Hung V. Pham

Diels–Alder Reactions of Allene with Benzene and Butadiene: Concerted, Stepwise, and Ambimodal Transition States

Multiconfigurational complete active space methods (CASSCF and CASPT2) have been used to investigate the (4 + 2) cycloadditions of allene with butadiene and with benzene. Both concerted and stepwise radical pathways were examined to determine the mechanism of the Diels–Alder reactions with an allene dienophile. Reaction with butadiene occurs via a single ambimodal transition state that can lead to either the concerted or stepwise trajectories along the potential energy surface, while reaction with benzene involves two separate transition states and favors the concerted mechanism relative to the stepwise mechanism via a diradical intermediate.

Intramolecular Diels–Alder Reactions of Cycloalkenones: Stereoselectivity, Lewis Acid Acceleration, and Halogen Substituent Effects

The intramolecular Diels–Alder reactions of cycloalkenones and terminal dienes occur with high endo stereoselectivity, both thermally and under Lewis-acidic conditions. Through computations, we show that steric repulsion and tether conformation govern the selectivity of the reaction, and incorporation of either BF3 or α-halogenation increases the rate of cycloaddition. With a longer tether, isomerization from a terminal diene to the more stable internal diene results in a more facile cycloaddition.

Dicyanovinylnaphthalenes for neuroimaging of amyloids and relationships of electronic structures and geometries to binding affinities

The positron-emission tomography (PET) probe 2-(1-[6-[(2-fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene) (FDDNP) is used for the noninvasive brain imaging of amyloid-β (Aβ) and other amyloid aggregates present in Alzheimer’s disease and other neurodegenerative diseases. A series of FDDNP analogs has been synthesized and characterized using spectroscopic and computational methods. The binding affinities of these molecules have been measured experimentally and explained through the use of a computational model. The analogs were created by systematically modifying the donor and the acceptor sides of FDDNP to learn the structural requirements for optimal binding to Aβ aggregates. FDDNP and its analogs are neutral, environmentally sensitive, fluorescent molecules with high dipole moments, as evidenced by their spectroscopic properties and dipole moment calculations. The preferred solution-state conformation of these compounds is directly related to the binding affinities. The extreme cases were a nonplanar analog t-butyl-FDDNP, which shows low binding affinity for Aβ aggregates (520 nM Ki) in vitro and a nearly planar tricyclic analog cDDNP, which displayed the highest binding affinity (10 pM Ki). Using a previously published X-ray crystallographic model of 1,1-dicyano-2-[6-(dimethylamino)naphthalen-2-yl]propene (DDNP) bound to an amyloidogenic Aβ peptide model, we show that the binding affinity is inversely related to the distortion energy necessary to avoid steric clashes along the internal surface of the binding channel.

The intramolecular Diels–Alder reaction of tryptamine-derived Zincke aldehydes is a stepwise process

Computational studies show that the base-mediated intramolecular Diels-Alder of tryptamine-derived Zincke aldehydes, used as a key step in the synthesis of the Strychnos alkaloids norfluorocurarine and strychnine, proceeds via a stepwise pathway. The experimentally determined importance of a potassium counterion in the base is explained by its ability to preorganize the Zincke aldehyde diene in an s-cis conformation suitable to bicyclization. Computation also supports the thermodynamic importance of the generation of a stable enolate in the final reaction step. The thermal cycloreversion reaction of the Diels-Alder products is also found to proceed in a stepwise manner.

Studies on the Himbert Intramolecular Arene/Allene Diels–Alder Cycloaddition. Mechanistic Studies and Expansion of Scope to All-Carbon Tethers

The unusual intramolecular arene/allene cycloaddition described 30 years ago by Himbert permits rapid access to strained polycyclic compounds that offer great potential for the synthesis of complex scaffolds. To more fully understand the mechanism of this cycloaddition reaction, and to guide efforts to extend its scope to new substrates, quantum mechanical computational methods were employed in concert with laboratory experiments. These studies indicated that the cycloadditions likely proceed via concerted processes; a stepwise biradical mechanism was shown to be higher in energy in the cases studied. The original Himbert cycloaddition chemistry is also extended from heterocyclic to carbocyclic systems, with computational guidance used to predict thermodynamically favorable cases. Complex polycyclic scaffolds result from the combination of the cycloaddition and subsequent ring-rearrangement metathesis reactions.

Nitrone Cycloadditions of 1,2-Cyclohexadiene.

We report the first 1,3-dipolar cycloadditions of 1,2-cyclohexadiene, a rarely exploited strained allene. 1,2-Cyclohexadiene is generated in situ under mild conditions and trapped with nitrones to give isoxazolidine products in synthetically useful yields. The reactions occur regioselectively and exhibit a notable endo preference, thus resulting in the controlled formation of two new bonds and two stereogenic centers. DFT calculations of stepwise and concerted reaction pathways are used to rationalize the observed selectivities. Moreover, the strategic manipulation of nitrone cycloadducts demonstrates the utility of this methodology for the assembly of compounds bearing multiple heterocyclic units. These studies showcase the exploitation of a traditionally avoided reactive intermediate in chemical synthesis.

Computation and Experiment Reveal that the Ring-Rearrangement Metathesis of Himbert Cycloadducts Can Be Subject to Kinetic or Thermodynamic Control

Unusual observations in the ring-rearrangement metathesis of Himbert arene/allene cycloadducts to form fused polycylic lactams led to a more in-depth experimental study that yielded conflicting results. Differences in reactivity within related systems and unexpected changes in diastereoselectivity among other similar substrates were not readily explained on the basis of the experimental results. Computational investigations demonstrated substrate-dependent changes in reaction pathways (ring-opening metathesis/ring-closing metathesis [ROM/RCM] cascade vs ring-closing metathesis/ring-opening metathesis [RCM/ROM] cascade). Furthermore, some reactions were judged to be under thermodynamic control and others under kinetic control. The greater understanding of the most likely reaction pathways and their energetics provides a reasonable explanation for the previously irreconcilable results.

Palladium hydride promoted stereoselective isomerization of unactivated di(exo)methylenes to endocyclic dienes.

The exomethylenes of 2,6-disubstituted bicyclo[3.3.1]nonan-9-ones 2 are readily isomerized over a palladium catalyst under an atmosphere of hydrogen to predominantly form the isomer 3 with C2 symmetry with very little formation of the analogous product with Cs symmetry. A hydrogen source is essential to effect the rearrangement.

Thermodynamic Control of Isomerizations of Bicyclic Radicals: Interplay of Ring Strain and Radical Stabilization

The rearrangements of 4-substituted bicyclo[2.2.2]oct-5-en-2-yl radicals, generated from the corresponding Diels-Alder adducts with phenylseleno acrylates by radical-induced reductive deselenocarbonylations, give the 2-substituted bicyclo[3.2.1]oct-6-en-2-yl radicals with some substituents, e.g., alkoxy and phenyl, but not for silyloxymethyl or benzyl substituents. Theoretical calculations with DFT give the thermodynamics of these reactions and the origins of these processes.