Enantioselective catalytic alkynylation of carbonyl compounds

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Enantioselective catalytic alkynylation of carbonyl compounds


Author: Lu, Gui
Title: Enantioselective catalytic alkynylation of carbonyl compounds
Degree: Ph.D.
Year: 2003
Subject: Hong Kong Polytechnic University -- Dissertations
Enantioselective catalysis
Carbonyl compounds
Department: Dept. of Applied Biology and Chemical Technology
Pages: xiii, 185 leaves : ill. ; 30 cm
Language: English
InnoPac Record: http://library.polyu.edu.hk/record=b1732864
URI: http://theses.lib.polyu.edu.hk/handle/200/4569
Abstract: Chiral propargylic alcohols are useful building blocks for the enantioselective synthesis of high-valued pharmaceuticals and chiral intermediates. The preparation of propargylic alcohols via the addition of alkynes to aldehydes is of high interest because both the C-C bond and the chiral center can be formed in one step. Unlike the research on asymmetric alkylzinc additions to carbonyl compounds, nucleophilic alkynylation has enjoyed only very limited success. From both fundamental and practical standpoints, it is highly desirable to develop new catalysts for this reaction. We have designed and synthesized a series of amino alcohol ligands with binaphthyl backbones. One of these ligands was found to be highly effective in the asymmetric alkynylation of aldehydes. In the presence of dimethylzinc, a variety of aromatic aldehydes were converted to the corresponding chiral propargylic alcohols in 61-93 % e.e. We have also developed a simple and practical method for the production of chiral propargylic alcohols from aldehydes and alkynes. In the presence of a titanium alkoxide catalyst prepared in situ from titanium tetraisopropoxide and (R)-H8-binaphthol, a series of chiral propargylic alcohols were obtained with very good enantioselectivities (up to 96 % e.e.) and yields. It was clear that the enantioselectivities of reactions catalyzed by (R)-H8-BINOL were higher than those obtained using (R)-BINOL. The new catalyst system is of particularly high scientific and practical interest owing to its simplicity, excellent enantioselectivity and high reactivity. The self-assembly of several components into a highly enantioselective catalyst for asymmetric reaction is a new field in organic synthesis. We report here the first example of a chiral self-assembled titanium catalyst for asymmetric alkynylation, and the use of (S)-BINOL and chiral sulfonamide is proved to be the best combination in the reaction. Both the catalytic activity and enantioselectivity (99.7% e.e) are substantially better than all previously reported catalysts. In addition , the activation of chiral titanium ( IV ) complexes by achiral activators , e.g.phenol , was also found to provide higher levels of enantioselectivity than that attained by using enantiopure catalyst alone in the alkynylation of both aromatic and aliphatic aldehydes .It affords access to optically pure propargylic alcohols in low catalyst loading . Asymmetric additions of alkynylzinc to aromatic ketones were carried out using a catalytic amount of chiral camphorsulfonamide and Cu(OTf)2 to give the corresponding tertiary propargylic alcohols in high yields and up to 97 % e.e. To the best of our knowledge, this is the first report of the enantioselective addition of dialkynylzinc reagents to ketones.

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