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.

Fig. 1

The Curtius rearrangement route to isocyanates, amines and amine derivatives.

Fig. 2

Stieglitz’s mechanism via carbonylnitrene intermediate.

Scheme 1

Thermal and photochemical decomposition of pivaloyl azide.

Scheme 2

Concerted thermal Curtius rearrangement mechanism.

Scheme 3

Photochemical formation of acylnitrenes.

Scheme 4

Photolysis of alkoxycarbonyl azide.

Scheme 5

Preparation of acyl azides.

Scheme 6

Preparation of 8,9,15-trihydroxypentadecylamine using the Naegeli modification.

Scheme 7

Synthesis of amino acid derivatives from α-cyanoacetic esters.

Scheme 8

Synthesis of DPPA and modified Curtius rearrangement.

Scheme 9

Overman procedure for the Curtius rearrangement.

Scheme 10

General procedure developed by Lebel.

Scheme 11

Protocol for the Curtius rearrangement by Li and co-workers.

Scheme 12

Knoechel protocol for quaternary carbon centers.

Scheme 13

Synthesis of orthogonally protected diaminopropionic acid.

Scheme 14

Synthesis of optically active cyclopropylamines.

Scheme 15

Synthesis of a cyclopentano-oxazolidinone.

Scheme 16

Synthesis of peptidomimetic derivatives.

Scheme 17

Synthesis of macrocylic derivatives.

Scheme 18

Synthesis of spirocyclic lactam derivatives.

Scheme 19

Synthesis of triquinacene.

Scheme 20

Synthesis of haemanthidine.

Scheme 21

Synthesis of saxitoxin.

Scheme 22

Synthesis of colchicine.

Scheme 23

Synthesis of streptonigrin and streptonigrone.

Scheme 24

Synthesis of camptothecin.

Scheme 25

Synthesis of huperzine A.

Scheme 26

Synthesis of calyculin A.

Scheme 27

Synthesis of zampanolide.

Scheme 28

Synthesis of salicylihalamide.

Scheme 29

Synthesis of gelsemine.

Scheme 30

Synthesis of methoxatin.

Scheme 31

Synthesis of sinefungin.

Scheme 32

Synthesis of AI-77-B.

Scheme 33

Synthesis of brostallicin.

Scheme 34

Synthesis of belactosin A.

Scheme 35

Synthesis of the himandrine skeleton.

Scheme 36

Synthesis of welwitindolinones.

Scheme 37

Synthesis of diisocyanoadociane.

Scheme 38

Synthesis of mycalamide A.

Scheme 39

Synthesis of altemicidin core.

Scheme 40

Synthesis of pancratistatin.

Scheme 41

Synthesis of NP25032.

Scheme 42

Synthesis of dievodiamine.

Scheme 43

Synthesis of lyconadin C.

Scheme 44

Synthesis of lundurine B.

Scheme 45

Synthesis of axisonitrile and axamide.

Scheme 46

Synthesis of aspeverin.

Scheme 47

Synthesis of cyclindricine core.

Scheme 48

Retrosynthetic approach to cephalotaxine.

Scheme 49

Synthesis of azaspiro[4.4]nonane-2,6-dione 204.

Scheme 50

Synthesis of (−)-esermethole.

Scheme 51

Synthesis of psymberin.

Scheme 52

Synthesis of the mycalamide nucleus.

Scheme 53

Synthesis of pederin.

Scheme 54

Synthesis of mycalamide B.

Scheme 55

Synthesis of echinocandin C.