59th Annual Report on Research 2014

Progress Report

Introduction. Methods for the rapid synthesis of structurally diverse ligands or catalysts can significantly accelerate the pace of reaction discovery and optimization. A powerful approach involves the self-assembly of candidate structures through noncovalent or reversible covalent interactions such as metal–ligand coordination, hydrogen bonding and ion pairing. Catalysts are generated by simple pairwise mixing of components, thus obviating the need for time-consuming purification and isolation steps. This project explores applications of reversible covalent interactions between boronic acids and diols as the basis for catalyst assembly. Organoboron–diol interactions are specific, strong and reversible, and have been exploited extensively in the molecular recognition field. The tolerance of these reversible covalent interactions to a range of solvents and reaction conditions, and the availability of diverse, chiral diol feedstocks constitute unique potential advantages in the context of applications in catalyst self-assembly.  

Libraries of chiral phosphines prepared by three-component condensations of 2-formylphenylboronic acid. Self-assembly of chiral phosphine ligands through boronic acid–diol interactions was among the initial aims of the project. The non-trivial synthesis of boronic acid-functionalized phosphine components presented an early hurdle. To solve this problem, we adopted a modified strategy, using three-component condensations of phosphine-functionalized amines, diols and 2-formylphenylboronic acid, generating imine–boronate ligands where the boronic acid component serves as a linchpin. The ligand assembly reactions proceed rapidly and to very high conversion, generating water as the only byproduct. NMR spectroscopy studies and computational modeling of transition metal complexes, along with preliminary structure–activity relationships for a representative Pd(0)-catalyzed allylic alkylation reaction, suggested a P,N-coordination mode for these novel ligands.

Scheme 1. Self-assembly of functionalized phosphine ligands by imine-boronate condensation.

            A library of 100 phosphines was generated from selected combinations of four aminophosphines, three formyl-functionalized boronic acids and ten diols. The ligands were tested in a Pd(0)-catalyzed allylic substitution reaction (Scheme 2). Each of the three components of the ligand was found to influence enantioselectivity, and matching/mismatching effects were evident for certain pairs of components. A ligand that gave rise to high enantiomeric excess (93% ee) for this benchmark substrate combination was identified.

Scheme 2. Evaluation of a library of 100 self-assembled P,N-ligands for asymmetric allylic alkylation.

            Our recent research has been aimed at applying these libraries of structurally novel self-assembled ligands to more challenging substrate combinations and/or types of reactivity. From this perspective, one of the key limitations of our initial library was the lack of electronic or steric diversity at the diarylphosphino moiety in building blocks 1a–1d. It is known that variation of the phosphine component of P,N-ligands can dramatically influence the reactivity and selectivity of their derived transition metal complexes. We were particularly interested in modifying the aryl groups of aminophosphines such as 1c, which provided the highest selectivities in our initial library screen. A further advantage of components such as 1c is their synthetic accessibility from amino acids, thus allowing straightforward variation of the substituent on the amine-bearing chirality center. However, our attempts to adapt the reported synthesis of 1c (via opening of a cyclic sulfamidate with potassium diphenylphosphide) to other diarylphosphide nucleophiles were unsuccessful. To solve this problem, we developed a new variant of this method in which a metalated secondary phosphine oxide was employed as the nucleophile, and then reduced to the corresponding phosphine in the final step of the process. This protocol enabled incorporation of electron-deficient (e.g., 1e) and sterically encumbered (e.g., 1f) diarylphosphino moieties that had previously proved challenging. We anticipate that this modified route will allow us to systematically vary the properties of the phosphine group while constructing ligand libraries.

Scheme 3. Modified synthesis of amino alcohol-derived diarylphosphines.

            Among the reactions for which imine–boronate ligands provided interesting preliminary results was the enantioselective, decarboxylative allylation shown in Scheme 4. However, control experiments revealed that it was the amine-phosphine component of the ligand assembly (of general structure L*) alone that gave rise to the observed enantioselectivity. While it is clear that the ligand self-assembly strategy was not fruitful in this case, it is noteworthy that, for this particular substrate, a structurally simple and readily accessible ligand provided superior results to the optimum phosphinooxazoline ligand employed by Stoltz and co-workers for such transformations. We are exploring straightforward structural modifications of this type of amine-phosphine ligand to optimize its activity and enantioselectivity in decarboxylative allylation reactions.  

Scheme 4. Enantioselective, Pd-catalyzed decarboxylative allylation using a chiral aminophosphine ligand.