Browsing by Author "Malcolmson, Steven J"

Heteroarenes bearing nitrogen centers such as pyridines and quinolines are ubiquitous in pharmaceuticals, agrochemicals, and other small molecules of medicinal interest. Among them, quinoline derivatives belong to a significant class of bioactive molecules in the field of drugs and pharmaceuticals and they also display significant activity against numerous viruses and bacterium. Previous studies on enantioselective synthesis of α-heterocyclic amine derivatives include diastereoselective addition of organometallics to enantiopure pyridyl imines derived from Ellman auxiliary, and enantioselective reduction of a pyridyl ketone, conversion to a leaving group, and azide displacement followed by the reduction to obtain the amine. In addition, numerous other methods have been developed to prepare alkylated N-heteroarenes. However, protocols for enantioselective synthesis are rather limited and these stereospecific transformations require stoichiometric amounts of optically pure reagents and do not create new stereogenic centers. Considering the aforementioned limitations, the Ge group investigated addition of a chiral Cu‒alkyl species, generated by insertion of alkenes into a chiral Cu‒H complex to quinoline N-oxides to produce chiral 2-alkylated quinolines. This strategy that utilizes quinoline N-oxide as an electrophile inspired us to expand the methodology to afford enantioenriched chiral 2-aminoalkyl quinolines from quinoline N-oxide and 2-azadienes via a copper-catalyzed process. However, there are possible challenges to this reaction including a reductive dimerization of 2-azadiene, reduction of quinoline N-oxides to quinolines, and potential catalyst deactivation. If these challenges can be overcome, this strategy could represent a practical protocol to prepare chiral aminoalkylated quinolines from readily available quinoline N-oxides and alkenes.

New methodologies to prepare alpha-functionalized amines, especially chiral amines have been studied in this work. Specifically, we focused our work on introducing alpha-functionalization to amines through C–C forming processes. This thesis work is inspired by the vitamin B6 transamination process: forming ketimines or aldimines to increase the acidities of alpha-C–H protons of amines, thereby enabling the alpha-C–H deprotonation accessible under mild reaction conditions for further derivation. Based on this known process mechanism, we first explored the umpolung functionalization of amines through deprotonation of ketimines/aldimines, then a migratory insertion process from metal-hydrides to 2-azadienes have been further developed. Of these processes, this thesis work will specifically focus on the research exploration of three synthons: 2-azaallyl anion, 2-azaaalyl radical and 2-azadiene.

We began investigating processes to access alpha-amino anions directly through alpha-deprotonation of imines (formation of 2-azaallyl anions). The alpha-amino anion was then utilized in two further reactions: 1. enantiospecific ring-opening of aziridines to access 1,3-diamines and 2. enantioselective Pd-catalyzed allylation to obtain homoallylic amines.

Following our research of 2-azaallyl anions, we developed a metal-free cross-coupling reaction between 2-azaallyl radicals and single-electron acceptors such as 1,4-dicyanobenzene. The reaction efficiently delivered the desired two-component product at room temperature without additional catalysts. This reaction indicated the formation of radical pairs : 2-azaallyl radicals from 2-azaallyl anions and radical anions from the single-electron acceptors. We then examined a few plausible three-component coupling reactions to utilize alkene to intercept the radical pairs to prepare more complicated functionalized amines.

In the last part, we have developed 2-azadienes as platforms to access functionalized amines via alpha-amino transition metal species. Through migratory insertion of a copper hydride into 2-azadienes, we could access alpha-aminoalkyl metal species, which could be further used in reactions with various electrophiles. Two applications were examined in this chapter: 1) addition to ketones to access 1,2-amino tertiary alcohols and 2) addition to aldimines/ketimines to access 1,2-diamines.

Chiral amines are a common motif among many important natural products and biologically active molecules. For this reason, methods to synthesize chiral amines have long been sought by organic chemists. Hydroamination is an appealing route to access chiral amines due to the atom economy of the transformation and simplicity of the starting materials. Despite the allure of such reactions, few methods exist for intermolecular hydroaminations, let alone enantioselective versions. Herein, we report the first enantioselective intermolecular hydroamination of 1,3-dienes with alkyl amines. Transformations with a Pd–phosphinooxazoline catalyst are efficient (up to 96% yield) and enantioselective (up to 96.5:3.5 e.r.) for a broad range of substituted dienes and amines. Diene geometry and electronics as well as isotope effects significantly affect product distribution. Preliminary investigations indicate that enantioselectivity diminishes over time with secondary acyclic amines. All chiral products are formed as allylic amines with an alkene poised for downstream functionalization.

Amines are ubiquitous in medicinal compounds and essential to human health. We have addressed the limitations of amine synthesis by significantly expanding the utility of 2-azaallyl anions and 2-azaallyl anion-like reagents in the production of imine-protected amines (Scheme 1).

Chapter Two

We have developed the first intermolecular, stereoselective reactions that directly generate 1,3-amino alcohols bearing three contiguous stereogenic centers through a coupling of 2-azaallyl anions with substituted epoxides. This method tolerates an expansive range of substrates, including variations on the substitution patterns of the epoxide and the azaallyl anion nucleophile. Both cis- and trans-1,2-disubstituted epoxides, electron-rich and electron-poor, readily react. Alkyl groups, including heteroatom containing ones, α-branching, and aromatic groups are tolerated within styrenyl epoxides. Terminal epoxides are also effective coupling partners, providing wide access to a range of primary, secondary, and tertiary alcohol products. Several azaallyl anions, including those with aryl, heteroaryl, vinyl, and alkynyl substituents, are excellent partners for transformations with trans-disubstituted epoxides. Importantly, these products can be further functionalized through deprotection and Mitsunobu reaction to access highly-substituted azetidines.

Chapter Three

Fluorine is known to enhance the pharmacology of compounds in several important ways, including improving pharmokinetics, lipophilicity, cell permeability, and metabolic rates. To improve access to these crucial compounds, we have developed a method for chiral α-CF3 amines through generation of an α-CF3-substituted azaallyl–Ag intermediate that is coupled with aryl iodides through a Pd-catalyzed process. We were able to expand this method to over twenty examples of electron-rich and electron-poor aryl iodides with various substitution patterns as well as one heteroaromatic compound. These products are immensely useful and we have explored their utility by developing a concise, 3-step synthesis of an HDAC6 inhibitor. Through spectroscopic studies, we were also able to elucidate the structure of the intermediate in this reaction, demonstrating that the likely species is an azaallyl–Ag intermediate and the formation of this intermediate is likely catalyzed by XPhos.

Chapter Four

Chiral α-amino boronates are found in medicinal compounds with great significance to human health, such as bortezomib and ixazomib, proteasome inhibitors used for treatment of cancer. We have begun to develop a method for hydroboration of 2-azadienes to afford α-amino boronates. Utilizing our 2-azadiene substrate, we can access these moieties regioselectively, enantioselectively, and in high yield. Ongoing work will expand substrate scope through broadening the substitution patterns of the azadiene.

The prevalence of nitrogen-containing compounds in medicinal chemistry has driven the need for the development of methodologies for the construction of chiral amines in organic synthesis. Amongst these chiral amines, a-trifluoromethyl and alkyl amines are an important subclass that have been sought after because of their relevance in drug discovery. With respect to a-trifluoromethyl amines, the role of fluorine in altering lipophilicity, influencing pKa, and affecting conformational bias of bioactive compounds has caused a surge in the development of new synthetic strategies for the construction of this functionality. Umpolung methods are robust technologies that enable streamlined synthesis of different types of chiral amines that are more challenging to obtain with a normal polarity approach. For example, the addition of nucleophiles to electrophilic imines, which is one commonly used strategy, limits the chemical space that may be generated for the preparation of chiral amines. Thus, other enabling strategies are desired.In this work, we describe three methods for the preparation of different chiral amine motifs, detailing 1) the synthesis of a-trifluoromethyl benzylic amines through a vicinal fluoroarylation of difluoroazadienes, 2) the diastereo- and enantioselective synthesis of a-trifluoromethyl homoallylic amines via a catalytic hydroalkylation of dienes as well as 3) the enantioselective synthesis of alkyl amines enabled by a 5,6- hydroalkynylation of substituted 2-azatrienes.

The construction of complex structural motifs from simple precursors is a compelling goal in organic synthesis. Within this context, enantioselective hydrofunctionalization of carbon–carbon multiple bonds is an attractive strategy due to the broad accessibility and/or simple preparation of starting materials and because of the inherent atom economy of this process. The hydrofunctionalization of conjugated multiple bonds provides additional opportunities and challenges. Conjugated dienes and enynes can be more reactive in transition metal catalysis than isolated olefins or alkynes; however, such hydrofunctionalization processes frequently give rise to multiple stereo- and regioisomers. Achieving both site and facial selectivity for nucleophile additions to these requires careful catalyst design. This research describes the development of palladium catalysts bearing electron-deficient phosphinooxazoline (PHOX) ligands for highly efficient regio- and enantioselective addition of amine and carbon-based nucleophiles to conjugated dienes and enynes. These reactions proceed under exceptionally mild conditions to afford a variety of high-value enantioenriched products. Throughout these studies, questions regarding the mechanisms of these transformations have been answered using an experimental approach.

Nitrogen-substituted stereogenic centers are ubiquitous throughout naturally occurring, synthetically useful, and biologically active molecules. Among these, the 1,3-diamine and 1,3-amino alcohol scaffolds are important and commonly occurring motifs. Despite the frequent occurrence of these moieties in complex molecules, few methods exist that allow for their direct, stereoselective, and redox-efficient synthesis. Herein, we report the stereoselective synthesis of over sixty-five 1,3-diamines and amino alcohols via 2-azaallyl anion nucleophilic ring-opening of aziridines (Chapter 1) and epoxides (Chapter 2). Transformations occur stereospecifically (>98%), diastereoselectively (up to >20:1 d.r.), site-selectively (up to >98%), and efficiently (up to >98% yield) to generate 1,3-diamines and amino alcohols bearing 2–3 stereogenic centers in a redox-efficient manner. The products generated readily undergo a variety of synthetic manipulations, including imine hydrolysis and heterocycle synthesis.