The Design And Synthesis Of Novel Chiral Spiro Ligands And Their Applications In Asymmetric Catalytic Reactions

The chiral spiro compounds are widely occurring in natural products and biologically active molecules and are important in organic chemistry.Over the last two decades,many chiral spiro compounds have been used as priviledged ligands in asymmetric catalysis.On the other hand,so far it is relatively difficult to obtain optically pure spiro compounds in an efficient approach.Therefore,the development of new asymmetric catalytic methods for efficient construction of this type of structures is of great significance in organic chemistry.In the thesis,we have developed a new methodology for enantioselective synthesis of cyclohexyl-fused chiral spirobiindanes.A convenient approach has also been developed for the practical synthesis of cyclohexyl-fused spirobiindanediol,which was used as the skeleton for the synthesis of various novel chiral spiro ligands.These ligands demonstrated high activity and excellent enantioselectivity in some transition metal catalyzed asymmetric reactions.1.Enantioselective synthesis of cyclohexyl-fused chiral spirobiindanes and scalable asymmetric synthesis of cyclohexyl-fused chiral spirobiindanediolThe ?,?'-bis-?arylidene?cyclohexanones 44 were hydrogenated into?,?'-bis?benzyl?ketones?S,S?-45 by Ir/^tBu-PHOX catalyst,with excellent diastereoselectivities?trans/cis>20/1 by ¹H-NMR?and extremely high enantiopurities??99%ee?.A facile enantioselective synthesis of cyclohexyl-fused chiral spirobiindanes 46 has been accomplished,in high yields and excellent stereoselectivities?up to>99%ee?,via a sequence of Ir-catalyzed asymmetric hydrogenation of?,?'-bis?arylidene?ketones and TiCl₄ promoted asymmetric spiroannulation of the hydrogenated chiral ketones.Mechanistically,the TiCl₄promoted spiroannulation would involve electrophilic activation of the carbonyl group by lewis acid,followed by two successive intramolecular Friedel-Crafts?FC?reactions of the nucleophilic phenyl groups,leading to stereogenic formation of the spiro carbon center,and concomitant loss of an equivalent of water.The protocol can be performed in one-pot and is readily scalable,and has been utilized in a 25-gram scale asymmetric synthesis of cyclohexyl-fused spirobiindanediol?1S,2S,2'S?-48,in>99%ee and 67%overall yield for four steps.2.Evaluation of chiral spiro phosphoramidite ligands in benchmark metal-catalyzed reactionsThe crystal structures of the precatalysts[Rh?cod???1S,2S,2'S?-53a?₂]?BF₄?·?CH₂Cl₂?₂?54?and[Rh?cod?Cl·??1S,2S,2'S,S_N,S_N?-53c?]?55?revealed a close resemblance with their correspornding complexes bearing spirobiindane backbone ligand..The close structural resemblance suggested that a reaction catalyzed by the precatalysts is much likely to follow the same stereochemical course,hence giving almost identical results in the reaction.Facile derivations of?1S,2S,2'S?-48 provided straightforward access to chiral monodentate phosphoramidites 53b?53c and a tridentate phosphorus-amidopyridine 56,which were evaluated as chiral ligands in several transition-metal catalyzed enantioselective reactions?hydrogenation,hydroacylation,and[2+2]reaction?catalyzed by transition metal?Rh,Au,and Ir?.Preliminary results from comparative studies showcased the excellent catalytic performances of these ligands,with a competency essentially equal to the corresponding well-established privileged ligands bearing a regular spirobiindane backbone.