Synthesis of Piperazine-2,5-diones

It is well known that derivatives of a-amino acids, especially the esters, can undergo cyclodimerization to form piperazine-2,5-diones. The stereochemistry of such self-condensation of //-aminoacid esters has been investigated [86JCS(P1)1557], Piperazinediones with a cis orientation of substituents were preferentially formed at the initial stages but increasing amounts of the trans product were formed later. The results have been interpreted as reflecting the difference in the rates of cyclization of the two diastereomeric dipeptide esters. 

The earliest method for such a cyclization was that of Fischer, which involves the action of excess ammonia on dipeptide methyl esters (06CB2893). However, this method is known to lead to a considerable amount of racemization. 

A significant improvement in the method was developed by Nitecki et al. (68JOC864). In this process, A-l-butyloxycarbonyl derivatives of dipeptide esters are deblocked by formic acid (room temperature, 2 h) and the excess formic acid is distilled off. The formate salt of the dipeptide ester left behind is heated with sec-butanol and toluene for 2-3 h under azeotropic distillation conditions to form the cyclodipeptide. The yields 

The Nitecki method has been extensively used by several other groups over the last two decades. 

Three methods have thus emerged for the cyclization of dipeptide esters base-catalyzed cyclization (Fischer) cyclization without any added catalyst, under essentially neutral conditions (autoaminolysis Nitecki) and acetic acid-catalyzed cyclization (Suzuki). 

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A reaction of this kind has recently been carried out by Okawara et al.53,5 who have reported an efficient synthesis of piperazine-2,5-diones (22) via PTC cyclization of a-halocarboxamides (21). 

When solid-phase peptide synthesis was initially being developed, the question of whether or not a separate neutralization step is necessary was considered. Since it was known from the work of others that the chloride ion promotes racemization during the coupling step in classical peptide synthesis, and since we were deprotecting the Boc group with HC1, it seemed advisable to neutralize the hydrochloride by treatment with TEA and to remove chloride by filtration and washing. This short, additional step was simple and convenient and became the standard protocol. Subsequently, we became aware of three other reasons why neutralization was desirable (1) to avoid weak acid catalysis of piperazine-2,5-dione formation, 49 (2) to avoid acid-catalyzed formation of pyroglutamic acid (5-oxopyr-rolidine-2-carboxylic acid), 50 and (3) to avoid amidine formation between DCC and pro-tonated peptide-resin. The latter does not occur with the free amine. 

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. 

The methylene groups at positions 3 and 6 of piperazine-2,5-diones are known to undergo facile condensation with aldehydes to form the corresponding a,/3-unsaturated amides. Two earlier reviews have dealt with this subject. (75FOR51 80FOR251). The review by Sammes covers the literature to 1972 on the synthesis, stereochemistry, and reactivity of... 

The major impetus for the massive amount of research on the synthesis and reactivity of the 3-thia and 3,6-dithia derivatives of piperazine-2,5-dione has been the discovery of this moiety in several microbial metabolites of the gliotoxin group. 

The spontaneous formation of piperazine-2,5-diones occurs mainly during N-deprotection or the acylation step to dipeptide esters (usually unhindered esters such as Me, Et, Bzl, and Pac esters) that contain an TV-alkyl amino acid especially at the C-terminusJ152 In some cases the formation of piperazine-2,5-diones becomes the major reaction product and thus prevents peptide elongation by the [1+2] or [1+3] segment condensation strategy in solution synthesis or elongation of the peptide from the C-terminus in SPPS. Piperazine-2,5-dione formation... 

Peptides that contain amidated Pro or other Af-alkyl amino acids at their C-terminus are less prone to formation of piperazine-2,5-diones in SPPS. Apparently, the use of a benzhy-drylamine-type resin exerts enough steric hindrance to slow down piperazine-2,5-dione formation. In some cases, e.g., the synthesis of peptide amides that have -D-Pro-Pro-NH2 or -Aib-Pro-NH2 sequences, the use of the 4-benzyloxy-4 -4"-dimethoxytrityl amine resin (BDMTA resin, Scheme 34) 187 is recommended. 

A problem in solid-phase peptide synthesis arises when an ester linkage between the peptide and the solid support is used and results in the undesirable formation of piperazine-2,5-diones (DKP). This side reaction occurs during the deprotection of the N-temporary... 

Reactions of piperazine-2,5-diones with phosphorus pentachloride and phosphorus pentabromide have been described in Sections V.ID and V.IF, respectively. Aromatic aldehydes condense with 3-methylpiperazine-2,5-dione in the presence of acetic anhydride to form mainly mono-A -acetyl derivatives of trans-3-arylidene-6-methylpiperazine-2,5-diones (e.g., 96, R = Ac) (1066). In these products the acetyl group was shown to be attached to position 1 and the 4,5-amide group was found to be sterically hindered. Photolysis formed the cis isomers. Both isomers were deacetylated with methanolic potassium hydroxide (1066). Condensation of 1,4-diacetylpiperazine-2,5-diones with aldehydes has been applied to the synthesis of unsymmetrical 3,6-diarylidenepiperazine-2,5-diones and the reaction has been extended to l,4-diacetyl-3,6-dimethylpiperazine-2,5-diones (1624). Treatment of (96, R = H) with triethyloxonium tetrafluoroborate in dichloromethane gave the monoimino ether, 5-benzylidene-6-ethoxy-3-hydroxy-2-methyl-2,5-dihydropyrazine (97) (1066). l-Methylpiperazine-2,5-dione similarly treated gave 5-ethoxy-l-methyl-2-oxo-l,2,3,6-tetrahydropyrazine (which was condensed with anthranilic acid at 150° to 2-methyl-l,2-dihydropyrazino[2,l-fi]quinazoline-3(4/0.6-dione (98) (1625), and l,4-dimethylpiperazine-2,5-dione gave 5-ethoxy-l,4-dimethyl-2-oxo-1,2,3,4-tetrahydropyrazine and 5,5-diethoxy-l,4-dimethylpiperazin-2-one (1626). 

The formation of a second ring, based on the generation of a six-membered carbanion followed by alkylation with a difunctional electrophile and further cyclization, was also exploited in the synthesis of hexahydropyrrolo[l,2-tf]pyr-azine-l,4-dione 235 starting from alkoxycarbonyl piperazine-2,5-dione 233. When the key precursor was treated with 2equiv of NaH and 1,3-dibromopropane, the bicyclic compound 234 was obtained in acceptable yield and further transformed into compound 235 by deprotection and decarboxylation (Scheme 30) <2005T8722>. 

Once it is part of a cyclic dipeptide, the prolyl residue becomes susceptible to enantiomerization by base (see Section 7.22). The implication of the tendency of dipeptide esters to form piperazine-2,5-diones is that their amino groups cannot be left unprotonated for any length of time. The problem arises during neutralization after acidolysis of a Boc-dipeptide ester and after removal of an Fmoc group from an Fmoc-dipeptide ester by piperidine or other secondary amine. The problem is so severe with proline that a synthesis involving deprotection of Fmoc-Lys(Z)-Pro-OBzl produced only the cyclic dipeptide and no linear tripeptide. The problem surfaces in solid-phase synthesis after incorporation of the second residue of a chain that is bound to the support by a benzyl-ester type linkage. There is also the added difficulty that hydroxymethyl groups are liberated, and they can be the source of other side reactions. 

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). 

A. Synthesis of Lactim Ethers from Piperazine-2,5-diones. 254... 

N-arylation has also formed the basis of the synthesis of analogs of aranotins (77JOC948). In this case, the N,N-bis-arylated product (37) has been obtained in 32% yield from piperazine-2,5-dione (Cu2I2, K2C03, CH3CN). 

Cyclols Stable molecules obtained by the addition of a heteroatom nucleophile to the carbonyl group of lactams are not very common. The side-chain moiety of the ergot alkaloids (e.g., 50) is one of the earliest examples of such a cyclolic structure (75FOR51) identified. This has given rise to a number of studies on the synthesis and chemical transformations of such units. The discussion below is confined to cyclols related to or arising from piperazine-2,5-diones. 

The entire gamut of N-alkylation protection, deprotection, aldol condensation, etc., is nicely brought out in the synthesis of isomeric 1- (or 4)methyl-3-arylmethyl-piperazine-2,5-diones from the same starting material (88CPB2607) (Scheme 29). 

Position 3 of the piperazine-2,5-dione nucleus has been alkylated by Michael addition of the enol to a suitable acceptor. This route has been successfully utilized for the total synthesis of bicyclomycin (83TL5627). The addition proceeded stereospecifically to give only one product (Scheme 30). 

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