The total synthesis of the naturally occurring antibiotic GE81112A, a densely functionalized tetrapeptide, is reported. Comparison of spectral data with those of the natural product and the lack of biological activity of the synthesized compound led us to revise the published configuration of the 3-hydroxypipecolic acid moiety. This hypothesis was fully validated by the synthesis of the corresponding epimer.

Synthesis of 1,3-substituted cyclobutyls enabled by zinc insertion into functionalized iodocyclobutyl derivatives followed by Negishi coupling with halo-heteroaromatics is reported. Two distinct sets of conditions were developed; the first involved a two-step batch protocol using activated Rieke zinc, and the second involved a multistep continuous flow process. Both methods showed complementarity and allowed for rapid access to these medicinally relevant motifs, the possibility of scaling up, and automation for library synthesis.

Herein we describe the practical synthesis of a novel VLA-4 antagonist 1 as a potential treatment for multiple sclerosis. The key step is based on the Povarov reaction of an imine with an alkene to access a tetrahydroquinoline intermediate, leading to the corresponding quinoline core after an oxidative aromatization step. The development of the synthesis of 1 led to decreased complexity and the elimination of chromatographic purifications. These improvements were demonstrated at scale by the production of 32 kg of 1 in high yield with excellent purity.

Die erste Totalsynthese des antibiotischw irksamen Naturstoffs GE81112A, eines hoch funktionalisierten Tetrapeptids,w urdea bgeschlossen. Der Vergleichd er NMR-Daten und der biologischen Aktivitätd er synthetischen Verbindung mit den Daten fürd en Naturstoff führte zur Korrektur der publizierten absoluten Konfiguration eines stereogenen Zentrums der 3-Hydroxypipecolinsäure-Einheit und zur Synthese des biologischa ktiven GE81112A mit der korrekten Konfiguration.