Mitsunobu with oxygen nucleophiles

HSAB is particularly useful for assessing the reactivity of ambident nucleophiles or electrophiles, and numerous examples of chemoselective reactions given throughout this book can be explained with the HSAB principle. Hard electrophiles, for example alkyl triflates, alkyl sulfates, trialkyloxonium salts, electron-poor car-benes, or the intermediate alkoxyphosphonium salts formed from alcohols during the Mitsunobu reaction, tend to alkylate ambident nucleophiles at the hardest atom. Amides, enolates, or phenolates, for example, will often be alkylated at oxygen by hard electrophiles whereas softer electrophiles, such as alkyl iodides or electron-poor alkenes, will preferentially attack amides at nitrogen and enolates at carbon. 

In the Mitsunobu reaction, the C-O bond of the alcohol is broken because the alcohol becomes the electrophile and the acid derivative must be a nucleophile so an acid is better than an acid chloride. The ester is formed with inversion. Note the fate of the oxygen atoms, ester formation from a secondary alcohol with inversion by the Mitsunobu reaction... 

The Mitsunobu reaction proceeds via the activated oxyphosphonium derivatives 48a and 50a, respectively. From the (E)-configuration of 49 and 51 we know that the reactive conformations of 48a/50a must be exo as shown. From the configuration of the products we conclude that the nucleophile attacks anti to the leaving group. For 48a this means that the nucleophile has to cope with the dipole repulsion of the acetonide oxygens. 50a, by contrast, is devoid of such a repulsion. That the acetonide oxygens indeed exert such a repulsive effect is also demonstrated by the regiochemistry of the reaction (Fig. 23). 

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