Chapter 4 Computational Studies of the Role of Glycopyranosyl Oxacarbenium Ions in Glycobiology and Glycochemistry
Introduction
Unraveling the mechanistic details of the myriad of glycosyl processing enzymes (GPEs)1, 2, 3, 4 is a major endeavor of numerous scientists since these enzymes are essential to many industries, ranging from such biomass utilization industries as bioethanol and paper production through the varied fermentation processes of the food and beverage industries, to the production of aminoglycoside antibiotics and carbohydrate conjugate vaccines by the pharmaceutical industries.5 Behind all this glycobiology are the decades of developments by carbohydrate chemists to isolate, identify, and synthesize the substrates and products of many of these enzymes. Such studies are an integral part of elucidating the fundamental structure–function relationships that underlie the practical application of these compounds.6, 7, 8 Many of these processes involve the formation or breaking of glycosidic bonds. Consequently, an understanding of the formation and breaking of glycosidic linkages is at the core of both glycobiology and glycochemistry.
With only a few exceptions, both the formation and breaking of glycosidic linkages involve processes that proceed through species having a high degree of oxacarbenium ion character. Thus, in the chemistry of, glycofuranosyl and glycopyranosyl groups, as the two commonest ring forms of sugars, an understanding of oxacarbenium ions is a very important area of research. Because of the transient nature of oxacarbenium ions, their properties are very difficult to establish experimentally.9, 10 For this reason one of the strategies for establishing their structures and their conformational preferences is to perform quantum mechanical (QM) studies. QM is the computational method of choice, since the ions by definition contain a trigonal carbon atom and one must consider subtle charge‐delocalization effects, and neither factor is readily amenable to any other computational method. In the past 10 or so years computational resources and software have become available that allow for the practical study of such species.11, 12 Since a number of these studies have been conducted in the author's laboratory in Ottawa, this chapter presents a study of the d‐galactopyranosyl system, prepared specifically for this contribution. It should enable those readers having access to the appropriate software and hardware, to perform their own studies of sugars of interest. Here the results for the galactopyranosyl system are compared and contrasted with published results for other carbohydrates, and in this way pertinent examples from the literature are presented. A diligent attempt has been made to provide both recent and classical references to the fundamental principles and relevant experimental studies. No detailed understanding of computational chemistry is expected of the reader, but some familiarity with either or both of chemical glycosylation reactions and GPE‐catalyzed reactions is helpful.
Section snippets
Background
In what is generally considered a classic paper in carbohydrate chemistry, Edwards provided compelling evidence that galactopyranosides are hydrolyzed faster than their gluco counterparts.13 In a variety of other situations this higher reactivity seems to be general; galactopyranosyl donors are almost always more reactive than glucopyranosyl donors having the same protecting and leaving groups, in chemical glycosylations under similar reaction conditions.14 The simplest explanation of this
Summary of Glycosylation Reaction Mechanisms
Selected points from the vast glycosylation literature have been presented which are intended to complement the results shown for galactopyranosyl oxacarbenium ions related to 2 and 17. A number of little recognized parameters previously described for other glycopyranosyl oxacarbenium ions have been identified for 2 and 17 that help to suggest their generality. A summary is made below:
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The 5S1 conformation of glycopyranosyl oxacarbenium ions with O‐2 equatorial and the remaining substituents
Acknowledgments
The author acknowledges the assistance of various collaborators, visiting scientists, and postdoctoral fellows who have made this research possible. These include J. J. Krepinsky, T. Nukada, A. Bérces, M. Z. Zgierski, L.‐J. Wang, and A.R. Ionescu.
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