Chiral diketopiperazines

Stereospecific reduction of chiral diketopiperazine derivatives from proline and a-keto acids also provide a versatile route to a-amino acids (eq 6). The selectivity of the reduction is highly dependent on the nature of the R group on the nitrogen atom. 

Chiral diketopiperazines in enantioselective Strecker reactions 03CRV2795. 

Coupling may also occur between an electric transition moment in one chromophore and the transition quadrupole moment generated by an n - 7t transition in a neighbouring chirally disposed chromophore (Tinocco, 1962). This m-p mechanism may give rise to substantial rotatory strengths, e.g. in chiral diketopiperazines (Hooker et al., 1974). 

Intermediate diketopiperazine derivatives have been employed in the diastereoselective synthesis of benzyltetra-hydroisoquinoline by 1,4-chirality transfer. iV-Cbz-Proline was coupled with 2-(3,4-dimethoxyphenyl)ethylamine and the resulting amide 109, after deprotection, was reacted with phenylpyruvic acid (Cbz = carbobenzyloxy group). Compound 110 underwent acid-catalyzed Pictet-Spengler condensation to yield final tetracyclic... 

Murray and colleagues199 developed some 2,5-diketopiperazines as new chiral auxiliaries and examined their asymmetric induction in the Diels-Alder reactions of their A-acryloyl derivatives with several dienes. Some of their results with dienophile 320 have been summarized in Table 19 (equation 89). When the benzyl group on 320 was substituted by an isopropyl or /-butyl group, the diastereofacial selectivity dropped dramatically. It was proposed that tv-tt stacking between the phenyl group and the electron-poor double bond provided a more selective shielding of one face of the double bond in this special case. 

Borthwick AD, Davies DE, Exall AM, Livermore DG, Sollis SL, Nerozzi F, Allen MJ, Perren M, Shabbir SS, Woollard PM, Wyatt PG (2005) 2, 5-Diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 2. Synthesis, chirality, and pharmacokinetics. J Med Chem 48(22) 6956-6969... 

The spiropyrazohnes obtained from 51 were converted into enantiopure A -pyrazoline-3-carboxylates and 1 -(hydroxyethyl)cyclopropane-1 -carboxylates (128). Those obtained from 54 and 55 were transformed into optically active a-spirocyclopropyllactones and 3-amino-3-(hydroxyethyl)pyrrolidin-2-ones (130). The spiropyrazoline obtained from a chiral propylidene-diketopiperazine and diazomethane was converted into (+)-(lR,25)-l-amino-2-ethyl)cyclopropane-l-carboxylic acid (allocoronamic acid) (135). 

The alkylated 3,6-dialkoxy-2,5-dihydropyrazines are hydrolyzed by treatment with 0.25 N hydrochloric acid (2 equivalents of H+) at room temperature to give the hydrochlorides of the corresponding alkylglycine methyl ester 3 and the chiral auxiliary amino acid methyl ester 2. Hydrolysis of the dihydropyrazines 1 under more drastic conditions (10-30 equivalents of 6 N hydrochloric acid) yields the corresponding diketopiperazines which are very stable to further hydrolysis. Basification of the hydrochlorides with aqueous ammonia liberates the free a-amino esters. In general, the chiral auxiliary amino ester is separated by distillation. 

An enantioselective synthesis of CR)-amino acids has been developed which utilizes L-valine as the chiral auxiliary (81AG(E)798). The diketopiperazine cycZo-(L-Val-Gly) (780) was converted to its bis-lactim ether (781) by methylation with Meerwein s salt, and the ether metallated in the glycine portion by n-butyllithium. Alkylation of the delocalized... 

Chiral chromatography can also be used in order to obtain resolution of stereoisomers from aspartame, its precursors, and its degradation products. Lin et al. (84), using a Chiracel OD column and a mobile phase of 2-propanol -hexane (1 1, v/v), achieved complete separation of aspartame precursors, dd-, dl-, LL-, and LD-[(Z)-AspOS-Bzl)-Phe-OCH3], Motellier and Wainer (85) separated four stereoisomers of aspartame, two of diketopiperazine, and three of aspartyl-phenylalanine using a stationary phase composed of a chiral crown either coated on a polymeric support—CrownPack CR( + )—a mobile phase of aqueous perchloric acid, pH 2.8, and modified... 

The situation is further complicated by chiral autoinduction, first reported by Danda et al. for the hydrocyanation of 3-phenoxybenzaldehyde [39]. It was found that the enantiomeric excess of the product increases with reaction time, and that addition of small amounts of optically pure cyanohydrin at the beginning of the reaction led to high ee of the bulk product, irrespective of catalyst ee. It was concluded that the active catalyst is not the diketopiperazine alone but a 1 1 aggregate with the product cyanohydrin of the opposite configuration (e.g. (R,R)-1 plus S-mandelonitrile) [39]. Lipton et al. later developed a mathematical model for this effect and exploited it to improve the enantioselectivity of the hydrocyanation of... 

Enantiospecific syntheses have utilized the chirality available in D-alanine and L-alanine. For instance, coupling and cyclization (after the necessary deprotection) of N-allyl-N-BOC-D-alanine with L-alanine methyl ester, followed by lithium aluminum hydride reduction of the diketopiperazine provided (—)-(2R,5S)-l-allyl-2,5-dimethylpiperazine (Scheme 6) [27,39], Ra-cemization was not observed during the synthesis. 

This article deals with results achieved with the 2,5-dimethoxy-3,6-dihydropyra-zines, the heterocycles of type I. Results obtained with the imidazolinones III are discussed elsewhere 6). At first glance the heterocycles I look rather esoteric. However, the yare nothing but the bis-lactim ethers of the well known 2,5-diketopiperazines, the cyclic dipeptides. — At first, experiments with the symmetrical bis-lactim-ether (6) of cyclo(L-Ala-L-Ala) (5) are described and then results with several mixed bis-lactimethers. Symmetrical bis-lactimethers — i.e. those, build up from two identical amino acids — do have one disadvantage, inherent in the system, namely, only one half of the chiral auxiliary is recovered, the other half is incorporated in the product. But they are easily prepared and, hence, are good models to commence a study. 

Mixed bis-lactim ethers of type (20) are best prepared by the following route, outlined for the bis-lactimether (20a) of Cyclo(L-Val-Ala). L-Val, the chiral auxiliary, is converted with phosgene into its N-carboxyanhydride (L-Val-NCA, Leuchs anhydride) (17)l5). This gives with D,L-Ala-OCH3 the dipeptide (18) which on heating in toluene cyclizes to the diketopiperazine (19). This is converted into the bis-lactim ether (20a) [(3RS, 6S)-2,5-dimethoxy-6-isopropyl-3-methyl-3,6-dihydropyra-zine] with methyl Meerwein s salt. 

The first synthesis of a siderophore was the preparation of ferrioxamine B over 20 years ago in order to confirm the chemical structure of this natural product67). Synthesis of the other hydroxamate containing siderophores has as a central problem preparation of the constituent to-N-hydroxy amino acid in an optically pure form. The most important such subunit in hydroxamate siderophores is Ns-hydroxy ornithine. This is a chiral building block of the diketopiperazine-containing siderophores (rhodo-torulic acid 68), dimerum acid 69), coprogen 70) and coprogen B 69>), the cyclic hexa-peptides of the ferrichrome family27), the fusarinines 71 -73) and the antibiotic ferri-chrome derivatives albomycines Sl5 S2 and e 61-62). 

One stoichiometric method that avoids the use of an expensive chiral auxiliary and allows for the use of nonpyrophoric bases is based on diketopiperazine chemistry. The use of this system as a chiral auxiliary is associated with a method that was developed for the preparation of the sweetener aspartame. At the same time, we were looking at the alkylation reactions of amino acid derivatives and dipeptides. These studies showed that high degrees of asymmetric induction were not simple, were limited to expensive moieties as the chiral units, and required the use of large amounts of lithium [25,26]. The cyclic system of the diketopiperazine has been used successfully by other investigators [27,28], and we also chose to exploit the face selectivity of this unit. L-Aspartic acid was chosen as the auxiliary unit because it is readily available and cheap. All of the studies were performed with sodium as the counterion because it is a more cost-effective metal at scale. Finally, we concentrated in the use of aldehydes rather than alkyl halides to allow for a general approach and so as not to limit the reaction to reactive alkyl halides. 

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. 

Analysis of the nature of Cn axes suggests that one can create high-symmetry chiral figures by proper arrangement of n AS units with the same chirality around appropriate axes. A simple example of this procedure can be found in the planar diketopiperazine (3) (Figure 3) of C2 symmetry, which is constructed by combining two AS units of the same chirality, that is, two molecular fragments of (+)-(S)-alanine. 

These bromides are useful for the synthesis of asymmetric diketopiperazines. In order to obtain bromoglycine derivatives for use in stereocontrolled synthesis, chiral auxiliaries have been attached to the amino and carboxy groups of glycine before bromination. For example, the bromides 1-4 have been prepared in this manner [16-19]. They were obtained as various mixtures of diastereomers, but this stereochemistry is not particularly important as their reactions mostly involve intermediates that are planar at the a-carbon. 

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