Total Synthesis of (−)-Lasonolide A

Abstract

The lasonolides are novel polyketides that have displayed remarkable biological activity in vitro against a variety of cancer cell lines. Herein we describe our first generation approach to the formal synthesis of lasonolide A. The key findings from these studies ultimately allowed us to go on and complete a total synthesis of lasonolide A. The convergent approach unites two highly complex fragments utilizing a Ru-catalyzed alkene-alkyne coupling. This type of coupling typically generates branched products, however through a detailed investigation we are now able to demonstrate that subtle structural changes to the substrates can alter the selectivity to favor the formation of the linear product. The synthesis of the fragments features a number of atom economical transformations which are highlighted by the discovery of an engineered enzyme to perform a dynamic kinetic reduction of a β-ketoester to establish the absolute stereochemistry of the southern tetrahydropyran ring with high levels of enantioselectivity.

Dinuclear Metal‐ProPhenol Catalysts: Development and Synthetic Applications

“…Another elegant illustration of the aldol addition of an ynone was shown in the total synthesis of (À)-lasonolide A 62 (Scheme 16). [34] During the ProPhenol-catalyzed step, a significant amount of b-hydroxy elimination was observed when the reaction was performed at 25 8C. Fortunately, this unfavored process could be suppressed by running the reaction at À20 8C, affording 60 in 78 % yield and 99 % ee.…”

“…[47] Recently, the asymmetric alkynylation of acetaldehyde with propyne was used in the total synthesis of piericidin A 102 (Scheme 23). [34] The general protocol was adjusted to accommodate gaseous propyne 96 as the nucelophile. Diethyl zinc and an atmospheric pressure of 96 was used to generate the desired propynyl zinc reagent for the asymmetric addition to acetaldehyde 89 delivering propargylic alcohol 97 in high enantioselectivity (92 % ee).…”

Conformational Design Principles in Total Synthesis

“…Tr ost and co-workers reported the total synthesis of (À)-lasonolide A, featuring interesting tuning of the conformation in 2016 (Scheme 14). [43] Thea uthors first focused on the macrolactonization on 14-1 to construct the 20-membered macrolide.T he rigid conformation of trans-fused bicycles with an axial C21 hydroxyl group and an equatorial side chain, shown as 14-a,b ecame an obstacle for the esterification. To promote the mobility of the C21 alcohol to access amore favorable conformation for the esterification, 14-3 with an open ester was prepared and examined.…”

“…Constrainto fconformation by the trans-fused rings by Trost and co-workers. [43] Scheme 15. Homologation by adelicate conformation tuning by Hsung and co-workers.…”

Zweikernige Metall‐ProPhenol‐Katalysatoren: Entwicklung und Anwendungen in der Synthese

“…[ [47] Kürzlich wurde die asymmetrische Alkinylierung von Acetaldehyd mit Propin bei der Totalsynthese von Piericidin A 102 eingesetzt (Schema 23). [34] In Anbetracht der faszinierenden biologischen und physikalischen Eigenschaften von Fettsäure-abgeleiteten Polyin-Naturstoffen [49] wurde eine katalytische asymmetrische Addition terminaler 1,3-Diine entwickelt (Schema 24). [ [51] Die Arbeitsgruppe von Fürstner hat die Zn-ProPhenolkatalysierte asymmetrische Addition von 1,3-Diinen für eine kurze Totalsynthese von Ivorenolid B 112 genutzt (Schema 25).…”