In our synthetic organic chemistry projects, we aim to demonstrate the utility of catalytic methodologies by incorporating them in at least one of the key steps. In earlier years, we did this by employing/modifying established methodologies reported by others. Recently, we have started to employ our own catalytic methodologies for the synthesis of biologically interesting molecules.

Projects on (Catalytic) Organic Synthesis

A Concise Asymmetric Synthesis of Torcetrapib”, M. Guino, P. H. Phua, J-C. Caille and K. K. Hii, J. Org. Chem., 2007, 72, 6290-6293.

doi:10.1021/jo071031g

Abstract: Optically active torcetrapib was synthesized in seven steps from achiral precursors without the need for protecting groups, utilizing an enantioselective aza-Michael reaction to achieve asymmetry.

Delineating Ligand Effects in Intramolecular Aryl Amidation Reactions: Formation of a Novel Spiro-Heterocycle by a Tandem Cyclisation Process, E. L. Cropper, A. P. Yuen, A. J. P. White, A. Ford and K. K. Hii, Tetrahedron, 2008, in press, TET-D-08-01562.

doi:10.1016/j.tet.2008.10.098

Abstract: Ligand effects for intramolecular Pd-catalysed aryl amidation reaction were examined for the synthesis of 7-membered benzolactam rings. In an attempt to produce an 8-membered ring, tandem C-N/C-O bond forming reactions occurred to give a novel spiro-benzofuran-lactam structure.

Ligand Effects in the Synthesis of N-Heterocycles by Intramolecular Heck Reactions, E. L. Cropper, A. J. P. White, A. Ford and K. K. Hii, J. Org. Chem., 2006, 71, 1732.

doi: 10.1021/jo0522660

Abstract: Chemo- and regioselectivity of intramolecular Heck reactions are dependent on the type of ligand employed. Six- to eight membered benzolactams are produced in good yields using PPh3 as ligand. In contrast, a biaryl coupling occurred preferentially under ligandless conditions to form a dihydrophenanthridine product. Conformations of the seven- and eight-membered benzolactams in the solid state were examined by X-ray crystallography.

Synthesis of 2-Substituted 1-Benzyl-2,3,4,5-Tetrahydro-1-Benzazepines by Palladium Catalysis. Observation of a Competitive beta-Hydride Elimination Pathway, M. Qadir, R. E. Priestley, T. W. D. F. Rising, T. Gelbrich, S. J. Coles, M. B. Hursthouse, P. W. Sheldrake, N. Whittall and K. K. Hii, Tetrahedron Lett., 2003, 44, 3675.

doi: 10.1016/S0040-4039(03)00676-2

Abstract: A synthetic route to 1-benzyl-tetrahydro-1-benzazepine is reported, which also permits access to analogous structures with alkyl and aryl substituents at position-2 of the aliphatic ring. Palladium catalysis is utilized in 2 of the 3 steps, constructing the 7-membered rings effectively from 2-bromoiodobenzene. Competitive beta-hydride elimination was observed in the attempted C-N bond formation with a sterically bulky substrate (when R = tert-butyl).

Conformation Analyses, Dynamic Behaviour and Amide Bond Distortions of Medium-sized Heterocycles. 1. Partially and Fully Reduced 1-Benzazepines, M. Qadir, J. Cobb, A. J. P. White, P. W. Sheldrake, N. Whittall, K. K. Hii, P. N. Horton and M. B. Hursthouse, J. Org. Chem., 2005, 70, 1545.

doi:10.1021/jo048118b

Abstract: Five 1-benzazepine heterocycles were synthesized by utilizing transition-metal-catalyzed processes in key bond-forming steps. exo-Methylene and methyl substituents were introduced at position 5, as well as a unit of unsaturation between positions 3 and 4, with benzoyl or benzyl N-substituents. Solution- and solid-state structures were examined, using dynamic NMR spectroscopy and X-ray crystallography, corroborated by molecular mechanics calculations. Greater amide distortion is associated with a more stable ground-state structure, which is in turn more reluctant to undergo conformational changes.

 

Conformation Analyses, Dynamic Behaviour and Amide Bond Distortions of Medium-sized Heterocycles. 2. Partially and Fully Reduced 1-Benzazocines, Benzazonines and Benzoazecines, M. Qadir, J. Cobb, A. J. P. White, P. W. Sheldrake, N. Whittall, K. K. Hii, P. N. Horton and M. B. Hursthouse, J. Org. Chem., 2005, 70, 1552.

doi:10.1021/jo048117j

Abstract: Partially and fully reduced forms of benzo-fused 8- to 10-membered nitrogen heterocycles (1-benzazecines, 1-benzazonines and 1-benzazecines) have been prepared. Conformational features, transannular distances and dynamic behavior were studied using X-ray crystallography and VT NMR spectroscopy. The amide moiety in the 9-membered benzazonine ring favors N-pyramidization, whereas the 10-membered benzazecine adopts an amide twist. Molecular mechanics calculations reveals a correlation between the amide twist and ring stability. The dynamic behavior of the heterocycles in solution were also found to be dependent on the extent and nature of the amide distortion. We thus conclude that ring strain of these medium-sized heterocyclic rings is relieved through amide distortion, which leads to a more stable structure.