Transition States of Vicinal Diamine-Catalyzed Aldol Reactions

The transition states of aldol reactions catalyzed by vicinal diamines are characterized with density functional calculations. It was found that a cyclic transition state involving a nine-membered hydrogen-bonded ring is preferred. The crown (chair–chair) conformations of the transition state account for the observed stereoselectivity of these reactions

Origins of Stereoselectivity of Enamine–Iminium-Activated Nazarov Cyclizations by Vicinal Diamines

The mechanism and sources of asymmetric induction in Nazarov reactions reported by Tius and co-workers have been determined with quantum chemical calculations. A chiral vicinal diamine forms an enamine–iminium adduct with α-ketoenones, and this undergoes a cationic conrotatory electrocyclization. The chiral diamine imparts stereocontrol in the enamine–iminium complex by forming a six-membered ring that favors one helicity of the electrocyclization transition state

Origins of Stereoselectivity of Chiral Vicinal Diamine-Catalyzed Aldol Reactions

The sources of asymmetric induction in aldol reactions catalyzed by cinchona alkaloid-derived amines, and chiral vicinal diamines in general, have been determined by density functional theory calculations. Four vicinal diamine-catalyzed aldol reactions were examined. The cyclic transition states of these reactions involve nine-membered hydrogen-bonded rings in distinct conformations. Using nomenclature from eight-membered cycloalkanes, the heavy atoms of the low-energy transition states are in crown (chair–chair) and chair-boat conformations. The factors that control which of these are favored have been identified

Arynes and Cyclic Alkynes as Synthetic Building Blocks for Stereodefined Quaternary Centers

We report a facile method to synthesize stereodefined quaternary centers from reactions of arynes and related strained intermediates using β-ketoester-derived substrates. The conversion of β-ketoesters to chiral enamines is followed by reaction with in situ generated strained arynes or cyclic alkynes. Hydrolytic workup provides the arylated or alkenylated products in enantiomeric excesses as high as 96%. We also describe the one-pot conversion of a β-ketoester substrate to the corresponding enantioenriched α-arylated product. Computations show how chirality is transferred from the <i>N</i>-bound chiral auxiliary to the final products. These are the first theoretical studies of aryne trapping by chiral nucleophiles to set new stereocenters. Our approach provides a solution to the challenging problem of stereoselective β-ketoester arylation/alkenylation, with formation of a quaternary center

P450-Mediated Coupling of Indole Fragments To Forge Communesin and Unnatural Isomers

Dimeric indole alkaloids are structurally diverse natural products that have attracted significant attention from the synthetic and biosynthetic communities. Here, we describe the characterization of a P450 monooxygenase CnsC from Penicillium that catalyzes the heterodimeric coupling between two different indole moieties, tryptamine and aurantioclavine, to construct vicinal quaternary stereocenters and yield the heptacyclic communesin scaffold. We show, via biochemical characterization, substrate analogues, and computational methods that CnsC catalyzes the C3-C3′ carbon-carbon bond formation and controls the regioselectivities of the pair of subsequent aminal bond formations to yield the communesin core. Use of ω-<i>N</i>-methyltryptamine and tryptophol in place of tryptamine led to the enzymatic synthesis of isocommunesin compounds, which have not been isolated to date

Model for the Enantioselectivity of Asymmetric Intramolecular Alkylations by Bis-Quaternized Cinchona Alkaloid-Derived Catalysts

A model for the stereoselectivity of intramolecular alkylations by <i>N</i>,<i>N</i>′-disubstituted cinchona alkaloids reported by Xiang et al. was established using density functional theory (DFT) calculations. The stereocontrol is based on the minimal distortion of the transition state (TS) and catalyst required to achieve favorable electrostatic interactions in the favored TS. Counterions must be included in computational modeling of ion-paired catalysis in order to reproduce experimental enantioselectivity