Synthesis of Spiroligomer-Containing Macrocycles

Zhao, Qingquan; Schafmeister, Christian E.

doi:10.1021/acs.joc.5b01109

Cited by 16 publications

(8 citation statements)

References 60 publications

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“…Just as cyclization is known to stabilize folded peptide conformations, [20][21][22][23][24] so have similar strategies been successful at achieving pre-organized spiroligomer 25 and peptoid macrocycles. [26][27][28][29][30][31][32][33][34] Indeed, preorganization due to cyclization helps explain the prevalence of cyclic designs in the modest corpus of peptoid crystal structures that have been solved to date.…”

Section: Introductionmentioning

confidence: 99%

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

Hurley¹,

Northrup²,

Ge³

et al. 2021

Preprint

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<div>The rational design of foldable and functionalizable peptidomimetic scaffolds requires the concerted application of both computational and experimental methods. Recently, a new class of designed peptoid macrocycle incorporating spiroligomer proline mimics (Q-prolines) has been found to pre-organize when bound by monovalent metal cations. To determine the solution-state structure of these cation-bound macrocycles, we employ a Bayesian inference method (BICePs) to reconcile enhanced-sampling molecular simulations with sparse ROESY correlations from experimental NMR studies. The BICePs approach circumvents the need for bespoke force field parameterization, instead relying on experimental restraints to help narrow the possible set of cis/trans amide isomers in solution. Conformations predicted to be most populated in solution were then simulated in the presence of explicit cations to yield trajectories with observed binding events, revealing a highly-preorganized all-trans amide conformation, whose formation is likely limited by the slow rate of cis/trans isomerization. Interestingly, this conformation differs from a racemic crystal structure solved in the absence of cation. Free energies of cation binding computed from distance-dependent potentials of mean force suggest Na+ has higher affinity to the macrocycle than K+, with both cations binding much more strongly in acetonitrile than water. The simulated affinities are able to correctly rank the extent to which different macrocycle sequences exhibit preorganization in the presence of different metal cations and solvents, suggesting our approach is suitable for solution-state computational design.</div>

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Section: Introductionmentioning

confidence: 99%

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

Hurley¹,

Northrup²,

Ge³

et al. 2021

Preprint

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“…This is important as all possible configurations of stereocenters have been used previously. 10,11,16,17,19 On top of that, this strategy of hydantoin alkylation can be applied to a spiroligomer dimer, as shown in Scheme 2 (for a more detailed scheme showing a complete structure of 33 and synthesis of 32, please see Scheme SI-1 on page 121 of the Supporting Information.) We synthesized a spiroligomer dimer to which we applied one of our alkylation methods.…”

Section: The Journal Of Organic Chemistrymentioning

confidence: 99%

“…We have successfully attached alkyl, allyl, and benzyl halides to both the imide and amide position of the hydantoin. The application of this alkylation method to the synthesis of spirocyclic ring systems allows the utilization of these highly diverse bifunctionalized 4-hydantoin-proline derivatives as small molecules or as the termini of larger spiroligomer structures . Herein, we detail the synthesis of nine of the numerous potential variants of these substituted 4-hydantoin-proline derivatives.…”

mentioning

confidence: 99%

“…The different stereochemical configurations react similarly in that neither the yield nor the time required to alkylate a given position depends on the stereochemistry of the starting material (data for the enantiomers not shown). This is important as all possible configurations of stereocenters have been used previously. ,,,, On top of that, this strategy of hydantoin alkylation can be applied to a spiroligomer dimer, as shown in Scheme (for a more detailed scheme showing a complete structure of 33 and synthesis of 32 , please see Scheme SI-1 on page 121 of the Supporting Information.) We synthesized a spiroligomer dimer to which we applied one of our alkylation methods.…”

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confidence: 99%

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One-Pot Synthesis of Chiral, Spirocyclic 4-Hydantoin-Proline Derivatives for Incorporation into Spiroligomer-Based Macromolecules

2017

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Derivatives of 4-hydantoin-proline have been synthesized via a direct two-step alkylation method. This method is valuable in the development of applications of N,N'-disubstituted hydantoin bearing α-amino acids by improving yields, reducing the time and number of steps required to synthesize these substituted molecules, and enabling late stage functionalization of spiroligomer termini. Over 20 unique electrophiles have been tested, highlighting the inherent versatility of this chemistry.

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“…Just as cyclization is known to stabilize folded peptide conformations, − so have similar strategies been successful at achieving preorganized spiroligomer and peptoid macrocycles. − Indeed, preorganization due to cyclization helps explain the prevalence of cyclic designs in the modest corpus of peptoid crystal structures that have been solved to date . Interestingly, it has been found that cyclic peptoids can host metal cation adducts through the coordination of backbone carbonyl groups, , reminiscent of natural products such as mycotoxins …”

Section: Introductionmentioning

confidence: 99%

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

Hurley

Northrup

et al. 2021

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

The rational design of foldable and functionalizable peptidomimetic scaffolds requires the concerted application of both computational and experimental methods. Recently, a new class of designed peptoid macrocycle incorporating spiroligomer proline mimics (Q-prolines) has been found to preorganize when bound by monovalent metal cations. To determine the solution-state structure of these cation-bound macrocycles, we employ a Bayesian inference method (BICePs) to reconcile enhanced-sampling molecular simulations with sparse ROESY correlations from experimental NMR studies to predict and design conformational and binding properties of macrocycles as functional scaffolds for peptidomimetics. Conformations predicted to be most populated in solution were then simulated in the presence of explicit cations to yield trajectories with observed binding events, revealing a highly preorganized all-trans amide conformation, whose formation is likely limited by the slow rate of cis/trans isomerization. Interestingly, this conformation differs from a racemic crystal structure solved in the absence of cation. Free energies of cation binding computed from distance-dependent potentials of mean force suggest Na+ has a higher affinity to the macrocycle than K+, with both cations binding much more strongly in acetonitrile than water. The simulated affinities are able to correctly rank the extent to which different macrocycle sequences exhibit preorganization in the presence of different metal cations and solvents, suggesting our approach is suitable for solution-state computational design.

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Synthesis of Spiroligomer-Containing Macrocycles

Cited by 16 publications

References 60 publications

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

One-Pot Synthesis of Chiral, Spirocyclic 4-Hydantoin-Proline Derivatives for Incorporation into Spiroligomer-Based Macromolecules

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

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