Asymmetric Synthesis of the Aminocyclitol Pactamycin, a Universal Translocation Inhibitor

Abstract

An asymmetric total synthesis of the aminocyclopentitol pactamycin is described, which delivers the title compound in 15 steps from 2,4-pentanedione. Critical to this approach was the exploitation of a complex symmetry-breaking reduction strategy to assemble the C1, C2, and C7 relative stereochemistry within the first four steps of the synthesis. Multiple iterations of this reduction strategy are described, and a thorough analysis of stereochemical outcomes is detailed. In the final case, an asymmetric Mannich reaction was developed to install a protected amine directly at the C2 position. Symmetry-breaking reduction of this material gave way to a remarkable series of stereochemical outcomes leading to the title compound without recourse to non-strategic downstream manipulations. This synthesis is immediately accommodating to the facile preparation of structural analogs.

Preparation and biological evaluation of synthetic and polymer-encapsulated congeners of the antitumor agent pactamycin: Insight into functional group effects and biological activity

“…19 By contrast, our synthesis of 1 utilized an early-stage N–H insertion reaction to install the urea. 20 Synthetic diversification from this early intermediate would be a significant challenge. Consequently, we envisaged a similar isocyanate formation/trapping strategy from carbinol intermediate 11 via the acid-catalyzed elimination of dimethylamine (Fig.…”

“…2). 20 Critical to our approach was to assemble the molecule in a fashion such that key functional groups were installed both in their native form and in a late-stage fashion; we surmised that this approach would provide the greatest possible flexibility, facilitating investigations of structure-activity relationships at all critical branch points. To this end, we envisaged a synthon such as 9 in which exploitation of appropriate functional handles at the correct stage would install the requisite functionalities.…”

“…20 Nucleophilic methylation of 10 proceeded in good yield to provide carbinol 11 in 75% yield of a single diastereomer at C5. Sc(OTf) 3 -promoted addition of m -acetylaniline installed the substituted C3-aniline necessary for elaboration to 1 , upon which silyl deprotection afforded tetraol 12 .…”

Totalsynthese von Nosiheptid

“…[250][251][252][253][254] In frühen Berichten wurde für die Umsetzung von Salicylsäureestern in apolaren Medien eine intramolekulare Katalyse des Protons im nicht ionisierten Phenol A 1 postuliert (Schema 4.15, Pfad A). [247] Alternativ wurde für Transformationen in polar, protischen Lösungsmitteln die intramolekulare Assistenz des gebildeten Phenolats B 1 vorgeschlagen (Pfad B).…”

Synthesis of several novel 14-membered ketolides bearing modified 5-O-4′-[1,2,3] triazol desosamine side chain

“…In the process, acetic acid (1%) was needed to overcome the alkalinity of the dimethylamino group, otherwise the reaction would be tedious with low yield. 10,11 Then compound 2 was treated with methylsulfonyl chloride in pyridine to afford compound 3 in 90% yield. And an azido group was introduced to the C-4 position of compound 3 by reacting with sodium azide in dimethyl formamide at 100°C.…”