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New bottromycin derivatives have been prepared using flexible Ugi and Matteson reactions. The Ugi reaction allows the fast and direct assembly of sterically hindered peptide fragments, while the Matteson homologation is excellently suited for the stereoselective synthesis of unusual amino acids like β-methylphenylalanine. Some of the new compounds show excellent activity against Streptococcus pneumoniae .

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 .

A novel synthesis of the naturally occurring HDAC inhibitor WF-3161 is described. Key steps include the Matteson homologation to generate the stereogenic centres in the side chain, and Pd-catalysed C-H functionalisation to connect the side chain to the peptide backbone. WF-3161 was found to be highly selective for HDAC1, whereas no activity was observed towards HDAC6. High activity was also found against the cancer cell line HL-60.

Myxoprincomide, a secondary metabolite of the myxobacterium Myxococcus xanthus DK 1622, is synthesised for the first time. The central, unusual α-ketoamide is generated at the end of the synthesis to avoid side reactions during the synthesis of this rather reactive subunit. Nevertheless, the synthetic natural product is obtained as an isomeric mixture. Detailed analytical investigations show that the identical isomeric mixture is found in the isolated natural product.

Covering: 1950s up to the end of 2020Bottromycins are a class of macrocyclic peptide natural products that are produced by several Streptomyces species and possess promising antibacterial activity against clinically relevant multidrug-resistant pathogens. They belong to the ribosomally synthesised and post-translationally modified peptide (RiPP) superfamily of natural products. The structure contains a unique four-amino acid macrocycle formed via a rare amidine linkage, C-methylation and a D-amino acid. This review covers all aspects of bottromycin research with a focus on recent years (2009-2020), in which major advances in total synthesis and understanding of bottromycin biosynthesis were achieved.

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.

2-(Methylthio)aniline (MTA) directed C(sp3)-H functionalisations are efficient and straightforward protocols for the selective β-modification of N-methylated amino acids. The decreased reactivity of MTA in comparison with the 8-aminoquinoline (AQ) directing group allows for selective monoarylations in high yields without the formation of side products. The protocol is also suitable for the introduction of highly functionalised side chains onto the C-terminal alanines of dipeptides. The MTA directing group can easily be removed, providing free carboxylic acids as valuable building blocks.

The marine natural products cyclomarins have remarkable anti-mycobacterial and antiplasmodial activities. The heptapeptic structure of this compound class comprisis four highly interesting non-canonical amino acids, including a rather unusual syn β-methoxyphenylalanine. To get a deeper insight into the structure-activity realtionship of cyclomarines, a straightforward protocol for the stereoselective synthesis of this building block was developed, based on diazonium chemistry.

Chelate enolate Claisen rearrangements are powerful reactions for constructing amino acid scaffolds. They generally proceed via chair-like transition states with excellent transfer of stereogenic information. Utilizing this reaction in natural product synthesis gives access to non-proteinogenic amino acids such as (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoic acid (Aoe), the unusual amino acid of a series of histone deacetylase inhibitors (HDACi). Herein the first total synthesis of Cyl-1, a cyclotetrapeptide from Cylindrocladium scoparium, is described.

Removing the β-hydroxy group from the prenylated tryptophan moiety of cyclomarins simplifies the synthesis of these interesting natural products significantly, without having a noteworthy effect on the anti-tuberculosis activity of the cyclomarins. In contrast, cyclomarazines did not show biological activity.

Cyclomarins are cyclic heptapeptides containing four unusual amino acids. New synthetic protocols toward their synthesis have been developed, leading to the synthesis and biological evaluation of three natural occurring cyclomarins. Interestingly, cyclomarins address two completely different targets: Clp C1, a subunit of the caseinolytic protease of Mycobacterium tuberculosis (MTB), as well as PfAp3Ase of Plasmodium falciparum. Therefore, cyclomarins are interesting lead structures for the development of drugs against tuberculosis and malaria.

Functionalized indoles and tryptophans can be obtained from stannylated alkenes and o-iodoanilines via Stille coupling. Subsequent azidation and photochemical nitrene generation results in the formation of the heterocyclic ring systems via C-H insertion.

Reverse N-prenylated 3-hydroxytryptophan, the rather exotic amino acid of the cyclomarins, is obtained in enantio- and diastereomerically pure and fully protected form by a combination of a highly stereoselective addition of a zincated indole toward protected serinal and subsequent palladium-catalyzed N-prenylation.

The Ugi reaction is found to be a very powerful tool for the synthesis of (pre)tubulysin derivatives, allowing the introduction of various functionalized side chains in only one step. While polar groups such as amides are not well tolerated, unpolar side chains such as allyl or propargyl ether are well accepted. These functionalities also allow subsequent modifications in the side chain, e.g. via ring closing metathesis or Click reaction.

Pd-catalyzed allylations are excellent tools for stereoselective peptide modifications, showing several advantages compared to normal alkylations. Reactions of internal peptide amide enolates with Pd-allyl complexes proceed not only with high yields of up to 86%, they show also high regio- and diastereoselectivities (88-99%), giving rise to the trans-configured products. Therefore, this protocol is a powerful synthetic tool for the synthesis of natural product and drug molecules.

Microtubules (mt) are highly dynamic polymers composed of alpha- and beta-tubulin monomers that are present in all dividing and non-dividing cells. A broad variety of natural products exists that are known to interfere with the microtubule network, by either stabilizing or de-stabilizing these rope-like polymers. Among those tubulysins represent a new and potent class of cytostatic tetrapeptides originating from myxobacteria. Early studies suggested that tubulysins interact with the eukaryotic cytoskeleton by inhibition of tubulin polymerization with EC₅₀ values in the picomolar range. Recently, pretubulysins have been described to retain the high tubulin-degradation activity of their more complex tubulysin relatives and represent an easier synthetic target with an efficient synthesis already in place. Although tubulin has been suggested as the dedicated target of tubulysin a comprehensive molecular target analysis of pretubulysin in the context of the whole proteome has not been carried out so far. Here we utilize synthetic chemistry to develop two pretubulysin photoaffinity probes which were applied in cellular activity-based protein profiling and imaging studies in order to unravel and visualize dedicated targets. Our results clearly show a remarkable selectivity of pretubulysin for beta-tubulin which we independently confirmed by a mass-spectrometry based proteomic profiling platform as well as by tubulin antibody based co-staining on intact cells.

Stannylated allylic carbonates are suitable substrates for Pd-catalyzed allylic aminations. In DMF and with [allylPdCl](2) as catalyst the stannylated allyl amines formed can be directly coupled with electrophiles according to the Stille protocol, giving rise to highly functionalized building blocks in excellent yields.

Pd-catalyzed allylations are an excellent tool for stereoselective peptide modifications, being clearly superior to normal alkylations. The reactions proceed not only in high yield, but also high regio- and diastereoselectivities, and trans-products are formed exclusively. Therefore, this is a powerful synthetic tool for natural product and drug synthesis.

A wide range of 5-substituted thiazoles are easily accessible via cross coupling of thiazolyl triflates. These activated thiazoles can be obtained by Ugi reactions using thioacids (thio-Ugi-reaction) and subsequent cyclisation of the endo thiopeptides formed with triflic anhydride. In addition, cyclisations with acyl halides give rise to 5-acyloxysubstituted derivatives.

A straightforward approach towards gamma-glutamyl boletine is described, based on a diastereotopos-differentiating allylic alkylation of chelated amino acid ester enolates. Independent of the configuration of the leaving group in the allylic substrate, the allylation product is obtained as a single stereoisomer. Its configuration is solely controlled by the stereogenic center adjacent to the pi-allyl complex formed.

Chelated enolates are versatile nucleophiles for palladium-catalysed allylic alkylations. Even with complex allylic substrates the reaction proceed without significant isomerisation. This allows the stereoselective introduction of polyhydroxylated allylic sidechains into amino acids and peptides with retention of the olefin geometry.

Chelated enolates are versatile nucleophiles for Michael additions to alpha,beta-unsaturated allylic esters. By quenching the reaction with TMSCl and heating a subsequent Ireland-Claisen rearrangement can occur. Direct cyclisation of the rearrangement product gives rise to highly substituted pyroglutamic acid derivatives.

Endothiopeptides can easily be obtained via Ugi reaction using thio acids as acid components. If isonitriles with an acetal group are applied, the endothiopeptides can directly be converted into thiazoles using TMSCl-NaI under microwave irradiation.

Allenylcarbinols undergo regioselective hydrostannation in the presence of MoBl3, a catalyst which was developed for the hydrostannation of propargyl alcohols and derivatives; allylstannanes are formed preferentially, which can easily be converted into allyl iodides.

N- and C-terminal diallylated peptides are obtained by several approaches, such as peptide Claisen rearrangement, N- and O- allylation, and the Ugi reaction of allyl-protected components. These diallylated peptides are suitable substrates for ring-closing metathesis and the success of this cyclisation was investigated with respect to the ring size, the position of the allyl moieties and the reaction parameters. In general, excellent yields are obtained for cyclisation of allyl glycine subunits and N-allylated amides, while allyl esters and allyl carbamates often presented serious problems. However, yields of up to 73% were obtained under optimised conditions, and the new generated double bond is formed with excellent trans-selectivity.

A simple approach to several cyclopeptidmimetics containing an N-alkylated amino acid was found via a multicomponent reaction followed by a ring-closing metathesis starting from readily available precursors. The combinatorial technique has the advantage that different polar, hydrophilic or hydrophobic moieties can be placed at any position in the cycles and unnatural amino acids can also be incorporated.

Diastereomer ratios of up to 95:5 and enantiomeric excesses of up to 95% were achieved in Pd-catalyzed asymmetric alyllic substitutions with zinc enolates of glycine esters as nucleophiles; a remarkable effect of the ligand on the diastereoselectivity of the substitution was found.