1 - piperazine conformation

To round out this group of drugs in which the piperazine ring appears to serve primarily as a basic spacer unit, or a conformationally restricted ethylene-diamine unit, reaction of N-phenylpiperazine (135) with acrylonitrile produces nitrile 136. Conversion... 

C-Alkylations of l,4-dihydro-27/-pyrazino[2,l-A]quinazoline-3,6-diones at positions C-l and CM were studied in detail. Compounds of type 57 could be alkylated diastereoselectively at C-l, owing to the geometry of the piperazine ring, which is locked in a flat boat conformation with the R4 or R1 substituent in a pseudoaxial position to avoid steric interaction with the nearly coplanar C(6)-carbonyl group. Alkylation of 57 (R2 = Me, Bn, R4 = Me) in the presence of lithium hexamethyldisilazide (LHMDS) with benzyl and allyl halides resulted, under kinetic control, in the 1,4-trans-diastereomer 59 as the major product, with retention of the stereocenter at CM (Scheme 5). 

Alkylation of the 3-lactim ether, (4A)-3-ethoxy-4-isopropyl-l,4-dihydropyrazino[2,l-3]quinazolin-6-one with BnBr gave pure l,4-/ra r-diastereomer. The higher diastereoselectivity - as compared to the lactams - was explained by the fully boat conformation of the piperazine ring in the lactim ethers <2005TA3160>. 

FIGURE 8. MM2-85 calculated lp—N—C—H rotational potential curve (C in the tricyclic ring system) for 68, with a pseudoequatorial piperazine ring. The conformations A (dashed line) and B (solid line) are defined in Scheme 6. Reproduced with permission from Reference 108... 

Scheme 3 Synthetic aspects of two conceptually different strategies for the introduction of piperazines via isocyanide based MCRs and two representative 3D conformations of 18A (blue) and 18B (cyan). An intramolecular hydrogen bond in compound 18B was shown in red dots...

Scheme 6 Use of Lewis acid catalyst for 3-CR 2-imino-piperazine synthesis and representative 3D conformations of the cis- and trans-stereoisomer 39 are shown. Two 3D structures of the cis- and trans-stereoisomer 39 are shown...

Scheme 32 Synthesis of piperazine incorporating fused azepine-tetrazoles 183 and two representative 3D conformations of 183A blue) and 183B cyan)...

Piperazines and derivatives are archaetypical scaffolds and can be considered as efficient, however, structurally simple peptidomimics. The scaffolds combine conformational rigidity with peptide-like spacial placement of amino acid side chains or isosteres thereof. Moreover, piperazines can be used to confine compounds with beneficial properties such as water solubihty. Piperazines are therefore in the center of synthetic interest and many different synthetic pathways have been designed [16-19]. A preferred way to synthesize different piperazine scaffolds with plenty of variabihty provides MCR chemistry. Several piperazine scaffolds are currently only accessible by isocyanide-based MCR. Likely they could be assembled by sequential synthesis as well however, the synthetic efficiency, the diversity, and the size of the alternative chemical space will be inferior. The application of... 

The objective of the present review is to discuss all aspects of the chemistry of piperazine-2,5-diones and their synthesis, physical chracter-istics, chemical reactivity and applications. Earlier reviews had focused on certain specific topics thus the review by Sammes (75FOR51) is mainly oriented toward natural products containing the piperazine-2,5-dione ring, whereas the one by Anteunis (78BSB627) deals exhaustively with conformational aspects of the ring, as well as those of the side chains. 

Cyclic dipeptides, especially when N-alkylated, undergo extremely fast epimerization (79JA1885). For example, cyclo(L-Pro-L-Phe) is rapidly converted to its diastereomer, cyclo(D-Pro-L-Phe) (80% conversion), by treatment with 0.5 N NaOH at 25°C for 15 min. This diastereomer is the one in which the proline residue has epimerized and not the more activated phenylalanine. CNDO/2 calculations seem to provide a rationale for this. It is not yet completely clear why such base-catalyzed epimerizations of piperazinediones are so easy the conformation of the molecule may play a role in this (79MI1). It is also worth noting that even in linear peptides, rm-amides of N-alkyl-amino acids, which consist of s-trans and s-cis rotamers of almost equal energy, are more prone to racemization than the sec-amides, which exist only in the s-trans configuration. Of course, the amide functions of piperazine-2,5-diones are obliged to assume the s-cis conformation. 

In the solid state of cis-l,4-dibenzoyl-2,5-dimethylpiperazine, the Z,Z-form is present, with the phenyl groups twisted (77AX(B)3568) with respect to the amide plane. In solution (77TL2895), the cis-isomer of the 2,5-dimethyl and 2,5-diethyl derivatives shows the presence of only one conformer (Z,Z, with the piperazine ring in the twist-boat conformation), while the tra s-form consists of an equilibrium mixture of nearly equal amounts of the four axial alkyl rotamers. 

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