Pericyclic reactions are a class of transformations that comprise sigmatropic rearrangements, group transfer reactions, cycloadditions and electrocyclic reactions. Since Woodward and Hoffmann rationalized the mechanism and stereochemistry of pericyclic reactions they have become powerful synthetic tools. Whilst sigmatropic rearrangements and cycloadditions are cornerstones of contemporary synthetic methodology, many electrocyclic reactions are not fully exploited currently; there are no general methods for the asymmetric catalysis of electrocyclic reactions and as a consequence, opportunities for exerting stereocontrol in these manifolds are limited. We aim to establish general methods for the asymmetric catalysis of 6π electrocyclic reactions. Our initial studies are focused on a pentadienyl anion moiety due to the greater ease of cyclization observed with such systems in comparison to the corresponding neutral hexatriene systems.

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Over the past two decades and continuing on, carbonyl allylation chemistry has been a very useful and popular tool for the stereocontrolled formation of carbon-carbon bonds in the field of organic synthesis. In the context of natural product synthesis, the efficiency and status of aldehyde allylboration method is only matched by the asymmetric and diastereoselective aldol methodology. Unfortunately, prior to the new millennium, the means to control the absolute stereoselectivity in the addition of allylic boron reagents had been restricted to stoichiometric chiral directors, appended onto the metal center. In 2002, the research groups of Hall and Miyaura reported a new Lewis acid-catalyzed allylboration reaction manifold, which raised intriguing mechanistic questions and also paved the way for a catalytic enantioselective methodology development. Chapter 2 of this thesis details mechanistic studies related to the new Lewis acid-catalyzed allylboration. In this chapter, various control experiments and kinetic studies are presented, the results of which allowed us to propose a hypothesis involving the electrophilic boronate activation as the key factor for the observed rate enhancement. Chapter 3 describes the initial phase of our research to develop a catalytic enantioselective allylboration methodology. We discovered that Brnsted acid catalysts derived from diolSnCl4 complexes were promising catalysts for the asymmetric addition of air and moisture stable and commercially available allylic pinacol boronates. Under this 1st generation catalyst-system, the corresponding homoallylic alcohols were obtained in moderate to good enantioselectivity and excellent diastereoselectivity. The development of a novel chiral Brnsted acid catalyst for the highly enantio- and diastereoselective allylboration reaction methodology is the single most important result to come from this thesis. Chapter 4 outlines the development of the 2nd generation catalyst system. A systematic study of the diol component of the catalyst system led us to arrive at a novel diol nicknamed Vivol on behalf of my contribution. The resulting Brnsted acid derived from VivolSnCl4 now provided the corresponding homoallylic alcohol products in very good to excellent enantioselectivity. Preliminary mechanistic studies along with the X-ray diffraction structure of the catalyst system are also presented. Based on this information, an even better performaning diol (termed F-Vivol) was developed. This 3rd generation catalyst system derived from F-VivolSnCl4 complex was shown to display consistently superior reactivity and selectivity over its 2nd generation predecessor. Chapter 5 describes our efforts to expand the reagent scope of the Brnsted acid catalyzed allylboration methodology. Furthermore, this chapter also describes the successful application of the catalytic process towards the synthesis of simple and complex molecules. Accordingly, the preparation and application of the Brnsted acid-catalyzed addition of 2-bromoallyl boron pinacolate is described. The successful transformation of the corresponding bromo-homoallylic alcohols to a compelling class of -butyrolactones is also presented. The later part of the Chapter presents the synthesis of natural products (+) dodoneine and palmerolide A.

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I. Catalytic Conjugate Allylation of Alkylidene Malonates Nucleophilic conjugate addition of allylsilanes and allylstannanes to alkylidene malonates under the action of ytterbium catalysis in the presence of hexafluoro-isopropanol has been developed. Enantioselective conjugate allylation of alkylidene malonates under ytterbium or scandium catalysis using chiral bis(oxazoline) ligands allows access to the conjugate addition products in an enantiomerically-enriched form. Furthermore, elaboration of the allylated substrates via decarboxylation and an oxidative cleavage was demonstrated. II. Catalytic Enantioselective Conjugate Addition of Azaarylacetates and Acetamides to Nitroalkenes An enantioselective nickel-catalysed Michael addition of azaarylacetates and acetamides to nitroalkenes has been developed. A range of azaaryl pronucleophiles were shown to react with a variety of nitroalkenes to generate highly functionalised Michael addition products with impressive diastereo- and enantiocontrol. A possible mechanism for this process is proposed and crystal structures of the addition products have also been attained, allowing determination of the absolute stereochemistry. Elaboration and further functionalisation of these products was also possible under a range of conditions.

This PhD thesis project was concerned with the use of alkali metal amide Brønsted bases and alkali metal alkoxide Lewis bases in (asymmetric) catalysis. The first chapter deals with formal allylic C(sp3)–H bond activation of aromatic and functionalized alkenes for subsequent C–C and C–H bond formations. The second chapter is focused on C(sp3)–Si bond activation of fluorinated pro-nucleophiles in view of C–C bond formations. In the first chapter, a screening of various metal amides, hydrides, and alkyl reagents resulted in the observation that alkali metal amides were effective Brønsted bases to trigger allylic C(sp3)–H bond activation of aromatic alkenes at room temperature. Sodium hexamethyldisilazide was found to be most efficient compared with other s-, p-, d-, and fblock metal amides. This unique transition metal-free methodology was exploited to activate a variety of alkene pro-nucleophiles, which were shown to undergo γ-selective C–C bond formation with various aromatic aldimines as well as one aliphatic substrate. The corresponding homoallylic amine derivatives were obtained in high yields with excellent E:Z ratios. The reaction mechanism was investigated and attempts to detect and/or isolate key intermediates were undertaken. Importantly, it was shown that metal-free superbases of the Schwesinger or Verkade type were not apt to catalyse this challenging C–C bond formation. The asymmetric version of this rare sodium amide catalysis has been achieved by using a commercially available enantiopure bisoxazoline ligand (46% ee). Subsequently, the catalytic use of sodium and potassium amides was applied to the isomerization of terminal aromatic alkenes to generate the thermodynamically more stable internal olefins in excellent yields with high E:Z ratios. Furthermore, functionalized metalloid (B, Si) and metal-free alkenes were found to undergo alkali metal amide-triggered (chemoselective) allylic C(sp3)–H bond activation in view of isomerization and/or C–C bond formation with aldimines. In the second chapter, the catalytic C–Si bond activation of an important difluoromethylation reagent, HCF2SiMe3, was investigated. Here, alkali metal alkoxides were shown to be more effective Lewis base triggers than other metal alkoxides or metal-free superbases. This novel method was successfully used to transfer the nucleophilic difluoromethyl fragment to electrophiles such as a variety of amides and lactams, whereas unsaturated amides failed to undergo the intended conjugate C–C bond formation. In this context, it is noted that the α-hydrogen of certain amides was tolerated. This unprecedented catalytic difluoromethylation of unactivated carbonyl electrophiles was achieved using potassium tert-butoxide at room temperature, and the corresponding fluorinated ‘hemiaminal’ products were obtained in high yields.

This thesis contains the preparation of a new design of ligand for the palladium catalysed allylic substitution reaction. The phosphine oxazoline ligands detailed in the thesis give high levels of enantiocontrol when used in conjunction with symmetrical allyl systems in the palladium catalysed allylic substitution reaction. For unsymmetrical allyl systems the palladium catalysed allylic substitution process proceeds with complete regiocontrol and high levels of stereocontrol are again observed. The products from the palladium catalysed allylic substitution reaction can be readily converted to succinic acids, γ-lactones and aryl propanoic acids.

Thesis advisor: James P. Morken / This dissertation will discuss in depth four main projects pertaining to the synthesis and utility of organoboronates for the construction of enantioenriched small molecules. First, reaction optimization and substrate scope expansion of the platinum-catalyzed enantioselective diboration of alkenes are reported. Based on extensive experimental and computational mechanistic analysis, a preliminary stereochemical model is also proposed. A practical boron-Wittig reaction is presented in which synthetically challenging di- and trisubstituted vinyl boronates can be accessed in a highly stereoselective fashion from readily available starting materials. The enantioselective diboration of cis- and trans-vinyl boronates furnished novel 1,1,2-tris(boronate) esters in up to 95:5 er. The intermediate tris(boronate) esters were employed successfully in deborylative alkylations to furnish enantioenriched internal vicinal bis(boronates) in excellent diasteoselectivity. In the final chapter, an enantioselective palladium-catalyzed intramolecular Suzuki-Miyaura coupling between allyl boronates and aryl electrophiles is disclosed. The newly developed transformation provides enantioenriched 5, 6, and 7-membered carbocycles in up to 93:7 er. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: James P. Morken / Described herein are methods for asymmetric allylation. Chapter 1 describes the scope of the Pd-catalyzed asymmetric diboration of prochiral allenes. The products of this process possess both a chiral allylboronate functional group and a vinylboronate moiety. The allylboronate functionality can subsequently be used for imine allylation, without isolation of the diboron intermediate, resulting in the formation of atypical allylation products through a tandem, one-pot sequence. Furthermore, enantioselection in the catalytic diboration and chirality transfer in the subsequent imine allylation are high; thus, non-racemic, protected homoallylic amines, and other derivatives, are produced in high enantiomeric excess. Chapter 2 describes the discovery and development of a transition-metal-catalyzed asymmetric conjugate allylation of allylboronate ester nucleophiles to activated enones. The scope, utility, and mechanistic aspects of this new reaction are discussed. / Thesis (PhD) — Boston College, 2008. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.