Azides, Mitsunobu reaction, alcohol-amine conversions

The major application of the Mitsunobu reaction is the conversion of a chiral secondary alcohol 1 into an ester 3 with concomitant inversion of configuration at the secondary carbon center. In a second step the ester can be hydrolyzed to yield the inverted alcohol 4, which is enantiomeric to 1. By using appropriate nucleophiles, alcohols can be converted to other classes of compounds—e.g. azides, amines or ethers. 

The addition of l-pentenyl-5-magnesium bromide to epoxide 48 furnished alcohol 51a. This was converted to amine 51b by reduction of an azide, obtained by the Mitsunobu reaction,55 and conversion to 52 by known methods. The final product was secured by a three-step sequence involving amination, hydroboration and debenzylation. 

We pointed out in chapter 27 that Schultz s asymmetric Birch reduction can be developed with iodolactonisation to remove the chiral auxiliary and set up new chiral centres. Now we shall see how he applied that method to alkaloid synthesis.1 The first reaction is the same as in chapter 27 but the alkyl halide is now specified this gave diastereomerically pure acetate in 96% yield and hydrolysis gave the alcohol 4. Mitsunobu conversion of OH to azide and enol ether hydrolysis gave 5, the substrate for the iodolactonisation. Iodolactonisation not only introduces two new chiral centres but cleaves the chiral auxiliary, as described in chapter 27. Reduction of the azide 6 to the amine with Ph3P leads to the imine 7 by spontaneous ring closure. 

The conversion of an alcohol to an amine can be achieved in a one-pot reaction the alcohol 1 is treated with hydrazoic azid (HN3), excess triphenylphosphine and diethyl azodicarboxylate (DEAD). The initial Mitsunobu product, the azide 14, further reacts with excess triphenylphosphine to give an iminophosphorane 15. Subsequent hydrolytic cleavage of 15 yields the amine—e.g. as hydrochloride 16 ... 

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