Synthesis of Enantiomerically Pure 5-Substituted Piperazine-2-Acetic Acid Esters as Intermediates for Library Production

Abstract

The piperazine heterocycle is housed within a large number of FDA-approved drugs and biological probe compounds. Structurally, however, these compounds are mostly confined to substitutions on the two ring nitrogen atoms, rationalizing the expansion of piperazine chemical diversity through carbon substitutions. On the basis of the concept of systematic chemical diversity, a divergent six-step synthesis was developed in which chiral amino acids were transformed, with high diastereoselectivity, into either cis or trans 5-substituted piperazine-2-acetic acid esters that could be chromatographically rendered diastereomerically homogeneous. Starting from six commercially available amino acids or their respective amino alcohols (both antipodes), we obtained a complete set of 24 protected chiral 2,5-disubstituted piperazines, as single stereoisomers in multigram quantities. These diverse and versatile piperazines can be functionalized on either nitrogen atom, allowing them to be used as starting materials for parallel library synthesis and as intermediates for the targeted production of more complex C-substituted piperazine compounds.

Heterocyclic Merging of Stereochemically Diverse Chiral Piperazines and Morpholines with Indazoles

“…Our previous studies preparing 2,5-and 2,6-substituted piperazines hinted towards a method of synthesizing indazolefused piperazines and morpholines with a previously unreported merged heterocyclic structure. [17,19] Specifically, in efforts to conduct a base promoted aza-Michael reaction to generate the desired piperazine skeleton, we observed the product resulting from a Smiles rearrangement (Scheme 2B-D). [22,23] To form the desired piperazine products, we circumvented the Smiles rearrangement by developing non-basic conditions leading to efficient aza-Michael cyclization.…”

“…[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.…”

“…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).…”

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

“…Toward achieving this goal, we have previously reported the synthesis of a family of chiral disubstituted piperazine-2-acetic acid esters. Starting from amino acids (natural and unnatural), we constructed 3-, 5- and 6- substituted piperazine-2-acetic acid esters comprising both relative and absolute stereoisomers as single compounds [ 16 , 17 , 18 , 19 , 20 ].…”

Expanding Complex Morpholines Using Systematic Chemical Diversity

“…Finally, subjection of 4a to annulation reaction conditions with bromoethyldiphenylsulfonium triflate and sodium hydride 27,28 afforded the anticipated 3-methyl morpholine-2-acetic acid esters as a mixture of diastereomers (5a/6a, cis/trans) in 2:1 ratio (based on crude NMR, Scheme 2). The diastereomeric morpholines were purified by silica gel column chromatography, and the relative stereochemistry of the isolated compounds was determined using NMR techniques, including 1 H, 13 C, and 2D NMR (COSY, HMBC, HSQC, and NOESY; Supporting Information). In keeping with the goal of SCD, we next replicated the reaction sequence, commencing from Bocprotected (R)-alanine 1b, to yield diastereomeric products 5b/ 6b (opposite enantiomers of 5a/6a, Scheme 2).…”