The Total Synthesis of Chondrochloren A

Article abstract of DOI:10.1002/anie.202016072

The first total synthesis of chondrochloren A is accomplished using a 1,2-metallate rearrangement addition as an alternative for the Nozaki-Hiyama-Kishi reaction. This transformation also avoids the inherent challenges of this polyketide segment and provides a new, unprecedented strategy to assemble polyketidal frameworks. The formation of the Z-enamide is accomplished using a Z-selective cross coupling of the corresponding amide to a Z-vinyl bromide.

Full text of DOI:10.1002/anie.202016072

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Total Synthesis
Hot Paper
The Total Synthesis of Chondrochloren A
Yannick Linne, Elisa Bonandi, Christopher Tabet, Jan Geldsetzer, and Markus Kalesse*
In memory of Professor Wittko Francke (1940–2020)
Abstract: The first total synthesis of chondrochloren A is
accomplished using a 1,2-metallate rearrangement addition as
an alternative for the Nozaki-Hiyama-Kishi reaction. This
transformation also avoids the inherent challenges of this
polyketide segment and provides a new, unprecedented strategy
to assemble polyketidal frameworks. The formation of the Z-
enamide is accomplished using a Z-selective cross coupling of
the corresponding amide to a Z-vinyl bromide.
T
he chondrochlorens A and B were isolated during a screen-
ing campaign for biologically active natural products from
myxobacterium Chondromyces crocatus (Cmc5) by the
groups of Hçfle and Reichenbach in 2003 (Figure 1).[1] The
antibiotic potential of the chondrochlorens is barely tapped.
So far, only agar diffusion tests were reported disclosing only
weak antibiotic activity against Micrococcus luteus, and
Schizosaccharomyces bombe. Only traces of inhibition
against B. subtilis, and Staphylococcus aureus were
observed.[1]
Figure 1. Structures of chondrochloren A and B and their retrosynthetic
analysis. TBS=tert-butyldimethylsilyl, TIB=2,4,6-triisopropylbenzoyl,
pin=pinacolato.
established aldol chemistry,[4] proved synthetic challenges
which we solved using a 1,2-metallate rearrangement. Here
this strategy was employed for the first time and its
incorporation into a successful total synthesis proves it to be
a powerful alternative to the Nozaki-Hiyama-Kishi reac-
tion.[5]
The challenge of generating polyketide fragments of this
kind was already described by Evans and co-workers in
1991.[4] They described different E- and Z-enolates of alpha-
chiral ethyl ketones and their stereochemical outcome in
aldol reactions. As shown in Scheme 1, both the Z and E-
enolate generate the product with the methyl groups on both
sides of the keto group syn to each other. This analysis would
therefore exclude constructing this fragment through an aldol
reaction as shown below.
Due to our interest in polyketide-peptide hybrids[2] we
initiated the synthesis of chondrochloren A (1) as it exhibits
three distinct segments with synthetically challenging sub-
units. One can envision the synthesis of the Z-enamide moiety
through a Z-selective Buchwald-type cross coupling[3] using
the corresponding amide and Z-vinyl bromide and the middle
triol segment to be derived from ribonolactone (Figure 1).
However, the western polyketide segment (C7 to C14) which
looks as if it could be easily made accessible through
Equally, an aldol disconnection between C8 and C9 would
not provide the desired isomer as it would require an E-
enolate, which is disfavored due to the allylic strain situation.
Both disconnections were investigated in the course of our
synthetic endeavors and did not yield any useful yield and/or
selectivities (Scheme 2).
[*] Y. Linne, Dr. E. Bonandi, C. Tabet, Prof. Dr. M. Kalesse
Institute for Organic Chemistry
Gottfried Wilhelm Leibniz Universitꢀt Hannover
Schneiderberg 1B, 30167 Hannover (Germany)
E-mail: markus.kalesse@oci.uni-hannover.de
Prof. Dr. M. Kalesse
Being aware of these analyses and having them confirmed
by not being able to establish either one of these aldol
disconnections in our laboratories, we turned our focus to 1,2-
metallate transformations that were developed by Matteson
and Hoppe[6] and brought to a new level of applications by
Aggarwal.[7] It should be pointed out that this 1,2-metallate
rearrangement serves as an attractive alternative to the
Nozaki-Hiyama-Kishi reaction[5] and can be performed in
a stereoselective manner. It provides the additional advant-
age that one would be able to add the completely established
polyketide segment without the necessity to adjust oxidation
states later on as was required for the disconnection depicted
in Scheme 3.
Centre of Biomolecular Drug Research (BMWZ)
Gottfried Wilhelm Leibniz Universitꢀt Hannover
Schneiderberg 38, 30167 Hannover (Germany)
Dr. J. Geldsetzer, Prof. Dr. M. Kalesse
Helmholtz Centre for Infection Research (HZI)
Inhoffenstrasse 7, 38124 Braunschweig (Germany)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202016072.
ꢁ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution Non-Commercial
NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-
commercial and no modifications or adaptations are made.
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The synthesis of the polyketide segment 3 starts with
a Myers alkylation.[8] Reduction of the so-obtained product
provides alcohol 14 which was oxidized using PCC to obtain
its corresponding aldehyde. The desired stereotriade was
generated through an Oppolzer aldol reaction with TiCl4 as
the Lewis acid.[9] The configuration was confirmed at this
point through an X-ray analysis of the TBS-protected
secondary alcohol 16. Reductive removal of the chiral
auxiliary and introduction of the TIB-group via a Mitsunobu
reaction[10] provides the C7-C14 segment (3) of chondrochlor-
en A (1) in 42% yield over 7 steps ready to undergo a 1,2-
metallate rearrangement for coupling with the middle seg-
ment 12 (Scheme 4).
The synthesis of the polyoxygenated middle fragment
commenced with a known four-step sequence starting from
ribonolactone (17) (Scheme 5).[11] Ester 18 was double TBS-
protected and the primary hydroxy group liberated by
treatment with PPTS in MeOH at room temperature. The
primary OH group was then TES protected in order to have it
later selectively liberated for the alkyne formation. A three-
step sequence of reduction, TBS protection and selective TES
deprotection generated pentaol 20 with one primary hydroxyl
available for the aforementioned alkyne formation. This was
achieved using the Ohira–Bestmann protocol.[12] Finally, the
alkyne was methylated with nBuLi and MeI in THF-HMPA.
For the hydroboration we relied on a copper-mediated
hydroboration using bis(pinacolato)diboron[13] to provide
vinyl boronic ester 12 in 42% over 10 steps starting from
literature known ester 18.[11] This set the stage for the 1,2-
metallate rearrangement with TIB ester 3. We deliberately
chose this bond for the pivotal disconnection as one would not
have to control the configuration at C7 since this center would
be oxidized in the course of the synthesis. As we will describe
Scheme 1. Retrosynthetic analysis of the C7 to C14 aldol segment.
Scheme 2. Retrosynthetic analysis of the C8 to C9 aldol disconnection.
Scheme 4. Synthesis of the C7 to C14 segment (3).[18] DIAD=diiso-
propyl azodicarboxylate, PCC=pyridinium chlorochromate, TMS=tri-
methylsilyl, TBS=tert-butyldimethylsilyl, Tf=trifluoromethanesulfonyl,
THF=tetrahydrofuran, TIB=2,4,6-triisopropylbenzoyl, o/n=overnight,
o2s=over two steps, o3s=over three steps.
Scheme 3. Formation of the C6-C7 carbon bond through 1,2-metallate
rearrangement. TBS=tert-butyldimethylsilyl, TIB=2,4,6-triisopropyl-
benzoyl, pin=pinacolato.
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Scheme 5. Synthesis of chondrochloren A (1). CSA=camphor-10-sulfonic acid, DMEDA=N,N’-dimethylethylenediamine, DMP=Dess–Martin
periodinane, EDC=N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride, HMPA=hexamethylphosphoramide, HOBt=1-hydroxybenzo-
triazole, pin=pinacolato, PPTS=pyridinium p-toluenesulfonate, TES=triethylsilyl, TBS=tert-butyldimethylsilyl, Tf=trifluoromethanesulfonyl,
THF=tetrahydrofuran, TIB=2,4,6-triisopropylbenzoyl, TMEDA=n,N,N’,N’-tetramethylethylenediamine, o/n=overnight, o2s=over two steps,
o3s=over three steps.
in detail below, standard protocol with sparteine[6,7] gave only
poor yields. On the other hand, deprotonation of 3 with sBuLi
in the presence of TMEDA provided the lithiated species 22
and subsequent treatment with vinyl boronic ester 12 afforded
the 1,2-rearranged product 23. Unexpectedly, it provided the
desired product in very good yields (85%) and as a single
stereoisomer. With compound 23 in hand, the synthesis
continued with the aforementioned oxidation of the secon-
dary alcohol and liberation of the primary hydroxy group,
which was oxidized to its corresponding acid.[14] Amide
formation to give 25 was achieved with EDC, HOBt and
NH3.[15] This set the stage for the endgame of the synthesis.
Using Z-vinyl bromide 5[11] and CuI, DMEDA and Cs2CO3
led to the envisioned Buchwald coupling.[3] In contrast to
previous model studies, we observed the emergence of the E-
isomer.[11] We believe that this is due to subsequent isomer-
ization as we observe varying amounts of the isomers on
different reaction times and in samples of the authentic
material. Finally, the synthesis of chondrochloren A (1) (23
linear steps from ribonolactone (17), 0.8% yield) was enabled
by a global TBS-deprotection with HF·NEt3.
As mentioned above, our early attempts on the synthesis
of this natural product used aldol strategies, which failed
miserably (see Supporting Information). We were therefore
very pleased to notice that the 1,2-metallate rearrangement
worked so well and can be used as a powerful tool for setting
ꢀ
up C C bonds. This transformation is widely underexploited
and can serve as a valuable alternative to the Nozaki-Hiyama-
Kishi reaction,[5] in particular as it can be performed in
a stereoselective manner. To investigate this in more detail we
ꢀ
performed this particular C C bond formation in the
presence of sparteine and with the Cb group instead of TIB.
Surprisingly, in the presence of (+)-sparteine, only traces of
the rearranged product were observed and switching the TIB
to a Cb group led to the opposite stereoisomer. The sense of
chirality generally induced by (+)-sparteine is opposite to the
one observed in the transformation of 3 to 23 (Scheme 6).
Obviously, the inherent selectivity overrules the stereo-
controlling properties of (+)-sparteine which is supported
by the higher yields of the same transformation (3!23) using
(ꢀ)-sparteine. The low yields are therefore the consequence
of the mismatched situation for this substrate. Hoppe already
reported selected examples in which a diastereoselective
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selectivity by changing from a TIB to a Cb group. As this
serves as an alternative for the Nozaki-Hiyama-Kishi reac-
tion,[5] the generation of diastereomeric alcohols through
alteration of the carbanion-stabilizing group holds the
potential to become a new highly valuable tool for total
synthesis. The scope and limitations of this protocol with
other substrates will be reported in due course.
In summary, we have accomplished the first total synthesis
of chondrochloren A (1), a complex secondary metabolite
from myxobacteria. The synthesis relied on a 1,2-metallate
rearrangement in one of the key steps in order to overcome
the inherent selectivity problems of the polyketide portion.
The endgame of the synthesis used a Z-selective Buchwald-
type of cross coupling to complete the first total synthesis of
this natural product.
Acknowledgements
We are very grateful to Dr. Rolf Jansen (HZI) for authentic
chondrochloren A. A generous gift of B2pin2 from Allychem
is also appreciated. We thank Dr. J. Fohrer, M. Rettstadt and
D. Kçrtje for detailed NMR analysis, A. Schulz and R.
Reichel for mass spectra and Dr. G. Drꢀger for X-ray analysis.
In terms of preparation of this manuscript, we thank Alina
Eggert, Giada Tedesco and Daniel Lꢁcke. Open access
funding enabled and organized by Projekt DEAL.
Conflict of interest
The authors declare no conflict of interest.
Keywords: 1,2-metallate rearrangement · chondrochloren ·
Hoppe anion · natural product synthesis · polyketides
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Manuscript received: December 2, 2020
Revised manuscript received: January 13, 2021
Accepted manuscript online: January 15, 2021
Version of record online: February 25, 2021
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