Commencement Program, May (1997)

https://red.mnstate.edu/commencement/1166/thumbnail.jp

Molecular Recognition in Asymmetric Counteranion Catalysis: Understanding Chiral Phosphate-Mediated Desymmetrization

We describe the first theoretical study of a landmark example of chiral anion phase-transfer catalysis: the enantioselective ring-opening of <i>meso</i>-aziridinium and episulfonium cations promoted by asymmetric counteranion-directed catalysis (ACDC). The mechanism of ion-pairing, ring-opening, and catalyst deactivation have been studied in the condensed phase with both classical and quantum methods using explicitly and implicitly solvated models. We find that the stability of chiral ion-pairs, a prerequisite for asymmetric catalysis, is dominated by electrostatic interactions at long range and by CH···O interactions at short range. The decisive role of solvent upon ion-pair formation and of nonbonding interactions upon enantioselectivity are quantified by complementary computational approaches. The major enantiomer is favored by a smaller distortion of the substrate, demonstrated by a distortion/interaction analysis. Our computational results rationalize the stereoselectivity for several experimental results and demonstrate a combined classical/quantum approach to perform realistic modeling of chiral counterion catalysis in solution

Molecular Recognition in Asymmetric Counteranion Catalysis: Understanding Chiral Phosphate-Mediated Desymmetrization

We describe the first theoretical study of a landmark example of chiral anion phase-transfer catalysis: the enantioselective ring-opening of <i>meso</i>-aziridinium and episulfonium cations promoted by asymmetric counteranion-directed catalysis (ACDC). The mechanism of ion-pairing, ring-opening, and catalyst deactivation have been studied in the condensed phase with both classical and quantum methods using explicitly and implicitly solvated models. We find that the stability of chiral ion-pairs, a prerequisite for asymmetric catalysis, is dominated by electrostatic interactions at long range and by CH···O interactions at short range. The decisive role of solvent upon ion-pair formation and of nonbonding interactions upon enantioselectivity are quantified by complementary computational approaches. The major enantiomer is favored by a smaller distortion of the substrate, demonstrated by a distortion/interaction analysis. Our computational results rationalize the stereoselectivity for several experimental results and demonstrate a combined classical/quantum approach to perform realistic modeling of chiral counterion catalysis in solution

Origins of Asymmetric Phosphazene Organocatalysis: Computations Reveal a Common Mechanism for Nitro- and Phospho-Aldol Additions

We report a hybrid density functional theory–molecular mechanics study of the mechanism of the addition of nitroalkanes and phosphonates to benzaldehyde catalyzed by a chiral phosphacene catalyst developed by Ooi and co-workers. Our results are consistent with a reaction mechanism in which a catalyst molecule simultaneously interacts by hydrogen bonds with the nucleophile and the electrophile, transferring a proton to the aldehyde in concert with carbon–carbon bond formation. Despite the <i>C</i>₂ symmetry of this class of organocatalyst, substrate recognition, and asymmetric induction in both reaction classes studied relies on interactions with nonequivalent N–H bonds that break symmetry. The origin of the stereo and diastereoselectivity is discussed in terms of steric effects and of the conformations adopted by the reactants, and the most favorable transition structure results from minimal geometric distortion energies. A rational model for predicting the major stereoisomer of reactions catalyzed by this chiral phosphacene, based on the qualitative assessment of steric interactions, is given

Dynamic Intermediates in the Radical Cation Diels–Alder Cycloaddition: Lifetime and Suprafacial Stereoselectivity

Cation radical Diels–Alder cycloadditions proceed via an acyclic intermediate that exists on a flat region of the potential energy surface. Competition between cyclization and C–C bond rotation results in varying levels of suprafacial stereoselectivity. Quasi-classical trajectories were used to explore reaction dynamics on this surface. Even though there is no discernible energy barrier toward cyclization, a dynamically stepwise process is found, for which the acyclic intermediate is found to reside for several hundreds of femtoseconds. In a small number of cases, exceptionally long lifetimes (>1000 fs) are found, leading to a loss of alkene stereochemistry

<i>C</i>‑Alkylation of Chiral Tropane- and Homotropane-Derived Enamines

The synthesis and alkylation of chiral, nonracemic tropane- and homotropane-derived enamines is examined as an approach to enantioenriched α-alkylated aldehydes. The two bicyclic N auxiliaries, which differ by a single methylene group, give opposite senses of asymmetric induction on alkylation with EtI and provide modestly enantioenriched 2-ethylhexanal (following hydrolysis of the alkylated iminium). The observed stereoselectivity is supported by density functional studies of ethylation for both enamines

Concise Substrate-Controlled Asymmetric Total Syntheses of Dioxabicyclic Marine Natural Products with 2,10-Dioxabicyclo-[7.3.0]dodecene and 2,9-Dioxabicyclo[6.3.0]undecene Skeletons

We report a completely substrate-controlled approach to the asymmetric total synthesis of representative dioxabicyclic bromoallene marine natural products with either a 2,10-dioxabicyclo[7.3.0]­dodecene or 2,9-dioxabicyclo[6.3.0]­undecene skeleton from commercially available glycidol as a common starting material. The former include (−)-isolaurallene (<b>1</b>), the enantiomeric form of natural (+)-neolaurallene (<b>2</b>), and (+)-itomanallene A (<b>3c</b>), and the latter are (+)-laurallene (<b>4</b>) and (+)-pannosallene (<b>5a</b>). In addition, our first syntheses of <b>3c</b> and <b>5a</b> established the structure and absolute stereochemistry of both natural products. Our general approach to establish the α,α′-relative stereochemistry of the medium-ring (oxonene or oxocene) and tetrahydrofuran, respectively, involved the judicious pairing of our protecting-group-dependent intermolecular amide enolate alkylation (either chemoselective chelation-controlled or dianion alkylation) with either our intramolecular amide enolate or nitrile anion alkylation. Remarkable selectivity was achieved through the use of the appropriate alkylation steps, and this approach offered us optional access to any of these dioxabicyclic bromoallene marine natural products. In addition, a computational analysis was performed to investigate conformational effects on the rate of oxonene formation via RCM, a key step in these approaches. The results suggested an alternative rationale for reactivity based on the avoidance of eclipsing torstional interactions in the <b>AS2</b>-type ring conformation

Divergent Photocyclization/1,4-Sigmatropic Rearrangements for the Synthesis of Sesquiterpenoid Derivatives

Combined experimental and computational efforts have demonstrated the utility of divergent photocyclization/1,4-sigmatropic rearrangement reactions for developing a general strategy toward the synthesis of cubebane-, spiroaxane-, and guaiane-type sesquiterpenes and related analogues. The configuration of the bridgehead substituent, the choice of solvent, and the wavelength of irradiation all impact diastereoselectivity in this tandem reaction process

Concise Substrate-Controlled Asymmetric Total Syntheses of Dioxabicyclic Marine Natural Products with 2,10-Dioxabicyclo-[7.3.0]dodecene and 2,9-Dioxabicyclo[6.3.0]undecene Skeletons

We report a completely substrate-controlled approach to the asymmetric total synthesis of representative dioxabicyclic bromoallene marine natural products with either a 2,10-dioxabicyclo[7.3.0]­dodecene or 2,9-dioxabicyclo[6.3.0]­undecene skeleton from commercially available glycidol as a common starting material. The former include (−)-isolaurallene (<b>1</b>), the enantiomeric form of natural (+)-neolaurallene (<b>2</b>), and (+)-itomanallene A (<b>3c</b>), and the latter are (+)-laurallene (<b>4</b>) and (+)-pannosallene (<b>5a</b>). In addition, our first syntheses of <b>3c</b> and <b>5a</b> established the structure and absolute stereochemistry of both natural products. Our general approach to establish the α,α′-relative stereochemistry of the medium-ring (oxonene or oxocene) and tetrahydrofuran, respectively, involved the judicious pairing of our protecting-group-dependent intermolecular amide enolate alkylation (either chemoselective chelation-controlled or dianion alkylation) with either our intramolecular amide enolate or nitrile anion alkylation. Remarkable selectivity was achieved through the use of the appropriate alkylation steps, and this approach offered us optional access to any of these dioxabicyclic bromoallene marine natural products. In addition, a computational analysis was performed to investigate conformational effects on the rate of oxonene formation via RCM, a key step in these approaches. The results suggested an alternative rationale for reactivity based on the avoidance of eclipsing torstional interactions in the <b>AS2</b>-type ring conformation

Concise Substrate-Controlled Asymmetric Total Syntheses of Dioxabicyclic Marine Natural Products with 2,10-Dioxabicyclo-[7.3.0]dodecene and 2,9-Dioxabicyclo[6.3.0]undecene Skeletons

We report a completely substrate-controlled approach to the asymmetric total synthesis of representative dioxabicyclic bromoallene marine natural products with either a 2,10-dioxabicyclo[7.3.0]­dodecene or 2,9-dioxabicyclo[6.3.0]­undecene skeleton from commercially available glycidol as a common starting material. The former include (−)-isolaurallene (<b>1</b>), the enantiomeric form of natural (+)-neolaurallene (<b>2</b>), and (+)-itomanallene A (<b>3c</b>), and the latter are (+)-laurallene (<b>4</b>) and (+)-pannosallene (<b>5a</b>). In addition, our first syntheses of <b>3c</b> and <b>5a</b> established the structure and absolute stereochemistry of both natural products. Our general approach to establish the α,α′-relative stereochemistry of the medium-ring (oxonene or oxocene) and tetrahydrofuran, respectively, involved the judicious pairing of our protecting-group-dependent intermolecular amide enolate alkylation (either chemoselective chelation-controlled or dianion alkylation) with either our intramolecular amide enolate or nitrile anion alkylation. Remarkable selectivity was achieved through the use of the appropriate alkylation steps, and this approach offered us optional access to any of these dioxabicyclic bromoallene marine natural products. In addition, a computational analysis was performed to investigate conformational effects on the rate of oxonene formation via RCM, a key step in these approaches. The results suggested an alternative rationale for reactivity based on the avoidance of eclipsing torstional interactions in the <b>AS2</b>-type ring conformation