Studies On Ketone Cyanosilylation

Asymmetric ketone cyanosilylation is a straightforward method for the synthesis of tertiary chiral cyanohydrins, versatile building block for the synthesis of a number of value-added products. Despite much attention has been devoted to this research, there is still much to explore. For example, aliphatic ketones still present as a problematic substrates, and the use of TMSCN as cyanation reagent leads to compromised atom-economy. This thesis focuses on the development new catalytic system and new cyanating reagent to address the aforementioned unsolved problems and has finished the following work.1) Phosphorane is indentified as a type of effective Lewis bases to activate chiral (salen)AlCl complex to form a highly effective cationic catalyst; This mechanistic insight is supported by NMR, MS, electrical conductivity experiments and DFT calculations. Accordingly, a three-component catalytic system consisting of (salen)AlCl, phosphorane and Ph3PO is developed as a powerful tool for the highly enantioselective cyanosilylation of linear aliphatic ketones and ?,?,?,?-unsaturated enones. The synthetic utility of these highly enantioselective reactions has been demonstrated by the formal synthesis of Fostriecin (natural antibiotic), AMG 221 (potent dehydrogenase inhibitor) and the total synthesis of (S)-CPB pheromone from Colorado potato beetle.2) A bifunctional cyanosilylation reagents ClCH2(Me)2SiCN is developed, which exhibited higher reactivity than TMSCN in ether solvents, when chiral (salen)AlCl/phosphorane complex is used as the catalyst. A variety of aromatic and acyclic aliphatic ketones, as well as vinyl and ethynyl ketones, could react well to give high to excellent ee values. A one-pot ketone cyanosilylation/functional group transfer sequence is further developed for the highly enantioselective synthesis of tertiary alcohols with a chloromethyl ketone moiety. Since the chloromethyl group on the silicon could be transferred to final product, ClCH2(Me)2SiCN is therefore more atom-economic than TMSCN. Based on these reactions, a formal synthesis of 15(R)-Me-PGD2 (potent selective DP2-receptor agonist) and a one-pot total synthesis of (S)-CPB pheromone are further achieved.3) Carbonyl stabilized phosphorane was found to be an effective promoter for ketone cyanosilylation in our previous study. Further optimization reveals that the amount of phosphorane could be lowered down to 0.01 mol%. Various ketones including aliphatic ketones, mono- and di-aryl ketones are all viable substrates for this highly efficient cyanosilylation. Initial electrical conductivity experiments show that phosphorane is more powerful than phosphine and nitrogen oxides in activating TMSCN, which demonstrates the potential of carbonyl stabilized phosphorane to act as effective Lewis base. The detailed mechanism of carbonyl stabilized phosphorane mediated ketone cyanosilylation has not yet been confirmed.