Total Synthesis of (+)-Herboxidiene from Two Chiral Lactate-Derived Ketones

Abstract

A substrate-controlled synthesis of (+)-herboxidiene from two lactate-derived chiral ketones is described. Remarkably, most of the carbon backbone was constructed through highly stereoselective titanium-mediated aldol reactions and an Ireland-Claisen rearrangement. Furthermore, an oxa-Michael cyclization and a high-yield Suzuki coupling were used to assemble the pyran ring and the diene moiety respectively.

Pre-mRNA Splicing-Modulatory Pharmacophores: The Total Synthesis of Herboxidiene, a Pladienolide–Herboxidiene Hybrid Analog and Related Derivatives

“…The sulfone 19 can be derived from alcohol 18 , which is conveniently prepared by an efficient method reported by Urpi and co-workers. 35 …”

“…This concise route towards the tetrahydropyran core of 1 represents a significant advancement in the syntheses of the key intermediate 14a . 35–39 …”

“…Removal of the tert -butyldimethylsilyl group in 20a and 20b with HCl, followed by C18 hydroxyl directed selective epoxidation of alcohols 21a and 21b with catalytic VO(acac) 2 provided the pure diastereomers 22a and 22b in good yields, as expected based on the literature precedence. 35–38 The purification step at this point also readily removed the minor C9,C10-Z isomer as shown in Scheme 3 (see SI), which had been carried over from 16a/16b . Hydrolysis of the methyl esters 22a and 22b under basic conditions afforded pure herboxidiene ( 1 ) and C6-norherboxidiene ( 23 ).…”

Identification of the Herboxidiene Biosynthetic Gene Cluster in Streptomyces chromofuscus ATCC 49982

“…Because of its promising biological activities, several chemical synthetic approaches toward compound 1 have recently been attempted (5,7,8,26). One of the most recent chemical syntheses of compound 1 was accomplished from two lactate-derived chiral ketones in 14 steps with an 8% overall yield (21). However, these multistep chemical processes are not efficient and flexible enough for the synthesis of new herboxidiene analogs.…”

Microbial and Natural Metabolites That Inhibit Splicing: A Powerful Alternative for Cancer Treatment

“…Later attempts used several routes, including a stereochemical synthesis in 18 steps [67], an enantioselective synthesis in 16 steps [68], or an alternative synthesis in 16 steps with a global yield of 3.4% [69]. An additional chemical synthesis reported was performed starting from two chiral ketones derived from lactate in 14 steps with a global yield of 8% [70]. A total enantioselective synthesis of Herboxidiene was reported in 2014 and the obtained product showed a mild inhibitory activity on the spliceosome [71].…”