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Non‐proteogenic amino acids and functionalized peptides are important motifs in modern drug discovery. Here we report that Ala^Bcan serve as universal building blocks in the synthesis of a diverse collection of modified amino acids, peptides, and proteins. First, we develop the synthesis of Ala^Bfrom redox‐active esters of aspartic acid resulting in a series of β‐boronoalanine derivatives. Next, we show that Ala^Bcan be integrated into automated oligopeptide solid‐phase synthesis. Ala^Bis compatible with common transformations used in preparative peptide chemistry such as native chemical ligation and radical desulfurization as showcased by total synthesis of Ala^B‐containing ubiquitin. Furthermore, Ala^Breagents participate in Pd‐catalyzed reactions, including C−C cross‐couplings and macrocyclizations. Taken together, Ala^Bsynthons are practical reagents to access modified peptides, proteins, and in the synthesis of cyclic/stapled peptides.

 

Non‐proteogenic amino acids and functionalized peptides are important motifs in modern drug discovery. Here we report that Ala^Bcan serve as universal building blocks in the synthesis of a diverse collection of modified amino acids, peptides, and proteins. First, we develop the synthesis of Ala^Bfrom redox‐active esters of aspartic acid resulting in a series of β‐boronoalanine derivatives. Next, we show that Ala^Bcan be integrated into automated oligopeptide solid‐phase synthesis. Ala^Bis compatible with common transformations used in preparative peptide chemistry such as native chemical ligation and radical desulfurization as showcased by total synthesis of Ala^B‐containing ubiquitin. Furthermore, Ala^Breagents participate in Pd‐catalyzed reactions, including C−C cross‐couplings and macrocyclizations. Taken together, Ala^Bsynthons are practical reagents to access modified peptides, proteins, and in the synthesis of cyclic/stapled peptides.

 

Thiopeptides are a class of potent antibiotics with promising therapeutic potential. We developed a novel Mo( vi )-oxide/picolinic acid catalyst for the cyclodehydration of cysteine peptides to form thiazoline heterocycles. With this powerful tool in hand, we completed the total syntheses of two representative thiopeptide antibiotics: micrococcin P1 and thiocillin I. These two concise syntheses (15 steps, longest linear sequence) feature a C–H activation strategy to install the trisubstituted pyridine core and thiazole groups. The synthetic material displays promising antimicrobial properties measured against a series of Gram-positive bacteria.