Acyl Hydrazone Chemistry

The small-molecule-based machine conceived by von Delius, Geertsema, and Leigh [45] is a linear (for reviews, see [46], [100]) motor based on dynamic covalent chemistry [19-24] (forming, breaking, and reforming of dynamic covalent bonds with relatively fast equilibration in response to stimuli), namely on acyl-hydrazone and disulfide exchanges. The motor consists of a track that has four functional groups disposed alternately aldehyde-thiol-aldehyde-thiol which are the positions 1,2, 3, and 4 of the track, a walker NH2-NH-CO-(CH2)5-SH which has the feet A (hydrazide or acyl-hydrazine) and B (thiol), and a placeholder with a foot C of type thiol (Fig. 10). 

Zuercher, W.J., Gaillard, S., Orband-Miller, L.A., Chao, E.Y., Shearer, B.G., Jones, D.G., Miller, A.B., Collins, J.L. et al. (2005) Identification and structure-activity relationship of phenolic acyl hydrazones as selective agonists for the estrogen-related orphan nuclear receptors ERRfJ and ERRy. Journal of Medicinal Chemistry, 48, 3107-3109. 

Acyl hydrazone exchange has also been probed as reversible chemistry for the generation of oligotopic and directional carbohydrate DCLs of larger size [45]. 

In light of recent mechanistic data on the cycloaddition chemistry of acyl hydrazones, we have developed a series of enantioselective transformations between hydrazones and dienes. Unlike most imine equivalents, acyl hydrazones have the potential to react as 3-atom or 2-atom coupling partners in cycloaddition reactions. We have exploited this dual reactivity of hydrazones by coupling them with various dienes. As a result, we have developed silicon-mediated enantioselective [3+2] and [4+2] cycloadditions. For the first time, the scope of dienes in the enantioselective aza-Diels Alder reaction has been extended to include acyclic dienes that are traditionally unreactive in concerted [4+2] processes. 

This would support the fact that PEG-HZ-PE conjugates containing hydrazone bond derived from the aliphatic aldehyde are more prone to hydrolytic degradation. Aromatic aldehyde-derived hydrazone bond is too stable for the purpose of pH-triggered drug release. Careful selection of an aldehyde and an acyl hydrazide would be necessary for the application of the hydrazone-based chemistry for the development of pH-sensitive pharmaceutical nanocarriers. 

An earlier application of 1,4-conjugate additions employing azaallyllithium reagents formed from ketone dimethylhydrazones is Kelly s hydrazone version of the classical Knoevenagel route to substituted pyridine derivatives.71 In this chemistry, a mixed cuprate derived from a dimethylhydrazone lithio anion and copper thiophenoxide was first allowed to react with an a,p-unsaturated ketone. The product enolate can then be acylated or protonated to yield either a diketo hydrazone or a keto hydrazone. Addition of... 

---