Some New Methods in Sialic Acid Chemistry

Abstract

Gangliosides (G) are sialic acid-containing cell surface glycosphingolipids capable of forming lactones, i.e. inner esters. Some gangliosides are tumor-associated antigens, and they may serve as immunogens in their lactone form, where the latter is comparatively more abundant on the surface of malignant cells. Due to improved hydrolytic stability, lactam (inner amide) analogues of gangliosides should be better immunogens than the corresponding lactones while still being conformationally nearly identical. Hence, a lactam-specific antibody which cross-reacts with the corresponding lactone is possible to prepare. As target molecule for this work was chosen an [8,9]-lactam analogue of GD3, a tumor-associated antigen for human malignant melanoma.



The alfa-2-8 coupling of two sialic acid residues proved to be the critical and most difficult step in the synthesis, and a novel potent tetra-O-acetylated-3-(S)-phenylthio ethylthioglycoside sialyl donor was therefore developed (Papers I-II).



Sialylation of a 9-azido acceptor was accomplished in 28% yield with the novel donor, and the subsequently prepared bis-sialic acid lactam was shown to be conformationally nearly identical with a lactone analogue, where the latter was also prepared by means of the novel sialyl donor (Paper III).



Removal of the auxiliary 3-(S)-phenylthio group was however difficult in some instances, and a 3-(S)-phenylseleno phosphite donor was therefore prepared. Although the 3-(S)-phenylseleno group was easily removable, it did not confer any powerful sialylation capability in terms of yield, albeit the stereoselectivity was excellent. Both the weak C-Se bond and a conformational phenomena explained this result (Paper IV).



Two 3-(S)-(2-methoxyphenyl)thio methylthioglycoside sialyl donors were also prepared, and they provided good yields in bis-sialo couplings, albeit the stereoselectivity was unsatisfactory. The removal of the 3-(S)-(2-methoxyphenyl)thio group was also unexpectedly difficult.



Many promoter systems of thioglycosides are available, such as NIS/TfOH and MeSBr/AgOTf, but they all have some practical disadvantages. In order to overcome this, the novel promoter system ICl/AgOTf was developed, and it proved to be both versatile and especially convenient to use (Paper V).

• author: Ercegovic, Teddy
• supervisor: [unknown] [unknown]
• opponent: Professor Boons, Gert-Jan, Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602, USA
• organization: Centre for Analysis and Synthesis
• publishing date: 2001
• type: Thesis
• publication status: published
• subject: Organic Chemistry
• keywords: thioglycoside promoter, ganglioside, Tumor-associated antigen, lactam, lactone, sialic acid, N-acetylneuraminic acid, Neu5Ac, sialyl donor, auxiliary group, 3-(S)-phenylthio, bis-sialic acid lactam, 3-(S)-phenylseleno, silver trifluoromethanesulfonate, iodine monochloride, Organic chemistry, Organisk kemi
• pages: 64 pages
• defense location: Sal B Center for Chemistry and Chemical Engineering, University of Lund
• defense date: 2001-03-23 10:15:00
• ISBN: 91-628-4623-X
• language: English
• LU publication?: yes
• additional info: The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Organic chemistry (S/LTH) (011001240)
• id: 57c8ab99-dcb7-4b33-914e-3acf1f89a991 (old id 41336)
• date added to LUP: 2016-04-04 11:25:19
• date last changed: 2018-11-21 21:04:45