Cyclization piperazinediones

Preparation of diketopiperazine as part of a bicyclic system was developed by a one-pot Ugi-4-center-3-component reaction (U-4C-3CR) [50]. A 3-keto or aldo acid 155 was used as bifunctional educt for an intramolecular Ugi reaction forming a five-membered ring. The application of C-protected amino acids 156 as amine components enables an intramolecular cyclization forming 2,6-piperazinediones 158 (Scheme 26). 

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 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. 

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). 

Cyclizations involving bond formation between N-1 of the piperazinedi-one and C-2 of the indole ring of tryptophan have been reported. A few cyclodipeptides incorporating tryptophan have been shown to undergo cyclization in acid medium. The mechanism probably involves initial /3-protonation followed by addition of the piperazinedione to the iminium ion (85CPB4783) (Scheme 13). 

Oxidative cyclizations of cyclodipeptides incorporating tryptophan have also been reported (81TL5323). Thus, irradiation of the piperazinedione (39) in formic acid in the presence of a sensitizer such as proflavine or chloranil gave the hydroxypyrroloindole (40). Oxidation with thallium (III) trifluoroacetate gave the dimer (41) in 3% yield. 

Cyclization of the dipeptide and cyclol formation can be carried out in a single step (90MI1). The substrate in this case was the p-nitrophenyl ester (-ONp) of A-salicyloylphenylalanylproline. Treatment of this active ester (55) in benzene solution with DBU gave the oxacyclol (56) in 40% yield. It has been shown that this involves cyclization to the piperazinedione, epimerization of the proline C—aH and then cyclol formation. The l3C-NMR spectrum of the product shows only two carbonyl signals in addition, there is a signal at 102.38 ascribed to the quaternary carbon... 

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... 

Dipeptides, cyclization to piperazinediones, 57, 189 Diphenylamine, in Skraup reaction, 55, 302 Diphosphabenzvalene,... 

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). 

To prepare an intermediate en route to brevianamide B the stereoselectivity of the base-catalyzed cyclization of the piperazinedione (212) was investigated in detail [93]. 

The synthesis of 3,5-diaroylpiperidines by the double Michael-addition of an amine to 2,4-bismethylene-l,5-diketones has been described by a Russian group (Scheme 99). The Raney Nickel-catalysed reduction of the tricyclic cyanoester (213) gave the lactam (214) which is a useful diterpene alkaloid intermediate. 4-Substituted-2,6-piperazinediones (215) have been easily prepared by the cycliz-ation of the appropriate dicarboxylic acids with formamide or ammonium carbonate. ... 

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