Dipeptides oxidative cyclization

Last year Rawal and Cava gave a preliminary account of their studies into the photocyclization of 1,2-dipyrrolyl-ethylenes and related systems and pointed out that such photo-oxidative cyclization may be employed as the key step to the tricyclic ring structure present in the antitumour antibiotic dipeptide CC-1065t The same workers have reported further on the photochemistry of... 

Reaction with Organometallic Derivatives. Similarly, the lesser reactivity of NIS compared with NBS allows it to be used for the s)uithesis of vinyl iodides by iodination of vinylaluminum intermediates in the presence of reactive alkenic groups. NIS has also been found to be an excellent reagent for the oxidative cyclization of dipeptide dianions to 8-lactams (eq 1). ... 

In NRPs and hybrid NRP-PK natural products, the heterocycles oxazole and thiazole are derived from serine and cysteine amino acids respectively. For their creation, a cyclization (or Cy) domain is responsible for nucleophilic attack of the side-chain heteroatom within a dipeptide upon the amide carbonyl joining the amino acids [61]. Once the cyclic moiety is formed, the ring may be further oxidized, to form the oxazoline/thiazoline, or reduced, to form oxazolidine/thiazolidine (Figure 13.20). For substituted oxazoles and thiazoles, such as those... 

Bicyclic [33] and 7,5-bicyclic [34, 35] dipeptides (Scheme 24) have been syn-thetized by a one-step electrochemical cyclization from various dipeptides. The selective anodic amide oxidation... 

In NRPS, the cyclization domain catalyzes cyclization of the side-chain nucleophile from a dipeptide moiety such as AA-Ser or AA-Cys (AA = amino acids) to form a tetrahedral intermediate, followed by dehydration to form oxazolines and thiazolines (Scheme 7.1) [20]. The synthesis of a 2-methyl oxazoline from threonine follows a similar mechanism. Once a heterocycle is formed, it can be further modified by reductase to form tetrahydro thiazolidine in the case of pyochelin biosynthesis. Conversely, oxidation of the dehydroheterocycles lead to heteroaro-mahc thiazoles or oxazoles as in the case of epothilone D (Figure 7.2) [21]. 

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]. 

Methoxypiperazine-2,5-diones have been obtained by the formic acid cyclization of the corresponding linear peptides (91T563). The latter were obtained by electrochemical oxidation of normal dipeptides (Scheme 4). The electrolysis was performed in MeOH-lithium perchlorate (0.1 M) containing NaCl at a platinum anode and was found to be totally regiose-lective. 

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. 

Like aspartame, alitame also undergoes a/P-rearrangement. Both isomers hydrolyze slowly to give L-aspartic acid and D-alanine amide, which is excreted either directly or as the glucuronide. A small part is oxidized to sulfoxides and sulfone. Cyclization to diketopiperazine which is typical of dipeptide methylesters does not occur. 

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