Stereoselective synthesis of polysubstituted piperazines and oxopiperazines. Useful building blocks in medicinal chemistry.
Many pharmaceutical agents include piperazines or oxopiperazines as part of their core structures. The presence of substituents on these heterocycles has a significant influence on the biological activity, thus the search for efficient routes to control the substitution at different ring positions might have a crucial impact, especially to promote the use of such scaffolds in SAR studies. Many research groups have been engaged in the stereoselective synthesis of polysubstituted piperazines and oxopiperazines and in the majority of cases the stereochemistry of the final compounds is dependent on the starting material configuration. In the present minireview we have summarized some of the most significant approaches towards the stereoselective synthesis and functionalization of substituted piperazines and oxopiperazines, with a particular focus on our own contributions mainly based on readily available natural amino-acids as "chiral pool" starting materials. An efficient and scalable route to orthogonally protected 2-oxopiperazines has been developed using the corresponding diamines as key intermediates: diastereoselective elaboration of the resulting heterocycles was possible by metalation and reaction with electrophiles, leading to anti 3,5-disubstituted-oxopiperazines, in agreement with the model for a conventional 1,3-asymmetric induction. Both piperazines and tetrahydropyrazines could be prepared via LiAlH4-mediated reduction of 2-oxopiperazines, depending on reaction conditions. Finally, the diastereoselective synthesis of cyclopropane- containing analogs 2,5-diaza-bicyclo[4.1.0]heptanes was demonstrated by application of the classic Simmons-Smith reaction on enantiomerically enriched dihydro-2H-pyrazines.
Alessandro
A
Mordini
Gianna
G
Reginato
Massimo
M
Calamante
CNR - Istituto di Chimica dei Composti Organometallici (CNR-ICCOM), Via Madonna del Piano 10, 50019 Sesto Fiorentino, Italy. alessandro.mordini@unifi.it.
Lorenzo
L
Zani
D002626:Chemistry, Pharmaceutical; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
D010879:Piperazines