Nucleophilic Addition to Azoalkenes; Diastereoselective Synthesis of β-Hydroxy Ketones and β,γ-Fused γ-Lactams



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The α-alkylation of ketones and their derivatives by the addition of their corresponding enolates to alkyl halides is a fundamental synthetic transformation, but its utility is limited because the key bond-forming step proceeds in a bimolecular nucleophilic substitution fashion. Here in the first part of the dissertation, we describe how an umpolung strategy that involves the addition of Grignard reagents to α-epoxy N-sulfonyl hydrazones–directed by the alkoxide of 1-azo-3-alkoxy propenes formed in situ via base-induced ring opening of the epoxide–leads to the syn-selective production of α-alkyl-β-hydroxy N-sulfonyl hydrazones with α-quaternary centers. This transformation is remarkable in its ability to incorporate an unprecedented range of carbon-based substituents, which include primary, secondary, and tertiary alkyl, as well as alkenyl, aryl, allenyl, and alkynyl groups. Subsequent hydrolysis of the β-hydroxy N-sulfonyl hydrazone products produces the corresponding β-hydroxy ketones. In addition to hydrolysis, the hydrazone products are poised to undergo different known synthetic transformations via well-established chemistry, which would provide access to a wide array of useful structures.

The second part of this dissertation describes the development of a new functional group, namely the 3-amino-1-azopropene, and its use in the novel annulation strategies leading to nitrogen heterocycles, which are important structures found in drugs and biologically active natural products. The 3-amino-1-azopropene functional group possesses multiple nucleophilic and electrophilic sites and, as such, is expected to inspire the development of a wide range of new synthetic methods and/or find applications in the development of new drugs, and materials.



Azoalkene, Ketone alpha alkylation, 3-amino-1-azopropene