New Discoveries in Titanium and Phosphorus Mediated Carbonyl Additions

A method utilizing catalytic titanocene dichloride for the conjugate reduction of α,β-unsaturated carbonyls was developed and described herein. The chemoselective procedure employs an amine hydrochloride as the proton source during the catalytic modification as opposed to the difficult to handle and potentially explosive H₂ atmosphere. The scope of conjugated compounds includes cyclic and acyclic variations of ketones, esters, aldehydes, amides, as well as ynones, which contain an extra degree of unsaturation. Attempts to exploit the utility of titanocene-bound enolates led to the discovery of a Cp₂TiCl₂ accelerated organometallic formation. After a detailed investigation by Fleury, catalytic loadings of titanium as low as 1 mol% were demonstrated to be effective at catalyzing organozinc and organomagnesium reagents derived from allyl, alkyl, aryl, and vinyl species. Subsequently, a novel phosphorus redox process was constructed en route to synthesizing amides directly from carboxylic acids. The dual role of phosphorus includes activation of the carboxylic acid for electrophilic attack while decomposing an azide to reveal a hidden nucleophilic nitrogen source. The resultant array of amides from this process includes alkyl, aryl, and α,β-unsaturated amides as well as lactams and dipeptides. As an application of the highly chemoselective amidation procedure, a synthesis of LY573636 was completed in 3 steps from commercially available starting materials. This unique aspect of a reagent performing two separate crucial roles was further advanced by the creation of the first Staudinger ligation catalytic in phosphine. A diverse assortment of amides and imides can be produced in moderate to excellent yields when using 10 mol% Ph3P and a stoichiometric reductant.

These catalytic strategies involving redox chemistry of both transition metals and phosphorus enable a fast and resourceful approach towards the construction of valuable synthetic intermediates of saturated carbonyls, homoallylic alcohols, and substituted amides from the readily accessible starting materials.