Libraries of small molecules capable of exploring new areas of three-dimensional chemical space are of considerable value in drug discovery. 3-Substituted chiral cyclic hydrazines are a potentially attractive target as they offer multiple points for functionalization. They are also found in several medicinal agents and natural products, including sanglifehrin A, cilazapril and actinoramide A. A general strategy for the synthesis of aryl substituted cyclic hydrazines based on asymmetric transfer hydrogenation is reported. A range of ketohydrazines were prepared, then reduced with [(S,S)-Teth-TsDpenRuCl] (A) to give the corresponding secondary alcohols with high enantiomeric excess and in excellent yields (Scheme 1). The scope and limitations of this process is established, along with the subsequent cyclization to generate a series of 3-substituted cyclic hydrazines. Orthogonal removal of the protecting groups and further functionalization using a variety of N-functionalization reactions are also reported. Finally, X-ray crystallography proves that these compounds adopt an anti,anti configuration and that the positioning of the 3-substituents can be precisely tuned by varying the ring size.

Readily accessible sp3-rich cyclic hydrazine frameworks exploiting nitrogen fluxionality

2019 Fall National Meeting

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