Mitsunobu Reaction in the Ether Bond Formation

This reaction cycle is characterized by the use of hypervalent iodine species XII as the stoichiometric oxidant and a catalytic quantity, around 0.2 mol, of the oxidizing azo reagent XIII. The benefit of using XII is that the by-products, iodobenzene and acetic acid, are relatively simple to remove, while at the same time, the amount of hydrazine by-product XI formed is dramatically reduced. Under optimized conditions, the authors obtained aryl-carboxylic acid esters with chiral alcohols in 65% yield and with 100% e.e. 

An important aspect of this unique ether-bond-forming reaction lies in the formation of the alkoxy-phosphonium cation XVII by the less acidic alcohol as the weak nucleophile, from which XVIII is obtained. In the next step, inversion of configuration occurs in XVIII, in attack on the stereogenic C-atom by alkoxide generated from the more acidic alcohol or phenol. 

This tandem reaction proceeded at 20°C, whereas in the absence of alcohol, it required reflux conditions in acetonitrile [36]. 

In conclusion, the multistep synthesis of (/f)-K-13975, presented here, is a typical example of improvement of the critical synthetic steps in new drug synthesis to provide robustness, i.e. reproducibility of the process, easy separation of the product, and the required high yield. This is always a challenge for the synthetic organic chemist when a stmcturally well-defined lead molecule emerges and a workable synthetic route is needed. In view of the expectation that lead compound would be required in multi-kilo quantities, the synthetic chemists developed a process, presented in this chapter, that meets many criteria for alternative scale-up. 

Fmchart JC, Duriez P, Steals B (1999) Curr Opin Lipidol 10 245-248 

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