflated products. Moreover,
epimerization at the DKP ring was observed without
additional free ligand when the reaction was carried out
at high concentrations required for upscaling. With this
important modification, the double C–H activation
occurred in high yield (93%), and in a reproducible
manner on multigram quantities (8-9 g of 5 were
typically isolated per batch). This contributed to a short
and efficient (51% over 7 steps) synthesis of
intermediate 5, the structure and absolute configuration
of which was confirmed by X-ray diffraction analysis.
After having secured an efficient access to
intermediate 5, we turned to the synthesis of (–)-
epicoccin G (Scheme 2). Initial attempts to perform the
hydroboration/oxidation of the C4-C5/C4’-C5’ alkenes
with various boranes was met with little success. In
contrast, epoxidation occurred with high efficiency
using DMDO, leading to the bis-epoxide 13 with
complete cis diastereoselectivity with respect to the
angular C9/C9’ hydrogens, as confirmed by X-ray
diffraction analysis. However, attempts at regioselective
ring-opening of these epoxides in the presence of
various Lewis or Brønsted acids failed to provide useful
synthetic intermediates.
Figure 2. Retrosynthetic analysis
The enantiopure dialkene intermediate
5
was
synthesized in high overall yield from inexpensive
starting materials according to the seven-step sequence
depicted in Scheme 1. The most effective method to
access epoxide 8 was found to be List’s asymmetric
epoxidation of cyclohexenone 9, catalyzed by
cinchonanamine 10 and using aqueous hydrogen
1
7
peroxide as the oxidant. This method was routinely
performed on a decagram scale and provided an
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Scheme 1. Seven-Step Synthesis of Intermediate 5
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a
Measured by GC on a chiral stationary phase. b Measured by 19F NMR. c Thermal ellipsoids shown at 50% probability.
BOP-Cl = bis(2-oxo-3-oxazolidinyl)phosphinic chloride.
The best option was to perform an Upjohn
dihydroxylation, which likewise occurred with complete
cis diastereoselectivity, followed by oxidation of the
secondary alcohols at C5/C5’ with IBX, which gave bis-
hydroxy groups. To this purpose, tetraol 16, obtained
from the abovementioned Upjohn dihydroxylation of
intermediate 5, was protected as a bis-silylether, and
SOCl -mediated dehydration furnished dialkene 17 in
2

-hydroxyketone 14 in excellent yield (96% for two
good yield on a multigram scale.
steps). Then, samarium(II) iodide-mediated reduction of
Scheme 2. Synthesis of (–)-Epicoccin G
1
8
these hydroxyketones led to the thermodynamically
favored cis,cis-fused diketone, which was protected as a
dimethoxyketal and deacetylated in a one-pot fashion
(15). The next important step was the introduction of the
C2/C2’ thiomethyl groups, which was performed under
3
,6
conditions adapted from Nicolaou and co-workers.
However, whereas the later obtained, from a different
precursor, a 1.4:1 mixture of cis diastereoisomers
epimeric at both C2 and C2’, the thiolation of 15
occurred with a high diastereoselectivity in favor of the
desired C2 /C2’ diastereoisomer. This behavior could


arise from a directing effect of the C8 and C8’ hydroxy
groups, which according to molecular models are
spatially close to the C2’ and C2 positions, respectively,
and which were not present at the sulfuration stage in the
1
9
Nicolaou synthesis. Finally, iodine-mediated cleavage
of the C5/C5’ ketals led to epicoccin G (1) in 51% yield
for three steps. Overall, (–)-epiccocin G (23 mg) was
synthesized in 19.6% yield over 14 steps from
cyclohexenone 9, which represents
a
major
improvement compared to the first synthesis (1.5% over
3
,6
1
7 steps).
Then, we set out to explore the synthesis of (–)-
rostratin A (Scheme 3). Different strategies were
considered to install the challenging trans,trans ring
junctions. In particular, attempts at performing directed
hydrogenations of C3–C4/C3’–C4’ double bonds from
allylic C5 /C5’ or C2 /C2’ hydroxy groups failed to
a
Thermal ellipsoids shown at 50% probability. DMDO =
dimethyldioxirane; NMO = N-methylmorpholine N-oxide;
IBX
bis(trimethylsilyl)amide.
= 2-iodoxybenzoic acid; LiHMDS = lithium




provide the desired relative configuration. These failures
led us to consider a sterically controlled hydrogenation
of C3–C4/C3’–C4’ alkenes using C5 /C5’ -protected


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The examination of the DFT-optimized structure of an
A-B-C truncated model A indicated that the  face of the
C3–C4/C3’–C4’ alkenes should be efficiently shielded
by the silyloxy groups. Consistent with this analysis, the
hydrogenation of 17 led to the desired trans,trans-fused
product, as determined by NOESY NMR. TBAF-
mediated deprotection provided diol 18, the trans,trans
configuration of which was confirmed by X-ray
diffraction analysis. At this stage, attempts to invert the
configuration of the C5/C5’ alcohols by Mitsunobu or
related reactions failed, due to the propensity of
compound 18 to undergo dehydration, regenerating the
C4–C5/C4’–C5’ double bonds. Indeed, the X-ray
structure of 18 shows that the C5OH and C5’OH groups
lie at axial positions of the chair-like rings A and E with
a mean dihedral angle H–C4(C4’)–C5(C5’)–O of
ketone in favor of the C5 alcohol, and indeed attempts
at reducing diketone 19 with standard achiral reagents
furnished unproductive diastereomeric mixtures.
Consequently, we turned to the use of a reagent-based
stereochemical control, and found that the use of
catalytic (R)-(+)-2-methyl-CBS-oxazaborolidine in

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combination
with
the
borane•2,6-diethylaniline
20
complex, conditions well adapted to aliphatic ketones,
afforded the desired C5 /C5’ diol 21 exclusively and


without epimerization at C4/C4’. The cleavage of the
C8/C8’ acetates led to the corresponding tetraol, but the
latter was found to be insoluble in usual aprotic solvents
required for the subsequent step. Overcoming this
additional problem required a more indirect strategy.
TBS-diprotection and acetate cleavage afforded a less
polar diol 22, which was submitted to sulfuration with
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75.7°, hence almost perfectly aligned for anti-
LiHMDS and S as above for 15 in the synthesis of
8
elimination. To solve this problem, we turned to an
oxidation-reduction strategy. IBX-mediated oxidation of
diol 18 led to diketone 19, which easily epimerized at
C4/C4’ in the presence of acids or bases to give the
thermodynamic cis,cis diastereoisomer, as shown with
the formation of 20 upon transesterification from 19.
The truncated DFT-optimized model B showed no
particular steric preference for the reduction of the C5
Scheme 3. Synthesis of (–)-Rostratin A
epiccocin G. However, in contrast to 15, which provided
a mixture of C2/C2’ epipolysulfides as reported by
3
,6
Nicolaou and co-workers, the desired 2,2’-epidisulfide
was the major product of the sulfuration of the TBS-
protected diol 22. This fortunate result suppressed the
need for an additional reduction/reoxidation sequence,
which would have been otherwise necessary.
a
4
Thermal ellipsoids shown at 50% probability. TBS = tert-butyldimethylsilyl; TBAF = n-Bu NF.
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Journal of the American Chemical Society
(
2) (a) Guo, H.; Sun, B.; Gao, H.; Chen, X.; Liu, S.; Yao, X.; Liu,
In addition, similar to epiccocin G, the sulfuration of 22
occurred with exclusive C2/C2’ diastereoselectivity.
1
2
3
4
5
6
7
8
9
X.; Che, Y. Diketopiperazines from the Cordyceps-
Colonizing Fungus Epicoccum nigrum. J. Nat. Prod. 2009,
21
Finally, the scandium triflate-mediated mild cleavage
7
2, 2115-2119. (b) Wang, J.-M.; Ding, G.-Z.; Fang, L.; Dai,
of the TBS groups directly provided (–)-rostratin A (2),
J.-G.; Yu, S.-S.; Wang, Y.-H.; Chen, X.-G.; Ma, S.-G.; Qu, J.;
Xu, S.; Du, D. Thiodiketopiperazines produced by the
endophytic fungus Epicoccum nigrum. J. Nat. Prod. 2010, 73,
the physical properties of which matched the reported
4
data. Rostratin A was synthesized for the first time in
1
240-1249.
1
2.7% yield over 17 steps. This synthetic sequence was
(
3) Nicolaou, K. C.; Lu, M.; Totokotsopoulos, S.; Heretsch, P.;
Giguère, D.; Sun,Y.-P.; Sarlah, D.; Nguyen, T. H.; Wolf, I.
C.; Smee, D. F.; Day, C. W.; Bopp, S.; Winzeler, E. A.
Synthesis and biological evaluation of epidithio-, epitetrathio-
reproducible and scalable, allowing to obtain 556 mg of
synthetic rostratin A.
In conclusion, we successfully achieved the
enantioselective total synthesis of the natural
dithiodiketopiperazines (–)-epicoccin G and (–)-rostratin
A in 14 and 17 steps, respectively, and with high overall
yields from inexpensive starting materials. The common
precursor to both target molecules was readily
synthesized using an enantioselective organocatalytic
,
and
methodology, enantioselective total synthesis of epicoccin G,
,8′-epi-ent-rostratin B, gliotoxin, gliotoxin G, emethallicin E,
bis-(methylthio)diketopiperazines:
synthetic
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and haematocin and discovery of new antiviral and
antimalarial agents. J. Am. Chem. Soc. 2012, 134, 17320-
17332.
(4) Tan, R. X.; Jensen, P. R.; Williams, P. G.; Fenical, W.
Isolation and structure assignments of rostratins A−D,
cytotoxic disulfides produced by the marine-derived fungus
Exserohilum rostratum. J. Nat. Prod. 2004, 67, 1374-1382.
(5) (a) Middleton, M. D.; Peppers, B. P.; Diver, S. T. Studies
directed toward the synthesis of the scabrosins: validation of a
tandem enyne metathesis approach. Tetrahedron 2006, 62,
3
epoxidation and a double C(sp )–H activation as key
steps. The most challenging target, rostratin A,
possessing two trans ring junctions was synthesized for
the first time on a 500 mg scale thanks to a careful
analysis of steric features and through a combination of
substrate- and reagent-based stereochemical control.
This study further demonstrates the power of C–H
activation to, combined with more established methods,
streamline the access to complex biologically active
natural products.
1
0528-10540. (b) Gross, U.; Nieger, M.; Bräse, S.
Stereoselective synthesis of the epicoccin core. Org. Lett.
2009, 11, 4740-4742. (c) Gross, U.; Nieger, M.; Bräse, S. A
unified strategy targeting the thiodiketopiperazine mycotoxins
exserohilone, gliotoxin, the epicoccins, the epicorazines,
rostratin A and aranotin. Chem. Eur. J. 2010, 16, 11624-
1
1631. (d) Zipfel, H. F.; Carreira, E. M. An efficient synthesis
strategy to the core structure of 6-5-6-5-6-membered
epipolythiodiketopiperazines. Org. Lett. 2014, 16, 2854-2857.
ASSOCIATED CONTENT
(
e) Belov, D. S.; Ratmanova, N. K.; Andreev, I. A.; Kurkin,
A. V. Synthesis of bicyclic proline derivatives by the
aza‐Cope-Mannich reaction: formal synthesis of
±)‐acetylaranotin. Chem. Eur. J. 2015, 21, 4141-4147. (f)
Supporting Information
The Supporting Information is available free of charge on
the ACS Publications website at DOI:
(
Zhong, S.; Sauter, P. F.; Nieger, M.; Bräse, S. Stereoselective
synthesis of highly functionalized hydroindoles as building
blocks for rostratins B-D and synthesis of the pentacyclic core
of rostratin C. Chem. Eur. J. 2015, 21, 11219-11225. (g)
Zipfel, H. F.; Carreira, E. M. A unified strategy to 6-5-6-5-
X-ray diffraction data for 5, 13 and 18 (CIF)
Experimental
procedures,
spectral
and
characterization data for all compounds (pdf); coordinate
files for computational modeling (xyz).
6
‐membered epipolythiodiketopiperazines: studies towards
the total synthesis of scabrosin diacetate and haematocin.
Chem. Eur. J. 2015, 21, 12475-12480.
AUTHOR INFORMATION
(
6) Nicolaou, K. C.; Totokotsopoulos, S.; Giguère, D.; Sun,Y.-P.,
Corresponding Author
Sarlah, D. Total synthesis of epicoccin G. J. Am. Chem. Soc.
*olivier.baudoin@unibas.ch
2
011, 133, 8150-8153.
(7) Codelli, J. A.; Puchlopek, A. L. A.; Reisman, S. E.
Enantioselective total synthesis of (–)-acetylaranotin,
dihydrooxepine epidithiodiketopiperazine. J. Am. Chem. Soc.
012, 134, 1930-1933.
ORCID
a
Olivier Baudoin: 0000-0002-0847-8493
2
Notes
(
8) Fujiwara, H.; Kurogi, T.; Okaya, S.; Okano, K.; Tokuyama,
H. Total synthesis of (–)‐acetylaranotin Angew. Chem. Int.
Ed. 2012, 51, 13062-13065.
9) Wang, H.; Regan, C. J.; Codelli, J. A.; Romanato, P.;
Puchlopek-Dermenci, A. L. A.; Reisman, S. E.
Enantioselective synthesis of (–)-acetylapoaranotin. Org. Lett.
The authors declare no competing financial interest.
(
ACKNOWLEDGMENT
This work was financially supported by the University of
Basel. We thank Brian Freudiger and Philipp Meyer for
preparative work, Dr. Markus Neuburger and Dr.
Alessandro Prescimone for X-ray diffraction analyses, Dr.
Daniel Häussinger for assistance with NMR experiments,
and Dr. Michael Pfeffer for MS analyses.
2
017, 19, 1698-1701.
(10) (a) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. C–H bond
functionalization: emerging synthetic tools for natural
products and pharmaceuticals. Angew. Chem. Int. Ed. 2012,
51, 8960-9009. (b) Chen, D. Y.-K.; Youn, S. W. C–H
activation: a complementary tool in the total synthesis of
complex natural products. Chem. Eur. J. 2012, 18, 9452-
9474.
(c)
Karimov,
R.
R.;
Hartwig,
J.
F.
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