Enantioselective Total Synthesis and Structural Revision of Dysiherbol A

Article abstract of DOI:10.1002/anie.202105733

A 12-step total synthesis of the natural product dysiherbol A, a strongly anti-inflammatory and anti-tumor avarane meroterpene isolated from the marine sponge Dysidea sp., was elaborated. As key steps, the synthesis features an enantioselective Cu-catalyzed 1,4-addition/enolate-trapping opening move, an Au-catalyzed double cyclization to build up the tetracyclic core-carbon skeleton, and a late installation of the C5-bridgehead methyl group via proton-induced cyclopropane opening associated with spontaneous cyclic ether formation. The obtained pentacyclic compound (corresponding to an anhydride of the originally suggested structure for dysiherbol A) showed identical spectroscopic data as the natural product, but an opposite molecular rotation. CD-spectroscopic measurements finally confirmed that both the constitution and the absolute configuration of the originally proposed structure of (+)-dysiherbol A need to be revised.

Full text of DOI:10.1002/anie.202105733

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Accepted Article
Title: Enantioselective Total Synthesis and Structural Revision of
Dysiherbol A
Authors: Julian Baars, Isabelle Grimm, Dirk Blunk, Jörg-Martin
Neudörfl, and Hans-Günther Schmalz
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202105733
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10.1002/anie.202105733
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Total Synthesis and Structural Revision of
Dysiherbol A
Julian Baars,[a] Isabelle Grimm,[a] Dirk Blunk,[a] Jörg-Martin Neudörfl[a] and Hans-Günther Schmalz*[a]
Dedicated to K. Barry Sharpless on the occasion of his 80th birthday
[a]
J. Baars, I. Grimm, PD Dr. Dirk Blunk, Dr. J.-M. Neudörfl, Prof. Dr. H.-G. Schmalz
University of Cologne, Department of Chemistry
Greinstraße 4, 50939 Cologne, Germany
E-Mail: schmalz@uni-koeln.de
Supporting information for this article is given via a link at the end of the document.
Abstract: A 12-step total synthesis of the natural product dysiherbol
A, a strongly anti-inflammatory and anti-tumor avarane meroterpene
isolated from the marine sponge Dysidea sp., was elaborated. As key
steps, the synthesis features an enantioselective Cu-catalyzed 1,4-
addition/enolate-trapping opening move, an Au-catalyzed double
cyclization to build up the tetracyclic core-carbon skeleton, and a late
installation of the C5-bridgehead methyl group via proton-induced
cyclopropane opening associated with spontaneous cyclic ether
formation. The obtained pentacyclic compound (corresponding to an
anhydride of the originally suggested structure for dysiherbol A)
showed identical spectroscopic data as the natural product, but an
opposite molecular rotation. CD-spectroscopic measurements finally
confirmed that both the constitution and the absolute configuration of
the originally proposed structure of (+)-dysiherbol A need to be
revised.
Considering the promising biological activities of dysiherbol A
and the challenge of stereoselectively constructing the tetracyclic
6/6/5/6-fused carbon skeleton with five adjacent (mostly
quaternary) stereocenters, we decided to tackle its synthesis. We
report here the first enantioselective total synthesis of dysiherbol
A, which also led to a revision of both the constitution and the
absolute configuration of the natural product.
O
OH
OH
OH
17
16
D
15
20
14
C
HO
H
HO
HO
HO
O
13
1
10 B
8
A
H
5
3
6
HO
HO
HO
HO
12
11
dysiherbol A (1)
dysiherbol B (2)
dysiherbol C (3)
dysideanone E (4)
OH
MeO
O
Me
HN
O
OH
In 2016 Jiao et al. reported the isolation and structural elucidation
of dysiherbols A-C (1-3) and dysideanone E (4) as metabolites of
the sponge Dysidea sp. collected in the South China Sea
(Figure 1).[1] Initial biological testing revealed dysiherbol A (as the
most active of these compounds) to exhibit cytotoxic activity
towards the cancer cell line NCI H-929 at sub-micromolar
concentrations. Furthermore, 1 showed strong inhibition of NF-κB,
a protein involved in the regulation of inflammatory, immuno-
logical and carcinogenic processes.[1,2] From a structural point of
view, dysiherbol A (1) and its congeners 2 and 3 belong to the
hydroquinone sesquiterpenes, a large family of meroterpenes of
mixed biosynthetic origin.[3] More specifically, the dysiherbols are
members of the avarane sub-family, according to the substitution
pattern of the decalin AB ring system. Since the discovery of
avarol (5) in 1974[4] as a multi-bioactive compound,[5] a variety of
avarane meroterpenoids have been described, among them
aureol B (6)[6] and the cycloaurenones (such as 7 and 8),[7] the
latter featuring the same carbon skeleton as the dysiherbols,
however, with a cis-configuration of the decalin system.
HO
O
H
O
O
avarol (5)
aureol B (6)
cycloaurenone B (7) cycloaurenone C (8)
Figure 1. Proposed structure of dysiherbols A-C, dysideanone E and selected
related meroterpenoids with an avarane skeleton.
As outlined in Scheme 1, our strategic plan was to synthesize
dysiherbol A (1) from the simplified tetracyclic precursor 9 by late-
stage (diastereoselective) introduction of the methyl groups in ring
A. We envisioned that ketone 9 could possibly be obtained from
aldehyde 10 through Lewis acid-mediated twofold (cationic)
cyclization and subsequent oxidation. In this key step, the
tetracyclic ring skeleton would be diastereoselectively built up
under concomitant formation of two strategic C-C bonds.
Due to their interesting structural and biological properties,
meroterpenoids of the avarane family have attracted much
attention of synthetic chemists.[8-10] In 2017, Echavarren and co-
workers succeeded in synthesizing simplified compounds dis-
playing the tetracyclic carbon ring system of dysiherbols and
cycloaurenones.[11] However, the total synthesis of these natural
products remained an unsolved challenge.
OMe
OMe
OMe
OMe
I
MeO
MeO
MeO
12
MeO
O
1
O
H
O
O
9
10
11
13
Scheme 1. Retrosynthetic analysis of dysiherbol A.
1
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10.1002/anie.202105733
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COMMUNICATION
We further reasoned that the synthesis of the required
cyclization precursor 10 could be achieved from the cyclo-
hexanone derivative 11 which in turn could be prepared through
enantioselective Cu-catalyzed conjugate addition of a methyl
anion equivalent to 2-methyl-2-cyclohexenone (13)[12] followed by
diastereoselective alkylation of the resulting enolate with the
benzylic iodide 12, in analogy to a report by Cramer and
coworkers.[13]
Having thus achieved the chirogenic opening step with high
enantioselectivity on a multi-gram scale, the next task was the
conversion of ketone 11 into aldehyde 10 under introduction of a
C4 chain. For this purpose, ketone 11 was first converted into the
enol triflate 14 by treatment with LDA and N-phenyl triflimide.
Suzuki-Miyaura cross-coupling of 14 with the borane prepared in
situ from TBS-protected homoallylic alcohol 15 and 9-BBN then
proceeded cleanly under the chosen conditions (cat. Pd(dppf)Cl2,
Cs2CO3, H2O, DMF)[18] to deliver 16 in excellent yield. The
cleavage of the TBS group was achieved with catalytic amounts
of Bi(OTf)3 in the presence of water,[19] and the resulting alcohol
was directly subjected to oxidation with the Dess-Martin
periodinane (DMP) to give 10 in high yield (68% overall from 11).
According to this plan, we started our investigation by reacting
13[14] with AlMe3 in the presence of a catalyst generated in situ
from copper(I) thiophene-2-carboxylate (CuTC) and the (R)-
BINOL-derived chiral phosphoramidite ligand L*.[15] After
activating the resulting aluminium enolate as an ate-complex by
addition of methyllithium, the subsequent C-alkylation with iodide
12[16] proceeded smoothly in the presence of tripyrrolidino-
phosphoric acid triamide (TPPA) as a cosolvent[17] to afford
ketone 11 (96% ee, HPLC) in 59% yield as a single diastereomer
after chromatographic purification (Scheme 2).
With substantial amounts of the aldehyde 10 in our hands, we
went on to investigate the planned twofold cyclization. Initial
experiments revealed that treatment of 10 with common Lewis
.
acids (such as BF3 OEt2, AlCl3 or SnCl4) only resulted in the
formation of complex product mixtures usually containing the
ketone 22 as a major component. However, after extensive
screening of various Lewis acids, we succeeded in identifying
AuCl3 as the only catalyst capable of achieving the desired
transformation (under elimination of water) to give the olefin 17 as
a sole major product according to GC-MS analysis. On a pre-
parative scale, this unique reaction proved to be insensitive
towards air and moisture and proceeded within minutes in the
presence of only 5 mol% of AuCl3. After chromatographic
purification, 17 was obtained in 38% yield, and its structure was
secured by X-ray crystallography (Scheme 3). To explain the
unique performance of AuCl3 in this transformation, we suppose
that, in contrast to all other Lewis acids tested, AuCl3 is able to
convert the primary cyclization intermediate 23 rapidly into a more
stable allylic cation (24) under formation of the AuCl3(OH)- anion.
The cation 24 is then attacked by the electron-rich aromatic ring
to yield the observed product 17 in a SEAr cyclization under
regeneration of the catalyst (AuCl3). To support this mechanistic
proposal, we separately treated a sample of compound 25[20] with
4 mol% of AuCl3, which is known to catalyze substitution reactions
of allylic alcohols.[21,22] And indeed, in this case the tetracyclic
olefin 17 was again formed, even in an improved yield of 50%.
OMe
OMe
a) AlMe3, CuTC/L*
MeLi, 12, TPPA
b) LDA, THF
PhNTf2
MeO
MeO
O
O
TfO
*
59%
(e.r. 98:2)
83%
13
11
14
Ph
O
O
L*
P
N
c) 9-BBN, THF
TBSO
97%
Pd(dppf)Cl2
Cs2CO3
Ph
15
OMe
OMe
OMe
d) Bi(OTf)3
MeCN/H2O
e) DMP, CH2Cl2
f) AuCl3
(5 mol%)
CH2Cl2
MeO
MeO
MeO
38%
83%
O
OTBS
17
g) BH3 THF,
H2O2, NaOH
h) DMP, CH2Cl2
10
16
83%
OMe
OMe
OMe
i) LiH, TPPA
160 °C
then MeI
j) ZnEt2
CH2I2
DCE
MeO
MeO
MeO
76%
77%
H
O
MeO
MeO
9
18
19
k) aq. HCl
MeOH
OMe
OMe
81%
MeO
OMe
OMe
AuCl3
CH2Cl2
MeO
Me-[M]
MeO
MeO
1
O
10
17
LA
HO
O
AuCl3
various
LAs
[X-ray]
OMe
21
20
+ H2O
[X-ray]
OMe
OMe
OMe
Scheme 2. Synthesis of key intermediate 9 and unsuccessful attempts at its
conversion to 1. Reagents and conditions: a) AlMe3, CuTC/L* (2.4 mol%), Et2O,
–30 °C, 4.5 h; then MeLi, 12, TPPA, –30 to 25 °C, 17 h; b) LDA, THF, PhNTf2,
-78 to 25 °C, 3 h; c) 15, 9-BBN, THF, 25 °C, 2 h; then 14, Pd(dppf)Cl2 (3 mol%),
Cs2CO3, H2O, DMF, 25 °C, 1 h; d) Bi(OTf)3 (4 mol%), CH3CN/H2O, 25 °C, 1.5 h,
97%; e) DMP, CH2Cl2, 0 to 25 °C, 2 h, 86%; f) AuCl3 (5 mol%), CH2Cl2, 0 °C, 11
MeO
MeO
MeO
MeO
AuCl3
H
HO-AuCl3
24
O
O
OH
Cl3Au
22
23
25
.
min; g) BH3 THF, THF, 0 to 30 °C, 10 h; then NaOH, H2O2, THF/H2O, 0 to 25 °C,
14 h; h) DMP, CH2Cl2, 0 to 30 °C, 2 h; i) LiH, TPPA, 160 °C, 1.5 h; then MeI,
25 °C, 20 h; j) ZnEt2, CH2I2, DCE, 25 °C, 35 min; k) aq. HCl, MeOH, reflux, 35
min. CuTC = copper(I) thiophene-2-carboxylate, TPPA = tripyrrolidinophos-
Scheme 3. A mechanistic proposal for the AuCl3-catalyzed twofold cyclization
of aldehyde 10 to the tetracyclic olefin 17.
phoric acid triamide, LDA
= lithium diisopropylamide, TBS = tert-butyl-
dimethylsilyl, 9-BBN = 9-borabicyclo[3.3.1]nonane, dppf = 1,1′-bis(diphenyl-
phosphino)ferrocene, DMP = Dess-Martin periodinane, DCE = dichloroethane.
2
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10.1002/anie.202105733
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COMMUNICATION
Having developed a reliable protocol for constructing the
tetracyclic core structure of the dysiherbols by double cyclization
of aldehyde 10, the remaining challenge was the installation of the
two missing methyl groups as well as the hydroxy function at ring
A. To prepare for this, we first converted 17 into the originally
devised ketone 9 through hydroboration/oxidation and subse-
quent DMP oxidation (Scheme 2). As the introduction of the
bridgehead methyl group (C12) could not be achieved by direct α-
methylation of the ketone (due to the steric hindrance) we had to
take a deviation via opening of an enolether-derived cyclopropane
intermediate.[23] Remarkably, the regioselective, thermodyna-
mically controlled ketone deprotonation was achieved only by
treatment of 9 with LiH in TPPA at 160 °C, and the resulting lithium
enolate was O-alkylated with MeI to give the enolether 18. The
subsequent Simmons-Smith cyclopropanation[24] proceeded dia-
stereoselectively to give 19, from which the desired α-methyl
ketone 20 was obtained under acidic conditions (47% overall yield
from 9). To our disappointment, all attempts to convert 20 into the
chromatographic purification (Scheme 4). Notably, the crystal
structure of 26 displays an intramolecular hydrogen bond
between the OH and the methoxy group, once again pinpointing
the spatial proximity and the interaction of the functionalities at C4
and C20. The close structural relationship of 26 with the target
molecule 1 prompted us to investigate its deprotection. The triol
27, i.e. putative 12-nor-dysiherbol A, was obtained in high yield by
heating 26 with an excess of LiSEt in TPPA to 170 °C.[28] In
contrast, reaction of 26 with BBr3 in CH2Cl2 followed by hydrolytic
workup resulted in the formation of 28 under spontaneous
dehydrative cyclization. Besides characteristic changes in the
NMR spectrum, the structure of 28 was supported by its mass
spectrum which indicated the loss of one water molecule. It is
noteworthy that comparison of the NMR data for compounds 27
and 28 with those reported for dysiherbol A showed a much closer
relationship of the natural product to 28 compared to 27 (Table 1).
Table 1. Comparison of selected 1H and 13C NMR signals[a] of compounds 27
and 28 with those of dysiherbol A (taken from ref.[1])
tertiary alcohol 21, i.e. “dysiherbol
A dimethyl ether”, by
nucleophilic introduction of a methyl anion equivalent (MeMgBr,
MeLi, MeLi/CeCl3,[25] AlMe3 or ZrMe4[26]) failed. This result,
however, was not completely unexpected, as the crystal structure
of 20 not only confirmed the steric shielding of both faces of the
carbonyl group but also indicated an electronic deactivation, as
reflected by a distance of only 2.51 Å between the carbonyl C-
atom and the adjacent methoxy oxygen (n→π* interaction).[27]
27[b]
28[b]
dysiherbol A[c]
d (ppm)
C4
72.5
58.0
31.4
116.3
1.43
0.76
79.0
47.7
25.9
111.3
1.13
0.82
82.4
49.1
21.9
111.1
1.24
0.83
C10
C11
C19
H-8
OH
19
15
b) LiSEt
H-13
TPPA
170 °C
HO
13
11
4
OMe
OMe
10
8
94%
H-15a
H-15b
2.66
2.42
2.64
2.59
2.57
2.54
a) MeLi
CeCl3
THF
H
HO
20
27
MeO
MeO
OH
99%
[a] All spectra in CDCl3 (77.00 ppm); [b] 500 MHz (1H) / 126 MHz (13C); [c]
600 MHz (1H) / 150 MHz (13C).
4
c) BBr3
CH2Cl2
then H2O
H
H
26
HO
O
9
O
d) pTsOH
toluene, Δ
3Å MS
67%
We therefore reasoned that dysiherbol A might actually have
a similar pentacyclic structure as 28, which also opened a new
option for the end game of the synthesis, as the protolytic opening
of a cyclopropane (30) could possibly be linked to the installation
of the ether bridge (Scheme 4). Therefore, we proceeded with the
conversion of 26 to 30, which was achieved in two steps by acid-
mediated elimination of water and subsequent cyclopropanation
(ZnEt2, CH2I2) of the olefin 29. Much to our satisfaction, we then
succeeded in realizing the final key step. Under optimized
conditions, the reaction of cyclopropane 30 with an excess of BBr3
in the presence of water afforded compound 31 in 74% yield, the
structure of which (crystallized as an MeOH adduct) was secured
by X-ray crystallography. The spectroscopic data of 31 agreed
perfectly with those reported for natural dysiherbol A,[1] thus
confirming the necessary revision of the originally proposed
structure.
93%
OMe
H
28
MeO
29
e) ZnEt2
CH2I2
CH2Cl2
53%
[X-ray]
OH
OMe
f) BBr3/H2O
CH2Cl2
O
MeO
74%
H+
30
31
(-)-dysiherbol A
[X-ray]
Scheme 4. Completion of the synthesis of (–)-dysiherbol A. Reagents and
conditions: a) CeCl3, MeLi, THF, –78 °C to 25 °C, 18 h; b) LiSEt (10 equiv.),
TPPA, 170 °C, 4 h; c) BBr3, CH2Cl2, 25 °C, 25 h, then H2O, 25 °C, 1 h;
d) pTsOH x H2O, 3 Å MS, toluene, reflux, 4 h; e) ZnEt2, CH2I2, CH2Cl2, 25 °C, 2
h, 2 cycles; f) BBr3, H2O, CH2Cl2, 27 °C, 40 min. pTsOH = p-toluenesulfonic acid,
3 Å MS = molecular sieves (pore size: 3 Å).
To gain insight into the proton-induced cyclopropane opening
step, we also investigated the reaction of 30 with methanesulfonic
acid (MsOH) in toluene (Scheme 5). Interestingly, the aureane
derivative 33 was formed in high yield under comparably mild
conditions (2 equiv. MsOH, 25 °C) while the pentacyclic avarane
32 (i.e. dysiherbol A methyl ether) was formed as the only main
product in the presence of a large excess of MsOH at 55 °C. This
result indicates the regioselectivity of the primary cyclopropane
opening step being unimportant due to a Wagner-Meerwein
In contrast to 20, the non-methylated ketone 9 reacted
smoothly with MeLi/CeCl3 to give alcohol 26 as a single
diastereomer in virtually quantitative yield without the need of
3
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10.1002/anie.202105733
Angewandte Chemie International Edition
COMMUNICATION
rearrangement equilibrium between the two cationic interme-
diates 35 and 36. While at lower temperature the proton
elimination of 36 (to 33) is favored, the cyclization of 35 to 34 and
the subsequent cleavage of the O-Me bond occur only under
harsher conditions, under which, incidentally, 33 is converted to
32 in 40% yield, as shown in a separate experiment. Noteworthy,
the carbon skeleton of the tetracyclic aureane 33, has never been
found in nature (yet).
We therefore took a CD spectrum of 31 which clearly confirmed it
being the enantiomer of natural dysiherbol A (Figure 2).
In conclusion, we have elaborated a reliable and efficient
enantioselective synthesis of the unnatural enantiomer of
dysiherbol A (31). Structural assignments were confirmed by X-
ray crystal structure analyses.[29] The elaborated sequence (12
steps, 5% overall yield from 13) features some remarkable steps,
such as the Au-catalyzed two-fold cyclization of 10 to build up the
carbocyclic core, and the single-step conversion of cyclopropane
30 to the target.[30] As the enantiomer of the chiral ligand used in
the chirogenic opening step is readily available, we are now going
to use the developed protocol to also prepare substantial amounts
of the natural enantiomer of dysiherbol A in order to further
explore its biological properties.
OMe
OMe
OMe
a) MsOH
(20 equiv)
b) MsOH
(2 equiv)
toluene
55 °C
65 min
toluene
25 °C
40 min
MeO
MeO
O
43%
87%
32
33
30
The work presented here furthermore demonstrates the
importance of total synthesis in the context of structure elucidation.
Specifically, we have proven that the structures of the dysiherbols
have to be revised, both with respect to their constitution (as cyclic
ethers) and their absolute configuration. Noteworthy, the revised
structures (Figure 3) now display the same absolute configuration
at the stereocenters C8 and C9 as virtually all other avarane
meroterpenes from Dysidea sp. including the dysideanones.[3]
an avarane derivative
an aureane derivative
H
H
OMe
OMe
OMe
Me
O
MeO
MeO
34
35
36
OH
OH
OH
HO
O
O
O
O
9
8
HO
O
X
dysiherbol A
dysiherbol B
dysiherbol C
32 [X-ray]
33 [X-ray]
Figure 3. Revised structures of dysiherbols A-C and
representation idealizing the chair conformation of the trans-decalin ring system.
a general 3D
Scheme 5. Acid-mediated conversion of cyclopropane 30 to either the
pentacyclic avarane 32 or the aureane 33. MsOH = methanesulfonic acid.
Last but not least we would like to mention that while we were
in the process of finalizing this manuscript, a publication by Lu and
co-workers appeared describing a total synthesis of (racemic)
(±)-dysiherbol A following a different strategy.[31]
Another surprise was that the molecular rotation of synthetic
dysiherbol A (31) ([a]D = -23°; c = 0.5 in MeOH) did not match the
one reported for the natural product ([a]D = +23°; c = 0.1 in
MeOH).[1] While the absolute configuration of our sample was
secured by X-ray crystal structure analysis, the original configura-
tional assignment was based on the comparison of the experi-
mental CD spectrum with those calculated for 1.
Acknowledgements
This work was supported by the Fonds der Chemischen Industrie
(doctoral fellowship to J. B.), the Jürgen Manchot Stiftung
(doctoral fellowship to I. G.) and the University of Cologne.
Keywords: Natural products • enantioselectivity • gold catalysis
• cyclopropanes • rearrangement • cyclization
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4
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COMMUNICATION
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information).
5
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10.1002/anie.202105733
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
OMe
OMe
OMe
OH
cat.
AuCl3
BBr3
H2O
MeO
O
MeO
MeO
CHO
(-)-dysiherbol A (revised)
Gold makes the difference! In a key step of the first enantioselective total synthesis of the anti-inflammatory marine meroterpene
dysiherbol A, the tetra-carbocyclic core skeleton is set-up in a unique gold-catalyzed double cyclization, and the ether bridge of the
pentacyclic target structure is spontaneously formed under cyclopropane opening upon deprotection of a late intermediate.
6
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