Natural products Curtius rearrangement

The enantioselective total synthesis of the cytokine modulator (-)-cytoxazone using a syn-stereoselective aldol addition and a Curtius rearrangement as key steps was described by J.A. Marco et al. The key intermediate acid was treated with DPPA and triethylamine in toluene at reflux. This step furnished the oxazolidinone directly and in good yield through an in situ capture of the isocyanate group by the free secondary alcohol functionality. Removal of the protecting group led to the formation of the natural product. 

As in the case of azides 31 and 32, irradiation of nitro-substituted aroyl azides 33 and 34 leads both to photo-Curtius rearrangement (32 and 38% yields) and to the formation of products derived from the capture of singlet aroylnitrenes (37 and 38). The chemical and spectroscopic properties of nitrenes 37 and 38 indicate the singlet nature of their ground states. 

Curtius rearrangement of these azides leads to ketones via loss of an isocyanic acid (HN=C=0) equivalent, which can be trapped in situ as shown for 49 where benzophenone resulted and addition of aniline to the isocyanic acid gave urea 50. or-Alkoxy- and or-amino acyl azides, meanwhile, are precursors to hemiaminals and hisaminals, respectively. Examples in complex natural product synthesis are shown for 81 and 66 in the Variations and Improvements Section. 

Preservation of stereochemistry upon rearrangement is the key in these applications of the Curtius process in asymmetric synthesis. Additional examples featuring this stereospecificity, particularly directed toward natural product synthesis, are foimd in the Variations and Improvements Section. 

In 2012, the Fukuyama group reported the total synthesis of the entire family of amathaspiramides, including amathaspiramide F and the C3-epimeric amathaspiramides A-E. This was the first report of the synthesis of any amathaspiramide other than amathaspiramide F. Fukuyama s retrosynthetic analysis was based on a common cyclic imide 23, which could be elaborated to the entire family of natural products (Scheme 8). The cychc imide 23 would be assembled through a key Curtius rearrangement of alkylated lactone 24. 

---