Z-Selectivity in Olefin Metathesis with Chelated Ru Catalysts: Computational Studies of Mechanism and Selectivity

The mechanism and origins of Z-selectivity in olefin metathesis with chelated Ru catalysts were explored using density functional theory. The olefin approaches from the “side” position of the chelated Ru catalysts, in contrast to reactions with previous unchelated Ru catalysts that favor the bottom-bound pathway. Steric repulsions between the substituents on the olefin and the N-substituent on the N-heterocyclic carbene ligand lead to highly selective formation of the Z product

Enantioselective Synthesis of Dialkylated N-Heterocycles by Palladium-Catalyzed Allylic Alkylation

The enantioselective synthesis of α-disubstituted N-heterocyclic carbonyl compounds has been accomplished using palladium-catalyzed allylic alkylation. These catalytic conditions enable access to various heterocycles, such as morpholinone, thiomorpholinone, oxazolidin-4-one, 1,2-oxazepan-3-one, 1,3-oxazinan-4-one, and structurally related lactams, all bearing fully substituted α-positions. Broad functional group tolerance was explored at the α-position in the morpholinone series. We demonstrate the utility of this method by performing various transformations on our useful products to readily access a number of enantioenriched compounds

Iterative approach to computational enzyme design

A general approach for the computational design of enzymes to catalyze arbitrary reactions is a goal at the forefront of the field of protein design. Recently, computationally designed enzymes have been produced for three chemical reactions through the synthesis and screening of a large number of variants. Here, we present an iterative approach that has led to the development of the most catalytically efficient computationally designed enzyme for the Kemp elimination to date. Previously established computational techniques were used to generate an initial design, HG-1, which was catalytically inactive. Analysis of HG-1 with molecular dynamics simulations (MD) and X-ray crystallography indicated that the inactivity might be due to bound waters and high flexibility of residues within the active site. This analysis guided changes to our design procedure, moved the design deeper into the interior of the protein, and resulted in an active Kemp eliminase, HG-2. The cocrystal structure of this enzyme with a transition state analog (TSA) revealed that the TSA was bound in the active site, interacted with the intended catalytic base in a catalytically relevant manner, but was flipped relative to the design model. MD analysis of HG-2 led to an additional point mutation, HG-3, that produced a further threefold improvement in activity. This iterative approach to computational enzyme design, including detailed MD and structural analysis of both active and inactive designs, promises a more complete understanding of the underlying principles of enzymatic catalysis and furthers progress toward reliably producing active enzymes

Selective Enzymatic Oxidation of Silanes to Silanols

Compared to the biological world's rich chemistry for functionalizing carbon, enzymatic transformations of the heavier homologue silicon are rare. We report that a wild‐type cytochrome P450 monooxygenase (P450_(BM3) from Bacillus megaterium, CYP102A1) has promiscuous activity for oxidation of hydrosilanes to give silanols. Directed evolution was applied to enhance this non‐native activity and create a highly efficient catalyst for selective silane oxidation under mild conditions with oxygen as the terminal oxidant. The evolved enzyme leaves C−H bonds present in the silane substrates untouched, and this biotransformation does not lead to disiloxane formation, a common problem in silanol syntheses. Computational studies reveal that catalysis proceeds through hydrogen atom abstraction followed by radical rebound, as observed in the native C−H hydroxylation mechanism of the P450 enzyme. This enzymatic silane oxidation extends nature's impressive catalytic repertoire

Computational Design of a Tetrapericyclic Cycloaddition and the Nature of Potential Energy Surfaces with Multiple Bifurcations

An ambimodal transition state (TS) that leads to formation of four different pericyclic reaction products ([4 + 6]-, [2 + 8]-, [8 + 2]-, and [6 + 4]-cycloadducts) without any intervening minima has been designed and explored with DFT computations and quasiclassical molecular dynamics. Direct dynamics simulations propagated from the ambimodal TS show the evolution of trajectories to give the four cycloadducts. The topography of the PES is a key factor in product selectivity. A good correlation is observed between geometrical resemblance of the products to the ambimodal TS (measured by the RMSD) and the ratio of products formed in the dynamics simulationsWe are grateful to the National Science Foundation (CHE1764328 to K.N.H.) for financial support of this research and for access to XSEDE and UCLA Hoffman 2 for computer time and for this study. A.M.S. thanks the Madrid Government (Comunidad de Madrid-Spain) under the Multiannual Agreement with Universidad Autónoma de Madrid in the line Support to Young Researchers, in the context of the V PRICIT (SI3-PJI-2021-00463) and “Ministerio de Educación Cultura y Deporte” for funding (CAS18/00458

Metal-free α-amination of secondary amines: Computational and experimental evidence for azaquinone methide and azomethine ylide intermediates

We have performed a combined computational and experimental study to elucidate the mechanism of a metal-free α-amination of secondary amines. Calculations predicted azaquinone methides and azomethine ylides as the reactive intermediates and showed that iminium ions are unlikely to participate in these transformations. These results were confirmed by experimental deuterium-labeling studies and the successful trapping of the postulated azomethine ylide and azaquinone methide intermediates. In addition, computed barrier heights for the rate-limiting step correlate qualitatively with experimental findings. © 2013 American Chemical Society

Ground- and Excited-State Reactions of Norbornene and Isomers: A CASSCF Study and Comparison with Femtosecond Experiments

The ground-state and ^1(ππ^*)-state potential energy surfaces of norbornene and isomeric C_7H_(10) species were mapped using CASSCF theory and the 6-31G^* basis set and compared with the results of femtosecond experiments on norbornene retro Diels−Alder reactions. Computations explored stepwise and concerted retro Diels−Alder pathways, [1,3]-sigmatropic shifts, and [1,2]-sigmatropic shifts originating from the ^1(ππ^*)-state or ground-state surfaces. Extremely efficient decay occurs from the excited state to the ground state via two different conical intersections (surface crossings). The first of these crossing points is accessed by one-bond cleavage of C1−C6 (or C4−C5). Several possible subsequent ground-state reaction paths have been identified:  (a) ring-closure to form norbornene; (b) ring-closure to form bicyclo[3.2.0]hept-2-ene ([1,3]-sigmatropic shift); (c) formation of a metastable 1,3-biradical which closes to form tricyclo[3.2.1.0^(3,7)]heptane ([1,2]-sigmatropic shift); and (d) collapse of a gauche-in biradical to a vibrationally excited cyclopentadiene and ethylene, or norbornene. Excited-state one-bond cleavage of C4−C7 (or C1−C7) leads to the second conical intersection. Possible ground-state reaction pathways from this structure lead to the formation of bicyclo[4.1.0]hept-2-ene ([1,3]-sigmatropic shift product) or to a second 1,3-biradical leading to tricyclo[3.2.1.0^(3,7)]heptane ([1,2]-sigmatropic shift product). The vibrationally excited cyclopentadiene is the 220 fs lifetime species of mass 66 amu, consistent with the retro Diels−Alder reaction observed in the femtosecond laser experiments. It is proposed that biradicaloids formed after decay through the conical intersections are the 94 amu species, with an average lifetime of about 160 fs