Source of Rate Acceleration for Carbocation Cyclization in Biomimetic Supramolecular Cages.

The results of quantum chemical and molecular dynamics calculations reveal that polyanionic gallium-based cages accelerate cyclization reactions of pentadienyl alcohols as a result of substrate cage interactions, preferential binding of reactive conformations of substrate/H3O+ pairs, and increased substrate basicity. However, the increase in basicity dominates. Experimental structure-activity relationship studies in which the metal vertices and overall charge of the cage are varied confirm the model derived via calculations.

Structure Determination of a Chloroenyne from Laurencia majuscula Using Computational Methods and Total Synthesis.

Despite numerous advances in spectroscopic methods through the latter part of the 20th century, the unequivocal structure determination of natural products can remain challenging, and inevitably, incorrect structures appear in the literature. Computational methods that allow the accurate prediction of NMR chemical shifts have emerged as a powerful addition to the toolbox of methods available for the structure determination of small organic molecules. Herein, we report the structure determination of a small, stereochemically rich natural product from Laurencia majuscula using the powerful combination of computational methods and total synthesis, along with the structure confirmation of notoryne, using the same approach. Additionally, we synthesized three further diastereomers of the L. majuscula enyne and have demonstrated that computations are able to distinguish each of the four synthetic diastereomers from the 32 possible diastereomers of the natural product. Key to the success of this work is to analyze the computational data to provide the greatest distinction between each diastereomer, by identifying chemical shifts that are most sensitive to changes in relative stereochemistry. The success of the computational methods in the structure determination of stereochemically rich, flexible organic molecules will allow all involved in structure determination to use these methods with confidence.

Total Synthesis of (-)-Himalensine A.

The first enantioselective synthesis of (-)-himalensine A has been achieved in 22 steps. The synthesis was enabled by a novel catalytic, enantioselective prototropic shift/furan Diels-Alder (IMDAF) cascade to construct the ACD tricyclic core. A reductive radical cyclization cascade was utilized to build the B ring, and end-game manipulations featuring a molecular oxygen mediated γ-CH oxidation, a Stetter cyclization to access the pendant cyclopentenone, and a highly chemoselective lactam reduction delivered the natural product target.

The catalytic effect of the NH3 base on the chemical events in the caryolene-forming carbocation cascade.

Caryolene formation occur asynchronously in a concerted way through carbocationic rearrangements involving the generation of a secondary or a tertiary carbocation whether the reaction proceeds in the absence or in the presence of NH3 , respectively. Both caryolene formation mechanisms are analyzed within the general framework of the reaction force; the reaction force constant is used to gain insights into the synchronicity of the mechanisms and the reaction electronic flux helps to characterize the electronic activity taking place during the reaction. DFT calculations at the B3LYP/6-31+G(d,p) level show a clear difference in the mechanisms of the base promoted or base free caryolene formation reactions.

Caryolene-forming carbocation rearrangements.

Density functional theory calculations on mechanisms of the formation of caryolene, a putative biosynthetic precursor to caryol-1(11)-en-10-ol, reveal two mechanisms for caryolene formation: one involves a base-catalyzed deprotonation/reprotonation sequence and tertiary carbocation minimum, whereas the other (with a higher energy barrier) involves intramolecular proton transfer and the generation of a secondary carbocation minimum and a hydrogen-bridged minimum. Both mechanisms are predicted to involve concerted suprafacial/suprafacial [2 + 2] cycloadditions, whose asynchronicity allows them to avoid the constraints of orbital symmetry.

The many roles of quantum chemical predictions in synthetic organic chemistry.

This account discusses representative case studies for various applications of quantum chemical calculations in synthetic organic chemistry. These include confirmation of target structures, methodology development, and catalyst design. These examples demonstrate how predictions from quantum chemical calculations can be utilized to streamline synthetic efforts.