A mechanistic
study of the isothiourea-catalyzed enantioselective
[2,3]-rearrangement of allylic ammonium ylides is described. Reaction
kinetic analyses using 19F NMR and density functional theory
computations have elucidated a reaction profile and allowed identification
of the catalyst resting state and turnover-rate limiting step. A catalytically
relevant catalyst–substrate adduct has been observed, and its
constitution elucidated unambiguously by 13C and 15N isotopic labeling. Isotopic entrainment has shown the observed
catalyst–substrate adduct to be a genuine intermediate on the
productive cycle toward catalysis. The influence of HOBt as an additive
upon the reaction, catalyst resting state, and turnover-rate limiting
step has been examined. Crossover experiments have probed the reversibility
of each of the proposed steps of the catalytic cycle. Computations
were also used to elucidate the origins of stereocontrol, with a 1,5-S···O
interaction and the catalyst stereodirecting group providing transition
structure rigidification and enantioselectivity, while preference
for cation−π interactions over C–H···π
is responsible for diastereoselectivity.
We
report a new method for X-ray density ligand fitting and refinement
that is suitable for a wide variety of small-molecule ligands, including
macrocycles. The approach (called “xGen”) augments a
force field energy calculation with an electron density fitting restraint
that yields an energy reward during the restrained conformational
search. The resulting conformer pools balance goodness-of-fit with
ligand strain. Real-space refinement from pre-existing ligand coordinates
of 150 macrocycles resulted in occupancy-weighted conformational ensembles
that exhibited low strain energy. The xGen ensembles improved upon
electron density fit compared with the PDB reference coordinates without
making use of atom-specific B-factors. Similarly, on nonmacrocycles, de novo fitting produced occupancy-weighted ensembles of
many conformers that were generally better-quality density fits than
the deposited primary/alternate conformational pairs. The results
suggest ubiquitous low-energy ligand conformational ensembles in X-ray
diffraction data and provide an alternative to using B-factors as
model parameters.
Macrocyclic peptides are an important modality in drug discovery, but molecular design is limited due to the complexity of their conformational landscape. To better understand conformational propensities, global strain energies were estimated for 156 protein-macrocyclic peptide cocrystal structures. Unexpectedly large strain energies were observed when the bound-state conformations were modeled with positional restraints. Instead, low-energy conformer ensembles were generated using xGen that fit experimental X-ray electron density maps and gave reasonable strain energy estimates. The ensembles featured significant conformational adjustments while still fitting the electron density as well or better than the original coordinates. Strain estimates suggest the interaction energy in protein−ligand complexes can offset a greater amount of strain for macrocyclic peptides than for small molecules and non-peptidic macrocycles. Across all molecular classes, the approximate upper bound on global strain energies had the same relationship with molecular size, and bound-state ensembles from xGen yielded favorable binding energy estimates.
The measurement of a deuterium equilibrium
isotope effect (EIE)
for the aryl CH···Cl– interaction
of anion receptor 1H/1D is reported. Computations corroborate
the results of solution measurements for a small, normal EIE in the
full complex (KaH/KaD = 1.019 ± 0.010). Interestingly,
isotope effects involving fragments of the anion receptor (urea, aryl
ring, etc.) are predicted to produce an inverse effect. This points
to an unusual and subtle structural organization effect of the anion
receptor complex that changes the nature of the combined interactions
to a normal isotope effect. The reversal of EIE values suggests that
overall architecture of the anion receptor can dramatically impact
the nature of bonding in these complexes.
A direct decarboxylative strategy for the generation of aza‐o‐quinone methides (aza‐o‐QMs) by N‐heterocyclic carbene (NHC) catalysis has been discovered and explored. This process requires no stoichiometric additives in contrast with current approaches. Aza‐o‐QMs react with trifluoromethyl ketones through a formal [4+2] manifold to access highly enantioenriched dihydrobenzoxazin‐4‐one products, which can be converted to dihydroquinolones through an interesting stereoretentive aza‐Petasis–Ferrier rearrangement sequence. Complementary dispersion‐corrected density functional theory (DFT) studies provided an accurate prediction of the reaction enantioselectivity and lend further insight to the origins of stereocontrol. Additionally, a computed potential energy surface around the major transition structure suggests a concerted asynchronous mechanism for the formal annulation.
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