Synthesis of fused 1,2,5-triazepine-1,5-diones and some N2- and N3-substituted derivatives: potential conformational mimetics for cis-peptidyl prolinamides 1

Lenman, M. M.; Lewis, Arwel; Gani, David

doi:10.1039/a702107k

Cited by 38 publications

(18 citation statements)

References 18 publications

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“…The secondary amino group is sterically hindered relative to the primary amino groups of other amino acids and is conformationally restrained due to its location in a five-membered pyrolidine ring. Indeed, the poor nucleophilicity of proline compared to primary amino acids is well documented in peptide synthesis (21). Furthermore, 3Ј-O-prolyl adenosine has been found to be the worst 3Ј-O-aminoacyl adenosine substrate for peptidyl transferase activity in E. coli ribosomes, along with 3Ј-O-glycyl adenosine (22).…”

Section: Fmdv 2a Activity-an Alternative Hypothesismentioning

confidence: 99%

A Model for Nonstoichiometric, Cotranslational Protein Scission in Eukaryotic Ribosomes

Ryan

Donnelly

Lewis

et al. 1999

Bioorganic Chemistry

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Section: Fmdv 2a Activity-an Alternative Hypothesismentioning

confidence: 99%

A Model for Nonstoichiometric, Cotranslational Protein Scission in Eukaryotic Ribosomes

Ryan

Donnelly

Lewis

et al. 1999

Bioorganic Chemistry

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“…(3S,8aS)-Hexahydro-3-methylpyrrolo[1,2-a]pyrazine-1,4-dione (cis-10a) [19]. Prepared according to GP 2.…”

Section: H T U N G T R E N N U N G H 20 a C H T U N G T R E N N U Nmentioning

confidence: 99%

Diastereoselective Alkylation of a Proline-Derived Bicyclic Lactim Ether

Hendea¹,

Laschat²,

Baro³

et al. 2006

HCA

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Dedicated to Professor Dieter Hoppe on the occasion of his 65th birthday N-Boc-protected L-proline (6) was converted into the bicyclic lactim ether (8aS)-6,7,8,8a-tetrahydro-1-methoxypyrrolo[1,2-a]pyrazin-4(3H)-one (5) in four steps (Scheme 1). Deprotonation with LDA or LHMDS and subsequent alkylation resulted in the diastereoisomeric products cis-and trans-9. The diastereoselectivity was mainly dependent on the electrophile. Whereas small alkyl halides gave preferably cis-9, sterically more-demanding alkyl halides resulted in cis/trans mixtures. Electrophiles bearing a psystem favored the trans-products 9. Some isolated cis-and trans-lactim ethers 9 were converted to the corresponding diketopiperazines cis-and trans-10 by acid hydrolysis. The structures and configurations of several compounds were confirmed by NMR and NOE experiments, as well as by X-ray crystallography (Figs. 1 -4).Introduction. -In contrast to the well-known Schçllkopf bislactim-ether method for the synthesis of a-amino acids [1 -3], the alkylation of monolactim ethers has been rarely reported in the literature [4 -6]. Recently, we have published the preparation of tricyclic diketopiperazines with an annulated tetrahydroisoquinoline moiety via diastereoselective alkylation of the corresponding monolactim ethers and subsequent hydrolysis [7].Several secondary metabolites of microorganisms with interesting biological properties such as deoxybrevianamide E (1) [8], tryprostatins A and B (2a, b) [9], spirotryprostatin A (3) [10], and fumitremorgin C (4) [11] contain a proline-derived diketopiperazine as part of their molecular skeleton. Furthermore, this type of compound has been found in the bitter flavor of roasted coffee [12]. The diketopiperazine structural motif in these natural products was prepared in most cases by cyclocondensation [8 -11] [13] [14]. However, we were interested to synthesize related proline-based diketopiperazines via alkylation of the bicyclic lactim ether 5, followed by acidic hydrolysis. The results of our investigation are reported in this paper.

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“…[13][14][15][16][17][18][19][20][21] Also, the use of proline-mimetics has been pursued and several scaffolds have been proposed, either having bicyclic structures or four-to six-membered ring proline homologues, as among the naturally occurring amino acids proline is known to play a central role in the nucleation of reverse turn structures like b-turns and b-hairpins, because of its ability to form cis peptide bonds and to undergo cis/trans isomeriza-tion. [22][23][24][25][26] In fact, the cis geometry of proline amide bond causes the peptide backbone to fold in a type VI b-turn, in which proline occupies the i12 position, although proline is often observed at the i11 position of b-turn structures, generating a trans amide bond with the preceding amino acid at position i. 27 In addition, it has been demonstrated that the cis/trans isomerization at Xaa-Pro peptide bond is accelerated by changing the proline ring in size and structure and, as an example, pipecolates have served as proline substitutes in structure-activity studies of biologically relevant peptides.…”

Section: Introductionmentioning

confidence: 99%

Configurationally driven folding of model tetrapeptides containing L‐ or D‐morpholine‐3‐carboxylic acids as β‐turn nucleators

2008

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The conformational analysis by NMR, IR, and molecular modeling of tetrapeptides containing morpholine-3-carboxylic acid (Mor) as a proline surrogate is presented. The relationship between the chirality of the cyclic amino acid at position i+1 and the turn propensity is maintained with respect to the reference proline-containing peptides, although marked differences in the type of folded structures were observed. The conformational profile of morpholine-containing turn peptides as a function of the chirality of the cyclic amino acid indicated that the heterochiral tetrapeptide containing the D-isomer of the cyclic amino acid is more prone to nucleate compact folded structures, although with no resemblance to the beta-turn structures of D-proline-containing peptides. Also, the solvation system proved to influence the organization of folded structures, as in the more interactive CD(3)CN the model peptides showed more compact conformations. The L-Mor-containing peptide displayed two rotamers at the Val-Mor amide bond. The trans isomer did not experience any turn structures, nor any intramolecular hydrogen-bonds, whereas the cis isomer showed a strong preference for a type VI beta-turn structure, thus providing a different conformational asset with respect to the beta-turn structure as reported for the reference L-proline model peptide.

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Synthesis of fused 1,2,5-triazepine-1,5-diones and some N2- and N3-substituted derivatives: potential conformational mimetics for cis-peptidyl prolinamides 1

Cited by 38 publications

References 18 publications

A Model for Nonstoichiometric, Cotranslational Protein Scission in Eukaryotic Ribosomes

A Model for Nonstoichiometric, Cotranslational Protein Scission in Eukaryotic Ribosomes

Diastereoselective Alkylation of a Proline-Derived Bicyclic Lactim Ether

Configurationally driven folding of model tetrapeptides containing L‐ or D‐morpholine‐3‐carboxylic acids as β‐turn nucleators

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