Development and mechanistic investigations into metal-catalysed cycloisomerisation of enynamides

This thesis reports the work on investigations into the mechanism of palladium-catalysed enynamide cycloisomerisations (with Pd(OAc)2 / bis(benzylidene)ethylenediamine (bbeda) catalyst system in particular). Herein, it has been shown that the mechanism of this catalyst system is likely to proceed via a hydropalladation mechanism. In the course of study, we have uncovered the crucial influences of water, the pre-catalyst, and the ligand (bbeda) in this reaction. One of the key highlights is bbeda itself serves as a source of palladium(II) hydride during the reaction. In addition, kinetic isotope effects obtained from theoretical analysis are consistent with the experimental data. The computational studies also offer enhanced understanding in the stereoselectivity of the reaction..

Chiral Bifunctional Phosphine Ligand Enables Asymmetric Trapping of Catalytic Vinyl Gold Carbene Species

Bifunctional ligand-enabled cooperative gold catalysis accelerates nucleophilic attacks and offers a versatile strategy to achieve asymmetric gold catalysis. Distinct from the prior studies employing alkyne/allene as the electrophilic site, this work engages an in situ-generated alkenyl/acyl gold carbene in a ligand-facilitated attack by an alcoholic nucleophile. With an amide-functionalized chiral binaphthylphosphine ligand, γ-alkoxy-α,β-unsaturated imides are formed with excellent enantiomeric excesses. The intermediacy of a carbene species is supported by its alternative access via dediazotization. The reaction tolerates a broad range of alcohols and can accommodate dienynamide substrates, in addition to arylenynamides. This work avails a versatile strategy to enrich gold chemistry and achieve challenging enantioselective gold catalysis via ligand-facilitated enantioselective trapping of reactive intermediates

Computational ligand design in enantio- and diastereoselective ynamide [5+2] cycloisomerization.

Transition metals can catalyse the stereoselective synthesis of cyclic organic molecules in a highly atom-efficient process called cycloisomerization. Many diastereoselective (substrate stereocontrol), and enantioselective (catalyst stereocontrol) cycloisomerizations have been developed. However, asymmetric cycloisomerizations where a chiral catalyst specifies the stereochemical outcome of the cyclization of a single enantiomer substrate-regardless of its inherent preference-are unknown. Here we show how a combined theoretical and experimental approach enables the design of a highly reactive rhodium catalyst for the stereoselective cycloisomerization of ynamide-vinylcyclopropanes to [5.3.0]-azabicycles. We first establish highly diastereoselective cycloisomerizations using an achiral catalyst, and then explore phosphoramidite-complexed rhodium catalysts in the enantioselective variant, where theoretical investigations uncover an unexpected reaction pathway in which the electronic structure of the phosphoramidite dramatically influences reaction rate and enantioselectivity. A marked enhancement of both is observed using the optimal theory-designed ligand, which enables double stereodifferentiating cycloisomerizations in both matched and mismatched catalyst-substrate settings

An Asymmetric Approach toward the Aristotelia Alkaloid (−)-Penduncularine

We report a catalytic enantioselective total synthesis of an endocyclic alkene regioisomer of (−)-peduncularine, termed (−)-pseudo-peduncularine, and also a synthesis of its C7 epimer. Highlights of the syntheses include a new strategy for the construction of the peduncularine framework by palladium-catalyzed ynamide cycloisomerization/enamide reduction, which could be performed on a multigram scale. By introducing the indole side chain as a substituent on the ynamide, this approach contrasts with previous strategies that have relied on late-stage Fischer indole synthesis. Inversion of the C7 stereocenter installed in the cycloisomerization process could be readily achieved by temporary azabicycle ring opening, using an enamide hydrolysis/ketone reduction/Mitsunobu cyclization sequence. A catalytic asymmetric sulfonamidation of a racemic allylic benzoate enabled an enantioselective synthesis of (−)-pseudo-peduncularine

Rhodium-catalyzed cycloadditions to construct nitrogen heterocycles and progress towards the synthesis of ionomycin

2014 Spring.Includes bibliographical references.The ability to construct molecules in a rapid, atom-economical fashion is a major goal of organic chemistry. This work describes four topics; pyridone synthesis, mechanistic understanding in [2+2+2] cycloadditions, pyrimidinone synthesis, and progress towards ionomycin. The first chapter describes the synthesis of 4,6-substituted 2-pyridones and 3,5-substituted 4-pyridones from the rhodium-catalyzed [2+2+2] cycloaddition of two alkynes and an isocyanate. Our group demonstrated that an enantioselective rhodium-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and alkynes generates indolizidinone and quinolizidinone products. Although trends for product and regioselectivity were established, the underlying mechanism was unclear. The second chapter describes X-ray analysis of rhodium·phosphoramidite complexes in conjunction with other mechanistic work to elucidate a theory that explains product and regioselectivity in this reaction. This system is amazing in that it illuminates the factors contributing to oxidative cycloadditions in a spectacular fashion by delivering two different products. The third chapter describes the enantioselective synthesis of pyrimidinones from a rhodium-catalyzed [4+2] cycloaddition of α, β-unsaturated imines and isocyanates. The final chapter describes our group's progress toward the synthesis of ionomycin using rhodium-catalyzed desymmetrization of anhydrides with zinc nucleophiles

General Entry into o-,o’-Heteroatom-Linked N-(Hetero)aryl Imidazole Motifs by Gold-Catalysed Formal [3+2]-Dipolar Cycloaddition

A general redox-neutral approach into the o-,o’-heteroatom-linked N-(hetero)aryl imidazole family of heteroaromatics has been developed. New types of heteroatom substituted carbimidoyl nitrenoids are efficiently realised from robust, bench-stable N-(heteroaryl) pyridinium N-aminides by formal gold-catalysed [3+2]-dipolar cycloadditions across ynamides. Broad structural variety and functional group tolerance allows rapid access into diverse functionalised scaffolds, as exemplified by the preparation of 8 different heteroaromatic cores

Sequencing palladium-catalyzed cycloisomerization cascades in a synthesis of the gelsemine core

Transition metal-catalyzed cycloisomerization is a powerful strategy for the construction of cyclic organic molecules, and the use of palladium catalysts can deliver a wide range of monocyclic and bicyclic products. However, applications of cycloisomerizations in complex target synthesis in which more than one cycloisomerization process is deployed in a cascade context are rare. Here we report investigations of the relative rates of two different types of ene-ynamide cycloisomerization that form fused and spirocyclic rings, and use of these results to design a sequence-controlled cascade cycloisomerization that prepares the tetracyclic core of gelsemine in a single step. Crucial to this work was an evaluation of the kinetics of each cycloisomerization in competition experiments, which revealed a key influence of the ynamide electron-withdrawing group on the cycloisomerization reaction

Recent Topics of Cp*RuCl-Catalyzed Annulation Reactions

A wide variety of annulation reactions have been developed using Cp^∗RuCl(cod) and related complexes as precatalysts. This digest highlights recent progress in Cp^∗RuCl-catalyzed annulation reactions. State-of-the-art examples are outlined as follows: [2+2+2] cycloadditions, [2+2] cycloadditions, cyclizations of enynes, and other annulation reactions.journal articl

Sulfenyl Ynamides in Gold Catalysis: Synthesis of Oxo‐functionalised 4‐aminoimidazolyl Fused Compounds by Intermolecular Annulation Reactions

Functionalised N-heterocyclic pyridinium N-aminides have been designed and synthesised to evaluate a nitrenoid-based annulation strategy into imidazole-fused oxo-substituted frameworks of importance to medicinal and agrochemical discovery programmes. Sulfenyl substituted ynamides were identified as privileged reactants affording productive gold-catalysed annulation reactions with these and other nitrenoids. This annulation method provides selective and efficient access into geminally amino-sulfenyl substituted nitrogen heterocycles under mild reaction conditions. (Figure presented.).</p

Synthesis of indolines and indoles via intramolecular [4 + 2] cycloaddition of ynamides and conjugated enynes ; Synthesis of nitrogen heterocycles in supercritical carbon dioxide

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2005.Vita.Includes bibliographical references.A general amination strategy for the N-alkynylation of carbamates, sulfonamides, and chiral oxazolidinones and imidazolidinones is described. A variety of substituted ynamides are available by deprotonation of amide derivatives with KHMDS followed by reaction with CuI and an alkynyl halide. Ynamides react with conjugated enynes in intramolecular [4 + 2] cycloaddition to afford substituted indolines that undergo oxidation with o-chloranil to furnish the corresponding indoles. The cycloaddition substrates are easily assembled from derivatives of 3-butynylamine by Sonogashira coupling with alkenyl halides followed by copper-catalyzed N-alkynylation with acetylenic bromides. Diynamides participate as particularly reactive 2[pi] components in the cycloaddition, providing access to indolines with carbon substituents at the C-7 position. Enynamides serve as 4[pi] components in a complementary version of the cycloaddition strategy which provides access to indoles and indolines substituted with substituents at C-4. These enyne cycloadditions take place upon heating the substrates at 110-210⁰C in toluene or 2,2,2- trifluoroethanol and in some cases can be achieved at 0⁰C to room temperature in the presence of Lewis acids such as Me₂A1C1.(cont.) We have developed a "green" strategy to effect acyl-Pictet-Spengler reactions in multiphasic scCO₂/CO₂-expanded liquid media. These cyclizations of iminium ions provide tetrahydroisoquinolines and tetrahydro-[beta]-carbolines that have valuable medicinal properties. Critical to the success of these reactions is the in situ conversion of [beta]-arylethylamine reactants to c;arbamate derivatives by reaction with carbon dioxide and dialkyl carbonates. The application of this general strategy for utilizing amines in other carbon-nitrogen bond-forming reactions in environmentally-friendly media is under investigation.by Joshua Ross Dunetz.Ph.D