Synthesis of Structurally Diverse 3-, 4-, 5-, and 6-Membered Heterocycles from Diisopropyl Iminomalonates and SoftC-Nucleophiles

Abstract

Herein, we present a general synthetic strategy for the preparation of 3-, 4-, 5-, and 6-membered heterocyclic unnatural amino acid derivatives by exploiting facile Mannich-type reactions between readily available N-alkyl-and N-arylsubstituted diisopropyl iminomalonates and a wide range of soft anionic C-nucleophiles without using any catalyst or additive. Fully substituted aziridines were obtained in a single step when enolates of α-bromo esters were employed as nucleophiles. Enantiomerically enriched azetidines, γ-lactones, and tetrahydroquinolines were obtained via a two-step catalytic asymmetric reduction and cyclization sequence from ketone enolate-derived adducts. Finally, highly substituted γ-lactams were prepared in one pot from adducts obtained using acetonitrile-derived carbanions. Overall, this work clearly demonstrates the utility of iminomalonates as highly versatile building blocks for the practical and scalable synthesis of structurally diverse heterocycles.

Electrocatalytic Access to Azetidines via Intramolecular Allylic Hydroamination: Scrutinizing Key Oxidation Steps through Electrochemical Kinetic Analysis

“…Although multiple mechanistic scenarios warrant consideration regarding elucidating the catalytic resting state of the reaction mechanism, it is still important to note that the control experiments under a series of chemical oxidants without an electrical input significantly deteriorated the reaction efficiency when 9 was subjected as a substrate (Figure S3). This may suggest one or both of the followings: (1) the ability of electric current to be an ideal source to bypass the second oxidation event, (2) the difficulty of the intramolecular cyclization step associated with undesired conformational barriers with regards to synthesizing azetidines as previously reported. − , …”

“…This may suggest one or both of the followings: (1) the ability of electric current to be an ideal source to bypass the second oxidation event, (2) the difficulty of the intramolecular cyclization step associated with undesired conformational barriers with regards to synthesizing azetidines as previously reported. [5][6][7][8][9]21 To further investigate the possible involvement of carbocation intermediates in the reaction mechanism, we subjected a cation probe substrate to our optimized conditions (Figure 5A). When allylic alcohol 26 was employed, the ring expansion occurred to provide the mixture of 27 and 28, while the formation of intramolecular trapping product 29 was not observed.…”

“…Azetidines are privileged synthetic motifs in a broad area of scientific disciplines that recently gained increased interest for their potential as underexplored biologically active compounds and as ligands in metal-catalyzed transformations (Figure A). − However, as a consequence of their inherent ring strain energy (RSE), azetidines have unfavorable conformational requirements for their formation. − Hence, conventional methods that are effective in forming cyclic amines of other sizes often prove inadequate for synthesizing azetidines. − …”

Total Synthesis and Structural Verification of Isatindigotindoline C

“…1 The isatindigotindolines caught our attention due to our continued interest in the synthesis of bioactive nitrogenous compounds. 2 During the isolation studies, several isatindigotindolines were shown to inhibit β-amyloid aggregation. 1 Alongside with their demonstrated potential use in biology, the isatindigotindoline alkaloids are the first examples of secondary metabolites with a 3,3'-spiropyrrolidine oxindole core (Scheme B), this is a sharp contrast to the abundance of alkaloids with the isomeric 2,3'spiropyrrolidine oxindole structure (Scheme 1A).…”