1,3-Dipolar Cycloadditions of Chiral Nitrones

Keirs, David (1989) 1,3-Dipolar Cycloadditions of Chiral Nitrones. PhD thesis, University of Glasgow.

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The asymmetric synthesis of natural products via 1,3-dipolar cycloadditions of chiral nitrones to prochiral olefins has been an area of intense activity over the past decade. The work described in this thesis involves the application of two short, highly efficient asymmetric routes to the synthesis of compounds of biological (Chapter 2) and commercial (Chapter 3) interest. The key step in each synthesis involves dipolar cycloaddition of a chiral nitrone to a substituted dipolarophile. The Introduction gives an account of the mechanistic aspects of 1,3-dipolar cycloadditions and describes some recent examples of asymmetric syntheses involving nitrone-olefin cycloaddition reactions. Chapter 1 provides a short discussion on the general methods of preparation of aldonitrones, in particular the chiral aldonitrones used in the syntheses described in Chapters 2 and 3. The structure of aldonitrones is also briefly discussed in Chapter 1. Chapter 2 gives a detailed account of the asymmetric synthesis of beta-lysine (62). This is a continuation of the work described by Moffat and Overton who devised a general asymmetric route to B-amino acids involving 1,3-dipolar cycloaddition of chiral nitrones to vinyl acetate to yield isoxazolidines in which substituents have been placed in a regio- and stereoselective manner on the periphery of the five-membered ring, [Scheme I]. The isoxazolidines are formed as a crude mixture of four non-racemic diastereomers with the induced chiral centre at C-3 ultimately becoming the chiral centre of the final B-amino acid. The chiral centre at C-5 is destroyed via the subsequent synthetic steps. A chromatographic separation of diastereoisomeric 5-acetoxy isoxazolidines has allowed the enantioselective synthesis of optically pure (R)- and (S)-B-lysine. The work described in Chapter 3 involves a stereocontrolled synthesis of the dipeptide artificial sweetener, Aspartame [(S)-Aspartyl-(S)-Phenylalanine methyl ester] (95) via 1,3-dipolar cycloaddition of nitrones (119a,b,c) to the ketene equivalent 2-chloro-acrylonitrile. The same general sequence as that used for the asymmetric synthesis of beta-lysine was employed although 2-chloroacrylonitrile was shown to be far superior to vinyl acetate as a dipolarophile in terms of reactivity towards nitrones and chemical yields. The sequence also provides a potential general asymmetric route to aspartyl dipeptides. Chapter 4 records the conversion of various amines into imines by Swern oxidation [DMSO/(COCl2) , the most notable example being the conversion of indoline (141) into indole (143) in almost 90% yield, [Scheme II], This work arose out of an unexpected observation in the synthesis of beta-lysine. Although not directly related to the main topic of this thesis, the finding is of fundamental importance since Swern reagents have not been used previously for the dehydrogenation of amines into imines.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Organic chemistry
Date of Award: 1989
Depositing User: Enlighten Team
Unique ID: glathesis:1989-77827
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jan 2020 11:53
Last Modified: 14 Jan 2020 11:53
URI: http://theses.gla.ac.uk/id/eprint/77827

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