Deoxycholic derived biphenylphosphites: a new class of tropos ligands for asymmetric catalysis

This PhD thesis deals with synthesis, characterization and application as chiral inducers in asymmetric catalysis of a new class of tropos ligands derived from de- oxycholic acid. Following the longstanding interest of our research group in the use of bile acid derivatives in enantioselective processes, attention was addressed to the develop- ment of tropos biphenylphosphite ligands. Taking advance of the asymmetric ac- tivation approach, which proved to be successful for the development of different chiral auxiliaries for asymmetric synthesis (Chapter 1), the steroidal backbone of the deoxycholic acid was used as chiral activator in order to have a diastereomeric control and to induce a prevalent screw sense on the tropos biarylphosphite moieties. A family of seven deoxycholic derived biphenylphosphite ligands (Figure 1) was synthesized and stereochemically characterized by means of NMR and Circular Dichroism spectroscopies (Chapter 2), which demonstrated the tropos nature of the ligands along with the capability of the bile acid to induce a prevalent screw sense on the biphenylphosphite moieties. Moreover, the sense and the extent of this prevalence were determined, as well as the peculiar dependence of the sense of twist of the biphenyl moiety on the solvent: in Chapter 2, in fact, it is also showed that the M-P equilibrium, in the majority of the phosphites is shifted towards the M form in ACN and towards the P form in THF. This new family of ligands was first tested in the copper(I)-asymmetric conjugate addition of diethylzinc to enones (Chapter 3), affording the alkylation products with ees up to 65%. The extent of the enantioselectivity depended on the substitution on the biphenyl moiety of the phosphite, whereas the sense of the asymmetric induction depended on the reaction solvent. In fact, performing the reaction in toluene, where the biphenyl moiety of the phosphites 1-5 has M prevalent screw sense afforded the S-configured alkylation product, whereas using THF, where P sense of twist prevails, the R alkylation product was obtained. Biphenylphosphite ligands 1-6 were also applied in rhodium catalyzed reactions (Chapters 4-6). The Rh catalyzed asymmetric hydrogenation was first investigated, 31 in which very high values of asymmetric inductions were obtained. P-NMR and CD measurements on the rhodium complexes of some phosphites were also performed, allowing to shed light on nature and stereochemical features of the catalytic species as well as on the asymmetric induction process (Chapter 4). The study performed on the asymmetric addition of arylboronic acids to cyclic enones underlined the effectiveness of phosphites 1-6 as chiral ligands in rhodium catalyzed reactions: also in this case very high activities and enantioselectivities were observed. These ligands also showed a unique behavior, being able to afford mono or disubstituted Rh(I) complexes, depending on the P:Rh ratio used and the reaction time, both showing catalytic activity and enantioselectivity. The compari- son with the corresponding atropoisomeric analogues phosphites permitted to gain important information about the stereochemical outcome of the reaction. In ad- dition, the use of disubstituted complexes led to the formation of double addition products 1,3-diarylcyclohexanols, obtained with complete diastereoselectivity and ees up to 94% (Chapter 5). Taking into account the rare use of monodentate ligands in asymmetric hydro- formylation reactions, biphenylphosphites 1-6 were assayed also in this reaction: the task proved to be not a trivial one, since enantioselectivity without using a chelating ligand was often elusive, but nevertheless promising results for further investigations were obtained using ligand 5 (Chapter 6).