Synthesis and biological evaluation of moiramide B derivatives.

Moiramide B is a peptide-polyketide hybrid with a bacterial origin and interesting antibiotic activity. Besides its structurally conserved peptide part, it contains a highly variable fatty acid side chain. We modified this part of the molecule by introducing a terminal alkyne, and we then subjected it to click reactions and Sonogashira couplings. This provided a library of moiramide B derivatives with high and selective in vivo activities against S. aureus.

Thermal Proteome Profiling Reveals Insight to Antiproliferative and Pro-Apoptotic Effects of Lagunamide A in the Modulation of DNA Damage Repair.

Lagunamide A is a biologically active natural product with a yet unidentified molecular mode of action. Cellular studies revealed that lagunamide A is a potent inhibitor of cancer cell proliferation, promotes apoptosis and causes mitochondrial dysfunction. To decipher the cellular mechanism responsible for these effects, we utilized thermal protein profiling (TPP) and identified EYA3 as a stabilized protein in cells upon lagunamide A treatment. EYA3, involved in the DNA damage repair process, was functionally investigated via siRNA based knockdown studies and corresponding effects of lagunamide A on DNA repair were confirmed. Furthermore, we showed that lagunamide A sensitized tumor cells to treatment with the drug doxorubicin highlighting a putative therapeutic strategy.

Matteson Homologation-Based Total Synthesis of Meliponamycin A.

The first total synthesis of meliponamycin A, an antimicrobial cyclodepsipeptide isolated from Streptomyces, is reported. Two key building blocks, the substituted tetrahydropyranyl side chain and an azido analogue of protected ß-hydroxyleucine, were constructed via iterative Matteson homologations. A fragment coupling of a tetrapeptide, a depsidipeptide building block, macrocyclization, Staudinger reduction, and N-acylation are further steps in the synthesis.

Stereoselective Synthesis of a Protected Side Chain of Meliponamycin A.

The Matteson homologation was found to be a versatile tool for the construction of the linear polyketide side chain of meliponamycin and related compounds in only four steps. The ester dienolate version of this reaction allowed the introduction of the unsaturated ester moiety in a highly stereoselective fashion. Boronate oxidation/deoxygenation and Sharpless dihydroxylation are additional key steps in the stereoselective construction of this highly functionalized tetrahydropyran ring system, which is characteristic of this substance class.

Application of Allylzinc Reagents as Nucleophiles in Matteson Homologations.

Allylzinc reagents are versatile nucleophiles that can be used in Matteson homologations. The linear substitution products are formed almost exclusively, and excellent E selectivities are observed in reactions of reagents with sterically demanding or aryl substituents on the double bond. The allylated boronic esters obtained can be converted into trifluoroborates or subjected to further homologations. Ozonolysis of the double bond provides aldehydes or ketones, and therefore, allylzinc reagents are useful acetaldehyde or ketone enolate equivalents.

Total synthesis of apratoxin A and B using Matteson's homologation approach.

Apratoxin A and B, two members of an interesting class of marine cyclodepsipeptides are synthesized in a straightforward manner via Matteson homologation. Starting from a chiral boronic ester, the polyketide fragment of the apratoxins was obtained via five successive homologation steps in an overall yield of 27% and very good diastereoselectivity. This approach is highly flexible and should allow modification also of this part of the natural products, while previous modifications have been carried out mainly in the peptide fragment.

A Straightforward Synthesis of Polyketides via Ester Dienolate Matteson Homologation.

Application of ester dienolates as nucleophiles in Matteson homologations allows for the stereoselective synthesis of highly substituted α,ß-unsaturated δ-hydroxy carboxyl acids, structural motifs widespread found in polyketide natural products. The protocol is rather flexible and permits the introduction of substituents and functionalities also at those positions which are not accessible by the commonly used aldol reaction. Therefore, this ester dienolate Matteson approach is an interesting alternative to the "classical" polyketide syntheses.