Organotitanium (II): a versatile reagent for a rapid access to [5-7] bicycles and highly functionalized systems – TVA

In this proposal, several reactivities of versatile, inexpensive and readily available titanium (II) reagent (?2-propene)-Ti(OiPr)2 will be examined. At first, its strong affinity towards alkynes will be exploited in unprecedented carbocyclization as well as cyclocarbonylation reactions to respectively access complex [5-7]-bridged vibsane and [5-7]-fused guaiane frameworks. As a proof of concept, the ability of titanium (II) to form seven-membered rings has recently been demonstrated in our laboratory through preliminary cyclocarbonylation attempts. This unique reactivity could further be highlighted through the synthesis of various other natural backbones possessing a seven-membered rings and readily applied to the total synthesis of thapsigargin and vibsatin, currently under investigation in our laboratory.
In a second part, we will focus on the reactivity of Ti(II) towards alkoxyallenes and allenamides, leading to highly functionalized alkenic building blocks. To date, the direct complexation of low-valent titanium complexes onto O- or N- heterosubstituted allenes remains unprecedented, thus rendering the study very innovative. In the case of alkoxyallenes, a special focus will be devoted to readily available and relatively stable allene carbamates. From their reaction with low-valent titanium, access to highly functionalized O-ene carbamates is expected. Post-functionalization of the latters through nickel catalyzed cross-coupling would lead to stereocontrolled tri- or tetrasubstituted alkenes. A similar study will be performed with highly modular allenamines and allenamides, which should offer a straightforward access to a wide molecular diversity. As an ultimate goal, a diastereoselective version of the reaction will be proposed. Simultaneously to these survey, the unprecedented intramolecular cyclisation reactions of alkoxyallenes or allenamides having a tether bearing an alkyne function will be explored. Based on precedents in the literature on 1,2-diene-6-ynes, cyclization of 1,2-alkoxy (or amino) dien-6-ynes will be studied, leading to functionalized dienic building blocks.
All along these works, a special care will be devoted to render these transformations scalable, safer and even more eco-friendly for an easier transposition to industrial scale.

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