Advances in Aza‐Claisen‐Rearrangement‐Induced Ring‐Expansion Strategies

Abstract

The aza-Claisen rearrangement,a lso known as the 3-aza-Coper earrangement, has attracted significant attention because it can be used as ac omplimentarym ethodt o access ad iverse range of useful organic molecules. The presence of an itrogen atom at the 3-position enables the tethering of various-sized azacycles, thereby giving ring-expansion strategiest hat take advantage of the aza-Claisen rearrangementadistinct advantage comparedt oo ther [3,3]-sigmatropic rearrangements. Recent advances in aza-Claisen rearrangements have facilitatedo therwise-inaccessible ring expansions in ah ighly stereoselective manner. The utility of aza-Claisen-rearrangement-induced ring-expansion strategies has been exemplified in the synthesis of ad iverse range of naturalp roducts. This Focus Review summarizes recent advancesi na za-Claisen-rearrangement-induced ring-expansion strategy, in particular applicationsi nt he synthesis of bioactive alkaloids.

Unexpected Rearrangement of N-Allyl-2-phenyl-4,5-Dihydrooxazole-4-Carboxamides to Construct Aza-Quaternary Carbon Centers

“…We initially evaluated glycinamides as potential substrates for ACR (Table 1, Entries 1-5). Unfortunately, our attempts with glycinamide 1a, which had a free amine functional group, did not produce the desired ACR product (2). Unlike the results reported by Tsunoda et al and Suh et al [11][12][13][14][15], our substrate (1a) decomposed to unidentified compounds over time (Table 1, Entries 1 and 2).…”

“…This facilitates the construction of congested carbon centers in a highly stereo-controlled fashion. Numerous methods, protocols, and applications have been developed for rearrangement reactions, [3,3]-sigmatropic rearrangement being a textbook example [1][2][3][4]. Among the driving forces that have been discovered or developed to facilitate such rearrangements, the accelerating effects of various substituents continue to attract attention [5][6][7][8].…”

“…In our research on the synthesis of bioactive alkaloids and small molecules, we became interested in the accelerating effects of substituents in an aza-Claisen rearrangement (ACR) [2]. Much of the effort in the development of ACR has focused on cationic or zwitterionic ACR [9].…”

“…Anionic ACR is relatively unexplored, possibly because its activation energy is large [10]. Rate acceleration with the ionic involvement of a neighboring functional group could be utilized to overcome the activation energy barrier of anionic ACR [2]. For instance, Tsunoda et al [11,12] employed glycinamide for amide-enolate-induced ACR using an acyclic precursor, while Suh et al [13][14][15] did so with a cyclic precursor ( Figure 1A).…”

Investigation of Grignard Reagent as an Advanced Base for Aza-Claisen Rearrangement

“…More importantly, with ACR employed, chiral communication and induction of remote stereogenic centers were also reported in a highly selective manner [8,9] (Figure 1). However, this type of rearrangement also requires harsh reaction conditions and at times results in low yields [10]. ACR proceeds through deprotonation, [3,3]-sigmatropic rearrangement, and protonation, as shown in Figure 2.…”