Azides, Mitsunobu reaction, alcohol-amine

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. 

Several examples of reactions of allyl alcohols under Mitsunobu reaction conditions using diethyl azodicarboxylate (DEAD) and triphenyl phosphine giving allyl amines are known. An example is the reaction of the steroid 5 with azide nucleophiles under Mitsunobu reaction conditions, giving the corresponding azide 6 in 63 % yield (Eq. (3)) [5]. The reaction is regioselective with inversion of the configuration and no SN2/ substitution is observed. 

The enantioselective total synthesis of the complex bioactive indole alkaloid enf-WIN 64821 was accomplished by L.E. Overman and co-workers." This natural product is a representative member of the family of the C2-symmetric bispyrrolidinoindoline diketopiperazine alkaloids. The stereospecific incorporation of two C-N bonds was achieved using the Mitsunobu reaction to convert two secondary alcohol functionalities to the corresponding alkyl azides with inversion of configuration. The azides subsequently were reduced to the primary amines and cyclized to the desired ib/s-amidine functionality. 

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 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. 

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 ... 

An indirect method for generating an amino alcohol (124) is to open an epoxide with azide to give the azido-alcohol 123, and subsequent reduction (19-50) gives the amine group.Sodium azide and Oxone react with epoxides to give an azi-do-alcohol. Under Mitsunobu conditions (10-17), epoxides are converted to 1,2-diazides with The reaction of trimethylsilyl azide and an epoxide was... 

ADHs were screened for this purpose and ADH-A from Rhodoccocus ruber could furnish the (S)-enantiomer with perfect enantiopurity (>99% ee) and 93% isolated yield. Reducing equivalents were provided by isopropanol in a coupled-substrate approach and allowed the use of catalytic amounts of NADH. The product from the enzymatic reduction required stereoinversion of the stereogenic center en route to the more active (R)-form of ramatroban. This was performed by converting the alcohol into the amine via the azide form, in a combined Mitsunobu-Staudinger one-pot reaction at low temperature [27]. 

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