Synthesis and Applications of P-Chirogenic and Axially Chiral P,N-Phosphines as Ligands and Organocatalyst

Doctoral thesis, 2011

This thesis deals with the enantioselective synthesis of chiral mixed phosphorous/nitrogen compounds and some of their applications in asymmetric synthesis. For the most part, the compounds are P-chirogenic, with the chirality centered on the phosphorous atom. The last part of the thesis deals with axially chiral phosphoramidites. Papers I-III deals with the enantioselective synthesis of P-chirogenic mixed P,N-ligands. The chirality was placed on the phosphorous atom through the use of either asymmetric deprotonation of prochiral phosphine-boranes or through application of (-)-ephedrine as chiral auxiliary. These are well-known methods for preparing optically pure phosphorus and give high to excellent enantiomeric purity. We have used these methods to prepare P,N- P,N,N- and P,N,N,P-compounds with the chirality on phosphorus through α-formyl or α-carboxyphosphine intermediaries. The α-formylphosphines allow a one-step synthesis of β-aminophosphines in high yields. The α-carboxyphosphines meanwhile allow for the production of both amino- and amidophosphines. The described methodology is truly modular in nature, as the steric and electronic properties of both the phosphorous and amine parts can be varied easily. Moreover, we have shown that the use of microwave accelerated synthesis and solid phase purification is an efficient tool in the preparation of some of the final products. Paper IV presents the first study of exclusively P-chirogenic phosphines as organocatalysts. The asymmetric reaction chosen for this purpose was the [3+2]-cycloaddition of allenic esters to acrylates (the Lu reaction). A variety of phosphines with different steric and electronic properties were screened and shown to induce stereoselectivity, where the results can act as a guide to further development of organocatalysts with optically pure phosphorus. Paper V considers the use of axially chiral phosphoramidites as ligands in an asymmetric version of the Nicholas reaction. For the first time, a method that does not rely on chiral substrates or nucleophiles or chirality transfer protocols to introduce asymmetry is presented. The ligands were based on a BINOL-framework and were prepared with different aromatic, aliphatic and benzylic amines. In summary, the work detailed herein has furthered the preparation of P-chirogenic P,N-compounds by facilitating rapid and modular synthesis of such products. Furthermore, chiral P,N-ligands and organocatalysts have shown promise for further investigation. Keywords: asymmetric synthesis, P-chirogenic, phosphine, aminophosphine, modular synthesis, asymmetric hydrogenation, organocatalysis, Nicholas reaction, phosphoramidite