Cyclols

As was shown by Jacobs and Craig at the Rockefeller Institute and by Stoll and coworkers at Sandoz, the peptide moiety consists of the diketopiperazine from the amino acids L-proline and L-phenylalanine, combined with an a-hydroxy-L-alanine residue with its oxygen bound to the 6-membered ring thus forming a cyclol structure. 

As mentioned on p. 3, cyclols are potentially formed by addition of an NH of a peptide bond to an opposite carbonyl (C O) in the present case a hydroxyl group is added to a peptide bond, hence, generating an oxa-cyclol . 

In the synthesis of ergotamine by A. Hofmann et al. (1961) [1] the cyclol moiety is formed by addition of the OH group, set free by hydrogenation, in the a-carboethoxy-a-benzyloxypropionyl residue bound to L-phenylalanine-L-proline anhydride (diketopiperazine) (Fig. 2). The precursor of the oxacyclol part in the biosynthesis by Claviceps is an alanyl moiety into which aerial oxygen is introduced by enzymatic hydroxylation. 

The unique structure of the ergot peptides prompted several laboratories to investigate closer the chemistry of cyclols. The Swiss chemists by following the course of oxacyclol formation with simple model components obtained cystalline products from a-hydroxyacyl lactames as indicated in Fig. 3 in a supposed equilibrium reaction the cyclols here seem to be energetically favored. 

In a parallel study Soviet chemists engaged in cyclodepsipeptide research (p. 20), studied hydroxyacyl incorporation in more detail [3] and arrived at a 14-membered cyclic depsipeptide, serratamolide, by double insertion of jS-hydroxyacyl residues into a diketopiperazine (Fig. 4). Here, we would like to remind the reader of the early experiments of Max Bergmann in 1929 with N-acetyl-diketopiperazine, through which the activation of acyl residues on amide nitrogen first became apparent (p. 46). 

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C-H-stretching vibrations C=0-stretching of 5-membered ring lactam (cyclol)... 

Griot, R. G., and A.J. Frey The Formation of Cyclols from N-Hydroxy-acyllactams. Tetrahedron [London] 19, 1661 (1963). 

Ott, H., A. J. Frey, and A. Hofmann The Stereospccific Cyclolization of N-a-Hydroxyacyl-phenylalanydpirolin-lactam. Tetrahedron [London] 19, 1675 (1963). 

The formation of macrocycles through ring-enlargement reactions via bicyclic tetrahedral intermediates—i.e., the cyclols of general type 89 or 92 (the ionized forms are shown), which are mostly unstable and can be... 

All the cyclols isolated were isomerized into the corresponding macrocycles on basic catalysis. 

Scheme 7 Interconversion of Cyclic Tripeptides into Cyclols and Piperazine-2,5-diones Dehydration to Acyl-imidamide is an Almost Irreversible Transformation1199-202-2031...

Cyclols Stable molecules obtained by the addition of a heteroatom nucleophile to the carbonyl group of lactams are not very common. The side-chain moiety of the ergot alkaloids (e.g., 50) is one of the earliest examples of such a cyclolic structure (75FOR51) identified. This has given rise to a number of studies on the synthesis and chemical transformations of such units. The discussion below is confined to cyclols related to or arising from piperazine-2,5-diones. 

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. 

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... 

The proline-containing tricyclic system similar to the unit present in the ergot alkaloids, seems to be particularly efficient in stabilizing the cyclol structure. This is probably due to the conformational rigidity pro-... 

Azacyclols arising from amide-amide interaction have been extensively investigated. The p-nitrophenyl ester (60) of the linear tripeptide N-benzyloxycarbonyl-L-alanyl-L-phenylalanyl-L-proline undergoes a double cyclization when left in an aqueous buffer-dioxane (1 1) solution for 1 h, to produce cyclol (61) (7 ICC 1605). The hydroxyl group of the cyclol could be converted to the methyl ether by treatment with methyl iodide-silver oxide. The structure of the cyclol (61) could be confirmed by X-ray crystallography of the corresponding p-bromobenzyloxycarbonyl derivative (7 ICC 1607). 

The importance of the rigid tricyclic framework for the formation and stability of the cyclol has been examined by the Italian group. Cyclization of a similar tripeptide derivative containing cysteine as N-terminal residue... 

A tetracyclic azacyclol (66) has been obtained from the p-nitrophenyl ester of the linear tripeptide prolylphenylalanylproline (81TL3671). However, the tripeptide active ester Phe-Pro-Pro-ONp with an altered sequence did not lead to the cyclol (66). This suggests that in the former reaction the piperazinedione (65) is an intermediate (Scheme 20). 

In the above examples, the quaternary cyclolic carbon is located at the junction of a 5-membered and a 6-membered ring. However, when attempts were made to create a stable cyclol with two 6-membered rings [n = 2, in structure (52)], the cyclization either did not occur, or led to further transformation products. Thus, cyclol (67) could not be obtained from the N-protected linear tripeptide active ester Cbz-/3-Ala-Phe-Pro-ONp, incorporating a /3-amino acid [82JCS(P1)1311]. Cyclization of the same sequence having a free NH2 at the N-terminus gave the cyclotripeptide (68) with a 10-membered ring. 

Incorporation of anthranilic acid at the N-terminus instead of /3-alanine, led to the amidine (69). Finally, the cyclol (70) was obtained in 33% yield from the analog having N-methylanthranilic acid this reaction also gave the 10-membered cyclotripeptide in 17% yield (84TL5201). 

A similar result was obtained when the piperazinedione carried an N-sulfonyl group. Thus deprotection of the Af-carbobenzoxy taurine derivative (71) of cyclo(Phe-D-Pro) led to the 10-membered cyclic compound (73) via the cyclol (72) (89MI1). 

In order to check the role of proline at the C-terminus, linear tripeptides with other imino acids at that position have been subjected to cyclization. Both (74) and (76), the former having L-azetidine-2-carboxylic acid, and the latter sarcosine, gave the respective cyclols (75) and (77). The difference is that (75) can be dissolved in alkali and regenerated by acidification, whereas (77) is isomerized to the N-acylpiperazinedione and hydrolyzed under these conditions (78TL1009). 

Similar behaviour is found with other peptide derivatives. Thus the peptide lactone [16] on treatment with dry HC1 in chloroform yielded the cyclol ... 

Sheppard, 1963) and tripeptide oxazoline [18] spontaneously yields cyclol [19] when dissolved in ethyl acetate (Jones et al., 1963). The cyclol structure was confirmed by an X-ray structure determination for compound [21a] which was obtained by treatment of the peptide-nitrophenyl ester [20a] with 1 1 carbonate bicarbonate buffer in aqueous dioxan [21ft] was obtained similarly from [20ft] (Lucente and Romeo, 1971 Cerrini et al., 1971). 

The liquid heal capacities have been measured from -I7.VC 10 22o C for styrene. M 3liquid heat capacity uCeyclooctadicne was calculated. and the data for eye lope me nc and cyclohexene were extended by the methofl or Yuan and suel/" 1 ... 

High-performance liquid chromatography on silica is recommended470 for the separation of some, but not all, mixtures of ergot alkaloids an improved procedure, which is claimed to be satisfactory for the separation and determination of mixtures of cyclol ergot alkaloids obtained from fermentation media, involves the use of silica gel modified with alkylamines as the stationary phase, with gradient elution by diethyl ether-ethanol mixtures.476... 

Lucente and Romeo (38) were able to isolate the N-cyclol derivatives 41 from the open chain precursor 40 by treating the latter with a slightly alkaline dioxane-aqueous buffer solution. The stereochemistry of 41 was also proved by X-ray analysis (39). 

Attention has also been given to the development of improved cyclol ester syntheses thus, acylated dipeptides such as (76) can be converted efficiently into the related cyclol esters [e.g. (77)] by the reaction of their p-nitrophenyl esters with base in polar aprotic solvents (Scheme 6).51... 

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