Methodology Development for the Asymmetric Synthesis of Organophosphorus Compounds

This thesis describes the development of two methodologies for the preparation of P-stereogenic compounds.

The work described in Chapter 2 explores the application of anion-binding organocatalysis in the selective formation of ⍺-aminophosphinates bearing contiguous P- and C-stereogenic centres. It was proposed that an organocatalyst could induce enantioselective P-C bond formation and could also initiate an unprecedented stereoselective Arbuzov collapse to access these P-, C-stereogenic ⍺-aminophosphinates. Thus, a range of ⍺-aminophosphinates were prepared through a three-component catalytic asymmetric dearomatisation reaction between a prochiral phosphonite nucleophile, isoquinoline and Troc chloride in the presence of a thiourea organocatalyst. 13 examples of P-, C-stereogenic ⍺-aminophosphinates were prepared with yields up to 98%, enantioselectivities up to 96% ee and diastereoselectivities up to 30% de (although an outlier was prepared in 74% de). The mechanism of the reaction was studied to elucidate why the reaction proceeded with high enantioselectivity but poor diastereoselectivity. It was elucidated that the P-C bond formation step is selective, which results in good enantioselectivity at carbon. However, the phosphonium salt intermediate underwent a non-selective Arbuzov collapse to generate the phosphorus stereocentre with no selectivity, resulting in poor diastereoselectivity overall. A number of other organocatalytic systems for the preparation of compounds bearing P-stereocentres were also investigated but these did not give promising results. The work described in Chapter 3 involves the development of an efficient one-pot chiral auxiliary-based method for the preparation of enantioenriched P-stereogenic phosphines without the need to purify intermediates. Furthermore, P,P-dichlorophenylphosphine was utilised as the starting material, a P(III) compound which is commercially available. Thus, this reaction is redox-economic and avoids the need to use harsh reduction conditions to access tertiary phosphines. The P-stereogenic phosphines synthesised could be further derivatised (in one-pot) to phosphine boranes, phosphine oxides or phosphine sulfides. The synthesis of phosphine boranes was explored in detail using this methodology since they are typically challenging to access using current literature methods. A range of diarylalkyl phosphines (18 examples, up to 97% ee) and aryldialkyl phosphines (4 examples, up to 99% ee) were prepared, most isolated as the corresponding phosphine borane.