Lam, Hon Wai

Joensuu, Pekka Matias

2008-11-27T14:25:04Z

2008-11-27T14:25:04Z

2008

The chemistry of enolates can be considered one of the cornerstone areas in organic chemistry. Regioselective generation of an enolate in the presence of several enolisable sites can often prove to be a difficult task. Discoveries in recent years have led to new areas of enolate formation in the presence of other carbonyl groups. These include reductive aldol chemistry where direct reductive aldol coupling of an alpha,beta - unsaturated carbonyl group in presence of a carbonyl electrophile enables often perfectly regioselective reactions to occur. This tandem conjugate reductionelectrophilic trapping process enables the reaction to be performed in a “one-pot” manner. The first examples of asymmetric copper-catalysed reductive aldol reactions have been developed for the formation of a range of beta-hydroxylactone products. A combination of Cu(OAc)2.H2O with different bisphosphine ligands catalyses these intramolecular reductive aldol reactions. TMDS (1,1,3,3-tetramethylhydrosiloxane) is used as a stoichiometric hydride source. The reaction proceeds with high relative stereocontrol (>19:1 dr), while absolute stereocontrol remains modest (up to 83% ee). The yields range from moderate to good. A continuous search for improved reaction conditions led to the discovery that cobalt-catalysed reductive aldol reactions have an advantage over the coppercatalysed reaction in the cases where 4-hydroxypiperidin-2-one products are formed. When Co(acac)2·H2O is used together with Et2Zn as the stoichiometric reductant, an increased substrate scope is observed while the diastereoselectivity of the reaction remains high. Yields are also remarkably higher compared to the results obtained with the copper catalyst. These reaction conditions are also used to perform intermolecular reductive aldol reactions between a range of alpha,beta-unsaturated amides and ketones. The reactions proceed readily with high diastereoselectivities (up to >19:1 syn:anti) and good yields. Asymmetric variants have been studied by the use of a chiral oxazolidine auxiliary. Although good selectivities have been obtained, this method currently suffers from the fact that the chiral auxiliary is difficult to cleave. Ni(acac)2 was also found to perform the intramolecular reductive aldol reaction. Et2Zn was again used as the stoichiometric reductant. The nickel-catalysed reaction increased the reaction scope still further. This time both beta-hydroxylactone and 4-hydroxypiperidin-2-one products were readily formed. The former proceeded with increased yields compared to those obtained with the copper catalyst, and, the latter with comparable results to those obtained with the cobalt catalyst.

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http://hdl.handle.net/1842/2576

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Chemistry

organic chemistry

Development of Catalytic Stereoselective Reductive Aldol Reactions

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy