Total Synthesis of the Cyclic Depsipeptide Vioprolide D via its (Z)-Diastereoisomer

Article abstract of DOI:10.1002/anie.202002328

The first total synthesis of vioprolide D was accomplished in an overall yield of 2.0 % starting from methyl (2S)-3-benzyloxy-2-hydroxypropanoate (16 steps in the longest linear sequence). The cyclic depsipeptide was assembled from two building blocks of

Full text of DOI:10.1002/anie.202002328

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Accepted Article
Title: Total Synthesis of the Cyclic Depsipeptide Vioprolide D via its
(Z)-Diastereoisomer
Authors: Hanusch A. Grab, Volker C. Kirsch, Stephan A. Sieber, and
Thorsten Bach
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10.1002/anie.202002328
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Total Synthesis of the Cyclic Depsipeptide Vioprolide D via its (Z)-
Diastereoisomer
Hanusch A. Grab, Volker C. Kirsch, Stephan A. Sieber and Thorsten Bach*
Abstract: The first total synthesis of vioprolide D was accomplished
in an overall yield of 2.0% starting from methyl (2S)-3-benzyloxy-2-
hydroxypropanoate (16 steps in the longest linear sequence). The
cyclic depsipeptide was assembled from two building blocks of similar
size and complexity in a modular, highly convergent approach.
Peptide bond formation at the C-terminal dehydrobutyrine amino acid
of the Northern fragment was possible via its (Z)-diastereoisomer.
After macrolactamization and formation of the thiazoline ring, the (Z)-
double bond of the dehydrobutyrine unit was isomerized to the (E)-
double bond of the natural product. The cytotoxicity of vioprolide D is
significantly higher than that of its (Z)-diastereoisomer.
synthesis of macrocyclic precursors to the vioprolides but did not
succeed in establishing the required E-Dhb double bond by
elimination.[8] Our synthetic interest in the vioprolides was kindled
by the biological activity of the compounds both against fungi and
against human cancer cell lines.[1,9] In the latter context, it has
been recently found that vioprolide A targets nucleolar protein 14
that is essential for ribosome biogenesis.[9] Despite the higher
activity of vioprolide A we focused our synthetic attention on
vioprolide D, mainly because the individual building blocks (L-Pro)
are more readily available than L-Maz and/or L-Pip. Our synthetic
strategy aimed at the preparation of the (Z)-isomer (Z-1) of
vioprolide D and its late stage conversion into the natural product.
The vioprolides were first isolated by Schummer et al. from the
myxobacterium Cystobacter violaceus Cb vi35.[1] Four members
of the compound class were reported and were denominated as
vioprolides A-D. The compounds were found to be cyclic
depsipeptides[2] containing a sequence of eight amino acids or
amino acid-derived building blocks and L-glyceric acid (L-Gla).
Starting from the N-terminal site, the amino acid sequence of
vioprolide D (E-1, Scheme 1) can be identified as: L-Ala, D-Leu,
L-Pro, L-Cys, L-Thr, L-Pro, L-Thr, L-Me-Val. In vioprolides A and
C the L-Pro unit in the Northern part of the molecule is replaced
by (2S,4R)-4-methylazetidine carboxylic acid (L-Maz). In
vioprolides A and B, pipecolic acid (L-Pip) is incorporated in the
Western hemisphere of the molecule instead of L-Pro. The
vioprolides are nonribosomal peptides and their assembly
commences presumably with the generation of an O-acyl L-Gla
building block, which is linked to L-Ala.[3] The acyl group is located
at the secondary hydroxy group of the glycerate. The (E)-
dehydrobutyrine (E-Dhb) unit is likely formed by dehydration of L-
Thr[4] and the assignment of its relative configuration was based
on NOESY spectra.[1] Dehydration of the L-Pro and L-Cys
dipeptide leads biosynthetically to formation of the thiazoline ring.
All other amino acid fragments remain unaltered and the
cyclization occurs as macrolactonization between the terminal
primary hydroxy group of the O-acyl glyceric amide and the
carboxylic acid residue of L-Me-Val.[3]
Scheme 1. Retrosynthetic disconnection of vioprolide D (E-1) into fragment Z-
2 with a C-terminal (Z)-dehydrobutyrine (Z-Dhb) and into fragment 3 composed
of L-Pro, L-Thr, L-Me-Val, and a C-terminal L-glyceric acid (L-Gla).
Apart from the fact that the strategy avoided the formation of the
congested bond between E-Dhb and L-Pro it was also desirable
to access the (Z)-isomer of vioprolide D for its own sake. Although
the assignment of the double bond configuration rested on solid
NOESY data, a synthetic proof of the assignment was warranted.
This was the more true as most dehydrobutyrines occurring in
natural products[10,11] exhibit the thermodynamically preferred (Z)-
configuration. In addition, it was to be explored whether the
biological activity of Z-1 and E-1 were different or identical. In this
communication, we address these questions and report the total
synthesis of vioprolide D (E-1) via its (Z)-isomer Z-1.
In agreement with the findings of Thomas and co-workers[5c] we
had in simultaneous experiments discovered that the biomimetic
macrolactonization[3] was not suited for ring closure to a vioprolide
D precursor. Instead, we dissected the molecule retrosynthetically
between L-Gla and L-Ala which led after another retrosynthetic
disconnection between L-Pro and Z-Dhb to pentapeptide Z-2 and
tripeptidyl glycerate 3 as potential building blocks. The synthesis
of the Northern fragment Z-2 (Scheme 2) commenced with
thioamide formation between the known amino dipeptide 4[12] and
Synthetically, the vioprolides represent a significant challenge[5]
mainly due to the sensitivity of the thiazoline fragment[6] and due
to the difficult – if not impossible – bond formation between E-Dhb
and L-Pro.[7] The group of Thomas has extensively studied[5b,c] the
[*]
M.Sc. Hanusch A. Grab, M.Sc. Volker C. Kirsch, Prof. Dr. Stephan
A. Sieber and Prof. Dr. Thorsten Bach
Department Chemie
Technische Universität München
Lichtenbergstrasse 4, 85747 Garching, Germany
Fax: +49 (0)89 289 13315
E-mail: thorsten.bach@ch.tum.de
Homepage: http://www.oc1.ch.tum.de/home_en/
Supporting information and the ORICD identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org./10.1002/....
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10.1002/anie.202002328
Angewandte Chemie International Edition
COMMUNICATION
triazole 5. The latter compound serves to transfer a N-Boc
protected thioproline unit[13] which in turn was required to create
the thiazoline ring at a more advanced stage of the synthesis.
After tripeptide formation, dehydration at the C-terminal L-Thr was
initiated with methanesulfonyl chloride and triethylamine.[14] The
elimination led exclusively to the expected Z-Dhb diastereoisomer
without formation of the other diastereoisomer. The N-terminal
Boc group of tripeptide Z-6 was removed[15] to enable in the next
step peptide coupling between the proline nitrogen atom and the
carboxylic acid of known dipeptide 7.[5c] Coupling with HATU and
2,4,6-collidine[16] delivered diastereomerically pure product Z-2
successfully avoiding any epimerization by oxazolone formation
within the activated dipeptide.
Scheme 3. Exact conditions and yields: (a) 8 (1.10 eq.), PPh3 (1.00 eq.), DIAD
(1.05 eq.), (THF), r.t., 18 h, 87%; (b) HNEt2 (46.0 eq.), (CH2Cl2), 0 °C, 5 h, 98%;
i
(c) N-Boc-Thr(O-TBS) (1.40 eq.), HOAt (0.50 eq.), HATU (1.40 eq.), Pr2NEt
(2.00 eq.), (CH2Cl2), 0 °C  r.t., 18.5 h, 87%; (d) TFA (14.6 eq.), (CH2Cl2), 0 °C;
70 min; (e) N-Boc-Pro (1.76 eq.), HOBt∙H2O (1.76 eq.), EDC∙HCl (3.56 eq.),
iPr2NEt (2.67 eq.), (CH2Cl2), 0 °C  r.t., 19.5 h, 64% over two steps; (f) TMSOTf
(6.00 eq.), 2,6-lutidine (8.00 eq.), (CH2Cl2), 0 °C, 3.5 h, 92%; DIAD = Di-iso-
propyl azodicarboxylate, EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,
Fmoc = fluorenylmethoxycarbonyl, HOAt = 1-hydroxy-7-azabenzotriazole, HOBt
= 1-hydroxy-benzotriazole, Pro = L-proline, TFA = trifluoroacetic acid, Thr =
L-threonine.
Scheme 2. Exact conditions and yields: (a) (THF), 0 °C, 5 min, 85%; (b) MsCl
(1.54 eq.), NEt3 (3.07 eq.), (CH2Cl2), 0 °C  r.t., 94%; (c) TMSOTf (6.00 eq.),
2,6-lutidine (8.00 eq.), (CH2Cl2), 0 °C, 3 h; (d) 7 (1.05 eq.), HATU (1.10 eq.),
2,4,6-collidine (1.00 eq.), (CH2Cl2), 0 °C  r.t., 14.5 h, 70% over two steps; Boc
=
tert-butyloxycarbonyl, coll = collidine, HATU = 1-[bis(dimethylamino)-
The selective hydrolysis of the methyl ester Z-13 was successfully
performed with trimethyltin hydroxide generating a free carboxylic
acid at the C-terminal site. Under the chosen conditions,[22] the
valine-glycerate ester bond remained intact. However, the
cleavage of a single TBS protecting group was recorded after
acidic work-up and purification. Removal of the Boc protecting
group at the N-terminal site of the depsipeptide set the stage for
the macrolactamization.[16] In this step, the partial loss of additional
TBS groups was observed. Without further purification the
macrolactamization product was globally deprotected with
hydrofluoric acid. The complete four-step reaction sequence was
performed on a scale of up to 3.6 g and the final product Z-14 was
obtained by column chromatography. The compound was not
diastereomerically pure but was contaminated by two other dia-
stereoisomers (diastereomeric ratio d.r. = 88/6/6). One of the
minor diastereoisomers turned out to be the E-Dhb depsipeptide
E-14 and seems to be formed during ester cleavage. The
constitution and configuration assignment was substantiated by
NOESY experiments and by conversion (see the SI for further
details) of this diastereoisomer into vioprolide D (E-1). The second
minor diastereoisomer is likely the epimeric D-Gla depsipeptide
which is formed in the macrolactamization step. The separation of
the three mentioned diastereoisomers was possible by semi-
preparative HPLC and the diastereomerically pure compound Z-
14 was obtained in an overall yield of 40% (over four steps).
Cyclization of the thiazoline ring under Mitsunobu conditions[23] led
to the initial target Z-1. Like vioprolide D (E-1),[1] the compound
also exists as a mixture of two rotamers, presumably due to
rotation around the Thr-Me-Val peptide bond.
methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, Ms
= methanesulfonyl, TBS = tert-butyldimethylsilyl, TMS = trimethylsilyl, Tf =
trifluoromethanesulfonyl.
The assembly of the Southern fragment 3 (Scheme 3) was
initiated by Mitsunobu esterification of Fmoc-protected N-methyl
valine (8)[17] with alcohol 9. The latter substrate was prepared from
a known glycerate precursor[18] which in turn was synthesized from
L-serine. The chosen procedure avoided carboxyl activation of the
sterically encumbered, racemization-prone amino acid. Basic
removal of the Fmoc group liberated the secondary amine at the
N-terminal site of 10 that was required for peptide coupling with
an appropriately protected threonine acid.[19] The final proline
entity was installed by another peptide coupling step after
releasing the N-terminal Boc protecting group in 11 under acidic
conditions. The ammonium salt was directly taken[20] into the
coupling with commercially available N-Boc protected proline and
delivered the desired depsipeptide 12. Preliminary experiments
had shown that deprotonation of the ammonium salt prior to coup-
ling leads to extensive formation of diketopiperazines.[21] Boc
deprotection of fragment 12 delivered the Southern part of
vioprolide D (3) which required ligation to the Northern part by
peptide bond formation between L-Pro and Z-Dhb. The desired
transformation was achieved after saponification of ester Z-2 by
peptide coupling to fragment 3 (Scheme 4).
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10.1002/anie.202002328
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COMMUNICATION
palladium on carbon.[26] The reaction is expected to be stereospe-
cific and led consequently to a mixture of E-1 and Z-1. Fortunately,
the separation of the two diastereoisomeric depsipeptides could
be achieved by semipreparative HPLC and allowed the isolation
of the pure natural product vioprolide D (E-1, 25% over two steps)
and the re-isolation of its diastereoisomer Z-1 (24% over two
steps). Despite the relative low yield for the final two-step
sequence, it was possible to isolate significant amounts (25 mg)
of vioprolide D from this transformation. The synthetic material
1
was identical in all its physical properties (IR, H and 13C NMR
spectra, MS, specific rotation) with the natural product (see the SI
for details).[1] The longest linear sequence towards vioprolide D
commences with a literature-known glycerate, methyl (2S)-3-
benzyloxy-2-hydroxypropanoate,[18] and includes a total of 16
steps with an overall yield of 2.0%.
The impact of the configuration of the dehydrobutyrine moiety on
the biological potency of vioprolide D was evaluated in a MTT [3-
(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide]
assay.[27] To this end, cells of the ALL (acute lymphoblastic leu-
kemia) cell line Jurkat were treated with vioprolide D (E-1) and (Z)-
vioprolide D (Z-1) in varying concentrations for 72 h. Whereas
synthetic vioprolide D exhibited cytotoxic activity with a half
maximal inhibitory concentration (IC50) of 679 nM, its diastereo-
isomer Z-1 (48.2 µM) showed a significantly reduced bioactivity.
Since the IC50 of the latter compound is approximately 70-fold
higher compared to vioprolide D, it can be concluded that the
configuration of the double bond is crucial for the biological activity
of the natural product. The observation also rules out an in vitro
epimerization of the two diastereoisomers. The determined
cytotoxicity of synthetic E-1 compares well with the previously
established cytotoxicity of vioprolide D extracted from the natural
producer.[9]
Scheme 4. Exact conditions and yields: (a) LiOH∙H2O (2.50 eq.), (H2O/THF),
0° C, 6 h; (b) 3 (1.00 eq.), HOAt (1.20 eq.), HATU (1.20 eq.), iPr2NEt (2.00 eq.),
(CH2Cl2), 0 °C  r.t., 15 h, 63% over two steps; (c) Me3SnOH (8.00 eq.), (DCE),
80 °C, 47.5 h; (d) (TFA/CH2Cl2), 0 °C, 1 h; (e) HATU (2.12 eq.), 2,4,6-collidine
(3.39 eq.), (CH2Cl2), r.t., 14.5 h; (f) HF (195 eq.), (H2O/MeCN), r.t., 24 h, 40%
over four steps; g) PPh3 (1.50 eq.), DIAD (1.50 eq.), (THF), r.t., 22 h, 78%; h)
NIS (0.95 eq.), DABCO (1.10 eq.), (CH2Cl2), r.t., 5 h; i) 5% Pd/C, NEt3 (1.20 eq.),
H2 (1 atm), (MeOH), r.t., 3 h, 25% E-1, 24% Z-1 (two steps); DCE = dichloro-
ethane, NIS = N-iodosuccinimide, DABCO = 1,4-diazabicyclo[2.2.2]octane.
The NMR signals of Z-1 were clearly different from the signals
reported for the natural product and its cytotoxicity was much less
pronounced (see below). While this result supported the previous
configuration assignment of the natural product,[1] the completion
of the total synthesis now rested on the challenging inversion of
the olefin configuration. Indeed, access to the (E)-diastereoisomer
by isomerization of the double bond of Z-1 required extensive
optimization (see the SI for details). Eventually, it was found that
a sequence of iodination and hydro-de-iodination was viable if
reported methods were properly adjusted. The first step, the
iodination of dehydrobutyrines, was adapted from an inversion
procedure which had previously been used only for less complex
substrates.[24] Simultaneous treatment of compound Z-1 with NIS
and DABCO evolved as the preferred procedure for initial
iodination and guaranteed high reproducibility combined with an
almost quantitative conversion. The reaction commences pre-
sumably with the formation of an -iodinated imine which
tautomerizes to an inseparable mixture of (E)- and (Z)-iodovio-
prolide D.[25] The subsequent hydro-de-iodination protocol relied
on the reductive power of hydrogen and NEt3 in the presence of
Figure 1. Dose-response curves and corresponding IC50 values from Jurkat
cells treated with vioprolide D (E-1) and (Z)-vioprolide D (Z-1) as determined by
MTT assay after 72 h incubation time. Data points represent the mean ± SEM
(standard error of the mean) of three independent replicates performed in
triplicates; rel. = relative; *IC50 values were determined with 95% confidence
interval as calculated using GraphPad Prism 8.
In summary, we have successfully completed the first total syn-
thesis of a vioprolide in a concise and convergent approach. The
hitherto unsolved challenge to access a natural product with a
peptide bond between the C-terminal end of E-Dhb and the L-Pro
nitrogen atom has been overcome by a late-stage double bond
isomerization. In addition, the reaction conditions avoid any signi-
ficant epimerization at stereogenic centers and suppress the
oxidation of the sensitive thiazoline ring. The chosen route should
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10.1002/anie.202002328
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COMMUNICATION
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Acknowledgements
We are grateful to Prof. Dr. R. Müller for providing reference NMR
spectra of vioprolide D. We kindly thank Dr. G. Gemmecker, C.
Schwarz, and T. Steiner for measuring high- and low-temperature
NMR spectra. O. Ackermann is acknowledged for his help with
HPLC purification.
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Keywords: antitumor agents • isomerization • macrocycles •
peptides • total synthesis
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10.1002/anie.202002328
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Better late than never: The key
linkage between a proline and an (E)-
dehydrobutyrine in vioprolide D was
successfully tackled by a late-stage
double bond isomerization. The first
member from this class of biologically
potent depsipeptides has thus been
efficiently synthesized (16 linear
steps, 2.0% overall yield).
H. A. Grab, V. C. Kirsch, S. A. Sieber, T.
Bach*
Page No. – Page No.
Total Synthesis of the Cyclic
Depsipeptide Vioprolide D via its (Z)-
Diastereoisomer
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