Introduction

The preparation of complex carbohydrates has emerged as a major focus in synthetic organic chemistry, and this is no doubt a result of the growing awareness of the many important roles of this class of molecules in biology [1]. Perhaps the most important reaction in the chemical synthesis of carbohydrates is the formation of the glycosidic bond, for this is the primary means for the controlled assembly of complex oligosaccharides and glycoconjugates from monosaccharide precursors. Thus a variety of methods have been developed to effect the glycosylation process. Much of the effort has focused on the general coupling strategy outlined in Scheme 1 [2]. In this strategy, one begins with a carbohydrate coupling partner (1), which is subjected to initial derivatization whereby the anomeric substituent is transformed into a latent leaving group (LG). The resulting intermediate 2, or glycosyl donor, is typically isolated, and in a second step the anomeric leaving group is activated with an appropriate glycosylation promoter or catalyst. This process usually takes place in the presence of a nucleophilic glycosyl acceptor (Nu-H), which undergoes an effective displacement of the leaving group to form the anomeric bond in the product gly-coside (3). Within the last century, a variety of leaving groups have been developed for the generation of various glycosyl donors that can undergo efficient coupling in the second step. Some of these are listed in Scheme 1, and all have proven to be useful to some extent in complex carbohydrate synthesis [2].

A far less developed strategy for glycosidic bond formation is a direct dehy-drative coupling procedure in which one begins with a 1-hydroxy carbohydrate (1)

R = protective group LG = latent leaving group Nu-H = nudeophilic glycosyl acceptor

Scheme 1 Traditional glycosylation strategies [2].

R = protective group LG = latent leaving group Nu-H = nudeophilic glycosyl acceptor

Scheme 1 Traditional glycosylation strategies [2].

as the glycosyl donor (Scheme 2). This approach offers a complementary if not more efficient strategy for glycosylation in that a distinct anomeric derivatization step to generate an isolable glycosyl donor 2 is obviated. As such, all the operations of anomeric derivatization, activation, and bond formation are combined into a one-pot procedure. Despite its potential advantages, however, this strategy has not been extensively employed in complex oligosaccharide synthesis. The establishment of a viable synthetic method calls for the overcoming of such inherent difficulties associated with this approach as the reversibility of the process and the propensity for hemiacetal self-coupling, in addition to the common glycosylation obstacles such as coupling efficiency and high anomeric stereoselectivity. This chapter summarizes recent advances in the development of nonenzymatic direct dehydrative glycosyla-tions with 1-hydroxy glycosyl donors.

The concept of direct dehydrative glycosylation is not a new one. One of the earliest glycosylation methods is the Fischer procedure [3], currently adopted for preparation of simple glycosides (Scheme 3). In this process an unprotected monosaccharide (4) is treated with an excess of an alkyl alcohol in the presence of an acid catalyst, resulting in the net loss of water and substitution at the anomeric position by the alcohol acceptor. Usually a desiccant is not present in this hemiacetal-to-acetal exchange process; as a result, the equilibrium can favor the formation of the glycoside product 5 only through the use of a large excess of the alcohol acceptor (typically employed as the reaction solvent or cosolvent). In the original glycosyla-tion procedure, HCl was used as the acid catalyst, with the coupling event usually proceeding at elevated temperatures. Over the years, a number of other Br0nsted acid catalysts have been found to be effective in this process, including various inorganic and sulfonic acids [4,5] as well as acidic resins [6]. In addition, a host of Lewis acid catalysts have been employed [7], giving rise to substrate-specific variants of the Fischer protocol. In fact, with selected Lewis acid promoters such as FeCl3

Scheme 2 Direct dehydrative glycosylations.

Scheme 2 Direct dehydrative glycosylations.

Scheme 3 Fischer glycosylation [3]. R = methyl, ethyl, «-propyl, ¡-propyl, amyl, allyl, benzyl, etc.

[8], it is possible to favor the formation of the kinetic furanoside product over the thermodynamically more stable pyranoside adducts [9]. While it is not the goal of this section of the chapter to present a comprehensive summary of Fischer glyco-sylation methods, it is worth emphasizing that this protocol and its variants have, over the last century, remained one of the most popular methods for the preparation of simple alkyl glycosides. Indeed, this venerable method, with its simplicity and versatility, has frequently been chosen as the starting point for the preparation of Cl-protected monosaccharide building blocks for complex molecule syntheses.

Despite the widespread use of the Fischer method, it has yet to be shown to be effective in the controlled assembly of complex oligosaccharides. Because of the acidic medium under which the acetal exchange process occurs, only simple alcohols devoid of acid-labile functionality are employed as glycosyl acceptors. Moreover, the necessity of a large excess of acceptor to favor equilibrium formation of glycoside 5 precludes the use of complex or valuable molecules as nucleophilic acceptors. Typically the preparation of oligosaccharides by modified Fischer protocols has been limited to the preparation of carbohydrate oligomers of varying size and complexity [10,11].

To establish a method for controlled glycosylation with 1-hydroxy carbohydrates, mild dehydrative coupling conditions are required that favor the cross-condensation of distinct hemiacetal donor and nucleophilic acceptor substrates. One approach toward this end is to employ a set of reagents that can rapidly and completely activate the C1-hydroxyl functionality in 1 to generate, in situ, a highly reactive intermediate that incorporates a transient leaving group at the anomeric position. The requirement for rapid activation of the anomeric hydroxyl is obviously necessary to minimize the extent of hemiacetal self-condensation, and the in situ formation of an extremely potent leaving group at C1 would allow for facile gly-cosidic bond construction with a nucleophilic acceptor without the need for isolation of an intermediate glycosyl donor.

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