No description available.

No description available.

Thesis advisor: Amir H. Hoveyda / Chapter 1. Part A: N-Heterocyclic Carbenes Catalyzed Enantioselective Boryl Conjugate Additions to α,β-Unsaturated Ketones, Esters, Weinreb Amides and Aldehydes. The first broadly applicable enantioselective boryl conjugate addition reactions to a variety of α,β-unsaturated carbonyls are reported. Transformations are promoted by 5.0 mol % of a chiral Lewis basic N-heterocyclic carbene. The distinctive feature of the reactions in chemoselectivity of the method compared to the Cu-catalyzed variants has been illustrated. Part B: Enantioselective Synthesis of Boron-Substituted Quaternary Carbon Stereogenic Centers through N-Heterocyclic Carbenes Catalyzed Boryl Conjugate Additions to Cyclic and Acyclic Enones The first examples of Lewis base catalyzed enantioselective boryl conjugate additions that afford products containing boron-substituted quaternary carbon stereogenic centers are presented. The carbon–boron bond forming reactions are promoted by 1.0–5.0 mol % of a chiral N–hererocyclic carbene. Cyclic or linear α,β–unsaturated ketones can be used as suitable substrates and the desired products are obtained in 63–95% yield and 91:9 to >99:1 enantiomeric ratio. The utility of the Lewis base-catalyzed approach is demonstrated in the context of an enantioselective formal synthesis of antifungal natural product crassinervic acid. Chapter 2. Enantioselectivity Fluctuations in Phosphine–Cu-Catalyzed Enantioselective Boron-Allyl Addition to Aryl-Substituted Olefins. Catalytic enantioselective multicomponent processes involving B2(pin)2, aryl or heteroaryl monosubstituted olefins, and allylic phosphates or carbonates are disclosed. Transformations promoted by a chiral Cu–phosphine complex afford products that contain a primary C–B(pin) bond and an allyl-substituted tertiary carbon stereogenic center in up to 84% yield and 98:2 enantiomeric ratio. The utility of the approach is showcased in the enantioselective formal synthesis of biologically active heliespirones A and C. Based on mechanistic and computational studies, we show that enantioselectivities variations can depend on electronic and/or steric factors of the alkene substrate and the allyl electrophile as well as their concentration. In most cases, selectivity loss can be minimized and that the resulting insights are also applicable to reactions involving Cu–H species. Chapter 3. Synthesis of Vicinal Diboronate Compounds through Practical Phosphine–Copper Catalyzed Three-Component Processes. The phosphine–Cu-catalyzed multicomponent processes have been developed for a practical and direct synthesis of vicinal diboronate compounds. Reactions of alkenyl–boronates, allylic phosphates, and diboron reagents are promoted by 2.5–10 mol % of a Cy3P–Cu complex affording a wide range of desirable vicinal diboronate products. The ability for easy access to either regioisomers of the products with a C–B(pin) and an adjacent C–B(dan) bond that can be site-selectively functionalized is a noteworthy feature of the method. / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Atropisomerism is a property exhibited by molecules where rotation about one or more bonds is restricted. Along with biaryls, which are widely utilised in asymmetric catalysis, several other classes of compounds display atropisomerism. These molecules have applications in enantioselective synthesis, asymmetric catalysis and have been used to relay stereochemical information. There are, however, a number of challenges associated with their asymmetric synthesis (Chapter 1). This thesis describes research carried out on the synthesis and asymmetric synthesis of atropisomeric diaryl ethers. Chapter 2.1 explains how these ethers are synthesised in multi-gram quantities and to allow the incorporation of large ortho substituents. Having a number of diaryl ethers with suitable substitution patterns to achieve atropisomerism, Chapter 2.2 goes on to report two novel and complimentary biocatalytic approaches to the enantioselective synthesis of diaryl ethers by desymmetrisation. This chapter also describes a possible route towards the synthesis of a diaryl ether based ligand. Chapter 2.3 reports the lateral lithiation of meso diaryl ethers to yield diastereomeric atropisomers stereoselectively. Our attempts to use (-)-sparteine in lateral lithiations to desymmetrise a diaryl ether enantioselectively is also described. We go on to determine the configurational integrity of our organolithiums and the reaction pathway that exists in lithium substitution. Finally, the diastereoselective synthesis of both a diaryl ether (via a stereoselective reduction of a pro-chiral ketone) and a diaryl sulfide (via an addition reaction) is described in chapter 2.4. This chapter also reports the conformational behaviour of a diaryl amide in solution.

No description available.

Thesis advisor: Amir H. Hoveyda / Homoallylic amines and alcohols, particularly those amenable to further functionalization, are among the most widely used building blocks in chemical synthesis and are typically accessed by addition of an allyl-metal compound to an electrophile. Studies discussed herein have focused on advancing stereoselective synthesis of versatile allylboron compounds and their utilization in catalytic regio-, diastereo-, and enantioselective addition to various electrophiles. Mechanistic principles have been central to the investigations described in this thesis, and it has been on this basis that catalytic strategies for practical synthesis of bioactive molecules were developed. Chapter One. Vicinal amino alcohols are ubiquitous in natural products and serve as versatile synthetic intermediates and we envisaged that diastereo- and enantioselective additions of O-substituted allyl boronates offers an attractive option to access these motifs. In the presence of zinc (II) methoxide as co-catalyst, it will be demonstrated that sequence of events may occur, wherein isomerization of an initially formed allyl complex occurs prior to addition of an aldimine with kinetic selectivity. As will be described, through the use of an optimal catalyst, N-protecting/activating group and appropriate reaction conditions, differentially protected vicinal amino alcohol derivatives may be synthesized in high enantiopurity. The utility of the approach is highlighted through synthesis of an NK1 agonist. Chapter Two. It will be demonstrated that additions of various organoboron compounds converts readily accessible and easy-to-handle silyl-substituted -tertiary amines. Contrary to additions to aldimines, isomerization of the initially generated aminophenol-allyl complex is preempted, suchthat linear products are favored. DFT analysis suggests that high enantioselectivity likely originates from attractive electrostatic interaction between a trifluoromethyl group and the catalyst’s ammonium moiety. The synthetic utility was highlighted through concise, enantioselective synthesis of a key intermediate of a recently reported BACE-1 inhibitor on gram scale. Chapter Three. This section details the development of a method for direct synthesis of homoallylic alcohols bearing a Z-alkenyl chloride, which may be directly subjected to stereo-retentive cross coupling without wasteful protection/deprotection or redox operations. Products were obtained in high regio- and enantioselectivity for aliphatic, alkenyl- and heteroaryl-substituted aldehydes. The approach was utilized in a concise, protecting group-free synthesis of anti-tumor agent mycothiazole. Chapter Four. A method for stereoselective synthesis of fluorine-containing trisubstituted allyl boronates will be presented. It will then be illustrated that in the presence of an appropriate aminophenol catalyst, a large assortment of homoallylic alcohols containing a quaternary fluoro- and trifluoromethyl-substituted stereogenic center may be obtained with efficiency and high diastereo- and enantioselectivity. The obtained products were then elaborated to the furanose core of Sofosbuvir, a recently approved treatment for hepatitis C. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

No description available.

<p> The reactions of methyllithium and phenyllithium with the iminium chloride, [(2R,3S)-2,3-dihydroxy-3-(6,7 -dimethoxy-3,4-dihydroisoquinolin-1-yl)]propionate hydrochloride, 34 as a means of preparing enantiomerically pure compounds are described. These reactions afford a single product in high yield. The nmr spectra of the products, 1-(1 ,2,3-trihydroxy-3,3-dimethylpropyl)-1 ,2,3,4-tetrahydro-6,7 -dimethoxy-1- methylisoquinoline 54 and 1-( 1,2,3-trihydroxy-3,3-diphenylpropyl)-1,2,3,4-tetrahydro-6,7- dimethoxy-1-phenylisoquinoline 62, are discussed and an explanation is given to account for the diastereoselectivity of the reaction. By this method, enantiomerically pure compounds bearing a quaternary centre at C-1 of the tetrahydroisoquinoline system may be prepared. Oxidative degradation of the hydroxylated side chain of compound 62 has led to the preparation of several other new compounds. </p> <p> The usefulness of the t-butoxycarbonyl group as a selective protecting group for nitrogen in the preparation of 2-t-butyloxycarbonyl-1,2,3,4-tetrahydro-1-(1,2,3- trihydroxy-3,3-dimethylpropyl)-6,7-dimethoxy-1-methylisoquinoline 59 is described. It has advantages over the ethoxycarbonyl group in that it not only selectively protects the amino group but also is easy to remove by short treatment with trifluoroacetic acid and water at room temperature. Treatment of 59 with sodium periodate afforded the aldehyde, 1-formyl-2-t-butyloxycarbonyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline, 60. An attempted oxidation of the aldehyde 60 to the acid is also described. </p> <p> A review of recent methods of inducing chirality at C-1 of the tetrahydroisoquinoline system is given in the Introduction. </p> / Thesis / Master of Science (MSc)

1. Enantioselective Pd(II)-Catalysed Nucleophilic Additions of 2- Alkylazaarenes The first project deals with enantio- and diastereoselective palladium(II)-catalysed nucleophilic additions of 2-alkylazaarenes to N-Boc imines and nitroalkenes. Under the optimised reaction conditions high levels of diastereo- and enantioselection of the addition products were achieved. Introduction of the electron-withdrawing group at the aryl ring of the substrate allows running the reaction under mild, experimentally convenient reaction conditions. The new described method allows the enantioselective synthesis of 2-(β-aminoalkyl)azaarenes, which are substructures found in drug candidates molecules for the treatment of type 2 diabetes and schizophrenia. 2. Synthesis of Spirocyclic Enones via Rh(III)-Catalysed C–H Functionalisation The second project describes the synthesis of spirocyclic enones by rhodium(III)- catalysed dearomatising oxidative annulation of 2-alkenylphenols with alkynes and 1,3-enynes. A good to high yield with great regioselectivity was obtained. The further synthetic utility of the product was also investigated and led to the formation of highly functionalised tetracycles via 1,6 conjugation addition reaction.

Amphibian alkaloids are attractive targets for synthesis due to their biological activity. An important class of amphibian alkaloids is the 2,5-disubstituted pyrrolidine-based family of compounds. There are many synthetic approaches for the preparation of the trans-2,5- disubstituted pyrrolidines, but methods for the construction of the cis-2,5-pyrrolidines are limited. Therefore, it was desired to develop an enantioselective approach for the preparation of cis-2,5-disubsituted pyrrolidines. (+)-Tropin-2-one derived from cocaine was used as starting material to exploit the inherent stereochemistry for construction of the cis-pyrrolidine ring. This permitted the unequivocal assignment of the absolute configuration of the target pyrrolidine. The structurally simple pyrrolidine alkaloid, 225H, was selected as a target to develop a general synthetic approach. The enantioselective synthesis of 225H was achieved in nine steps and good overall yield. The search for potent cannabinoid receptor partial agonist ligands as potential marijuana addiction therapeutic agents has led to an investigation of the synthesis of diaryl ether hybrid analogues of BAY 59-3074. A series of 2-(3-alkyl-5-hydroxyphenoxy)-6- (trifluoromethyl)benzonitriles, 3-(2-cyano-3-(trifluoromethyl)phenoxy)phenylalkanoates, and (3- (benzyloxy)phenoxy)-6-(trifluoromethyl)benzonitriles were synthesized and evaluated in vitro for CB1 affinity. The olivetol diaryl ether analogue was the most potent ligand of the alkyl series, but the diaryl ester analogues exhibited modest affinity for CB1 receptors. The most potent compound of the series was the 2-(3-(benzyloxy)phenoxy)-6- (trifluoromethyl)benzonitrile.