Synthesis of Complex Carbohydrates

Department of Chemistry, Wayne State University, Detroit, Mi 48202, USA 

The exceptional complexity and diversity of carbohydrate structures render them the perfect carrier of biological signals because they can use the shortest sequence to store the most information. Naturally, carbohydrates play an important role in many biological and pathological processes (2). On the other hand, the structural complexity and diversity of carbohydrates make their chemical synthesis much more difficult than the chemical synthesis of other biopolymers such as peptides and nucleic acids. 

The chemical synthesis of carbohydrates is subject to a number of difficulties. First, to realize the regioselective reactions at a particular position of a sugar unit, the hydroxyl group at this position has to be distinguished from all other hydroxyl groups in the structure, while all these hydroxyl groups have similar properties. Additionally, when a sugar unit has one or more branches attached to it, several 

It is impossible in a short review like this to cover all aspects of development in carbohydrate synthesis. Instead, this review will briefly summarize the types of glycosylation methods and synthetic strategies that are commonly used in carbohydrate synthesis. It will also illustrate the applications of some of these strategies in the chemical synthesis of a class of complex and biologically important glycoconjugates, namely, glycosylphosphatidylinositols (GPIs). 

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Asymmetric epoxidation is another important area of activity, initially pioneered by Sharpless, using catalysts based on titanium tetraisoprop-oxide and either (+) or (—) dialkyl tartrate. The enantiomer formed depends on the tartrate used. Whilst this process has been widely used for the synthesis of complex carbohydrates it is limited to allylic alcohols, the hydroxyl group bonding the substrate to the catalyst. Jacobson catalysts (Formula 4.3) based on manganese complexes with chiral Shiff bases have been shown to be efficient in epoxidation of a wide range of alkenes. 

The synthesis of complex carbohydrate structures can preferably be accomplished using several enzymes in one-pot or sequential mode. Crude intermediate products may be either directly processed by the follow-up enzyme, or a fast and simple purification step may be included like desalting, concentrating, etc. This approach saves both time and costs, however, it requires a relatively high specificity, regioselectivity and yields in all the steps, which somehow limits the choice of glycosidases available. 

We use the term programmable to describe the rational (and ideally, computer-aided and automated) approach to polysaccharide synthesis.20 To reduce the synthesis of complex carbohydrates to routine, we envision a four-step protocol (1) the sequence of interest is keyed into a computer, (2) the computer selects appropriate reagent combinations, (3) a laboratory worker (human or robotic) prepares the reagent... 

Little is known about the regulation mechanisms of the synthesis of complex carbohydrate in plants, through lipid intermediates. However, partial evidence indicates that lipid-mediated glycosylation in proteins could be a regulatory step. When glycosylation of carboxypeptidase Y is inhibited... 

This chapter focuses on the synthesis of complex carbohydrates. It begins with a consideration of the hexoses that are the building blocks of complex carbohydrates. Then some aspects of the synthesis of simple homopolysaccharides are examined followed by a brief consideration of heteropolymers that contain more than one hex-ose. A major portion of the chapter is concerned with glycoproteins that contain complex linear and branched carbohydrates attached to proteins. Finally the synthesis of the bacterial wall is examined. 

The major problem in the synthesis of complex carbohydrates outside the cell is the lack of an external energy source such as ATP. The biosynthesis of a bacterial cell wall such as the peptidoglycan occurs mainly inside the cell, the final step being the cross-linking of the peptidoglycan strands outside the cell. This reaction is a transpeptidation, which does not require any energy source. 

Koeller KM, Wong C-H (2000) Synthesis of complex carbohydrates and glycoconjugates enzyme-based and programmable one-pot strategies. Chem Rev 100 4465 1494... 

The combined use of enzymatic and chemical methods under the so-called chemoenzymatic synthesis offers the flexibility of chemical synthesis and the high regioselectivity and stereoselectivity of enzyme-catalyzed reactions to achieve highly efficient synthesis of complex carbohydrates. Chemoenzymatic glycosylation is... 

Chemoenzymatic approach served as an alternative method for the synthesis of complex carbohydrate-containing molecules. The use of biosynthetic enzymes not only provides high regioselectivity and stereoselectivity for the formation of glycosidic bonds but also solves the problems of protection and deprotection steps required by chemical synthesis. The discovery of bacterial counterparts and the advance in bioengineering technology led to breakthroughs in complex carbohydrate synthesis. 

Chemical Synthesis of Complex Carbohydrates. Nicolaou, K. G Boskovich, N. J. In Bioorganic Chemistry Hecht, M., Ed. Oxford University Press New York, 1999, pp 134-173. 

Nicolaou, K C, Bockovich, N J, Chemical synthesis of complex carbohydrates. In Bioorganic Chemistry Carbohydrates, Hecht, S M, Ed., Oxford University Press, Oxford, pp. 134-173, 1999. 

Nicolaou KC, Bockovich NJ (1999) Chemical Synthesis of Complex Carbohydrates. In Hecht... 

Recent trends in glycochemistry are presented in three parts synthesis, principles and applications. The first six chapters provide a comprehensive, up-to-date review on the chemical synthesis of complex carbohydrates for their potential use in biological systems. The following seven chapters reveal some fundamental principles that are used to design and exploit carbohydrates for their effects in biological settings. The remaining five chapters examine the applicability of enzymes towards the chemo-enzymatic synthesis and modification of carbohydrates and polysaccharides. 

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