Diketopiperazines conformation

The most common bicyclic 5-6 system with one bridgehead N-O and one extra heteroatom described in the period covered in this chapter has been the diketopiperazine derived from proline as it is present in natural products, in biologically active synthetic molecules, and has been used as starting material for the preparation of conformationally constrained peptidomimetics. The classical approach to this class of molecule is the ring closing of the dipeptide derived from proline and another amino acid via nucleophilic attack of the NH2 to the activated carboxylic group. This method has been applied several times to prepare different diketopiperazines for different uses. 

Scheme 26 Synthesis of bicyclic diketopiperazines and two representative 3D conformations of...

Scheme 42 Ugi/Pictet-Spengler formation of 2,5-diketopiperazine 228 and two representative 3D conformations of 228A (blue) and 228C (cyan)...

Diketopiperazines (DKPs) are the smallest naturally occurring cyclic peptides. They are folded head-to-tail and conformationally constrained by a six-membered ring with the side chains orientated in a spatially defined manner. The DKP core... 

Golebiowski et al. reported the solid-phase [92] and the solution-phase [93] syntheses of bycyclic diketopiperazines which were of great interest because their conformation was similar to the type-1 /i-turn motif. A Merrifield hydroxymethyl resin was esterified with a-N-Boc-fi-N-Fmoc-L-diaminopropionic acid and then mono-deprotected at the />-N with piperidine. Ugi-4CR of the resulting resin-bound amine gave the resin-bound adducts 168. Subsequent N-Boc deprotection and intramolecular N-alkylation afforded the ketopiperazines 169. The diketopiperazines 170 were formed via N-Boc amino acid coupling followed by N-Boc deprotection... 

The conformations [339] and [340] (R = 3-indolyl) have been suggested for the diastereoisomeric diketopiperazines related to the... 

Many studies, mainly by spectroscopic methods and calculation, have been devoted to the conformational behavior of the Inoue catalyst 1 (and 2) and its interactions with HCN and the substrate aldehydes [26, 34—36]. As noted originally by Inoue et al., however, the diketopiperazine 1 does not have catalytic activity and selectivity in homogeneous solution, i.e. in molecular dispersion. Instead, the diketopiperazine 1 is a heterogeneous catalyst - the active/selective state is a gel which forms, for example, in benzene or toluene, or just a suspension (e.g. in ether). As a consequence, catalyst performance is strongly influenced by the amorphous or crystalline character of the diketopiperazine from which the gel is formed. The best performance was achieved when amorphous materials were employed. The latter can... 

Several studies have tackled the structure of the diketopiperazine 1 in the solid state by spectroscopic and computational methods [38, 41, 42]. De Vries et al. studied the conformation of the diketopiperazine 1 by NMR in a mixture of benzene and mandelonitrile, thus mimicking reaction conditions [43]. North et al. observed that the diketopiperazine 1 catalyzes the air oxidation of benzaldehyde to benzoic acid in the presence of light [44]. In the latter study oxidation catalysis was interpreted to arise via a His-aldehyde aminol intermediate, common to both hydrocyanation and oxidation catalysis. It seems that the preferred conformation of 1 in the solid state resembles that of 1 in homogeneous solution, i.e. the phenyl substituent of Phe is folded over the diketopiperazine ring (H, Scheme 6.4). Several transition state models have been proposed. To date, it seems that the proposal by Hua et al. [45], modified by North [2a] (J, Scheme 6.4) best combines all the experimentally determined features. In this model, catalysis is effected by a diketopiperazine dimer and depends on the proton-relay properties of histidine (imidazole). R -OH represents the alcohol functionality of either a product cyanohydrin molecule or other hydroxylic components/additives. The close proximity of both R1-OH and the substrate aldehyde R2-CHO accounts for the stereochemical induction exerted by RfOH, and thus effects the asymmetric autocatalysis mentioned earlier. 

With regard to cyclic dipeptides containing histidine, conformational calculations have been made with Cydo-(Alanis) 106). Similar calculations in rdation to r tical activity have been made recoitty with alanine-p4iydroxypheny ycine diketopiper-azine 107) and alanine — proline diketopiperazine lOS). 

Later, the conformation of Cydo-(Tyr-His) in DjO was investigated by NMR spectroscopy (75). Analyds of the NMR data according to the principle described in Section 3.6 showed that the phenol side diain of tyro l residue stacks over the diketopiperazine ring. Due to the aromatic-amide interactions, the internal rotation arcMind the Tyr-C -< bond is stabilized. Furthermore,/h-c -cP-h Wsti-... 

On the basis of the NMR data, they depicted the most plausible conformation of the cyclic dipeptide as follows. In cyclo(L-Leu-L-His) 18, tire imidazole group is diielded by the isobutyl side drain and the diketopiperazine ring, so that its reaction with substrate is less favorable. In contrast, the two pendent groups are ideally situated in cycIo(D-Leu-L-His) i 7 for interaction with long-chain wbstrates. 

We were able to develop some simple rules in predicting the packing of molecules based on CA M in one dimensional tapes, but not for predicting the three-dimensional packing of these tapes [98,107,145-148]. Conformational polymorphism due to the diphenyl rings, in addition, increased the complexity of the problem in the CAM system. We have found that crystal structures based on diketopiperazines (DKP) are simpler to predict and rationalize than our previous systems, both from observations of existing structures, and from computational methods [30,109]. 

A simpler way to restrict the conformation of an enolate is to coniine it in aheterocycle and an important group of chiral enolates come from various derivatives of amino acids. The hrst successful such compounds were Schollkopf s bislactim ethers 41 derived from the diketopiperazines 40 formed when an amino acid such as alanine 39 condenses with itself.4 Treatment of 41 with butyl lithium creates a lithium enolate on one position in the ring the methyl group in the other position keeps the chirality intact. Alkylation occurs selectively on the opposite side to the remaining methyl group 42 and hydrolysis releases a new tertiary amino acid 43 and one of the original alanines. 

While equilibrium (3.29) for the uncatalyzed reaction of thiyi radicals with carbohydrates is located far to the left, the analogous equilibrium (3.30) with peptide and protein substrates may actually shift to the right-hand side. In equilibrium (3.30), the C radical of the amino acid moiety is displayed in a planar conformation in reality, this conformation may be approached in linear peptides by glycine (R=H) or cyclic peptide models, such as the diketopiperazines, but less likely by amino acid moieties different from glycine. 

To begin with, the conformation of the skeleton of cyclic dipeptide, i.e., the diketopiperazine (DKP) ring, will be considered. There are many possible conformations of the DKP ring 8) as shown in Fig. 14. For unsubstituted diketopiperazine, Cyclo-(Gly2) (R = R = H) a planar conformation (A) in crystalline state has been reported 95, 96). In solution, the planar conformation (A) or rapidly-inverting boat conformation (B) (C) may be supposed. This consideration was supported by NMR studies as described below. Monosubstituted diketopiperazines Cyclo-(Gly-X) (R or R = H) can assume two boat conformations, (B) and (C), as well as the planar conformation (A). The C -substituent R or R takes an axial position in (B) and an equatorial or bowsprit position in (C). Kopple and Ohnishi (97) jaroposed the possibility of a twist-boat conformation (D). Rotations around N—C and C —G... 

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