Two Concise Total Syntheses of (−)-Bitungolide F

Abstract

The enantioselective total synthesis of the dual-specificity phosphatase inhibitor (-)-bitungolide F has been achieved using two convergent routes. Both strategies feature an asymmetric boron-mediated pentenylation, a stereoselective aldol, and a hydroxyl-directed 1,3-anti-reduction in order to control the stereogenic centers at C4, C5, C9, and C11. Whereas the first total synthesis was achieved in 11 steps and 14.6% overall yield using an Evans-type asymmetric alkylation, the second was completed in 9 steps and 11.4% overall yield using a highly enantioselective organocatalytic Michael addition as a key step and a protecting group free strategy.

Metathetic Synthesis of Common and Medium-Sized Lactones: The State of the Art

“…Styryl lactones, just like cryptopyranmoscatone A1 60, cryptomoscatone D2 61, and cryptofolione 62, are present also in another wide family of pentenolides, that [115,116], two cytotoxic agents extracted from marine sponge Theonella cf. swinhoei (Scheme 24).…”

Organocatalysis in Total Synthesis

“…Illustrative examples are the syntheses of (+)-polyanthellin A [25], (+)-simplactone B [26], biyouyanagin A [27], ()-oseltamivir [28,29], and ABT-341 [29,30] (Fig XII.2). As an application of this enamine activation we describe the organocatalytic step in the construction of ()-bitungolide F (2) skeleton recently published by Cossy and co-workers (Scheme XII.1) [31]. This natural product is a polyketide isolated by Tanaka et al [32] from the Indonesian sponge Theonella cf.…”

Organocatalysis

“…Arseniyadis and Cossy have applied enamine organocatalysis in their elegant total syntheses of (-)-bitungolide F. 4 Compound 1 is prepared using an enantioselective organocatalysed Michael addition using the proline derived catalyst 2, originally reported by Chi and Gellman. A further eight steps afforded the natural product (-)-bitungolide F (Scheme 1).…”

“…The reaction was conducted in the presence of L-proline (20 mol%) and dibenzyl azodicarboxylate (1.5 equiv) as a source of electrophilic nitrogen in CH 3 CN at room temperature. After completion of the reaction, NaBH 4 and EtOH were added to reduce the aldehyde functionality. Monoprotected α-hydrazino 1,3-diols 11 and 12 were isolated in good yields of 75% and 76%, respectively, for the three steps.…”

“…35 List has reported the formal asymmetric synthesis of (+)-grandisol through desymmetrization of a meso-anhydride. 32 Arseniyadis and Cossy have applied enamine organocatalysis in their elegant total syntheses of (-)-bitungolide F. 4 Hong and co-workers have applied cascade enamine/iminium ion catalysis in the synthesis of (+)-conicol and didehydroconicol. 6 MacMillan has also reported the asymmetric synthesis of the angiogenesis inhibitor 18.…”