Ring size configuration effect and the transannular intrinsic rates in bislactam macrocycles

Guedez, Thanee; Núñez, Andrés; Tineo, Evis; Núñez, Oswaldo

doi:10.1039/b207233e

Cited by 14 publications

(15 citation statements)

References 9 publications

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“…The rate constants, k obs r and k obs f , were directly measured using a simulation program17 of the 1 HNMR line shape of the STI 1 HNMR AB (‐X‐CH 2 CO) system and the corresponding signals for the macrocycle form. Very similar results are obtained16 for X = NH 2 and n = 5 and 6. A resume of the obtained K , k 2 , and k ‐2 values for the three studied compounds is shown in Table 1.…”

Section: Resultssupporting

confidence: 86%

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Cleavages in stable tetrahedral intermediates' bonds and the role of water

Bethencourt

Vivas

Núñez

2010

J of Physical Organic Chem

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Using two‐dimensional energy diagrams, results on the formation and cleavage of detectable tetrahedral intermediates are used to predict the position of transition states involved in the cleavages of unstable and stable tetrahedral intermediates (STI). A late transition state (anti‐Hammond) for the former and synchronous cleavage for the latter are predicted and supported with experimental results. For instance, in the case of STI, intrinsic leaving abilities in the order CO > CNHCO ≫ CNH were experimentally observed, confirming the departure of these groups without full heteroatom protonation. The STI designed herein mimics serine proteases enzymes due to the thermoneutral relationship between the enzyme substrate (ES) and enzyme‐acyl tetrahedral intermediate (EATI) analogs. In the STI models, a dramatic change in pKa is observed when changing the lactam ring size due to the strain in the 3‐fused‐ring system of the STI‐H2O complex formed and exo‐anomeric effect. A plot of ΔSo (STI formation) versus pKa provides evidence for the STI–water interaction. Since only one water molecule is required to produce the effect it is also detected when using ‘pure’ CDCl3 as the solvent and therefore may also play a role in the active sites of serine proteases. Copyright © 2010 John Wiley & Sons, Ltd.

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Section: Resultssupporting

confidence: 86%

“…Depending on the intrinsic leaving abilities of the X and amide groups, the open form and/or the macrocycle form will be observed in equilibrium with the STI. We have synthesized12, 13, 15, 16 compounds where X = NH, O and in both cases, for n = 5, 6, and 7.…”

Section: Resultsmentioning

confidence: 99%

Cleavages in stable tetrahedral intermediates' bonds and the role of water

Bethencourt

Vivas

Núñez

2010

J of Physical Organic Chem

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“…However, for compounds 2 e , f , allowing the reactions to proceed at room temperature resulted in clean and complete conversion to the desired medium‐sized rings in just under 2 h. Neither the ring size nor the aromatic substituents adversely affected the reaction outcome, which showed promise in extending this methodology to more complex systems. Having secured a reliable route to medium‐sized rings from simple lactams, we investigated the possibility of using an α‐amino imide fragment . Using glycine‐derived α‐amino imide 3 as our model substrate we calculated the probability of forming a 9‐membered ring however, computational analysis predicted that the cyclol form of this system would be thermodynamically favored over the ring expanded product (see Supporting Information).…”

Section: Methodsmentioning

confidence: 99%

Cyclols Revisited: Facile Synthesis of Medium‐Sized Cyclic Peptides

Mendoza-Sanchez

Corless

Nguyen

et al. 2017

Chemistry A European J

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Medium-sized rings, particularly the corresponding cyclic peptides, are challenging synthetic targets. In the present study, we report an approach to medium-sized cyclic peptides through targeted formation and collapse of cyclol intermediates. This methodology operates on β-amino imides derived from 2,5-diketopiperazines and offers a straightforward transition from frequently examined scaffolds in drug discovery to a rarely visited class of medium-sized rings.

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“…Intramolecular collapse has indeed been observed even in relatively simple cyclic amide-containing molecules. 24 This process is also responsible for the formation of cyclols in the course of spontaneous cyclization of tripeptide sequences. 25 Cyclol-mediated transannular ring closure and condensation in cyclic peptides was also documented by Heimgartner and colleagues ( Fig.…”

Section: Synthesis Of Macrocyclesmentioning

confidence: 99%