Viability of a [2 + 2 + 1] Hetero-Pauson–Khand Cycloaddition Strategy toward Securinega Alkaloids: Synthesis of the BCD-Ring Core of Securinine and Related Alkaloids

Abstract

Preliminary results related to the development of [2 + 2 + 1]-oxa-hetero-Pauson-Khand cycloaddition strategy toward the Securinega alkaloids are reported. The critical tricyclic BCD-ring core was assembled in only nine linear steps from cheap 4-hydroxy-l-proline. The study provides valuable insight into the scope of a rare hetero-Pauson-Khand reaction, a powerful tool for the rapid construction of butenolide-containing natural products.

Structure simplification of the Securinine skeleton reveals the importance of BCD ring system for the cytotoxic activity on HCT116 and HL60 cell lines

“…The rational for the choice of these two cancer cell lines is linked to the previous results reported separately by the groups of Wald and Vidal, which showed a promising activity of securinine (1) and its C14-analogs In our previous work, we have reported a straightforward route to the critical BCD core 2 of securinine (1) and related alkaloids (Scheme 2). 20 The tricyclic core 2 can be considered on its own as a simplified securinine analog which would allow to study the contribution of the cycle A to the biological activity of 1. Moreover, BCD core 2 can be further explored as a starting point for the synthesis of analogs that are not otherwise accessible through the semi-synthetic route.…”

Tungsten-Promoted Hetero-Pauson–Khand Cycloaddition: Application to the Total Synthesis of (–)-Allosecurinine

“…5a,11 We recently proposed an efficient entry to this series with the use of a hetero-Pauson-Khand (HPK) strategy to construct the BCD core of the securinane/neosecurinane groups on a model compound. 12 Herein, we report our efforts to implement this cyclocarbonylation reaction to the synthesis of the securinane skeleton through the total synthesis of allosecurinine (3), the C2-epimer of securinine (1).…”

“…At this stage, installation of the Z-enyne motif was considered. The Julia-Kocienski procedure which was successfully applied in the model study 12 gave disappointing results with the aldehyde derived from ester 7. The yields were low, not constant, and purification of the reaction product from the residual sulfone proved to be difficult.…”

Securinega Alkaloids: Complex Structures, Potent Bioactivities, and Efficient Total Syntheses

“…By an intramolecular N ‐heterocyclic‐carbene‐catalyzed [3+2] cycloaddition using catalyst precursor 68 in the presence of titanium isopropoxide, the ynal and keto functions of compound 69 were cyclized in a single step to yield the protected Securinega alkaloid core 70 in 31 %. Inspired by this work, Porée and co‐workers developed a [2+2+1] cycloaddition approach featuring a hetero‐Pauson–Khand reaction . Thus, the precursor 71 carries a terminal alkyne and the missing C 1 unit is introduced by metal‐bound carbon monoxide.…”

“… Recent approach to the tricyclic core of Securinega alkaloids using N ‐heterocyclic carbene catalysis by Snyder et al . and an extension of the methodology using a hetero‐Pauson–Khand reaction by Porée et al …”