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Synthesis of [gamma]-aminoalcohol derivatives and study of the mechanism of Cp-Ti protonolysis

Authors Lo, Man-chu
Issue Date 1996
Summary Previous work in our laboratory has established that lithiated arylacetonitriles undergo anti-selective aldol reaction with aldehydes. The first chapter of the thesis summarizes attempts to modify the nitrile aldol reaction. First, efforts were made to improve anti-selectivity by replacing lithium with other metals, particularly those featuring short M-O & M-N bond lengths. Boron, titanium, zirconium and tin were explored, but the selectivity of lithiated nitriles still remains superior. Most of the transmetalated nitriles were found to react with poor selectivity, except for tin, which offers anti-selectivity similar to that of lithium. Secondly, efforts were made to achieve syn-selective nitrile aldol addition by forcing the reaction to proceed via an "open" transition state. Two strategies were explored: 1) attachment of a large metal fragment to the nitrile and 2) the use of cation complexation agents. The most successful example thus far obtained involved the addition of 6 eq. HMPA to lithiated nitriles in THF. The aldol addition of 1- and 2- naphthylacetonitriles to benzaldehyde changes from being moderately anti-selective (2.5 : 1) in pure THF, to moderately (1 : 2.4, for 2-naphthyl), or highly (1 : 7.8, for 1-naphthyl) syn-selective in THF/HMPA. The second chapter describes work on transformation of the diastereomerically pure β-hydroxynitriles to various γ-aminoalcohol derivatives. The γ-amino alcohol or ether moiety is present in a large number of "second-generation" serotonin selective reuptake inhibitor (SSRI) antidepressants, and it is anticipated that our diastereomerically pure γ-aminoalcohols would also possess antidepressant activity. The best reagent for reduction so far in terms of ease of handling and workup was found to be LiAlH4/AlCl3. Some of these γ-aminoalcohols have also been found to be non-competitive NMDA antagonists, with affinities of some compounds in the micromolar range. This raises the prospect that γ-aminoalcohols derived from diastereoselective nitrile aldol reaction might have the potential to be developed into neuroprotective agents. We also demonstrated that γ-aminoalcohols can be converted in moderate to good yields to the corresponding heterocyclic derivatives. The final chapter outlines kinetic experiments on the protonolysis of the Cp-Ti bond of Cp2 -Ti(NCO)2 in DMSO containing controlled amount of water. The hydrolytic stability of analogous titanocene compounds has attracted attention because of their demonstrated antitumor activity. The observation of saturation kinetics in [H2O] enables us to rule out protonolysis by simple bimolecular protonation of an η5- Cp ring. Two alternative mechanisms are put forward to account for the observed saturation kinetics, one involving the formation of an intermediate titanocene aqua complex, and the other involving the transient intermediacy of "ring-slipped" titanocene species.
Note Thesis (M.Phil.)--Hong Kong University of Science and Technology, 1996
Language English
Format Thesis
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