Quantum mechanical investigations of the mechanisms and selectivities of synthetic organic reactions --- From organocatalysis to transition metal catalysis to substrate controlled asymmetric reactions.

摘要

Chapter 1 recounts the development of catalysts for Mannich-type reactions that afford anti-products with excellent diastereo- and enantioselectivities. Based on principles gained from the study of (S)-proline and (S)-pipecolic acid catalyzed Mannich-type reactions that afford enantiomerically enriched syn-products, (3 R,5R)-5-methyl-3-pyrrolidinecarboxylic acid (RR5M3PC) has been designed to catalyze the direct enantioselective anti-selective Mannich-type reactions. In accord with the design principles and in quantitative agreement with the theoretical predictions, reactions catalyzed by this catalyst afforded anti-products in good yields with excellent diastereo- and enantioselectivities (anti:syn 94:6--98:2, >97-->99% ee). This work has been published in two journals---Mitsumori, S.; Zhang, H.; Cheong, P. H.-Y.; Houk, K. N. Tanaka, F.; Barbas, C. F., J. Am. Chem. Soc. 2006, 128(4), 1040-1041 and Cheong, P. H.-Y.; Zhang, H. L.; Thayumanavan, R.; Tanaka, F.; Houk, K. N.; Barbas, C. F., Org. Len. 2006, 8(5), 811-814.;Chapter 2 describes the computational investigations of the Hajos-Parrish-Eder-Sauer-Wiechert reaction catalyzed by various proline derivatives. Where available, quantitative agreements with experimental stereoselectivities were observed. Predictions were made for catalysts that have not been evaluated yet. Chapter 2 was published in two journals---Cheong, P. H.-Y.; Houk, K. N.; Warrier, J. S.; Hanessian, S., Adv, Synth. Cat. 2004, 396(9-10), 1111-1115 and Cheong, P. H.-Y.; Houk, K. N., Synthesis 2005, (9), 1533-1537.;Chapter 3 is the density functional theory study of the mechanisms, transition structures, regioselectivity and stereoselectivity of proline-catalyzed alpha-aminoxylation reactions. The most favorable transition structure involves the nucleophilic attack of the (E)-proline enamine to the oxygen of the nitrosobenzene with proton transfer from the carboxylic acid to the nitrogen. Enamine attacks to the oxygen are favored over the attack on the nitrogen due to the greater basicity of the nitrogen. Previously proposed zwitterionic enaminium pathways are highly disfavored due to the energetic penalty associated with charge separations. This has been published in Cheong, P. H.-Y.; Houk, K. N., J. Am. Chem. Soc. 2004, 126(43), 13912-13913.;Chapter 4 discusses the torsional steering control of stereoselectivity in the key epoxidation step of Guanacastepene A synthesis of Danishefsky. In this particular epoxidation reaction, the transition structure energetic difference is enhanced by the great asynchronicity of the forming C-0 bonds that intensifies the torsional interactions. This has been published in Cheong, P. H.-Y.; Yun, H.; Danishefsky, S. J.; Houk, K. N., Org. Lett. 2006, 8(8), 1513-1516.;Chapter 5 illustrates how substantial differences in reductive elimination barriers control the ease of organometallic reactions. Rhodium dimer [Rh(CO) 2Cl]2 efficiently catalyzes the intra- and intermolecular (5+2) reactions of vinylcyclopropanes with alkynes and allenes, but not alkenes. This difference in reactivity is attributed to the difficulty of reductive elimination for the alkene. The computed reductive elimination transition structures show that the participation of the second pi-orbital in acetylene and allene reduces the barrier by 9∼45 kcal/mol, compared to ethylene, for which no such interactions are possible.;Chapter 6 details the mechanism and origins of stereoselectivity for the Rh(I)-chiral bisphosphine hydrogenation of unprotected enamines. The hydrogenation step is found to be rate-determining. The origins of stereoselectivity were investigated by computing the hydrogenation transition structure involving the Josiphos ligand---the actual bisphosphine ligand used in the industrial process---and its various derivatives.;Chapter 7 reports the mechanisms and origins of selectivity for the tris-gold phosphine oxonium fluoroborate, [(Ph3PAu)3O]BF 4, catalyzed rearrangement of 1,5-allenynes to cross-conjugated trienes. Experimental and computational evidence shows that the ene reaction proceeds through a unique nucleophilic addition of an allene double bond to a gold phosphine complexed gold phosphine acetylide, followed by a 1,5-hydrogen shift.