Diastereoselective conjugate additions of Grignard reagents to homochiral fumarates derived from Oppolzer's sultam

Reid, Gary Patrick (2004) Diastereoselective conjugate additions of Grignard reagents to homochiral fumarates derived from Oppolzer's sultam. PhD thesis, University of Glasgow.

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Asymmetric conjugate addition to alpha,beta-unsaturated organic compounds is one of the most useful methods for producing b-substituted products in a stereoselective manner. It was shown that Grignard reagents add in a conjugate manner to N,N'-fumaroylbis[(2R)- bornane-10,2-sultam] i, readily available from Oppolzer's (2R)-bornane-10,2-sultam ii. The fumaramide system i was treated with a series of Grignard reagents to produce diastereomers iii in excess for a range of different Grignard reagents incorporating alkyl and aromatic groups. This selectivity results from attack on the re face of i. The mixtures of diastereomers were hydrolysed to the corresponding (2R)- substituted succinic acids iv. Enantiomeric excesses were determined by conversion of the diacids into dianilides v and analysis using chiral HPLC. Substituted succinic acids are important intermediates in organic synthesis. They are building blocks for the synthesis of enantiomerically pure B-substituted, p-amino acids. They also have a role as structural components in natural products. Using our methodology (2R)-Benzylsuccinic acid was obtained in high 92% ee. (2R)-Benzylsuccinic acid has previously been shown to be an inhibitor of carboxypeptidase A. The extent of diastereofacial differentiation of the conjugate addition was also system of the succinamide protons resonated at different frequency for each pair of diastereomers. The mixture of diastereomers were also reduced producing the (2R)-substituted butane-1,4-diols vi.O RIVVdetermined by analysis of the 1H NMR spectra of the diastereomeric mixtures. The ABX viii The enantiomeric excesses of the diols were estimated from 19F NMR spectra of the corresponding Mosher's esters vii.The addition of Grignard reagents to two differentially protected flimarates viii and ix was carried out. The Grignard reagent did not add exclusively in a 1,4 manner to viii and a mixture of 1,2-addition and 1,4-addition products was observed. The reaction of fumarate ix with Grignard reagents gave only conjugate addition products. Diastereomeric excesses could not be determined from the proton NMR spectra of the reaction mixtures. Therefore the diastereomeric excess was determined from the bis-Mosher ester of each diol. The stereoselectivity obtained with fumarates viii and ix was not as good as that observed using fumaramide i. The diastereomers iii were used to synthesise enantiomerically pure 2-substituted putrescines x. Removal of the chiral auxiliaries from iii using lithium aluminium hydride produced the corresponding enantiomerically enriched 2-substituted butane-1,4-diols vi. The enantiomeric excess of these diols was improved to >95% by separation of the diastereomers of iii using column chromatography or by recrystallisation. The diols vi were converted into the disulfonate esters xi, followed by substitution by sodium azide. The diazides were directly reduced to the diamines using lithium aluminium hydride and isolated as the dihydrochloride salts xii. Racemic 2-substituted putrescines were also prepared. Diamine oxidase (DAO) enzymes are involved in the terminal catabolism of polyamines, and putrescine xiii is a natural substrate for DAO. DAO catalyses the oxidation of diamines to aminoaldehydes. Some of the 2-substituted putrescines produced were shown to be substrates for pea seedling DAO.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: David Robins
Keywords: Organic chemistry
Date of Award: 2004
Depositing User: Enlighten Team
Unique ID: glathesis:2004-74196
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 23 Sep 2019 15:33
Last Modified: 23 Sep 2019 15:33
URI: https://theses.gla.ac.uk/id/eprint/74196

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