A Concise Synthetic Method for Constructing 3-Substituted Piperazine-2-Acetic Acid Esters from 1,2-Diamines

Abstract

We report a short synthetic route for synthesizing 2,3-substituted piperazine acetic acid esters. Optically pure amino acids were efficiently converted into 1,2-diamines that could be utilized to deliver the title 2,3-substituted piperazines in five steps with a high enantiomeric purity. The novel route facilitated, for the first time, the synthesis of 3-phenyl substituted-2-piperazine acetic acid esters that were difficult to achieve using other methods; however, in this case, the products underwent racemization.

Heterocyclic Merging of Stereochemically Diverse Chiral Piperazines and Morpholines with Indazoles

“…Hence, synthetic approaches targeting the effective and stereoselective generation of carbon‐substituted piperazine and morpholine compounds hold significant practical value [9–14] . We have previously reported methods leading to the systematic preparation of diverse enantiomerically pure piperazines and morpholines [15–21] . These studies led us to consider that a structurally unique collection of compounds could be achieved in the context of merging these stereodiverse ring systems with other biologically valuable heterocycles (Scheme 1).…”

“…[9][10][11][12][13][14] We have previously reported methods leading to the systematic preparation of diverse enantiomerically pure piperazines and morpholines. [15][16][17][18][19][20][21] These studies led us to consider that a structurally unique collection of compounds could be achieved in the context of merging these stereodiverse ring systems with other biologically valuable heterocycles (Scheme 1). Novel ring systems resulting from the formal union of two simpler heterocyclic scaffolds would expand shape diversity and offer additional vectors for substitution.…”

Expanding Complex Morpholines Using Systematic Chemical Diversity

“…Additionally, because all of the compounds are related through their common core scaffold, screening SCD-derived libraries delivers precise structure–activity relationships (SAR), which can be used to guide further optimization of the hits. We have previously documented the application of SCD for generating diverse compounds based on the well-known piperazine scaffold. − Here, we report the synthesis of a collection of morpholines inspired by SCD.…”

Iridium-Catalyzed Regio- and Diastereoselective Synthesis of C-Substituted Piperazines

“… Considerable efforts have been devoted to the development of synthetic routes yielding this privileged drug scaffold, which have traditionally focused on the reduction of diketopiperazines, the reductive amination of dicarbonyl compounds, and transition-metal-catalyzed cyclization reactions . These methods often require multistep synthesis, as well as protecting and deprotecting steps . More sustainable approaches include a “borrowing hydrogen” method, which uses 1,5-diols and primary amines, the synthesis of 2-substituted piperazines by an iridium photocatalyst, and biocatalytic reductive aminations of 1,2-dicarbonyl and 1,2-diamine substrates, which yield piperazines in an atom-economical fashion …”

“… 2 These methods often require multistep synthesis, as well as protecting and deprotecting steps. 3 More sustainable approaches include a “borrowing hydrogen” method, which uses 1,5-diols and primary amines, the synthesis of 2-substituted piperazines by an iridium photocatalyst, 4 and biocatalytic reductive aminations of 1,2-dicarbonyl and 1,2-diamine substrates, which yield piperazines in an atom-economical fashion. 5 …”