Semisynthesis of Libiguin A and Its Analogues by Trans-Lactonization of Phragmalin

Abstract

Libiguins are limonoids with highly potent sexual activity enhancing effects, originally isolated from the Madagascarian Meliaceae species Neobeguea mahafalensis, where they exist in only minute quantities. Their low natural abundance has hampered mapping of their biological effects. Here we describe an approach to the semisynthesis of libiguin A and its close analogues 1-3 starting from phragmalin, which is a limonoid present in high amounts in a commercially cultivated Meliaceae species, Chukrasia tabularis, allowing the preparation of libiguins in appreciable quantities.

Research progress of meliaceous limonoids from 2011 to 2021

“…trans -Lactonization in phragmalin is a key for the semisynthetic approach to libiguin-type compounds by 17-oxy functionality turned into 30-oxy functionality. 460 Natural phragmalin-type 1/8/9-orthoesters (major existence) were transformed from phragmalins with esterified substituent at the C-1 and hydroxyl groups at C-8 and C-9. 461 Tabulalin, as a fine precursor with free 1/8/9-hydroxy groups, may be converted into 1/8/9-orthoesters by acetylation and protonation.…”

Assembling the Methanoindene Cage of Phragmalin-Type Natural Products

“…The majority of phragmalin-type compounds feature methylation at C2 and C4 of the methanoindene cage moiety, a methanoester group at C8, and various degrees of oxygenation: virtually all compounds feature oxygenation at C1, C3a, and C7, while some compounds feature additional oxygenation at C7a, C5, and C6. While an example of the semisynthesis of a phragmalin-type compound has been reported, 18 total syntheses have not been developed to date. A significant milestone for the total synthesis of such natural products is the assembly of a tricyclic methanoindene cage with a sufficient degree of functionalization.…”

Assembly of the Limonoid Architecture by a Divergent Approach: Total Synthesis of (±)-Andirolide N via (±)-8α-Hydroxycarapin

“…While many limonoids, including andirolide N ( 5 ), are trace isolates from threatened rainforest environments, availability from citrus and neem fruits has allowed for investigations of some members of the limonoid class through the use of semisynthesis and relay synthesis . Independent, contemporaneous studies in the early 1970s by the groups of Connolly and Ekong examined the biomimetic oxidative fragmentation of the limonoid B-ring and reassembly through a 1,6-conjugate addition to form mexicanolide ( 3 ).…”