Open Access Dissertation
Date of Award
SYNTHESIS AND á-STEREOSELECTIVE SIALYLATION OF KDN AND LATE STAGE MODIFICATIONS OF NEURAMINIC ACID SIALOSIDES
CHANDRA SEKHAR NAVULURI
Advisor: Prof. David Crich
Degree: Doctor of Philosophy
Keto deoxy nonulosonic acid has gained prominence in the recent years after the discovery of its presence in humans and the consequent appreciation of its role in human development and disease, and because of its potential as a marker of disease states. The development of efficient á-KDN sialylation methodology, an investigation of the mechanistic aspects of such sialylations, and the synthesis of this sparsely occurring sialic acid are the focus of this thesis.
In the challenging area of á-sialylation, an efficient methodology was developed for the KDN series by means of a 4,5-O-carbonate group installed on the pyranose ring. The 4,5-O-carbonate moiety proved to be an excellent á-directing group in sialylation for a wide array of acceptors independent of the anomeric configuration of the donor, and provided high yields by inhibiting the glycal formation. The donor was further found to be compatible with popular sulphoxide-based activation systems. The lower yields and selectivities of sialylations conducted using the analogous carbonate-free peracetyl KDN donor highlight the benefical effect of the 4,5-O-carbonate group.
The origins of the excellent á-directing ability of the acetyl oxazolidinone, oxazolidinone and carbonate cyclic protections in neuraminic acid and KDN were investigated by mass spectrometry using in-source fragmentation of the corresponding sialyl phosphates. The trends of the onset cone voltages for fragmentation of the sialyl phosphates clearly indicate a strong electron withdrawing effect of the 4,5 trans cyclic protecting group when compared to their peracetyl counterparts. This effect correlates with the dipole moments of the individual protecting groups. The enhanced dipole moment of the cyclic protecting group in the mean plane of the pyranose ring destabilizes any oxocarbenium ion thus necessitating a higher cone voltage to initiate mass spectral fragmentation. By analogy the cyclic protecting group retards oxocarbenium ion formation in the course of glycosylation reactions and so promotes associative pathways with consequent high á-selectivity.
An efficient 5 step synthesis of KDN and a 6 step synthesis of peracetyl KDN were developed, which could be used to access gram quantities of this sparsely occurring sialic acid. A highly syn-stereoselective lactol reduction to gain rapid entry to the protected KDN core is central to this efficient strategy. An ozonolytic unmasking of a propargyl group provides a facile entry into the requisite ketoester functionality in this synthesis.
C-5 modified sialic acid containing oligosaccharides, used in glycan arrays and known to be important probes to investigate the binding affinities of various sialosides, were synthesized by late stage modifications of á-sialic acid oligosaccharides prepared using the N¬-acetyl 5N,4O-oxazolidinone technology. This oxidative deamination methodology was successful in late stage conversion of the C-5 acetamido group stereoselectively to the corresponding acetoxy, acetylthio, fluoro and propargyl alcohol functionalities of potential biologically importance. The system was applied to the conversion of a neuraminic acid containing branched tetrasaccharide to a KDN containg tetrasaccharide as well as to a number of other systems.
Navuluri, Chandra Sekhar, "Synthesis And Á-Stereoselective Sialylation Of Kdn And Late Stage Modification Of Neuraminic Acid Sialosides" (2012). Wayne State University Dissertations. 681.