Syntheses of Thailandepsin B Pseudo-Natural Products: Access to New Highly Potent HDAC Inhibitors via Late-Stage Modification

Article abstract of DOI:10.1002/chem.202002449

New Thailandepsin B pseudo-natural products have been prepared. Our synthetic strategy offers the possibility to introduce varying warheads via late stage modification. Additionally, it gives access to the asymmetric branched allylic ester moiety of the natural product in a highly diastereoselective manner applying rhodium-catalyzed hydrooxycarbonylation. The newly developed pseudo-natural products are extremely potent and selective HDAC inhibitors. The non-proteinogenic amino acid d-norleucine was obtained enantioselectively by a recently developed method of rhodium-catalyzed hydroamination.

Full text of DOI:10.1002/chem.202002449

Accepted Article
Accepted Article
Title: Syntheses of Thailandepsin B Pseudo-Natural Products: Access
to new highly potent HDAC Inhibitors via Late Stage Modification
Authors: Bernhard Breit, Monika Lutterbeck, Amelie Liebich, Manfred
Keller, Daniel Herp, Anja Vogelmann, Manfred Jung, and
Jana Brosowsky
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using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202002449
Link to VoR: https://doi.org/10.1002/chem.202002449
01/2020

10.1002/chem.202002449
Chemistry - A European Journal
COMMUNICATION
Syntheses of Thailandepsin B Pseudo-Natural Products: Access
to new highly potent HDAC Inhibitors via Late Stage Modification
Jana Brosowsky,[a] Monika Lutterbeck,[a] Amelie Liebich,[a] Manfred Keller,[a] Daniel Herp,[b] Anja
Vogelmann,[b] Manfred Jung,[b] and Bernhard Breit*[a]
Abstract: New Thailandepsin B pseudo-natural products have been
prepared. Our synthetic strategy offers the possibility to introduce
varying warheads via late stage modification. Additionally, it gives
access to the asymmetric branched allylic ester moiety of the natural
product in a highly diastereoselective manner applying rhodium-
catalyzed hydrooxycarbonylation. The newly developed pseudo-
natural products are extremely potent and selective HDAC inhibitors.
The non-proteinogenic amino acid D-norleucine was obtained
enantioselectively by a recently developed method of rhodium-
catalyzed hydroamination.
Thailandepsins are a family of natural products which had
been isolated from a culture broth of the gram-negative bacteria
Burkholderia Thailandensis E264. In 2011, Cheng et al.
identified thailandepsins A (1) and B (2) through systematic
overexpression of transcription factors.[1] The isolation of
thailandepsins C-F was reported by the same group in the
following year (figure 1).[2] At the same time, Brady et al.
independently observed the natural products burkholdac A (3)
and B (1) from the same bacterial strain and gene clusters.[3]
They were found to be identical to thailandepsins C (3) and A (1).
Figure 1. Thailandepsins A–F and FK228.
Thailandepsins show nanomolar inhibitory activity of histone
deacetylases (HDACs) comparable to the approved drug FK228
(romidepsin, 7)[4] with even enhanced isoform selectivity.
For thailandepsins, the same mechanism of action like in
HDAC1 (class I) is inhibited with IC50 values in a low nanomolar
FK228 is assumed; the disulfide bridge can be reduced to the
range whereas HDAC4 (class IIa) and HDAC6 (class IIb) are
free thiol which acts as the zinc-binding functional group
only inhibited in micromolar concentrations.[2] Besides being
(scheme 1).[1a] In accordance with a general structure model for
approved as anticancer agents, inhibitors of zinc-dependent
HDAC inhibitors proposed by Jung et al.,[9] thailandepsins
HDACs are promising for the treatment of further diseases like
contain
a macrocyclic backbone as cap group which is
inflammation, neurodegeneration or metabolic syndrome.[5]
For FK228, the disulfide prodrug is reduced intracellularly to
the zinc-binding thiol as enzyme inactivating group.[6] An
identical warhead is present in other depsipeptide natural
product HDAC inhibitors, e. g. in spiruchostatins.[7] Like
thailandepsins, they exhibit a statine unit (a β-hydroxy-γ-amino
acid) in their macrocyclic backbone. Largazole[8] contains the
thiol as a thioester prodrug which is hydrolyzed intracellularly to
give the free thiol.
suggested to be responsible for enzyme specificity. The cap
group is connected by an alkyl chain as spacer to the actual
enzyme inhibiting warhead. Thailandepsins A and C have been
synthesized by Ganesan et al.,[10] Xu and Ye et al.,[11] and Katoh
et al.[12] Total syntheses of thailandepsin B have been reported
by Cheng et al.[13] and Katoh et al.[14] The same group published
the syntheses of Thailandepsins D-F.[15]
[a]
[b]
Jana Brosowsky, Monika Lutterbeck, Dr. Amelie Liebich,
Dr. Manfred Keller, and Prof. Dr. Bernhard Breit
Albert-Ludwigs-Universität Freiburg
Institut für Organische Chemie
Albertstr. 21, 79104 Freiburg (Germany)
E-mail: bernhard.breit@chemie.uni-freiburg.de
Daniel Herp, Anja Vogelmann, and Prof. Dr. Manfred Jung
Albert-Ludwigs-Universität Freiburg
Scheme 1. Reduction of the disulfide in thailandepsins to generate the thiol as
zinc binding warhead.
Institut für Pharmazeutische Wissenschaften
Albertstr. 25, 79104 Freiburg (Germany)
Supporting information for this article is given via a link at the end of
the document.
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In this work, we envisioned the syntheses of thailandepsin B
11 is built up from a dipeptide (12) containing D-alanine and
N-protected D-norleucine and compound 13 with the chiral allylic
pseudo-natural products with varying warheads, e. g.
a
hydroxamic acid (compound 8, scheme 2). This functionality has
shown to be a highly potent zinc-binding group. It is present in
already approved drugs like SAHA.[16] For cyclic tetrapeptide
HDAC inhibitors, hydroxamic acid warheads have successfully
been introduced. These compounds inhibited HDAC1 at low
nanomolar concentrations.[17] Our syntheses are based on the
macrocyclic precursor 9 which enables the introduction of
varying warheads on late stage via cross metathesis.
ester
which
is
obtained
by
rhodium-catalyzed
non-
hydrooxycarbonylation (scheme 3). D-Norleucine is
a
proteinogenic amino acid. As an alternative to commercially
available D-norleucine, we show an elegant pathway applying
the recently developed method of enantioselective catalytic
hydroamination
(scheme 4)
for
its
synthesis.[22]
Benzophenonimine (14) is added to hepta-1,2-diene (15) using
[Rh(COD)Cl]2, a Josiphos-ligand and PPTS as an additive. The
adduct 16 is directly hydrolyzed by aq. HCl followed by
introduction of the protecting group Fmoc (17) or Cbz (18). For
17, an excellent enantiomeric excess of 96% ee was determined.
Scheme 2. Thailandepsin B pseudo-natural product 8 and retrosynthetic
approach: Macrocyclic precursor
modification to introduce varying warheads via cross-metathesis.
Disconnection of 8 via macrolactamization.
9 offers the possibility of late stage
Scheme 4. Synthesis of Fmoc-protected D-norleucine via rhodium-catalyzed
hydroamination. a) aq. HCl, Et2O, r.t., 24 h; b) PGCl, Na2CO3, dioxane, 0 °C to
r.t., 17 h; c) K2OsO2(OH)4, NMO, acetone, H2O, THF, 18 h, PG = Fmoc 79%,
PG = Cbz 91%; d) NaIO4, THF/H2O, 2 h; e) NaClO2, NaH2PO4, tBuOH/H2O,
PG = Fmoc 1.5 h 70%, PG = Cbz 20 h, 82%.
The chiral allylic ester in 9 was targeted to be obtained by
the recently developed atom economic and redox-neutral
rhodium-catalyzed addition of a carboxylic acid to an allene.[18]
This method gives access to branched allylic esters in a highly
enantio- or diastereoselective fashion. In preceding syntheses of
the thailandepsin natural products, the highlighted stereocenter
was obtained by stoichiometric amounts of a chiral auxiliary,[10-12]
use of L-malic acid[19] or the separation of two diastereomers
derived from a racemate.[15,20] D-cysteine in the cyclic backbone
is exchanged to D-alanine.[21] Retrosynthetically, compound 9 is
obtained by macrolactamization (scheme 2). Next, the carboxylic
acid 10 is yielded by deprotection of the primary silyl ether in 11
followed by oxidation of the alcohol (scheme 3).
Dihydroxylation of the double bond followed by oxidative
cleavage delivered the protected D-amino acids 19 and 20. The
high enantiomeric excess remained unchanged during these
transformations. Coupling of 19 to the tert-butyl ester of
D-alanine (21) using EDCI*HCl and HOBt followed by cleavage
of the tert-butyl ester under acidic conditions with TFA and
triethylsilane afforded dipeptide 12 (scheme 5).
Scheme 5. Synthesis of compound 12. a) EDCI*HCl, HOBt, NEt3, DCM, r.t.,
18 h, 76%; b) TFA, Et3SiH, DCM, r.t., 18 h, 81%.
The known statine[23] 23 was silylated with a TBS group at its
secondary alcohol to afford 24. The chiral allylic ester was built
up by addition of 24 to allene 25. Selected results of the
optimization for the rhodium-catalyzed hydrooxycarbonylation
are shown in table 1. [Rh(COD)Cl]2 and DIOP were used as
catalyst system.[18a] High diastereomeric ratios were achieved
with a temperature of 10 °C and a solution in DCE with a
concentration of 0.1 M. Increasing the catalyst loading from
2.5 mol% of [Rh(COD)Cl]2 and 5.0 mol% of (R,R)-DIOP to
Scheme 3. Retrosynthetic analysis.
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4.5 mol%/9.0 mol% at a reaction time of 48 h gave a high yield
of 80% and a very good dr of 88:12. Higher catalyst loadings or
longer reaction times increased the yield even more, but let the
diastereoselectivity drop. Use of (S,S)-DIOP delivered the other
diastereomer in an excellent ratio of 5:95. Apparently, here a
matched case of substrate and catalyst control is present. The
configuration of the newly constructed stereocenter of the allylic
ester in 26 was confirmed by the Mosher ester method.[24] For
use of (R,R)-DIOP, the ester in 26 was hydrolyzed and the
obtained chiral alcohol was esterificated with both the (R)- and
the (S)-Mosher's acid. Comparison of the 1H-NMR spectra of
both diastereomers of the Mosher esters led to the conclusion
that the newly formed chiral center shows the desired (S)
configuration[25] as expected from previous results.[18a]
Scheme 6. Synthesis of macrocyclic precursor 8. a) HNEt2 (10%), DMF, r.t.,
5 min; b) 12, HATU, HOBt, DIPEA, DCM, r.t., 24 h; c) HF*pyridine (70%),
pyridine, THF, 0 °C to r.t., 2 h, 58% over 3 steps; d) Jones reagent, acetone,
r.t., 55 sec, 60%; e) piperidine, DCM, r.t., 45 min, 90%; f) HATU, DIPEA, DCM
(1 mM), r.t., 16 h, 51%.
Table 1. Optimization of rhodium-catalyzed coupling of statine 24 to allene
25.
The macrocycle 9 with its terminal alkene offered the
possibility of functionalization via cross-metathesis. The thiol
was introduced as a thioester like in largazole.[8] We followed a
two-step-sequence which had successfully been applied in the
recent synthesis of homolargazole by our group.[26] The
introduction of homoallylic bromide (29) with Grubbs II catalyst
at 80 °C followed by nucleophilic substitution of the bromide with
thioacetate afforded the desired compound 32 (scheme 7). The
silylether was cleaved under acidic conditions to yield the
pseudo-natural product 33. For another pseudo-natural product
with the same depsipeptide backbone, but with a hydroxamic
acid warhead, 9 was subjected to cross-metathesis with 34
(scheme 7).[27] Removal of TBS with HCl in acetone followed by
cleavage of the Boc-groups with TFA and triethylsilane delivered
the desired hydroxamic acid 8. Formation of the Z isomers was
not observed during cross-metathesis of 9.
entry
time
48 h
48 h
48 h
96 h
48 h
[Rh(COD)Cl]2 / DIOP
2.5 / 5.0 mol% (R,R)
4.5 / 9.0 mol% (R,R)
7.5 / 15 mol% (R,R)
4.5 / 9.0 mol% (R,R)
4.5 / 9.0 mol% (S,S)
Yield[b]
45%
dr[c]
82:18
88:12
80:20
84:16
5:95
1
2
3
4
5
80%
98%
96%
71%
[a] TBSCl, imidazole, DMAP, r.t., 27 h, 54%; [b] Isolated combined yield of
diastereomers; [c] dr determined from 1H-NMR.
The product of the rhodium-catalyzed hydrooxycarbonylation
underwent Fmoc-deprotection with diethylamine in 5 min
(scheme 6). 13 was used in the coupling to dipeptide 12 with
HATU and HOBt without further purification. The primary alcohol
was deprotected selectively with HF*pyridine within 2 h. 27 was
obtained in a yield of 58% over three steps starting from 26. The
oxidation to carboxylic acid 10 turned out to be challenging.
Commonly used two-step-methods via the aldehyde using e. g.
DMP followed by Pinnick oxidation were unsuccessful. Only a
fast procedure using Jones reagent (CrO3 in H2SO4) delivered
the desired acid in a reasonable yield. Under these conditions,
oxidation takes place very fast which avoids the formation of
significant amounts of side products. A quick basic work-up is
required to save the secondary TBS-group. Fmoc-deprotection
was performed by piperidine. In situ macrolactamization to 9
with peptide coupling reagents was not possible. Purification of
the amino acid by reversed phase column chromatography was
necessary. Otherwise, the presence of piperidine adducts
avoided the formation of the macrocycle. Macrolactamization
was achieved using HATU and Hünig's base under high dilution
conditions.
The activity of compounds 9, 28, 32, 33, 35 and 8 was tested
in assay systems for HDAC1, 6 and 8 (table 2).[28] The ring
structures 9 and 28 without a warhead did not show inhibition for
any of the classes of HDACs. Compound 32 containing the
thioester and the alcohol protected by TBS showed a moderate
inhibitory activity of HDAC1 (class I) with an IC50 of 18.7 µM,
whereas HDAC6 (class II) was not inhibited. However, the
deprotected compound 33 showed a significantly higher activity
with an IC50 of 12.3 nM. Noteworthy is the outstanding HDAC1
selectivity. For the hydroxamic acid, the fully protected
compound 35 was not active in HDAC inhibition. With its free
hydroxy and hydroxamic acid, 8 had an IC50 of 28.0 nM for
HDAC1. Hence, it was in the same range like thioester 33 and
showed the same HDAC1 selectivity even with the hydroxamic
acid warhead as a very strong zinc-binding group. In comparison
to IC50 values of the reduced (free thiol) Thailandepsin B (2*,
table 2),[1a] our newly developed compounds 8 and 33 show
superior HDAC1 selectivity while preserving nanomolar potency.
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were obtained. Thioester 33 and hydroxamic acid 8 are highly
potent HDAC1 inhibitors with nanomolar IC50 values in vitro. The
synthetic strategy provides a platform for the introduction of
varying warheads to the cyclic depsipeptide backbone on late
stage. Different linker lengths and other zinc-binding functional
groups are the goal of future investigations.
Table 2. HDAC inhibition of prepared compounds using a ZMAL trypsin assay
for HDAC1 and 6 and a ZMTFAL trypsin assay for HDAC8;[26] IC50 or inhibition
@10 µM; n. i. = < 5% inhibition @10 µM.; n. d. = not determined. [a] literature
data; 2 was reduced to the active thiol prior to being assayed, for assay details
see SI[1a]
comp.
HDAC1
HDAC6
HDAC8
9
28
32
33
35
8
n. i.
n. i.
n. i.
n. i.
n. d.
n. d.
18.7 ± 8.9 µM
12.3 ± 1.6 nM
n. i.
n. i.
30%
Scheme 7. Late stage modification of 9. a) HCl, acetone, r.t., 2.5 h, 66%; b)
Grubbs II catalyst (20 mol%), toluene, 80 °C, 18 h, 69% brsm; c) HCl, acetone,
r.t., 3 h, 78%; d) potassium thioacetate, acetone, r.t., 3 h, 78%; e) HCl,
acetone, r.t., 3 h, 61%; f) Grubbs II catalyst (20 mol%), toluene, 80 °C, 18 h,
52% brsm; g) HCl, acetone, r.t., 2.5 h, 58%; h) TFA, Et3SiH, DCM, r.t., 5 min.
30%
22%
n. i.
n. d.
28.0 ± 2.0 nM
6.5 nM[1a]
39%
21%
2[a]
610 nM[1a]
1000 nM[1a]
Both pseudo-natural products 33 and 8 are highly selective
HDAC1 inhibitors. As expected, the newly introduced amino acid
D-alanine instead of D-cysteine compared to thailandepsin B did
not influence the inhibitory activity of the compounds. Most likely,
the macrocyclic depsipeptide as backbone drives the subclass
selectivity which was maintained with the strong zinc-binding
hydroxamic acid. Protection of the hydroxy group with bulky TBS
decreased the activity. The active compounds 32, 33 and 8 were
subjected to cellular testing. In cell viability tests with HL60
(acute promyelotic leukemia) and HeLa cells (cervix carcinoma),
micromolar GI50 values were obtained for 32 and nanomolar
ones for 33. 8 did not inhibit growth of HL60 cells in the MTS
assay at a concentration of 5 µM and 30% inhibition of cell
growth was detected for 8 at the same concentration in HeLa
cells. HDAC inhibition in cells was determined with a cellular
HDAC activity assay. Micromolar IC50 values were obtained for
32 for HL60 cells (66.3 ± 3.5 µM) and HeLa cells (58.6 ± 1.3 µM).
For 33, the IC50 values were nanomolar (HL60: 9.1 ± 0.8 nM;
HeLa: 34.0 ± 2.2 nM). Hence, they were in the same range as in
vitro. For 8, no HDAC inhibition was found in cells at a
concentration of 5 µM. Additionally, isotype selectivity for class I
HDACs in cells was investigated by western blotting. Constant
levels of acetylated α-tubulin and increasing levels of acetylated
Experimental Section
[Rh(COD)Cl]2 (4.9 mg, 0.010 mmol, 4.5 mol%), (R,R)-DIOP (9.9 mg,
0.020 mmol, 9.0 mol%) and statine 24 (113 mg, 0.220 mmol, 1.0 eq.)
were placed in a flame-dried argon-purged Young Schlenk round-bottom
flask. The flask was connected to high vacuum (4 h). Then, freshly
distilled DCE (2.2 ml, 0.1 M) was added. The solution was stirred for
5 min before allene 25 (52 mg, 0.26 mmol, 1.2 eq.) filtered over basic
allox was added at r.t. With addition of the allene, the color of the
reaction mixture turned from orange to light yellow. The reaction was
allowed to stir at 10 °C for 48 h. A crude NMR was taken to determine
the dr from the allylic signal. The crude was purified by column
chromatography (silica gel, PE:EA 95:5 – 90:10) to provide the product
26 as colorless oil (mixture of diastereomers, 119 mg, 0.168 mmol, 80%).
The dr was determined to be 88:12 from the crude 1H-NMR.
Acknowledgements
This work was supported by the DFG (Deutsche
Forschungsgemeinschaft) within CRC992 and Ju295/13-1. J.B.
histone
3 with increasing inhibitor concentration confirmed
selective inhibition of class I HDACs for compound 33 in cells.
Activity of 8 in vitro, but not in cells led to the conclusion that 8
might not be cell-permeable in contrast to the thioester prodrugs.
is
grateful
for
a
doctoral
fellowship
from
the
Landesgraduiertenförderung of the University of Freiburg. Skillful
technical support by Guenter Leonhardt-Lutterbeck, Karin
Schmidtkunz, Luca Zeyner and Tobias Heim (all University of
Freiburg) for laboratory assistance is acknowledged. Thomas
Niepel and Robin Warstat are acknowledged for preliminary
work.
In summary, we have developed a highly selective route for
the syntheses of new thailandepsin B pseudo-natural products.
Rhodium-catalyzed addition of the statine 24 to an allene was
applied to build up the chiral allylic ester stereoselectively with a
very high dr of 88:12. Thioester and hydroxamic acid warheads
were introduced via cross metathesis as
a late stage
Keywords: thailandepsin • pseudo-natural products • histone
modification of the macrocyclic backbone. The HDAC inhibitory
activity of the new pseudo-natural products was tested and
insights to the structure-activity-relationship of thailandepsins
deacetylase inhibitors • asymmetric catalysis • rhodium
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10.1002/chem.202002449
Chemistry - A European Journal
COMMUNICATION
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COMMUNICATION
New Thailandepsin B pseudo-
natural products have been
prepared applying rhodium-
catalyzed hydrooxycarbonylation.
This strategy gives access to the
asymmetric branched allylic ester
moiety in a highly
diastereoselective manner. Varying
warheads have been introduced via
late stage modification. The newly
developed compounds are
Jana Brosowsky, Monika Lutterbeck]
Amelie Liebich, Manfred Keller,
Daniel Herp, Anja Vogelmann,
Manfred Jung, and Bernhard Breit*
Page No. – Page No.
Syntheses of Thailandepsin B
Pseudo-Natural Products: Access
to new highly potent HDAC
Inhibitors via Late Stage
Modification
extremely potent and selective
HDAC inhibitors.
For internal use, please do not delete. Submitted_Manuscript
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