2,5-Piperazinediones synthesis

The method of piperazinedione synthesis [119] illustrated above (Scheme 22) is an example of scaffold proliferation by branching out from common intermediate structures ( divergent library design ). Resin-bound bromides such as 97 are suitable for bromine displacement with primary amines to obtain acyclic precursors of piperazinediones, but direct treatment with TFA also induces cycliza-tion, providing an efficient route to analogous morpholine derivatives. The intramolecular displacement of bromine by the carboxylate seems to occur in the cleavage solution, once the acyclic intermediate has been released from the solid support. 

An extremely interesting extension of this method has led to the synthesis of monoethers of piperazinediones (88JOC5785), which are not otherwise easily accessible. The dichloroacetyl derivative (22) of the glycina-mide (21) undergoes base-catalyzed condensation with alcohols to give the piperazinediones (23). This has been used to generate bicyclic [n.2.2] piperazinediones in which the second ring is created by C—C bond formation. Thus, the butenediol derivative (24) obtained by the procedure out-... 

This is a general method, leading to either 3-hydroxypiperazine-2,5-diones, or to the corresponding alkylidene derivatives (74CB2804). Thus A-pyruvoylproline methylamide cyclizes in water at pH 7.5 to yield the piperazinedione the cyclization appears to be highly stereoselective, leading to the kinetically controlled product (26). The scope of the method has been considerably expanded by Dutch workers, who have used it for the synthesis of l-hydroxypiperazine-2,5-dione derivatives (see Section VI). 

Cyclol formation on both carbonyl groups of the piperazinedione has been utilized for the synthesis of cyclotetradepsipeptides (Scheme 18). This strategy has been employed in the synthesis of serratamolide. 

Dipyridyldisulfide has been used as the electrophilic reagent by Williams and co-workers in their studies directed toward the synthesis of bicyclomycin (82JA6092). The enolate of (124) was generated by means of lithium diisopropyl amide (LDA) in tetrahydrofuran (THF) at -78°C and added to a solution of 2,2 -dipyridyldisulfide. This gave (125) as a single regio- and stereoisomer in 80-95% yield. Contrary to expectation, the two side chains of the piperazinedione in (125) were disposed cis to each other. 

Cyctization of piperazinediones. An efficient synthesis of the unusual ring system (3) of the antibiotic bicyclomycin is based on treatment of a protected piperazinedione (2) with 2.0equiv. of 1 at 25°. The reagent effects deprotection of the silyl group and removal of the pyridylthio residue prior to cyclization to give 3 in 90-99% yield in 2-3 minutes. The same overall transformation can be effected by treatment first with the HF-pyridine complex and then with AgC104 in yields of 60... 

The methodology was successfully extended to a one-pot total synthesis of complex heterocyclic systems such as pyrazino [2,1-b] quinazolines 79, encountered in nature as alkaloids 80-82 (Scheme 50) [125]. To assemble the pyrazino[2,l-fo]quinazoline core, N-Boc protected amino acid 76 was employed instead of carboxylic acid 72 (Scheme 49) in the synthesis of the corresponding intermediate benzoxazinones 77. The subsequent reaction with an amine moiety of another amino acid ester 78 was accompanied by concomitant cleavage of the N-Boc protecting group and diketopiperazine-like cyclization (for the one-pot deprotection-cyclization reaction of N-Boc dipeptide esters to afford 2,5-piperazinedione under microwave dielectric heating, see [128]) to afford the target heterocycle 79. Hence, the total... 

Many chiral auxiliaries are derived from 1,2-amino alcohols.7 These include oxazolidinones (l),7-9 oxazolines (2),10 11 bis-oxazolines (3),1213 oxazinones (4),14 and oxazaborolidines (5).15-17 Even the 1,2-amino alcohol itself can be used as a chiral auxiliary.18-22 Other chiral auxiliaries examples include camphorsultams (6),23 piperazinediones (7),24 SAMP [(S)-l-amino-2-methoxy-methylpyrrolidine] (8) and RAMP (ent-8),25 chiral boranes such as isopinocampheylborane (9),26 and tartaric acid esters (10). For examples of terpenes as chiral auxiliaries, see Chapter 5. Some of these auxiliaries have been used as ligands in reagents (e.g., Chapters 17 and 24), such as 3 and 5, whereas others have only been used at laboratory scale (e.g., 6 and 7). It should be noted that some auxiliaries may be used to synthesize starting materials, such as an unnatural amino acid, for a drug synthesis, and these may not have been reported in the primary literature. 

Gordon DW, Steele J, Reductive alkylation on a solid phase synthesis of a piperazinedione combinatorial library, Bioorg. Med. Chem. Lett., 5 47-50, 1995. 

Other recent repiorts of the automated synthesis of SP libraries of discretes include those of Wilson et al. (166), who prepared a library of more than 1000 aminohydantoins from a-hydrazino amino acids, amines, and aldehydes Perumattam et al. (167), who reported a 200-member library based on an anhydride template using anhydrides, primary amines, and a-amino acids Smith et al. (168), who described the synthesis of a library of more than 1000 piperazinediones from a-amino acids Crawshaw et al. (169), who presented a >200-member Ubrary of cyclohexanones from maleimides, nitrostyrenes, and aminobutadienes Shao et al. (170), who described a 96-member library of quina-zolinediones from anhydrides and amines Lebl et al. (21), presenting a 30,816-member... 

Werner S, Nielsen SD, Wipf P et al (2009) Eluorous parallel synthesis of a piperazinedione-fused tricyclic compound library. J Comb Chem 11 452-459... 

W. Zhang, Y. Lu, C. H.-T. Chen, D. P. Curvan, and S. Geib, Fluorous Synthesis of Hydrantoin-, Piperazinedione-, and Benzodiazepinedione-Fused Tricyclic and Tetracyclic Ring Systems, Eur. J. Org. Chem. (2006), 2055-2059. 

Piperazinediones are the keto forms of 2,5-dihydroxy-3,6-dihydropyrazines, and many 2,5-piperazinedione derivatives have been found in nature. Numerous synthetic investigations for these compounds <83H(20)1407, 93AHC(57)186> have been carried out, particularly in an approach to the total synthesis of the antibiotic bicyclomycin <85JA3253> and the synthesis of chiral a-amino acids known as the Schollkopf-Hartwig bislactim ether method. Direct introduction of a substituent on... 

N-aryl-2-piperazmones are of great interest as famesyl-transferase inhibitors, and both N-aryl-2-piperazinones and N-aryl-2,5-piperazinediones are synthetic precursors of N-arylpiperazines which are key elements in monoamine receptor-active drugs. Lange et al. enhanced the Goldberg reaction with microwaves for synthesis of N-arylpiperazinones, N-arylpiperazinediones, and N-aryl-3,4-dihydroquinolines [88]. Microwave irradiation greatly accelerates the reaction when NMP is used as solvent. 

Shin, C., M. Hayakawa, T. Suzuki, A. Ohtsuka, and J. Yoshimura a,p-Unsatur-ated Carboxylic Acid Derivatives. XIII. The Synthesis and Configuration of Alkyl 2-Acylamino-2-alkenoates and Their cyclized 2,5-Piperazinedione Derivatives. Bull. Chem. Soc. Japan 51, 550 (1978). 

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