Stereoselective Synthesis of Polysubstituted Piperazines and Oxopiperazines. Useful Building Blocks in Medicinal Chemistry

Abstract

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.

A practical catalytic reductive amination of carboxylic acids

“…These are a privileged class of compounds with biological activities including antifungals, antidepressants, antivirals, and serotonin receptor (5-HT) antagonists/agonists. 35 The conventional approach to N,N-disubstituted piperazines involves mono Boc-protection of piperazine followed by reductive amination or alkylation, carbamate cleavage and a second reductive amination or alkylation. Depicted in Scheme 1B is a more efficient approach using 2-oxopiperazine 27 as a building block in lieu of N-Boc piperazine.…”

Q-Tube®-Assisted Alkylation and Arylation of Xanthines and Other N-H-Containing Heterocycles in Water

“…Piperidine 11 and piperazine 12, in consideration of their relevance as pharmacophoric structures [31,32], were reacted with p-NO2-chlorobenzene, leading to a NMR of the crude evidenced the presence of BzOH and BzBr largely arising from the excess of the electrophile; the yield estimated by the 1 H-NMR of the crude was 66%; b The 1 H-NMR of the crude showed resonances compatible with those of the presence of the hydrolyzed product that is reasonably lost during the workup under basic conditions. c Isolated after acidification of the aqueous layers.…”

“…The crude was purified by silica gel chromatography, using as eluent DCM/MeOH 9:1, giving 200 mg of 17 as a yellow solid (65% yield), m.p. : 199-200 • C. GC-MS: m/z (relative intensity): 364 (48) [M + ], 70 (100), 334 (32), 317 (49), 228 (27), 227 (26), 217 (22), 215 (32), 214 (27), 207 (32), 203 (22), 202 (22), 201 (73), 189 (20), 188 (29), 187 (27), 173 (45), 172 (32), 171 (23), 160 (20), 159 (31), 158 (24), 146 (26), 86 (76), 71 (36), 58 (73), 57 (41), 56 (29). 1 H-NMR (400 MHz, CDCl 3 , 298 K, TMS): δ 8.71 (s, 1H), 6.30 (s, 1H), 3.24-3.22 (m, 8H), 2.65-2.62 (m, 8H), 2.40 (s, 6H) ppm.…”

“…In addition, since compound 21 was chiral and amphiphilic, it could have potential for use as an auxiliary in phase transfer catalysis. Based on these considerations, Piperidine 11 and piperazine 12, in consideration of their relevance as pharmacophoric structures [31,32], were reacted with p-NO 2 -chlorobenzene, leading to the arylated derivatives 14 and 15 in 70% and 37% yields, respectively, in accordance with the different pKa of the N-H activated by the base (Table 3, entries 1 and 2). More electron-deficient arenes, 2,4 dichloro-1,5 dinitro benzene, indeed afforded 16 in a 78% yield.…”

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

“…Interestingly, however, more than 80% of these compounds are devoid of substitutions on the methylene carbon atoms of the piperazine ring. Given their tetrahedral geometry, the lack of structural diversity involving the piperazine carbon atoms represent an untapped potential for expanding the 3-dimensional chemical space for improving molecular recognition toward a spectrum of biological targets [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. This encourages the development of new, efficient, and selective methods for accessing the carbon functionalization of the piperazine ring.…”