Synthesis of Structurally Diverse 3‑, 4‑, 5‑, and 6‑Membered Heterocycles from Diisopropyl Iminomalonates and Soft C‑Nucleophiles

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-aryl-substituted diisopropyl iminomalonates and a wide range of soft an...

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Veröffentlicht in:Journal of organic chemistry 2019-06, Vol.84 (11), p.7066-7099
Hauptverfasser: Kattamuri, Padmanabha V, Bhakta, Urmibhusan, Siriwongsup, Surached, Kwon, Doo-Hyun, Alemany, Lawrence B, Yousufuddin, Muhammed, Ess, Daniel H, Kürti, László
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Sprache:eng
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Zusammenfassung: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-aryl-substituted 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.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.9b00681