Cyclization dipeptide precursor

Cyclo(Gly-Gly) was the first cyclic dipeptide synthesized and elucidated, since then a wide variety of members of the cyclic dipeptide family have been synthesized by various methodologies. The cyclic dipeptides were initially prepared by the action of ammonia on the free dipeptide esters, liberated from the corresponding amine salts. The long duration of exposure to ammonia, required by the free dipeptide esters to effect cyclization, lead to extensive racemization when employing optically pure linear dipeptide precursors. Early cyclic dipeptide synthetic methods have involved the following ... 

DKPs may be produced without any difficulties and may form without particular activation of the carboxyl function of the dipeptide precursor. However, the cyclization reaction may be a slow process, justifying the need for specific activation of the carboxyl moiety. Kopple stated that there is no single perfect method for the cyclization of all peptides, only guidelines aiding in the judicious choice of combinations of procedures to limit the generation of unwanted by-products of peptide synthesis. 

It has been shown that glyeine amides of aminobenzophenones are readily converted to the corresponding benzodiazepines in vivo. Peptides which terminate in such a moiety should thus serve as a benzodiazepine prodrug after hydrolysis by peptidases. One of the glycine residues in lorzafone (194)is presumably removed metabolicaUy in this manner to give a benzodiazepine precursor which spontaneously cyclizes. Acylation of benzophenone 190 with the trityl protected dipeptide 191, as its acid chloride 192, affords the amide 193. Removal of the trityl protecting group with acid yields lorzafone (194) [50]. 

Modification of the amino acid residues located on the N-terminal side of Pro was shown to have a major influence on the rate of cyclic dipeptide formation. For the series of dipeptide analogues of X-Pro-/>NA, the half-lives of cyclic dipeptide formation in 0.5 molG phosphate buffer (pH 7) at 37 °C were reported as follows X = Gly 5.1 days, X = Val 2.5 days, X = Ala 1.1 days, X = /3-cyclohexylalanine 0.8 days, X = Arg 0.7 days, and X = Phe 0.5 days. Increased bulkiness of alkyl and aryl substituents have been previously shown to increase the rate of cyclization due to intramolecular reactions. This however does not seem true for the series studied by Goolcharran and Borchardt as the Ala analogue cyclized twice as fast as the bulkier analogue. From the study it is evident that simple steric bulk of substituents alone cannot be used to effectively explain the effects involved in the formation of cyclic dipeptides from various peptide precursors. 

Ugi reaction of acid 88 with isonitrile 85, isobutyraldehyde and isopropylamine furnished dipeptide 89 in 67% yield. Similar Ugi reactions with other components afforded linear cyclization precursors in yields up to 98%. The final macrocyclization was not straightforward (no similar reactions were described in literature), but after optimization of the reaction conditions (varying base, solvent, concentration and reaction time) cyclopeptide alkaloid analogue 90 was obtained in 96% yield after treatment with K2CO3 and catalytic 18-crown-6 in acetone. 

An alternative mechanism to form thiazoles and oxazoles is through oxidation of a dipeptide followed by cyclization from an enolate or thienolate precursor and subsequent dehydration (Scheme 7.2). This represents a higher-energy pathway and there is no accumulation of thiazoline or oxazoline intermediates [22-24]. 

A review of approaches to the design and synthesis of azabicycloalkane amino acids as constrained dipeptide mimetics has been reported. These approaches include 7-membered lactam ring formation by free radical cyclization from a substituted proline precursor <04SL1449>. 

Since L-isoleucine forms the )S-methylproline ring of paraherquamide A, cydo-L-Trp-L-j8-methylproline or cydo-L-Trp-L-Ile are plausible precursors. There are numerous possible sequences of events that might occur in the formation of the final )3-methylproline ring system. Formation of the dipeptides NH2-L-Ile-L-Trp-COOH or NH2-L-Trp-L-Ile-COOH and dehydration to cyclo-L-Trp-L-Ile followed by oxidation of the terminal carbon of L-Ile and cyclization to form the )3-methylproline moiety would result in cydo-L-Trp-L-)9-methylproline. Another possibility involves oxidation of the L-Ile followed by cyclization and reduction to afford )5-methylproline followed by coupling to L-Trp to give cyclo-L-Trp-L-j8-methylproline. Many other possibilities exist that would involve formation of the jS-methylproline ring at a later stage. 

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