Interconvertions between δ-Lactam and δ-Lactone Derivatives Initiated by Unique Transannular Interactions of the Rigid Cyclohexane Boat Structure in Pentacycloundecane

Kruger, Hendrik G.; Martins, Charles Ferreira; Viljoen, A. M.

doi:10.1021/jo0357723

Cited by 14 publications

(6 citation statements)

References 24 publications

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“…Spectroscopic evidence (vide infra) suggested that it is not a lactam. Additionally, if it would have been a lactam, the implied facile lactam‐to‐lactone conversion that must have taken place is unlikely when considering that this transformation is usually only observed in highly ring‐strained lactams, but such strains cannot be recognized here.…”

Section: Resultsmentioning

confidence: 99%

Surprising Outcomes of Classic Ring‐Expansion Conditions Applied to Octaethyloxochlorin, 2. Beckmann‐Rearrangement Conditions

Meehan

Zeller

et al. 2017

Eur J Org Chem

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The step‐wise conversion of synthetic porphyrins to derivatives that contain a non‐pyrrolic building block is an appealing method to generate functionalized porphyrinoids. Applied to octaethyloxochlorin oxime, a Beckmann rearrangement is potentially suited to generate a nitrogen‐expanded porphyrinoid. Unexpectedly, this reaction led to a ring‐expansion by an oxygen atom. The mechanism – an abnormal Beckmann reaction, followed by an intramolecular ring‐closing reaction and hydrolysis – was conclusively derived by trapping and structural characterization of the key secochlorin intermediate. The structural and UV/Vis spectral changes observed upon ring‐expansion of the oxochlorin are discussed. Other Beckmann‐rearrangement conditions failed to produce ring‐expanded products altogether. This work demonstrates in many ways how the extraordinary structural stability of the porphyrin macrocycle redirects the reactivity patterns of classic ring‐expansion reactions, which outlines the limits of the “breaking and mending of porphyrins” approach toward pyrrole‐modified porphyrins.

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Section: Resultsmentioning

confidence: 99%

Surprising Outcomes of Classic Ring‐Expansion Conditions Applied to Octaethyloxochlorin, 2. Beckmann‐Rearrangement Conditions

Meehan

Zeller

et al. 2017

Eur J Org Chem

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“…In this section, we considered the PCU-lactam, lactim and lactone models shown in Figure 5 . The two reported sets of 1 H NMR signals in various solvents suggested the lactim–lactam tautomeric equilibrium exists [ 19 , 20 ]. In (CD 3 ) 2 SO the major tautomer is the lactam form, while for dioxane the lactim is dominant.…”

Section: Resultsmentioning

confidence: 99%

“…We calculated the asymmetry parameters (η) and quadrupole coupling constants (χ) of nitrogen and oxygen atoms involved in the cage region of PCU-lactam, its tautomer lactim [ 19 , 20 ] and PCU-lactone models in vacuum and in solvent media (water, DMSO and dioxane). The solvation effect (aqueous solution) on the Gibbs free energy of solvation (ΔG sol ) were also evaluated utilizing the self-consistent reaction field (SCRF) keyword [ 90 ] with the solvation model on density (SMD) [ 91 ].…”

Section: Methodsmentioning

confidence: 99%

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Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study

et al. 2015

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BackgroundNovel pentacycloundecane (PCU)-lactone-CO-EAIS peptide inhibitors were designed, synthesized, and evaluated against wild-type C-South African (C-SA) HIV-1 protease. Three compounds are reported herein, two of which displayed IC50 values of less than 1.00 μM. A comparative MM-PB(GB)SA binding free energy of solvation values of PCU-lactam and lactone models and their enantiomers as well as the PCU-lactam-NH-EAIS and lactone-CO-EAIS peptide inhibitors and their corresponding diastereomers complexed with South African HIV protease (C-SA) was performed. This will enable us to rationalize the considerable difference between inhibitory concentration (IC50) of PCU-lactam-NH-EAIS and PCU-lactone-CO-EAIS peptides.ResultsThe PCU-lactam model exhibited more negative calculated binding free energies of solvation than the PCU-lactone model. The same trend was observed for the PCU-peptide inhibitors, which correspond to the experimental activities for the PCU-lactam-NH-EAIS peptide (IC50 = 0.076 μM) and the PCU-lactone-CO-EAIS peptide inhibitors (IC50 = 0.850 μM). Furthermore, a density functional theory (DFT) study on the natural atomic charges of the nitrogen and oxygen atoms of the three PCU-lactam, PCU-lactim and PCU-lactone models were performed using natural bond orbital (NBO) analysis. Electrostatic potential maps were also used to visualize the electron density around electron-rich regions. The asymmetry parameter (η) and quadrupole coupling constant (χ) values of the nitrogen and oxygen nuclei of the model compounds were calculated at the same level of theory. Electronic molecular properties including polarizability and electric dipole moments were also calculated and compared. The Gibbs theoretical free solvation energies of solvation (∆Gsolv) were also considered.ConclusionsA general trend is observed that the lactam species appears to have a larger negative charge distribution around the heteroatoms, larger quadrupole constant, dipole moment and better solvation energy, in comparison to the PCU-lactone model. It can be argued that these characteristics will ensure better eletronic interaction between the lactam and the receptor, corresponding to the observed HIV protease activities in terms of experimental IC50 data.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-015-0115-5) contains supplementary material, which is available to authorized users.

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“…With the structure of lactone 8 confirmed, we focused our attention on the connectivity of its precursor 7 OH for which a lactam structure seemed unlikely ( vide infra ). In addition to the spectroscopic indications listed above, a facile lactam-to-lactone conversion of 7 OH to derive lactone 8 also would have been unexpected since this transformation takes place only in highly ring-strained lactams, a circumstance that could not be recognized here.…”

mentioning

confidence: 86%

Octaethyl-1,3-oxazinochlorin: A β-Octaethylchlorin Analogue Made by Pyrrole Expansion

Meehan

Zeller

et al. 2015

Org. Lett.

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Treatment of the oxime of octaethyloxochlorin 4, available from octaethylporphyrin 3, under Beckmann conditions provided not the expected lactam, but octaethyl-1,3-oxazinochlorin 8, in which a pyrrole moiety of the parent oxochlorin was expanded by an oxygen atom to an 1,3-oxazinone moiety. Its mechanism of formation was demonstrated to occur along an "abnormal Beckmann" pathway, followed by intramolecular ring closure and hydrolysis. The work expands the methodologies known to convert octaethylporphyrin to pyrrole-modified porphyrin analogues.

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Interconvertions between δ-Lactam and δ-Lactone Derivatives Initiated by Unique Transannular Interactions of the Rigid Cyclohexane Boat Structure in Pentacycloundecane

Cited by 14 publications

References 24 publications

Surprising Outcomes of Classic Ring‐Expansion Conditions Applied to Octaethyloxochlorin, 2. Beckmann‐Rearrangement Conditions

Surprising Outcomes of Classic Ring‐Expansion Conditions Applied to Octaethyloxochlorin, 2. Beckmann‐Rearrangement Conditions

Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study

Octaethyl-1,3-oxazinochlorin: A β-Octaethylchlorin Analogue Made by Pyrrole Expansion

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