Synthesis of Protected Amines from Azadiene and Azaallyl Anion Building Blocks

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.