Reactions of (Arylimido)vanadium(V)–Trialkyl Complexes with Phenols: Effects of Arylimido Ligands and Phenols for Formation of the Vanadium Phenoxides

Reactions of a series of (arylimido)vanadium(V) trialkyl complexes, V(NAr′)(CH_2SiMe_3)_3 (Ar′ = C_6H_5, 2-MeC_6H_4, 2,6-Me_2C_6H_3, 2,6-Cl_2C_6H_3), with various phenols (ArOH, Ar = 2,6-F_2C_6H_3, 2,6-Cl_2C_6H_3, 2,6-Me_2C_6H_3, 2,6-^iPr_2C_6H_3, 2-^tBuC_6H_4, 2,6-^tBu_2C_6H_3; 1.0 equiv) affording V(NAr′)(CH_2SiMe_3)_2(OAr) were conducted in C_6D_6 at 25 °C, and the effects of both arylimido ligands and phenols on the substitution rate were explored. Sterically hindered arylimido ligands showed lower reactivity, and the reaction proceeded in the order: Ar′ = 2,6-Me_2C_6H_3 < 2,6-Cl_2C_6H_3 < 2-MeC_6H_4< C_6H_5. This order is somewhat different from that obtained from the chemical shifts in V(NAr′)(CH_2SiMe_3)_3 in the ^(51)V NMR spectra. The conversions with various disubstituted phenols increased in the order: 2,6-^iPr_2C_6H_3OH < 2,6-Me_2C_6H_3OH < 2,6-Cl_2C_6H_3OH < 2,6-F_2C_6H_3OH, irrespective of the kind of arylimido ligands. The reactions of V(NAr′)(CH_2SiMe_3)_3 with 2,6-^tBu_2C_6H_3OH (1.0 or 3.0 equiv) did not take place even upon heating at 60 °C. These results suggest that the reactions proceed via coordination of ArOH toward vanadium, and the reactivity is highly dependent on steric bulk of both the arylimido ligand and the phenol

I. Development of Nickel- and Palladium-Catalyzed Asymmetric Allylic Alkylation Reactions. II. Enantioselective Syntheses of Tetrahydroisoquinoline–Based Natural Products and Unnatural Analogs

Described in this thesis are four projects related to the development of synthetic methodologies for the preparation of enantioenriched building blocks, and the total syntheses of complex tetrahydroisoquinoline natural products. In Chapter 1, the development of nickel-catalyzed asymmetric allylic alkylation of lactones and lactams with allylic alcohols is presented. In Chapter 2, the development of palladium-catalyzed enantioselective decarboxylative allylic alkylation of silicon-containing heterocycles is detailed. In these chapters, the utilization of prochiral enolates as nucleophiles has enabled access to enantioenriched all-carbon quaternary stereocenters. Chapter 3 describes the total syntheses of bis-tetrahydroisoquinoline alkaloids, (–)-jorumycin and (–)-jorunnamycin A. A general synthetic strategy, which exploits the tandem cross-coupling/hydrogenation approach, represents the first non-biomimetic synthetic route and allows for an efficient construction of the pentacyclic core in a highly modular fashion. Additional bis-tetrahydroisoquinoline analogs were prepared, and preliminary studies to probe their cytotoxicity against cancer cell lines were conducted. Finally, an extension of the enantioselective and diastereoselective hydrogenation technology to include simple 1,3-disubstituted isoquinolines is described in Chapter 4.</p

Enantioselective synthesis of highly oxygenated acyclic quaternary center-containing building blocks via palladium-catalyzed decarboxylative allylic alkylation of cyclic siloxyketones

The development of a palladium-catalyzed enantioselective decarboxylative allylic alkylation of cyclic siloxyketones to produce enantioenriched silicon-tethered heterocycles is reported. The reaction proceeds smoothly to provide products bearing a quaternary stereocenter in excellent yields (up to 91% yield) with high levels of enantioselectivity (up to 94% ee). We further utilized the unique reactivity of the siloxy functionality to access chiral, highly oxygenated acyclic quaternary building blocks. In addition, we subsequently demonstrated the utility of these compounds through the synthesis of a lactone bearing vicinal quaternary-trisubstituted stereocenters

Nickel-catalyzed enantioselective allylic alkylation of lactones and lactams with unactivated allylic alcohols

The first nickel-catalyzed enantioselective allylic alkylation of lactone and lactam substrates to deliver products bearing an all-carbon quaternary stereocenter is reported. The reaction, which utilizes a commercially available chiral bisphosphine ligand, proceeds in good yield with a high level of enantioselectivity (up to 90% ee) on a range of unactivated allylic alcohols for both lactone and lactam nucleophiles. The utility of this method is further highlighted via a number of synthetically useful product transformations

Cycloadditions of Oxacyclic Allenes and a Catalytic Asymmetric Entryway to Enantioenriched Cyclic Allenes

The chemistry of strained cyclic alkynes has undergone a renaissance over the past two decades. However, a related species, strained cyclic allenes, especially heterocyclic derivatives, have only recently resurfaced and represent another class of valuable intermediates. We report a mild and facile means to generate the parent 3,4‐oxacyclic allene from a readily accessible silyl triflate precursor, and then trap it in (4+2), (3+2), and (2+2) reactions to provide a variety of cycloadducts. In addition, we describe a catalytic, decarboxylative asymmetric allylic alkylation performed on an α‐silylated substrate, to ultimately permit access to an enantioenriched allene. Generation and trapping of the enantioenriched cyclic allene occurs with complete transfer of stereochemical information in a Diels–Alder cycloaddition through a point‐chirality, axial‐chirality, point‐chirality transfer process

Nickel-catalyzed enantioselective allylic alkylation of lactones and lactams with unactivated allylic alcohols

The first nickel-catalyzed enantioselective allylic alkylation of lactone and lactam substrates to deliver products bearing an all-carbon quaternary stereocenter is reported. The reaction, which utilizes a commercially available chiral bisphosphine ligand, proceeds in good yield with a high level of enantioselectivity (up to 90% ee) on a range of unactivated allylic alcohols for both lactone and lactam nucleophiles. The utility of this method is further highlighted via a number of synthetically useful product transformations

The Enantioselective Synthesis of Eburnamonine, Eucophylline, and 16′-epi-Leucophyllidine

A synthetic approach to the heterodimeric bisindole alkaloid leucophyllidine is disclosed herein. An enantioenriched lactam building block, synthesized through palladium-catalyzed asymmetric allylic alkylation, served as the precursor to both hemispheres. The eburnamonine-derived fragment was synthesized through a Bischler–Napieralski/hydrogenation approach, while the eucophylline-derived fragment was synthesized by Friedländer quinoline synthesis and two sequential C−H functionalization steps. A convergent Stille coupling and phenol-directed hydrogenation united the two monomeric fragments to afford 16′-epi-leucophyllidine in 21 steps from commercial material

Cycloadditions of Oxacyclic Allenes and a Catalytic Asymmetric Entryway to Enantioenriched Cyclic Allenes

The chemistry of strained cyclic alkynes has undergone a renaissance over the past two decades. However, a related species, strained cyclic allenes, especially heterocyclic derivatives, have only recently resurfaced and represent another class of valuable intermediates. We report a mild and facile means to generate the parent 3,4‐oxacyclic allene from a readily accessible silyl triflate precursor, and then trap it in (4+2), (3+2), and (2+2) reactions to provide a variety of cycloadducts. In addition, we describe a catalytic, decarboxylative asymmetric allylic alkylation performed on an α‐silylated substrate, to ultimately permit access to an enantioenriched allene. Generation and trapping of the enantioenriched cyclic allene occurs with complete transfer of stereochemical information in a Diels–Alder cycloaddition through a point‐chirality, axial‐chirality, point‐chirality transfer process

Concise total syntheses of (–)-jorunnamycin A and (–)-jorumycin enabled by asymmetric catalysis

The bis-tetrahydroisoquinoline (bis-THIQ) natural products have been studied intensively over the past four decades for their exceptionally potent anticancer activity, in addition to strong gram-positive and -negative antibiotic character. Synthetic strategies toward these complex polycyclic compounds have relied heavily on electrophilic aromatic chemistry, such as the Pictet-Spengler reaction, that mimics their biosynthetic pathways. Herein we report an approach to two bis-THIQ natural products, jorunnamycin A and jorumycin, that instead harnesses the power of modern transition-metal catalysis for the three major bond-forming events and proceeds with high efficiency (15 and 16 steps, respectively). By breaking from biomimicry, this strategy allows for the preparation of a more diverse set of non-natural analogs

Concise total syntheses of (–)-jorunnamycin A and (–)-jorumycin enabled by asymmetric catalysis

The bis-tetrahydroisoquinoline (bis-THIQ) natural products have been studied intensively over the past four decades for their exceptionally potent anticancer activity, in addition to strong gram-positive and -negative antibiotic character. Synthetic strategies toward these complex polycyclic compounds have relied heavily on electrophilic aromatic chemistry, such as the Pictet-Spengler reaction, that mimics their biosynthetic pathways. Herein we report an approach to two bis-THIQ natural products, jorunnamycin A and jorumycin, that instead harnesses the power of modern transition-metal catalysis for the three major bond-forming events and proceeds with high efficiency (15 and 16 steps, respectively). By breaking from biomimicry, this strategy allows for the preparation of a more diverse set of non-natural analogs