Design, Synthesis, and Structural Analysis of <scp>d</scp>,<scp>l</scp>-Mixed Polypyrrolinones. 2. Macrocyclic Hexapyrrolinones

Smith, Amos B.; Xiong, Hui; Charnley, Adam K.; Brenner, Meinrad; Mesaros, Eugen F.; Kenesky, Craig S.; Costanzo, Luigi Di; Christianson, D.W.; Hirschmann, Ralph

doi:10.1021/ol101008y

Cited by 7 publications

(1 citation statement)

References 27 publications

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“…However, by playing on the flexibility and the length of the organic strands, the formation of mesocates could be favored . Whereas the question of the synthesis of heterochiral structures for purely organic macrocycles or metallo-macrocycles has already been tackled, the self-assembly process for circular helicates leads almost systematically to a homochiral architecture . The prevalence of homochiral structures in the field of circular helicate chemistry is undoubtedly a consequence of the specificity of the ligand design.…”

Section: Introductionmentioning

confidence: 99%

Circular Heterochiral Titanium-Based Self-Assembled Architectures

Mobian,

Pham,

Chaumont

et al. 2024

J. Am. Chem. Soc.

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Circular trinuclear helicates have been synthesized from a bis-biphenol strand (LH4), titanium isopropoxide, and various diimine ligands. These self-assembled architectures constructed around three TiO4N2 nodes have a heterochiral structure (C 1 symmetry) when 2,2′-bipyridine (A), 4,4′-dimethyl-2,2′-bipyridine (B), 4,4′-bromo-2,2′-bipyridine (C), or 4,4′-dimethyl-2,2′-bipyrimidine (D) is employed. Within these complexes, one nitrogen ligand is endo-positioned inside the metallo-macrocycle, whereas the other two diimine ligands point outside the helicate framework. This investigation highlights that the nitrogen ligand which does not participate in the helicate framework of the complex controls the overall symmetry of the helicate since the 2,2′-bipyrimidine chelate (F) ends in the formation of a homochiral aggregate (C 3 symmetry). The lack of symmetry found in the solid state for the trinuclear species ([Ti3L3(B)3], [Ti3L3(C)3], and [Ti3L3(D)3]) is observed for these complexes in solution (dichloromethane or chloroform). Remarkably, the 2,2′-bipyrazine ligand (ligand E) ends in the formation of a hexameric aggregate formulated as [Ti6L6(E)6], whereas the use of 4,4′-dimethyl-2,2′-bipyrimidine (ligand D) permits to generate the dinuclear complexes ([Ti2L(D)2(O i Pr)4] and [Ti2L2(D)2]) in addition to the trimeric structure [Ti3L3(D)3]. The behavior of [Ti3L3(A)3] in solution, on the other hand, is unique since an equilibrium between the homochiral and the heterochiral form is reached within 17 days after the complex has been dissolved in dichloromethane (C 3-[Ti3L3(A)3]/C 1-[Ti3L3(A)3] ratio = 0.3). In chloroform, the heterochiral form of [Ti3L3(A)3] is stable for the same period of time, evidencing the dependence of this stereochemical transformation toward the solvent medium. The thermodynamic and kinetic parameters linked to this stereochemical equilibrium have been obtained and point to the fact that the transformation is intramolecular and not induced by the presence of external ligands. The thermodynamic constant of the C 1-[Ti3L3(A)3]/C 3-[Ti3L3(A)3] equilibrium is found to be K = 0.34 ± 10%. Further evidence to rationalize this solvent-induced symmetry switch is obtained via a DFT calculation and classical molecular dynamics. In particular, this computational investigation elucidates the reason why the stereochemical transformation of a heterochiral architecture into a homochiral structure is possible only for a trinuclear assembly containing ligand A.

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Section: Introductionmentioning

confidence: 99%

Circular Heterochiral Titanium-Based Self-Assembled Architectures

Mobian,

Pham,

Chaumont

et al. 2024

J. Am. Chem. Soc.

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Heterocyclic Extended Peptide Surrogates for β-Strand Stabilization

Valle

2015

Topics in Heterocyclic Chemistry

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Pyrrolinone-Based Peptidomimetics.“Let the Enzyme or Receptor be the Judge”

2010

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Peptides and proteins, evolved by nature to perform vital biological functions, would constitute ideal candidates for therapeutic intervention were it not for their generally poor pharmacokinetic profiles. Nonpeptide peptidomimetics have thus been pursued because they might overcome these limitations while maintaining both the potency and selectivity of the parent peptide or protein. Since the late 1980s, we have sought to design, synthesize, and evaluate a novel, proteolytically stable nonpeptide peptidomimetic scaffold consisting of a repeating structural unit amenable to iterative construction; a primary concern is maintaining both the appropriate peptide-like side-chains and requisite hydrogen bonding. In this Account, we detail how efforts in the Smith–Hirschmann laboratories culminated in the identification of the 3,5-linked polypyrrolinone scaffold. We developed effective synthetic protocols, both in solution and on solid supports, for iterative construction of diverse polypyrrolinones that present functionalized peptide-like side-chains. As a result of the rigid nature of the pyrrolinone scaffold, control over the backbone conformation could be exerted by modulation of the stereogenicity of the constituent monomers and the network of intramolecular hydrogen bonding. The extended conformation of the homochiral 3,5-linked polypyrrolinone scaffold proved to be an excellent mimic for β-strands and β-sheets. Application to enzyme inhibitor design and synthesis led not only to modest inhibitors of the aspartic acid protease renin and the matrix metalloprotease class of enzymes, but importantly to bioavailable HIV-1 protease inhibitors with subnanomolar binding constants. The design and synthesis of a competent peptide–pyrrolinone hybrid ligand for the class II major histocompatibility complex (MHC) antigen protein HLA-DR1 further demonstrated the utility of the 3,5-polypyrrolinone motif as a mimic for the extended polyproline type II peptide backbone. Equally important, we sought to define, by synthesis, the additional conformational space accessible to the polypyrrolinone structural motif, with the ultimate goal of accessing pyrrolinone-based turn and helix mimetics. Towards this end, a mono-N-methylated bispyrrolinone was found to adopt an extended helical array in the solid state. Subsequent synthesis of d,l-alternating (heterochiral) tetrapyrrolinones both validated the expected turn conformations in solution and led to a functionally active mimetic of a peptidal β-turn (similar to somatostatin). Finally, the design, synthesis, and structural evaluation of both acyclic and cyclic heterochiral (that is, d,l-alternating) hexapyrrolinones yielded nanotube-like assemblies in the solid state. Taken together, these results illustrate the remarkable potential of the 3,5-linked polypyrrolinone scaffold as β-strand, β-sheet, β-turn, and potentially helical peptidomimetics.

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Design, Synthesis, and Structural Analysis of d,l-Mixed Polypyrrolinones. 2. Macrocyclic Hexapyrrolinones

Cited by 7 publications

References 27 publications

Circular Heterochiral Titanium-Based Self-Assembled Architectures

Circular Heterochiral Titanium-Based Self-Assembled Architectures

Heterocyclic Extended Peptide Surrogates for β-Strand Stabilization

Pyrrolinone-Based Peptidomimetics.“Let the Enzyme or Receptor be the Judge”

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