Practical and scalable synthesis of orthogonally protected-2-substituted chiral piperazines

A synthetic route to orthogonally protected, enantiomerically pure 2-substituted piperazines is described. Starting from α-amino acids, within four steps chiral 2-substituted piperazines are obtained. The key transformation involves an aza-Michael addition between an orthogonally bis-protected chira...

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Bibliographic Details
Published in:Organic & biomolecular chemistry 2020-11, Vol.18 (43), p.8844-8849
Main Authors: Chamakuri, Srinivas, Shah, Manuj M, Yang, David C. H, Santini, Conrad, Young, Damian W
Format: Article
Language:English
Subjects:
Amino acids
Diamines
NMR
Nuclear magnetic resonance
Protecting groups
Substitutes
Sulfonium salts
Synthesis
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Summary:A synthetic route to orthogonally protected, enantiomerically pure 2-substituted piperazines is described. Starting from α-amino acids, within four steps chiral 2-substituted piperazines are obtained. The key transformation involves an aza-Michael addition between an orthogonally bis-protected chiral 1,2-diamine and the in situ generated vinyl diphenyl sulfonium salt derived from 2-bromoethyl-diphenylsulfonium triflate. Further validation using different protecting groups as well as synthesis on multigram scale was performed. The method was also applied to the construction of chiral 1,4-diazepanes and 1,4-diazocanes. Additionally, the method was utilized in a formal synthesis of chiral mirtazapine. A synthetic route to orthogonally protected, enantiomerically pure 2-substituted piperazines is described.
ISSN:1477-0520
1477-0539
DOI:10.1039/d0ob01713b