Piperazine, chiral

Scheme 9 Synthesis of enantiopure piperazines by reductive coupling of chiral 2,5-diaza-1,5-dienes...

Hsin, L.-W., Dersch, C.M., Baumann, M.H. et al. (2002) Development of long-acting dopamine transporter ligands as potential cocaine-abuse therapeutic agents chiral hydroxyl-containing derivatives of l-[2-[bis (4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and l-[2-(diphenylmethoxy)ethyl]-4-(3-phe-nylpropyl)piperazine. Journal of Medicinal Chemistry, 45 (6), 1321-1329. 

Kwakman et al. [65] described the synthesis of a new dansyl derivative for carboxylic acids. The label, N- (bromoacetyl)-A -[5-(dimethylamino)naphthalene-l-sulfonyl]-piperazine, reacted with both aliphatic and aromatic carboxylic acids in less than 30 min. Excess reagent was converted to a relatively polar compound and subsequently separated from the derivatives on a silica cartridge. A separation of carboxylic acid enantiomers was performed after labeling with either of three chiral labels and the applicability of the method was demonstrated by determinations of racemic ibuprofen in rat plasma and human urine [66], Other examples of labels used to derivatize carboxylic acids are 3-aminoperylene [67], various coumarin compounds [68], 9-anthracenemethanol [69], 6,7-dimethoxy-l-methyl-2(lH)-quinoxalinone-3-propionylcarboxylic acid hydrazide (quinoxalinone) [70], and a quinolizinocoumarin derivative termed Lumarin 4 [71],... 

The enantioselective hydrogenation of prochirai heteroaromatics is of major relevance for the synthesis of biologically active compounds, some of which are difficult to access via stereoselective organic synthesis [4], This is the case for substituted N-heterocycles such as piperazines, pyridines, indoles, and quinoxa-lines. The hydrogenation of these substrates by supported metal particles generally leads to diastereoselective products [4], while molecular catalysts turn out to be more efficient in enantioselective processes. Rhodium and chiral chelating diphosphines constitute the ingredients of the vast majority of the known molecular catalysts. 

Lehotay, J. et al.. Separation of enantiomers of some 1,4-piperazine derivatives of aryloxy-aminopropanols on a vancomycin chiral stationary phase, Pharmazie, 54, 743, 1999. 

As mPE oligomers become longer, the aspect ratio of the helical cavity also increases, such that a rodlike shape complements the cavity better than a spherical shape. To take advantage of this change in aspect ratio a chiral, rodlike piperazine guest (40) was synthesized [58]. The affinity of a host-guest com-... 

Piperazine-2,5-diones can be symmetric or asymmetric. Symmetric DKPs are readily obtained by heating amino acid esters,1179-181 whereas asymmetric DKPs are obtained directly from the related dipeptides under basic or, more properly, acid catalysis, or by cyclocondensation of dipeptide esters.1182-185 As an alternative procedure hexafluoroacetone can be used to protect/activate the amino acid for the synthesis of symmetric DKPs or of the second amino acid residue for synthesis of the dipeptide ester and subsequent direct cyclocondensation to DKPs.1186 The use of active esters for the cyclocondensation is less appropriate since it may lead to epimerization when a chiral amino acid is involved as the carboxy component in the cyclization reaction. Resin-bound DKPs as scaffolds for further on-resin transformations are readily prepared using the backbone amide linker (BAL) approach, where the amino acid ester is attached to the BAL resin by its a-amino group and then acylated with a Fmoc-protected amino acid by the HATU procedure, N -deprotection leads to on-resin DKP formation1172 (see Section 6.8.3.2.2.3). 

Stereoselective formation of 3-alkyl-6-methoxy-2,5-piperazine-dione derivatives by the addition of methanol in the presence of NBS to 3-alkyl-6-alkylidene-2,5-piperazinediones was recently reported by Shin et al. 232 The asymmetric induction in this reaction was accomplished by the chiral center of a derivative of the natural proteinogenic chiral amino acid threonine. 

B. Chiral Induction in Piperazine-2,5-dione-Catalyzed Reactions. 277... 

The requisite hydroxylamine function for such cyclizations can also be generated from a precursor having a nitro group. This novel route has provided access to hitherto unknown l-hydroxy-6-allyl-, and -6,6-bisallyl-piperazine-2,5-diones (91UP1). The starting material is an W-nitroacetyl amino acid ester that can be either mono-or bis-allylated at the methylene adjacent to the nitro group. Reduction of the N02 to NHOH using zinc/ ammonium chloride, followed by cyclization, leads to the desired products (Scheme 76). Compound (215) is unique in that it possesses a chiral center at C-3 and a quaternary carbon at C-6 on a l-hydroxypiperazine-2,5-dione system. 

The enantiomerically pure (5)-4-(benzyloxycarbonyl)-l-(ferf-butoxycarbonyl)piperazine-2-carboxylic acid derivative 54 is also prepared by a multistep cyclization of chiral (5)-3-[(benzyloxycarbonyl)(prop-2-enyl)amino]-2-[(fert-butoxycarbonyl)amino]propanoic acid (53) as shown in Scheme ll/241 ... 

As in the case of dipeptide esters in solution, the rate of piperazine-2,5-dione formation in SPPS strongly depends on steric and chiral features of the original dipeptide structure.11501 The rate of the cyclization increases upon catalysis by weak carboxylic acids.11761 However, it was also reported that piperazine-2,5-diones are formed under basic conditions, e.g. removal of the Fmoc protecting group. Formation of piperazine-2,5-diones is generally overcome by... 

Hydrogenation of 4-formyl spiro-p-lactams like 180, Scheme 55, accessible from cyclic amino acids and chiral imines, resulted in the formation of bicyclic system like 181, which was reduced to piperazine 182 [139]. The reductive rearrangement leading to 181 proceeds in high yield and the scission of the C3-C4 bond is rationalized in terms of a retro-Mannich process. Unfortunately, however, isomerization occurs during rearrangement, leading to racemic products. 

Pyrrolidin-2-yltetrazole (100) (15 mol%), in conjunction with the chiral piperazine (101) (1 equiv.), has been shown to catalyse the asymmetric conjugate addition ... 

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