Towards the total synthesis of chondrochloren A: Synthesis of the (Z)-enamide fragment

Article abstract of DOI:10.3762/bjoc.16.64

The stereoselective synthesis of the (Z)-enamide fragment of chondrochloren (1) is described. A Buchwald-type coupling between amide 3 and (Z)-bromide 4 was used to generate the required fragment. The employed amide 3 comprising three chiral centers was o

Full text of DOI:10.3762/bjoc.16.64

Towards the total synthesis of chondrochloren A:
synthesis of the (Z)-enamide fragment
Jan Geldsetzer1 and Markus Kalesse*1,2,3
Full Research Paper
Open Access
Address:
Helmholtz Centre of Infection Research (HZI), Inhoffenstr. 7, 38124
Beilstein J. Org. Chem. 2020, 16, 670–673.
1
doi:10.3762/bjoc.16.64
Braunschweig, Germany, 2Leibniz Universität Hannover, Institute of
Organic Chemistry, Schneiderberg 1B, 30167 Hannover, Germany,
and 3Centre for Biomolecular Drug Research (BWMZ), Schneiderberg
Received: 04 February 2020
Accepted: 31 March 2020
Published: 14 April 2020
38, 30167 Hannover, Germany
Email:
Associate Editor: B. Nay
Markus Kalesse* - Markus.Kalesse@oci.uni-hannover.de
©
2020 Geldsetzer and Kalesse; licensee Beilstein-Institut.
*
Corresponding author
License and terms: see end of document.
Keywords:
cross coupling; myxobacteria; natural product; ribolactone; Z-enamide
Abstract
The stereoselective synthesis of the (Z)-enamide fragment of chondrochloren (1) is described. A Buchwald-type coupling between
amide 3 and (Z)-bromide 4 was used to generate the required fragment. The employed amide 3 comprising three chiral centers was
obtained through a seven-step sequence starting from ᴅ-ribonic acid-1,4-lactone. The (Z)-vinyl bromide 4 is accessible in four steps
from 4-hydroxybenzaldehyde. The pivotal cross coupling between both fragments was achieved after extensive experimentation
with copper(I) iodide, K2CO3 and N,N′-dimethylethane-1,2-diamine.
Introduction
In the course of our program to provide synthetic access to bio- coccus aureus [12]. The relative and absolute stereochemistry
logically active natural products we targeted complex polyke- of the molecule was elucidated by a combination of NMR, UV
tides and depsipetides [1-10]. One particular group of com- and IR spectroscopy and molecular dynamics calculations (MD,
pounds of particular focus in our research activities are natural MM2) [12]. However, its (Z)-enamide motif and the polyoxy-
products with enamide moieties [11]. Among these, chon- genated middle segment are synthetically challenging.
drochloren having a (Z)-enamide moiety features a rare struc-
Results and Discussion
tural motif. The myxobacterial metabolite chondrochloren A (1)
was isolated from Chondromyces crocatus (Cmc5) by the Synthesis of amide 3
groups of Höfle and Reichenbach in 2003 [12]. This PKS/ Here we report our investigations on the construction of the seg-
NRPS-derived natural product shows only weak antibiotic ments 3 and 4 as well as our results on the cross coupling be-
effects in agar diffusion tests against Micrococcus luteus, tween both fragments. Our retrosynthetic approach (Figure 1)
Schizosaccharomyces pombe, Bacillus subtilis and Staphylo- divides chondrochloren A (1) into three fragments of similar
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Beilstein J. Org. Chem. 2020, 16, 670–673.
Figure 1: Retrosynthetic analysis of chondrochlorene A (1).
complexity: amide 2, (Z)-bromide 4 and amide 3. For the cou- yields. A double TBS-protection and liberation of the primary
pling of amide 3 and (Z)-bromide 4 we decided to use a (Z)- alcohol provided alcohol 11 in an excellent yield which was
selective Buchwald-type reaction encouraged by the previous subjected to aminolysis to provide amide 3 in seven steps and
works of the Buchwald group on producing (E)-enamide cou- an overall yield of 16% [16-20].
pling products [13-15].
Synthesis of (Z)-bromide 4
The synthesis of the amide 3 started with TIPDS-protection of For the synthesis of (Z)-bromide 4 we chose a palladium-
commercially available ᴅ-ribonic acid-1,4-lactone (5) catalyzed, stereoselective dehalogenation as the key step
(
Scheme 1). A subsequent transesterification under mild condi- (Scheme 2). Therefore, 4-hydroxybenzaldehyde (12) was chlo-
tions with Bu2SnO provided dihydroxy ester 7 in 72% yield. rinated and phenol 13 was protected as TBS ether to afford
The 1,3-diol in 7 was methylated with an excess of the Meer- aldehyde 14 which was then converted into dibromoolefine 15
wein reagent and TIPDS-removal afforded ester 9 in good in good yields using the Corey–Fuchs protocol. Uenishi et al.
Scheme 1: Synthesis of amide 3 [16-20]. TIPDSCl2 = 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane, TBSOTf = tert-butyldimethylsilyl trifluoromethane-
sulfonate, proton sponge = 1,8-bis(N,N-dimethylamino)naphthalene.
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Beilstein J. Org. Chem. 2020, 16, 670–673.
Scheme 2: Synthesis of (Z)-bromide 4 using a palladium-catalyzed, stereoselective dehalogenation [21-24]. TBSOTf = tert-butyldimethylsilyl trifluoro-
methanesulfonate, NCS = N-chlorosuccinimide, 2,6-lutidine = 2,6-dimethylpyridine.
[
21] published an effective way of defunctionalizing dihalo- was confirmed by the indicative NMR coupling constants of
genated double bonds into the corresponding (Z)-monohalo- 9.6 Hz. Moreover, we observed a concentration dependent for-
genated derivatives using palladium(II) acetate, triphenylphos- mation of the undesired desilylated (Z)-enamide 17 (Table 1).
phine and tributyltin hydride. Following this procedure, we The best results were achieved using a 65 mM solution of the
were able to obtain (Z)-bromide 4 in four steps and an overall amide 3. Using dry potassium carbonate, purified copper(I)
yield of 39% [21-24].
iodide provided the best results for the cross-coupling reaction.
Cross coupling of fragments 3 and 4
Table 1: Concentration studies of amide 3 and (Z)-bromide 4 in the
The formation of the (Z)-enamide should occur in a copper-cat-
alyzed Buchwald-type reaction (Scheme 3). Based on a
previous work of Buchwald and his group [13], we decided to
use copper(I) iodide and N,N′-dimethylethylenediamine
Buchwald-type reaction.a
entry
c (amide 3, mM)
16
17
3
1
2
3
4
20
65
33
42
3
–
31
–
(
DMEDA) as the catalytic system in THF, which was reported
11
11
27
to be the solvent of choice in this type of coupling reaction.
Potassium carbonate was chosen due to the sensitivity of the
amide 3 towards harsh basic conditions. With these conditions
we were able to couple (Z)-bromide 4 with amide 3 selectively
to yield (Z)-enamide 16. The obtained double bond geometry
136
140
2
17
–
aConditions: amide 3 (1.0 equiv), (Z)-bromide 4 (1.0 equiv), DMEDA
0.60 equiv), CuI (0.30 equiv), THF, 65 °C. DMEDA = N,N′-
dimethylethylenediamine.
(
Scheme 3: Cross coupling of amide 3 and (Z)-bromide 4 (see Table 1 for conditions).
672

Beilstein J. Org. Chem. 2020, 16, 670–673.
1
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Conclusion
1
In summary, we established a (Z)-selective Buchwald-type cou-
pling reaction as a key step in the synthesis of an advanced frag-
ment of chondrochloren A (1). The required amide 3 can be
synthesized in seven steps with a 16% overall yield [16-20],
whereas the (Z)-bromide 4 can be generated in a four-step se-
quence with a 39% overall yield, including a palladium-
catalyzed, stereoselective dehalogenation [21-25].
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Supporting Information
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Supporting Information File 1
Experimental procedures and spectral data of the
synthesized compounds.
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Acknowledgements
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We thank Sarah Hoffmann for assistance with the manuscript
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school MINAS for funding this research.
1
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doi:10.1021/ol005800t
ORCID® iDs
Jan Geldsetzer - https://orcid.org/0000-0002-4155-7329
5.Yang, X.; Liu, H.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. Synlett 2010,
101–106. doi:10.1055/s-0029-1218530
Markus Kalesse - https://orcid.org/0000-0003-4858-3957
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