Bifunctional Iminophosphorane Superbase Catalysis: Applications in Organic Synthesis

To improve the field of catalysis, there is a substantial and growing need for novel high-performance catalysts providing new reactivity. To date, however, the set of reactions that can be reliably performed to prepare chiral compounds in largely one enantiomeric form using chiral catalysts still represents a small fraction of the toolkit of known transformations. In this context, chiral Bronsted bases have played an expanding role in catalyzing enantioselective reactions between various carbon- and heteroatom-centered acids and a host of electrophilic reagents. This Account describes our recent efforts developing and applying a new family of chiral Bronsted bases incorporating an H-bond donor moiety and a strongly basic iminophosphorane, which we have named BIMPs (Bifunctional IMinoPhosphoranes), as efficient catalysts for reactions currently out of reach of more widespread tertiary amine centered bifunctional catalysts. The iminophosphorane Bronsted base is easily generated by the Staudinger reaction of a chiral organoazide and commercially available phosphine, which allows easy modification of the catalyst structure and fine-tuning of the iminophosphorane pK(BH+). We have demonstrated that BIMP catalysts can efficiently promote the enantioselective addition of nitromethane to low reactivity N-diphenylphosphinoyl (DPP)-protected imines of ketones (ketimines) to access valuable chiral diamine and alpha-quaternary amino acid building blocks, and later extended this methodology to phosphite nudeophiles. Subsequently, the reaction scope was expanded to include the Michael addition of high pK(a) alkyl thiols to alpha-substituted acrylate esters, beta-substituted alpha,beta-unsaturated esters, and alkenyl benzimidazoles as well as the challenging direct aldol addition of aryl ketones to alpha-fluorinated ketones. Finally, BIMP catalysts were shown to be used in key steps in the synthesis of complex alkaloid natural products (-)-nakadomarin A and (-)-himalensine A, as well as in polymer synthesis. In most cases, the predictable nature of the BIMP promoted reactions was demonstrated by multigram scale-up while employing low catalyst loadings (down to 0.05 mol%). Furthermore, it was shown that BIMP catalysts can be easily immobilized onto a solid support in one-step for increased catalyst recycling and flow chemistry applications. Alongside our own work, this Account also indudes elegant work by Johnson and co-workers utilizing the BIMP catalyst system, when alternative catalysts proved suboptimal.