Hetero Diels−Alder Synthesis of 3-Hydroxypyridines:  Access to the Nosiheptide Core

Abstract

The 1-azadiene hetero Diels-Alder reaction of silylated enol oximes with alkynes was investigated and was optimized to furnish 2,5,6-trisubstituted 3-hydroxypyridines in high yields in one simple operation. Importantly, monosubstituted alkynyl ketones were found to lead to the formation of the 6-isomer with exceptional regioselectivity (>95:5). This methodology was applied to a scaleable synthesis of the core structure of the potent antibiotic nosiheptide. Protecting groups were optimized, which led to a racemization-free seven-step synthesis of the key building block.

Thiopeptide Antibiotics: Retrospective and Recent Advances

“…Pioneering work by the groups of Kelly [121,122,123,124], Shin [35], Moody [125,126], Nicolaou [127,128], Ciufolini [36,37], and Bach [127,129,130] developed different methodologies that led to the total synthesis of various thiopeptides. However, most efforts have been devoted to the construction of the central polyheterocyclic core [121,122,123,124,131,132,133,134,135,136,137,138], which have been synthesized by two well-distinguished main strategies: modification of an existing pyridine and construction of the central ring.…”

Totalsynthese von Nosiheptid

“…Kupfer-Salzen beobachtet. [37,163] Durch Diazotierung des Aminothiazols 153 mit tertButylnitrit gelang es, das Iodid 154 durch in situ Zersetzung des Diazoniumsalzes, in Gegenwart von Diiodmethan als Abfangreagenz, erfolgreich und in großem Maßstab mit einer Ausbeute von bis zu 75% nebenproduktfrei darzustellen. [108] Eine Sonogashira-Kupplung mit 3-Butin-2-ol ergab den Alkohol 155 in 88% Ausbeute, der mit Dess-Martin-Periodinan [214] glatt zum Alkinylketon 64 oxidiert wurde (79%).…”

From Amino Acids to Heteroaromatics—Thiopeptide Antibiotics, Nature's Heterocyclic Peptides

“…Recently, this approach has been extended to the synthesis of the complete nosiheptide pyridine core. [92] …”