Use of Aluminum Acetals in Radical Chemistry – Radic[Al]

5-Membered and 6-membered heterocycles constitute the framework of a plethora of molecules of biological interest and hence, they are attractive target for organic chemists. Among the extensive literature reporting on the preparation of these heterocyclic systems, the use of radical intermediates is of particular interest. For instance, carbon–carbon bonds can be formed under mild conditions with a unique functional group tolerance. Moreover, radical reactions can be highly regio- and stereoselective and their ability to be involved in cascade reactions makes them particularly attractive. Ueno and Stork have developed independently in 1980's the cyclization of alpha-haloacetals (the Ueno-Stork reaction) which has proved to be very efficient compared to the related cyclization of alpha-bromo esters under reductive conditions. However, the hydrolysis of the cyclic acetal moiety revealed sometimes difficult to achieve, especially in the case of acid-sensitive substrates. Moreover, the synthesis of the alpha-haloacetal precursors, as well as the enol ethers employed in their preparation, is not always straightforward and can be somewhat tricky.

We present herein an novel approach which allows to access lactols from easily available alpha-bromo esters in a one-pot reaction. The scope of the reaction will be extended to include the preparation of nitrogen-containing heterocycles. Moreover an asymmetric version of this new reaction will be developed.

During this ANR program, we will define the scope and limitation of the Radic[Al] methodology and study the reaction from the mechanistic standpoint with the help of molecular modelling studies. The environmental aspect will also be considered and we will tackle the challenging problem of supported-tin hydride-mediated radical reactions. We will illustrate the efficiency of this approach by preparing key building blocks for the synthesis of relevant target molecules.