The total synthesis of corallopyronin A and myxopyronin B

Article abstract of DOI:10.1002/anie.201206560

Leading the way: The synthesis of natural products with new biological targets is one of the driving forces for the development of new antibiotics. The synthesis of the two secondary metabolites corallopyronin and myxopyronin (see picture) have been achieved, which are prominent leads for the inhibition of bacterial RNA polymerase. Copyright

Full text of DOI:10.1002/anie.201206560

Angewandte
Chemie
DOI: 10.1002/anie.201206560
Natural Products
The Total Synthesis of Corallopyronin A and Myxopyronin B**
Andreas Rentsch and Markus Kalesse*
Dedicated to Professor Johann Mulzer on the occasion of his retirement
In 1984, Hçfle and co-workers isolated three closely related
corallopyronins (1, 2, 3) from the fermentation broth of
Corallococcus coralloides (strain Ccc127, DSM2550).[1] These
natural products exhibit large regions of structural homology
(C23–C14), both to one another as well as to the myxopyro-
nins (Scheme 1). The 4-hydroxy-a-pyrone moiety is the
NMR spectra that differed in parts from those reported by
Hçfle and co-workers (see the Supporting Information). So
far, the research groups of Panek and Lira have put forward
the only two reports on the racemic synthesis of myxopyro-
nin.[5]
Our retrosynthetic analysis disconnects both natural
products between the pyrone and the carbonyl group in the
side chain (Scheme 2). Our initial plan was to introduce the
Scheme 1. Structures of corallopyronin and myxopyronin.
Scheme 2. Retrosynthesis of corallopyronin.
central structural motif and has a side chain attached at C6.
This chain contains one stereogenic center at C7 and an a,b-
unsaturated methyl carbamate function. Since these natural
products, as well as ripostatin,[2] were found to target the
“switch region” within bacterial RNA polymerase (RNAP),[3]
they became prominent leads for biomedical research.
Additional questions regarding the structure arose when
the research group of Kçnig[4] reported their independent
isolation of the corallopyronins, for which they reported
unsaturated carbamate in the end game of the synthesis, but
we realized that the carbamate group has the required
stability to survive a multistep sequence.
In our synthesis, b-(ꢀ)-citronellene provides the stereo-
genic center at C7. The required functional groups were
introduced by oxidation of the trisubstituted double bond,
cleavage with periodate,[6] and transformation to the corre-
sponding alcohol. Subsequent protecting group manipula-
tions provided aldehyde 10. A vinylogous Mukaiyama aldol
reaction[7] followed by oxidation and a retro Diels–Alder
reaction[8] generated pyrone 13 (Scheme 3).
An additional challenge was the choice of the appropriate
protecting group for the hydroxy group on the pyrone ring.
Standard silyl protecting groups, such as TBS, as well as
acetal-containing groups, such as MOM or SEM, led to
decomposition during isolation or on their removal. Finally,
the tert-butyldimethylsilyloxymethyl group (SOM)[9] intro-
duced by Benneche and co-workers proved ideal for our
purposes. It combines the advantages of both the acetal-
[*] Dr. A. Rentsch, Prof. Dr. M. Kalesse
Institut fꢀr Organische Chemie and Centre of Biomolecular Drug
Research (BMWZ), Leibniz University Hannover
Schneiderberg 1B, 30167 Hannover (Germany)
and
Helmholtz Centre for Infection Research (HZI)
Inhoffenstrasse 7, Braunschweig (Germany)
E-mail: Markus.Kalesse@oci.uni-hannover.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(DFG Ka 913/16-1). We thank Dr. K. Gerth for a picture of
Corallococcus coralloides.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206560.
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Scheme 5. Synthesis of aldehyde 7. a) MnO2, CH2Cl2, b) 17, CH2Cl2,
88% over 2 steps, E/Z>19:1; c) mCPBA, CH2Cl2, ꢀ208C!RT, 80%;
d) H5IO6, THF, 08C!RT, 80%.
7. To prepare this aldehyde, geraniol was oxidized and
subjected to olefination. A final epoxidation followed by
cleavage with periodate provided the desired aldehyde
(Scheme 5).
Scheme 3. Synthesis of pyrone 13. a) mCPBA, NaOAc, CH2Cl2, ꢀ208C;
b) H5IO6, Et2O/THF; c) NaBH4, Et2O/THF, 75% over 3 steps;
d) TBSCl, imd, THF, 95%; e) O3, PPh3, CH2Cl2/MeOH, 90%;
f) BF3·OEt2, CH2Cl2, ꢀ788C, 78%; g) DMP, CH2Cl2, 97%; h) toluene,
reflux, 75%. mCPBA=3-chloroperbenzoic acid, TBSCl=tert-butyldime-
thylsilyl chloride, imd=imidazole, DMP=Dess–Martin periodinane.
The pivotal Walsh reaction[11] takes advantage of inter-
mediate 18, which is derived from the hydroboration of
bromoacetylene 6. Addition of dimethylzinc leads to cross-
coupling and simultaneous rearrangement to afford Z-vinyl-
borane 20. A subsequent transmetalation and reaction with
aldehyde 7 generates ester 22 (Scheme 6). At this stage the
secondary alcohol is established as a racemate. However,
a sequence of oxidation and reduction with (ꢀ)-DIPCl
provides the desired R enantiomer with useful selectivity
(95% ee). Here it should be pointed out that comparable
substrates with E-configured double bonds provide the
opposite enantiomer.[12] Irrespective of the theory of the
reaction, we were able to confirm the configuration by the
containing and the silyl protecting groups. Ultimately, we
were able to selectively cleave the TBS group at the primary
alcohol in the presence of the SOM group. The so-obtained
alcohol was oxidized with IBX and transformed to unsatu-
rated acid 15 through a Wittig–Horner reaction.[10] The Curtis
rearrangement described by Panek and co-workers during
their synthesis of myxopyronin was applied to generate the
vinyl carbamate (Scheme 4).[4a]
Another challenge was the synthesis of the secondary
alcohol next to the Z-configured double bond. We aimed to
install this functional group by adding vinylzinc intermediate
21, obtained from the preceding Walsh reaction, to aldehyde
Scheme 4. Synthesis of vinyl carbamate 5. a) TBSOCH2Cl, DIPEA,
CH2Cl2, 08C!RT, 37% + 23% TBS-deprotected product, (55% brsm);
b) PPTS, THF/MeOH, 89%; c) IBX, DMSO, 79%; d) nBuLi, THF,
ꢀ608C!RT; e) ClCO2Et, DIPEA, NaN3, acetone, H2O, f) toluene,
MeOH, reflux, 45% over 3 steps. DIPEA=N,N-diisopropylethylamine,
PPTS=pyridinium p-toluenesulfonate, IBX=2-iodoxybenzoic acid,
DMSO=dimethyl sulfoxide, brsm=based on recovered starting
material.
Scheme 6. Synthesis of the side chain through Walsh coupling.
a) BBr2H.SMe2, toluene, 708C; b) Me2Zn, toluene, ꢀ788C!08C then
aldehyde 7, 56%; c) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ788C, 80%;
d) (ꢀ)-DIPCl, THF, ꢀ308C; e) TBSOTf, 2,6-lutidine, CH2Cl2, 76% over
2 steps; f) CSA, CH2Cl2/MeOH, 75%. DIPCl=diisopinocampheyl-
chloroborane, CSA=camphorsulfonic acid.
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Mosher ester method. By using this route we generated
compound 24 in nine steps starting from 16 (Scheme 6).
After the successful reduction with (ꢀ)-DIPCl, functional
group manipulations afforded substrate 25 for the final
olefination. Both the Takai–Utimoto and the Julia–Kociensky
olefinations[13] provided the desired product, although in
unsatisfactory yields (Scheme 7). Consequently we decided to
exchange the functionalities in the two fragments.
Scheme 9. a) nBuLi, TMP, THF, ꢀ788C!RT, 47% (54% brsm);
b) MnO2, CH2Cl2, 80%; c) TBAF, THF, 33%. TMP=2,2,6,6-tetramethyl-
piperidine, TBAF=tetrabutylammoniumfluoride.
Scheme 7. a) CrCl2, CH3CHI2, THF, 30–40%; b) KHMDS, 26, DME,
ꢀ608C, 26%. KHMDS=potassium bis(trimethylsilyl)amide,
DME=1,2-dimethoxyethane.
The first steps in the end game of the synthesis involved
deprotonation of the pyrone with LiTMP and reaction with
aldehyde 4. The alcohol obtained was oxidized with MnO2
and the protecting groups removed with TBAF (Scheme 9).
All the spectroscopic data were in good agreement with
those obtained from the authentic sample. The difference in
optical rotation (synthetic: ꢀ69.1, authentic: ꢀ95.8)[1] was
attributed to the enantiomeric excess of the commercially
available b-(ꢀ)-citronellene (56% ee). The two diastereo-
mers were not visible as two separate sets of signals in the
NMR spectra, an observation we had made before for other
natural products that exhibit stereogenic centers in separate
regions of the molecule.[15]
The Mitsunobu reaction was utilized to introduce sulfide
28 in good yields, and 29 was oxidized to the corresponding
sulfone. Deprotonation with KHMDS and reaction with
acetaldehyde established the desired olefin.[14] The subse-
quent reduction/oxidation sequence completed the synthesis
of fragment 4 (Scheme 8).
During the spectroscopic analysis we were able to
reproduce the spectra reported by the research groups of
both Hçfle and Kçnig (see the Supporting Information). The
spectrum obtained depended on the final deprotection
conditions. Even though we are still not in a position to
pinpoint the reasons for this observation, we have evidence
that the coordination of different cations is likely the reason
for the observed changes in the chemical shifts. Remarkably,
extensive HPLC purification provided a third NMR spectrum
that is different from the two others.
The synthesis established for corallopyronin, but using
a different side chain, was also utilized for the synthesis of
myxopyronin. The required side chain was obtained by 1,4-
addition[16] to unsaturated ester 31, followed by establishing
the appropriate oxidation state for olefination with 17
(Scheme 10).
Coupling the side chain with SOM-protected pyrone 5
delivered, after oxidation and deprotection, the expected
natural product (Scheme 11).
In conclusion, we were able to complete the synthesis of
corallopyronin A and myxopyronin B and could demonstrate
that vinyl carbamates are sufficiently stable to survive multi-
step syntheses. The underexploited SOM group was essential
Scheme 8. Synthesis of 4. a) PPh3, DEAD, THF, 95%;
b) (NH4)6Mo7O24·4H2O, H2O2, EtOH, 76%; c) KHMDS, acetaldehyde,
DME, 90% (E/Z=6:1), d) DIBAl-H, CH2Cl2, ꢀ788C; e) MnO2, CH2Cl2,
79%. DIBAl-H=diisobutylaluminumhydride, DME=1,2-dimethoxy-
ethane, DEAD=diethyl azodicarboxylate.
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Scheme 11. a) nBuLi, TMP, THF, ꢀ788C!RT, 53%; b) MnO2, CH2Cl2,
80%; c) HF.pyridine, THF/pyridine, 45%. TMP=2,2,6,6-tetramethyl-
piperidine.
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protecting group for pyrones. Finally, the syntheses confirmed
the structures proposed by the research groups of Hçfle and
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myxopyronin demonstrates the robustness of this sequence
for the preparation of analogues, and opens the way for
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optimized pharmaceutical properties starting form building
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Received: August 14, 2012
Published online: October 8, 2012
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Keywords: corallopyronin · myxobacteria · protecting groups ·
RNA polymerase · Walsh coupling
.
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