An Accelerated Intermolecular Rauhut–Currier Reaction Enables the Total Synthesis of (−)-Flueggenine C

Abstract

The first total synthesis of dimeric securinega alkaloid (-)-flueggenine C is completed via an accelerated intermolecular Rauhut-Currier (RC) reaction. Despite the numerous reports on the total synthesis of monomeric securinegas, the synthesis of dimeric securinegas whose monomeric units are connected by a putative enzymatic RC reaction has not been reported to date. We have found that installation of a nucleophilic functional group at the γ-position of an enone greatly accelerates the rate of the diastereoselective intermolecular RC reaction. This discovery enabled an efficient and selective formation of the dimeric intermediate which was further transformed to (-)-flueggenine C.

Biosynthetically Inspired Syntheses of Secu′amamine A and Fluvirosaones A and B

“…[1] However,e lucidation of the exact biosynthetic pathway can be cumbersome given the challenges associated with the expression and purification of key enzymes,a sw ell as difficulties in the isolation of practically useful amount of biosynthetic intermediates.Incontrast, synthetic chemists can utilize the whole periodic table to efficiently access proposed key biosynthetic intermediates,s tudy their reactivities,a nd thus provide the biosynthetic community with invaluable information. [2] To maximize selective advantages,organisms often diversify the structure of certain secondary metabolites to structurally more complex molecules by the action of various enzymes and inherent chemical reactivities of biosynthetic intermediates.Securinega alkaloids are one of many families of natural products that display an array of structural diversity.Specifically,t he molecular evolution of monomeric tetracyclic congeners such as norsecurinine (1,S cheme 1), virosecurinine (2), allosecurinine (3), or viroallosecurinine (4) provides aplatform for such diverse complex molecules.One representative mode of diversification of securinega precursors is aRauhut-Currier reaction based carbon-carbon bond formation, [3] as exemplified by our recent total synthesis of flueggenine C (5). [4] Theother notable mode of derivatization involves oxidation(s).…”

“…[2] To maximize selective advantages,organisms often diversify the structure of certain secondary metabolites to structurally more complex molecules by the action of various enzymes and inherent chemical reactivities of biosynthetic intermediates.Securinega alkaloids are one of many families of natural products that display an array of structural diversity.Specifically,t he molecular evolution of monomeric tetracyclic congeners such as norsecurinine (1,S cheme 1), virosecurinine (2), allosecurinine (3), or viroallosecurinine (4) provides aplatform for such diverse complex molecules.One representative mode of diversification of securinega precursors is aRauhut-Currier reaction based carbon-carbon bond formation, [3] as exemplified by our recent total synthesis of flueggenine C (5). [4] Theother notable mode of derivatization involves oxidation(s). An oxidation of the tertiary amine moiety of the securinega precursors would yield the N-oxide derivative I that serves as ab ranching point to various highoxidation-state securinega alkaloids.F or example,aMeisenheimer rearrangement of I yields phyllantidine (7).…”

Strategies to diversify natural products for drug discovery

“…Once new molecules with attractive biological activity are isolated from natural resources and structurally characterized, they can be considered for target-oriented synthesis that can be planned effectively with retrosynthetic analysis. [262][263][264] The elaborated divergent total synthesis accesses a complex target or even a collection of targets for the straightforward preparation of natural products and their anlogues, 260,261 as exemplified by the synthetic efforts on compound 1. 265 It can work as an alternative source of many valuable natural products and relieve the supply crisis from limited natural resources, although the synthetic yield sometimes may be poor.…”

Total Synthesis of (±)‐Phyllantidine: Development and Mechanistic Evaluation of a Ring Expansion for Installation of Embedded Nitrogen‐Oxygen Bonds

“…The securinega alkaloids,i solated from the Euphorbiaceae family of plants,are aclass comprised of over 70 known members featuring unique bridged tetracyclic or pentacyclic cores (e.g., 1-11;F igure 1). [1,2] Thed iverse molecular architectures found within this class of natural products,combined with their wide-ranging biological activities,h ave inspired dozens of synthetic efforts aimed at their preparation, most of which have focused on the parent alkaloids securinine (2), allosecurinine (3), and their enantiomers (4 and 5). [1][2][3] As illustrated in Figure 1, as ubset of the securinega alkaloids contain an embedded nitrogen-oxygen (N À O) bond (e.g., 1 and 6-11), which offers an additional synthetic challenge not found in 2-5.…”