The Curtius rearrangement: mechanistic insight and recent applications in natural product syntheses

Abstract

The Curtius rearrangement is a versatile reaction in which a carboxylic acid can be converted to an isocyanate through an acyl azide intermediate under mild conditions. The resulting stable isocyanate can then be readily transformed into a variety of amines and amine derivatives including urethanes and ureas. There have been wide-ranging applications of the Curtius rearrangement in the synthesis of natural products and their derivatives. Also, this reaction has been extensively utilized in the synthesis and application of a variety of biomolecules. In this review, we present mechanistic studies, chemical methodologies and reagents for the synthesis of isocyanates from carboxylic acids, the conversion of isocyanates to amines and amine derivatives, and their applications in the synthesis of bioactive natural products and their congeners.

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

“…A large number of mild methods and a variety of reagents have been developed over the years. These methods have been reviewed in detail . In this section, we provide only a few selected convenient methods that have been used widely for medicinal chemistry applications.…”

“…There are other recent methods and protocols that have been covered in recent reviews . In this review, we now highlight applications of the Curtius rearrangement in medicinal chemistry and drug development.…”

“…Isocyanates can also be transformed into urethanes ( 6 ) by alcoholysis after workup or in situ by performing the rearrangement in alcoholic solvents. Alternatively, reaction of isocyanates with an amine would provide the corresponding urea derivatives ( 7 ) …”

“…The Curtius rearrangement has been extensively employed in the synthesis of a variety of natural products and numerous biomolecules. We recently reported the applications of Curtius rearrangement in the synthesis of natural products . As shown in Figure , Curtius rearrangement was employed in the total synthesis of (+)‐zampanolide ( 8 ) to install the N ‐acyl hemiaminal moiety .…”

“…During the thermolysis, molecular nitrogen is eliminated and at the same time a [ 1,2]-shift of the substituent attached to the carbonyl group takes place with retention of configuration. The resulting amine (5)h as ac arbon less, because the last step of the reaction entailst he loss of am olecule of CO 2 .I socyanates can also be transformed into urethanes( 6)b ya lcoholysis after workup or in situ by performing the rearrangementi na lcoholic solvents. Alternatively,r eaction of isocyanates with an amine would provide the corresponding urea derivatives (7).…”