Piperazine-2,5-diones alkylation

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. 

The Kishi group developed a second synthesis of 3,6-epidithia-2,5-piperazine-diones that is particularly useful for the synthesis of simpler systems on a large scale [Scheme 5,41 ] 77 The route benefits from the stereochemistry of the double 5-alkylation of 41.1 to give the cis-product 41.2 A second double enolate alkylation was again stereoselective, giving 413 in 83% yield. Finally treatment of the bis(0,5-acetal) 413 with trichloroborane gave the 3,6-epidithia-2,5-piper-azinedione 41,4 in 77% yield. 

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). 

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>. 

Azetidones (p-lactams) are generally obtained in high yield from (3-halopropion-amides (Table 5.18) and the low yield from the reaction of N-phenyl (3-chloropropi-onamide can be reconciled with the isolation of A-phenyl acrylamide in 58% yield [34]. The unwanted elimination reaction can be obviated by conducting the cyclization in a soliddiquid system under high dilution [35, 36]. Azetidones are also formed by a predominant intramolecular cyclization of intermolecular dimerization to yield piperazine-2,5-diones, or intramolecular alkylation to yield aziridones. Aone-pot formation of azetidones in 45-58% yield from the amine and P-bromocarboxylic acid chloride has also been reported [38]. 

N-alkylation and N-acylation of piperazine-2,5-diones are quite common and have been routinely employed in several synthetic sequences (see Section IV,C). Such operations have also been performed as measures for the temporary protection of the nitrogen during further synthetic maneuvers in other parts of the molecule. Three different alkyl groups have been employed as such protecting groups. Kishi has used the methoxymethyl group for N-protection (potassium r-butoxide, chloro-methyl methyl ether 0°C, 75% yield). Deprotection was achieved by cone. HCl-ethanol at reflux temperature (81T2045). 

Yoshimura has introduced the p-methoxybenzyl group for N-protection in piperazine-2,5-diones (83CL1001 85BCJ1413). The N-alkylation is carried out with sodium hydride and p-methoxybenzyl bromide in DMF at room temperature. Deprotection is achieved by ceric ammonium nitrate (CAN) in acetonitrile-water. 

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. 

If C-3 on the piperazine-2,5-dione is further activated by another carbonyl group, alkylation can be carried out easily. Kametani has used... 

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). 

R-X attacks from CX-face cis to the existing alkyl group) PDO= Piperazine-2,5-dione... 

The earliest report on such lactim ether formation was from Sammes [72JCS(P1)2494], who converted piperazine-2,5-dione to 2,5-diethoxy-3,6-dihydropyrazine (173) with an excess of triethyloxonium fluoroborate. Subsequently, Rajappa and Advani (73T1299) converted proline-based piperazine-2,5-diones into the corresponding monolactim ethers. The starting material was a piperazinedione in which one of the amino acid units was the secondary amino acid proline, and the other a primary amino acid. This naturally led to the regiospecific formation of a monolactim ether (169) (on O-alkylation) from the secondary amide, whereas the tertiary amide remained intact. This was later extended to piperazine-2,5-diones in which the secondary amino acid was sarcosine [74JCS(P 1)2122], leading to the monolactim ethers (170). 

Piperazine-2,5-diones, in which both amino acid units are primary, lead to bislactim ethers on O-alkylation with Meerwein s reagents. No selectivity in this reaction has been demonstrated so far. Such bislactim ethers (171) have been prepared and extensively used by Schollkopf and his school [79AG(E)863, and later papers]. During the preparation of these bislactim ethers, neutralization of the initially formed bis-tetrafluoroborate salt is carried out with phosphate buffer to avoid racemization. 

A similar 3-(2-bromoethyl) derivative has been utilized to synthesize 1-aminocyclopropane-1 -carboxylic acid by an intramolecular base-catalyzed cyclization. This was possible when position 6 was blocked by the presence of two substituents. Some unexpected stereochemical results also came up in this study (85MI2). The starting material was the piperazine-2,5-dione derived from (/ )-(+ )-2-methyl-3-phenylalanine and glycine. The bislactim ether derived from this, on treatment with butyl lithium in THF at -78°C, gave the lithio derivative. Alkylation of this with 2-haloethyl... 

Optically pure piperazine-2-carboxylic acid (22) and related derivatives, substituted at position 5, are synthesized from piperazine-2,5-diones 50 derived from Xaa-Ser dipeptides as educts, where the substitution R1 at position 5 depends on the side group of the aminoacyl moiety (Scheme 10). After reduction of the piperazine-2,5-diones 50 to 5-alkyl-2-(hy-droxymethyl)piperazines 51 and urethane-type protection of both the imino groups, the desired A,A -bis-protected piperazine-2-carboxylic acid or related 5-alkyl derivatives 52 are obtained by selective oxidation of the hydroxymethyl group. 240 ... 

Some peptide derivatives containing, /V-alkyl amino acids, especially Pro or Hyp, have a tendency to undergo cyclization to form piperazine-2,5-diones (diketopiperazines, DKP), or amino acid anhydrides.[149151] Formation of piperazine-2,5-diones is explained by the occurrence of the ds-isomer of the tertiary amide bond (Scheme 28)J19"21 ... 

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... 

Piperazine-2,5-dione formation can occur not only in the case of dipeptides esters or amides containing a free amino group, but also during the activation of N-blocked or protected IV-alkyl amino acids containing dipeptides or even tripeptides. Thus, the activated dipeptide Z-Gly-Pro-ONp (76) afforded the Z-protected piperazine-2,5-dione 77 when subjected to buffered dioxane solution at pH 8 (Scheme 29)J159 ... 

Formation of piperazine-2,5-diones from dipeptide esters containing Pro or other N-alkyl amino acids has also been observed during SPPS. The dipeptides most prone to cyclization are those that contain a C-terminal Pro or other IV-alkyl amino acids connected via an ester bond to a sterically unhindered handle.1171-1781 Scheme 33 depicts the formation of piperazine-2,5-diones 81 from dipeptides 80 in which the IV-alkyl amino acid is connected via a benzyl ester to the solid support. 

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. 

The lability of peptides and proteins to acidic conditions was first reported in 1920 by Dakin,12031 who found that acid hydrolysis of peptides or proteins that contain consecutive N-alkyl amino acids leads to the formation of piperazine-2,5-diones (DKP) this side reaction lowered their yield during amino acid analysis. For example, the piperazine-2,5-dione c[-Hyp-Pro-] was isolated from the hydrolyzate of gelatine. 

Other chlorinations have been effected with phosphorus pentachloride alone as follows piperazine-2,5-dione in carbon tetrachloride to 2,5-dichloro-3,6-dihydropyrazine (847, 849) [but at 250°/24hours to tetrachloropyrazine (850, 851)] 2[Pg.102]

Honzl (853) has described the preparation of alkyl(or aryl)-2-oxo-l, 2-dihydropyrazines by reaction of A,A -dialkyl(or aryl)piperazine-2,5-diones with phosphorus pentachloride. For example, 1,4-dicyclohexyl(or diethyl)piperazine-2,5-dione (85, R = cyclohexyl, Et) with phosphorus pentachloride in 1,2-dichloroethane gave... 

Hydrogenolysis of 4-benzylpiperazine-2,6-diones over palladium-charcoal produced 4-unsubstituted piperazine-2,6-diones in high yield. The amino group in l-phenylpiperazine-2,6-dione underwent alkylation with benzyl chloride and phenacyl bromide, but not with simple alkyl halides (1638). Oxidative dimerizations of piperazine-2,6-diones in nitrobenzene have been studied (1639). 2,6-Bis(hydroxy-imino)piperazine heated with palladium-charcoal in o-dichlorobenzene gave 2,6-diaminopyrazine (465). 

Another type of N-alkylation is provided by the Mannich reaction. 1,3-Dimethyl-8-azapurin-2,6-dione, formaldehyde, and morpholine, stirred in cold ethanol, gave l,3-dimethyl-7-(JV-morpholinylmethyl)-8-azapurine-2,6-dione in 70% yield. Lower yields were obtained from piperidine and some piperazines. 

Simplest of all the laboratory methods, in concept, are those general methods based on the alkylation of glycine derivatives shown in Scheme 6.3, particularly 2-acyl-amidomalonate esters (1), Schiff bases (2), oxazol-5(4H)-ones (alias azlactones , 3) and piperazin-2,5-diones (4). 

The typical ring positions available for the introduction of carbofunctional groups by exchange of hydrogen are the various -CONH— functions of pyrido[2,3-t/]pyrimidinones.87 265 322 324 For alkylation or acylation reactions of pyrido[2,3-cf]pyrimidine-2,4(l//,3//)-diones 4, in most cases the NH groups are converted into the respective anions by sodium hydride78 322 or sodium ethoxide.323 Mannich reactions with formaldehyde/piperazines have been reported,323 as has been the introduction of propynyl groups under Mitsunobu conditions.324... 

Amino acids. Through enolization piperazine-2,5-diones and perhydropyrim-idin-4-ones using LHMDS as the base for alkylation, a- and /3-amino acids are synthesized, respectively. The stereoselectivity can be manipulated by varying chiral substituents on the nitrogen atoms. 

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