Heterosubstituted olefin tandem metathesis – total synthesis of lycorine type alkaloids. – Lycomet

Ring closing metathesis is a reaction forming a cycle from double bonds that become crucial in organic chemistry, for which Y. Chauvint, Richard R. Schrock and Robert H. Grubbs received the Nobel prize in 2005 . One of the crucial step of our route to the family of lycorines rests on an unreported tandem metathesis (succession of two consecutive reactions of metathesis). It is partially thanks to this strategy that the skeleton of the aimed molecules will be obtained in an effective fashion. However, the realization of this key stage of tandem metathesis requires the preliminary synthesis of a precursor of cyclisation. The latter should be obtained by two transformations still not described in the literature allowing to reduce the number of steps in a logic of atom economy.

Our recent works show that the new chemical transformations envisaged for the synthesis of the precursor of cyclisation are practicable. Indeed, two new reactions were developed and are very soon going to be the object of publications in international journals. Besides the utility for our strategy of synthesis and the access to the family of lycorines, these methodologies will be applied to numerous substrates to prove their generality and potential utility for the whole organic chemistry community. The studies during these first two years, via the development of these novel reactions, led to originals compounds which will be the object of future developments both from biological tests and for other applications.

After these first encouraging results, our efforts now concern the key step of tandem metathesis. A first test on a model substrate, fairly close to the structure of the desired compound, showed positive allowing us to reach the tetracyclic skeleton of the family of lycorines. It now remains to apply it to the real substrate which will surely requires variation of the reaction conditions and of the catalyst. This study will then be applied to various substrates to estimate its flexibility and its potential in the total synthesis of natural products.

P1. “Asymmetric addition of alkoxy ethynyl anion to chiral N-sulfinyl imines” Verrier, C.; Carret, S.; Poisson, J.-F. Org. Lett. 2012, 14, 5122-5125.
P2. “Asymmetric addition of aryloxy ethynyl lithium derivatives to N-sulfinyl imines” Verrier, C.; Carret, S.; Poisson, J.-F. Monatshefte fur Chemie (Chemical Monthly). 2013, 144, 455-460
Special Isssue EuCheMS Young Investigator Workshop

Synthesis of natural products is the playground of choice for organic chemist to develop new methods. This project is based on the development of novel tandem sequences that will allow for the synthesis of complex natural products. More precisely, we will explore the unprecedented ene-ynol-ene and ene-yne-enol tandem RCM, an ideal combination for the synthesis of natural products of the amaryllidaceae family having a great potential as therapeutical agents. This particular tandem affords, in a single event, a decorated tetrahydroindole skeleton bearing an enol ether which is crucial in the post-functionalisation of the bicycle, allowing a straightforward and selective synthesis of numerous lycorine alkaloids not synthesized to date.

The synthesis of the acyclic precursors of the tandem metathesis step will rely on chiral sulfinamide chemistry. A tertbutylsulfinylamidine will be our starting material undergoing first a selective alkylation. Its reduction to the sulfinylimine and addition of various acetylenic anions will lead to the acyclic precursor of the tandem process, with a complete control of the three contiguous stereogenic centres. The scope and limitation of the ene-ynol-ene and ene-yne-enol sequences will then be evaluated in terms of possible substitution and efficacy of the transformation. The optimization will be correlated with computational studies to define a scale of reactivity through the calculation of the energies of activation of the reaction. This should eventually help to design better substrates for ring closing metathesis. The adequate pre-functionalisation of the tetrahydroindole skeleton, the result of this new RCM tandem, will enable the rapid first asymmetric total syntheses of (–)-siculinine, (–)-narcissidine, (–)-amarbelissine and of (–)-lycorine.