Organocatalytic Asymmetric Michael Addition of Aliphatic Aldehydes to Indolylnitroalkenes: Access to Contiguous Stereogenic Tryptamine Precursors

Abstract

Because of the importance of the indole framework and the versatile transformation of nitro and formyl groups, the efficient synthesis of optically pure 2-alkyl-3-(1H-indol-3-yl)-4-nitrobutanals, one type of tryptamine precursors are of great interest for pharmaceutical and biological research. Herein, the Michael addition of aliphatic aldehydes to indolylnitroalkenes has been developed using (S)-diphenylprolinol trimethylsilyl ether as an organocatalyst, which provides the desired optically pure syn 2-alkyl-3-(1H-indol-3-yl)-4-nitrobutanal derivatives in up to 98% yield with up to >99:1 dr and >99% ee. To show the synthetic usefulness of this methodology, optically active 2-alkyl-4-nitro-3-(1-tosyl-1H-indol-3-yl)butan-1-ol and tryptamine derivatives are readily obtained by stepwise systematic transformations.

Strategies for the asymmetric functionalization of indoles: an update

“…Scheme 37 Addition of aldehydes to indolylnitroalkenes. 109 explained by the authors surmising the transition states pictured in Scheme 37, in which p-p stacking favours, while steric repulsion disfavours, the transition state leading to the R-isomer.…”

“…The desired optically enriched syn-derivatives were recovered in 90-98% yield in 97 : 3-499 : 1 dr and always 499% ee (Scheme 37). 109 The authors claimed (1 0 R,2 0 S) stereochemistry for the products but they did not report experimental evidence of how this stereochemistry was elucidated. In addition, isobutyraldehyde was also used, but only 26% yield and 87% ee of the desired product were obtained.…”

Arenesulfonyl indole: new precursor for diversification of C-3 functionalized indoles

“…In recent times, indolyl nitroalkenes have been exploited as Michael acceptors with Michael donors to functionalize indole at C-3 position. 15,16 Another relatively new methodology involves the presence of leaving group at the benzylic C-3 position of indole, which includes gramines, 3-(1 0hydroxyalkyl)-indoles and arenesulfonyl indoles. These substrates undergo elimination under acidic or basic conditions to generate reactive alkylideneindolenine, a vinylogous imine intermediate, which upon nucleophilic addition leads to the C-3 functionalized indole adducts (Scheme 1).…”

Hybrid Peptide–Thiourea Catalyst for Asymmetric Michael Additions of Aldehydes to Heterocyclic Nitroalkenes

“…This catalyst was applied to synthetically highly relevant Michael additions featuring heterocyclic moieties. There are reports mentioning isolated examples of heterocyclic nitroalkenes or those focusing on a particular structure, such as indolylnitroalkenes . However, systematic investigations using heterocyclic nitroalkenes are very rare.…”