Total synthesis of (–)-flueggenine C via an accelerated intermolecular Rauhut–Currier reaction
Sunkyu Han and Sangbin Jeon in the Department of Chemistry have recently reported the first total synthesis of dimeric securinega alkaloid (−)-flueggenine C via an accelerated intermolecular Rauhut−Currier (RC) reaction.
Despite numerous reports on the total synthesis of monomeric securinega alkaloids, the synthesis of dimeric securinegas whose monomeric units are linked by a putative enzymatic RC reaction has not been reported to date.
The research team has discovered 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 finding enabled an efficient and selective formation of the dimeric intermediate which was further transformed to (−)-flueggenine C.
The total synthesis of natural products is a science of synthesizing secondary metabolites isolated from the living organisms in the laboratory through a series of planned and researched chemical reactions.
Each chemical reaction needs to be successful and well-orchestrated to produce the final target molecule.
For that reason, researchers working on natural product total synthesis are often called “molecular artists.”
Despite the numerous reports on total syntheses of monomeric securinegas, synthetic reports of dimeric securinegas whose monomeric units are connected by a putative enzymatic RC reaction have not been addressed by total synthesis.
The KAIST research team used a Rauhut-Currier (RC) reaction, a carbon-carbon bond forming reaction between two Michael acceptors first reported by Rauhut and Currier in 1963, to successfully synthesize the dimeric natural product, flueggenine C.
This features the first application of an intermolecular RC reaction in total synthesis.
The importance of this particular synthetic step should be more clearly described. The conventional intermolecular RC reaction had been driven non-selectively by a toxic nucleophilic catalyst at high temperature (reaction mixture heated over 150 °C) and by way of a highly concentrated reaction mixture.
Thus this method was never (successfully) applied to natural products total synthesis before.
To solve this long-standing problem, the Han group at KAIST placed a nucleophilic moiety at the -position of the enone derivative.
As a result, the RC reaction could then be induced by simple addition of base at ambient temperature and in dilute solution without the need of additional measures such as the use of a nucleophilic catalyst.
Using this newly discovered reactivity, the team successfully synthesized the natural product (-)-flueggenine C from the commercially available amino acid derivative in 12 steps.
Reference : Sangbin Jeon, Sunkyu Han* J. Am. Chem. Soc. 2017, 139, 6302.
* lab webpage : http://synthesis.kaist.ac.kr