Automated three-component synthesis of a library of γ-lactams

A three-component method for the synthesis of γ-lactams from commercially available maleimides, aldehydes, and amines was adapted to parallel library synthesis. Improvements to the chemistry over previous efforts include the optimization of the method to a one-pot process, the management of by-products and excess reagents, the development of an automated parallel sequence, and the adaption of the method to permit the preparation of enantiomerically enriched products. These efforts culminated in the preparation of a library of 169 γ-lactams.The authors are grateful to Ben Neuenswander for carrying out the purification of the libraries and to the National Institutes of General Medical Sciences for financial support through the University of Kansas Chemical Methodologies and Library Development center (P50 GM69663)

Palladium-catalyzed substitution of (coumarinyl)methyl acetates with C-, N-, and S-nucleophiles

The palladium-catalyzed nucleophilic substitution of (coumarinyl)methyl acetates is described. The reaction proceeds though a palladium π-benzyl-like complex and allows for many different types of C-, N-, and S-nucleophiles to be regioselectively added to the biologically active coumarin motif. This new method was utilized to prepare a 128-membered library of aminated coumarins for biological screening.We thank the National Institutes of Health KU Chemical Methodologies and Library Development Center of Excellence (P50 GM069663) for funding. We are indebted to Dr. Conrad Santini and Ben Neuenswander for help in library production and purification

Studies on vinyl-alkyl based transition metal catalyzed coupling reactions and synthetic approach to the fusicoccane diterpenoids

Work relating to the transition metal catalyzed cross coupling of sp3 hybridized carbons to sp2 hybridized carbons is reported along with an asymmetric synthetic approach to the fusicoccane diterpenoids. A novel cross-coupling reaction between alkyl bromides (such as 2.40) with vinylzinc and vinylmagnesium reagents was developed. A catalytic system (5 mol % Pd(OAc)2, 5 mol % PCy3) and reaction conditions (NMP, 66 °C) were found which provided slightly over 50 % yield with a minimum amount of side product formation. The use of this reaction was explored in a tandem carboalumination/macrocyclization protocol. The formation of unsaturated macrocycles by way of intramolecular Negishi cross-coupling reaction was investigated. Neopentyl iodides were found to cross-couple with vinyl iodides in the intermolecular stereospecific formation of trisubstituted alkenes, although extending this to the complementary intramolecular reaction was challenging. Reaction conditions were found which allowed for the selective zinc activation of an alkyl iodide in the presence of a vinyl iodide contained within the substrate. The synthesis of the advanced intermediate towards fusicoccadiene, 4.2 was achieved in twenty-one steps (longest linear sequence) from the known (S)-(+)-4-(tertbutyldimethylsilyl) oxymethyl-Y-butyrolactone (4.15). Model studies revealed that fusicoccadiene may be obtained from 4.2 in additional four steps through the use of an acid catalyzed cyclodehydration reaction to form the C-ring. The formation of the 8-membered B-ring was achieved through the use of ring closing enyne metathesis. Other key features of the synthesis include the preparation of the functionalized cyclopentane A-ring through the use of a stereoselective Pauson-Khand [2+2+1] cycloaddition to establish the C-10 and C-14 stereocentres followed by the Norrish Type I reaction and an asymmetric cyclopropanation reaction to establish the remote C-7 stereocentre. Significantly, all stereocentres but one are established by stereochemical relay of the stereochemistry present in 4.15.Science, Faculty ofChemistry, Department ofGraduat

Conformationally controlled reactions of unsaturated macrocyclic lactones and keto lactones

As part of a study of the chemistry of macrocyclic compounds in our laboratory, the 14-membered unsaturated lactones 29 and 30 were synthesized with high stereoselectivity (>16:1 EIZ) via the ring closing olefin metathesis (RCM) reaction of the open chain diene esters. The configuration of the double bond in these unsaturated lactones was determined by 1H homonuclear decoupling NMR experiments. Equilibrium studies demonstrated that the RCM reaction proceeds under thermodynamic control in the cases of 29 and 30. The keto lactones 67 and 68 were synthesized via the hydroboration of 30 followed by TPAP oxidation of the hydroxy lactone products. The conformationally controlled reactions of the macrocyclic lactones 29, 30, 67 and 68 were investigated. Treatment of the unsaturated lactone 29 with borane tetrahydrofuran complex, disiamylborane and 9BBN led to the formation of the hydroxy lactones 47 and 48 in a 1:1 regioisomeric ratio. Treatment of the unsaturated lactone 30 with the same hydroborating reagents led to the formation of the hydroxy lactones 51, 52, 53 and 54 in a 1:1 regioisomeric ratio but with good 7r-face selectivity (>7:1 using 9BBN). The epoxidation of 30 using MCPBA and methyl(trifluoromethyl)dioxirane, leading to epoxides 63 and 64 also showed moderate 7t-face selectivity (>3:1 using MCPBA at -78 °C). Treatment of keto lactones 67 and 68 with NaBH4 and K-Selectride under a variety of reaction conditions led to the formation of hydroxy lactones 52, 53 and 51, 54, respectively. The hydroxy lactones were obtained in good stereoselectivity (>10:1 using K-Selectride at -78 °C) in the case of 67, and in low stereoselectivity (1:1.5 using K-Selectride at -78 °C) in the case of 68. In general, the stereoselectivity exhibited in the reactions of these macrocyclic lactones could be rationalized from the conformational analysis of the starting materials or the products. The relative stereochemistry of the stereogenic centers within the compounds synthesized during the course of the project were successfully assigned with the use of chemical correlations and Xray analysis.Science, Faculty ofChemistry, Department ofGraduat