Exploration of the interrupted Fischer indolization reaction

Abstract

A convergent method to access the fused indoline ring system present in a multitude of bioactive molecules has been developed. The strategy involves the condensation of hydrazines with latent aldehydes to ultimately deliver indoline-containing products by way of an interrupted Fischer indolization sequence. The method is convergent, mild, operationally simple, broad in scope, and can be used to access enantioenriched products. In addition, our approach is amenable to the synthesis of furoindoline and pyrrolidinoindoline natural products as demonstrated by the concise formal total syntheses of physovenine and debromoflustramine B. The strategy will likely enable the synthesis of more complex targets such as the communesin alkaloids.

Figure 1

Parent indoline 1 and representative natural products 2–15

Figure 2

Grandberg’s syntheses of pyrrolidinoindoline 25 and furoindoline 28

Figure 3

Manipulation of the N-substituent.

Figure 4

Synthesis of enantioenriched 30.

Scheme 1

Approach to indoline 1.

Scheme 2

Proposed fragment coupling / cyclization cascade to access indoline 1.

Scheme 3

Lactols and hemiaminals as latent aldehydes.

Scheme 4

Synthesis of pyrrolidinoindoline 32.

Scheme 5

Formal total synthesis of physovenine (2).

Scheme 6

Formal total synthesis of debromoflustramine B (5).

Scheme 7

Synthesis of communesin indoline scaffold 45.

Scheme 8

Furoindoline synthesis using phosphoric acid promoter 46.

Scheme 9

Synthesis of arylhydrazine 50.