Curtius rearrangement synthetic utility

In contrast to the somewhat limited synthetic utility of nitrenes, there is an important group of reactions in which migration occurs to electron-deficient nitrogen. One of the most useful of these reactions is the Curtius rearrangement 16 This reaction has the same relationship to acylnitrene intermediates that the Wolff rearrangement does to acylcar-benes. The initial product is an isocyanate, which can be isolated or trapped by a nucleophilic solvent. 

The first step in the overall synthetic scheme (Scheme 6) is the condensation of an appropriate carboxylic acid with trifluoroacetaldehyde. The carboxylic acid is chosen to impart specificity for the target enzyme. In one example,[28 the dianion of cyclohexanepropanoic acid (29) was formed by the addition of LDA and then quickly condensed with trifluoroacetaldehyde to form the p-hydroxy acid 30 as a racemic mixture of erythro- and threo-isomers. The p-hydroxy acid 30 is then protected with TBDMSOTf forming 31. Diphenyl phosphorazidate, TEA, and benzyl alcohol were then utilized in a Curtius rearrangement of the protected alcohol 31, which proceeds through an isocyanate intermediate that yields the protected amino alcohol 32 upon reaction with benzyl alcohol. In order for this step to occur at an appreciable rate, a second equivalent of triethylamine had to be added. The amino alcohol 32 was then deprotected and coupled with Boc-Phe-Leu-OH to give the trifluoromethyl alcohol 33, which was oxidized to the corresponding trifluoromethyl ketone 34 as a 1 1.2 mixture of diastereomers using the Dess-Martin periodinane procedure. Thus far, the compound shown in Scheme 6 is the only compound that has been synthesized by this method, but it is reasonable to assume that many other similar fluoro ketones can be produced by this scheme. 

From the perspective of synthetic utility (see Section 1.1.4.4), a crucial mechanistic feature of the Curtius rearrangement is that migration of sp carbons occurs stereospecifically, with retention of configuration. Wallis showed that the product from rearrangement of enantiomerically enriched a-benzyl propionyl azide 13 remained optically active. Kenyon and coworkers proved that preservation of optical activity corresponded to retention of configuration by studying rearrangement of 15. The product 16 was obtained with > 99% retention of stereochemistry. ... 

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