A unique overview of the most important protecting group strategies in carbohydrate chemistry
Protecting Groups: Strategies and Applications in Carbohydrate Chemistry provides a detailed account of key strategies and methodologies for the protection of carbohydrates. Divided into two parts, the first focuses on groups that are used best to protect a specific position on a carbohydrate. In the second part, specific carbohydrate residues or compounds are discussed in the context of a specific protecting group strategy used to reach the desired regioisomer. This important book:
-Features chapters on protecting groups at the primary and secondary positions of carbohydrates
-Describes protecting group strategies towards sialic acid derivatives, glycofuranoses, sulfated glycosaminoglycans, and cyclodextrins
-Provides information on automated glycan assembly
-Includes a chapter on the industrial scale synthesis of heparin analogs
Written by a team of leaders in the field, Protecting Groups: Strategies and Applications in Carbohydrate Chemistry is an indispensable guide for academics and industrial researchers interested in carbohydrate and natural product synthesis, pharmaceutical chemistry, and biochemistry.
Sébastien Vidal, PhD, holds a CNRS position at the University of Lyon, France. His main area of research is the design of glycoclusters for anti-adhesive strategy against bacterial infections and enzyme inhibitors targeting glycogen phosphorylase with applications in type-2 diabetes. In 2014, he was given the young investigator award "Prix du Groupe Français des Glycosciences".
1. Protecting Group Strategies in Carbohydrate Chemistry (A. G. Volbeda, G. A. van der Marel, J. D. C. Codée)
2. Protecting Groups at the Primary Position of Carbohydrates (M. Donnier-Maréchal, S. Vidal, M. Fiore)
3. Protecting Groups at the Secondary Position of Carbohydrates (S. Vidal, P. G. Goekjian)
4. Regioselective Protection at the Secondary Position of Carbohydrates with Acyclic Protecting Groups (P. G. Goekjian, S. Vidal)
5. Protecting Groups at the Anomeric Position of Carbohydrates (C. Sakonsinsiri, W. Bruce Turnbull)
6. N-Protecting Groups for 2-Amino-2-Deoxy-Glycosides (S. Vidal)
7. One-Pot Multi-Step Regioselective Protection of Carbohydrates Catalyzed by Acids (J.-M. Beau, Y. Bourdreux, G. Despras, A. Gouasmat, G. San Jose, D. Urban, B. Vauzeilles)
8. Acyl Migrations in Carbohydrate Chemistry (F. S. Ekholm, R. Leino)
9. De Novo Asymmetric Synthesis of Oligosaccharides Using Atom-Less Protecting Groups (D. Ray, G. A. O'Doherty)
10. Protecting Group Strategies for Sialic Acid Derivatives (H. Amarasekara, S. Buda, A. Reddy Mandhapati, D. Crich)
11. Strategies Towards Protection of 1,2- and 1,3-Diols in Carbohydrate Chemistry (M. Schuler, A. Tatibouët)
12. Protecting Group Strategies Towards Glycofuranoses (V. Ferrières, L. Legentil, L. Lemiègre)
13. Cyclodextrin Chemistry via Selective Protecting Group Manipulations (J. M. Benito, J. M. García Fernández)
14. Protecting Group Strategies Towards Sulfated Glycosaminoglycans (H. Ledru, P. Matton, J.-M. Mallet, C. Lopin-Bon)
15. Applications of Fluorous and Ionic Liquid Tags in Oligosaccharide Synthesis (I. Sittel, M. Carmen Galan)
16. Orthogonally Protected Building Blocks for Automated Glycan Assembly (F. Pfrengle, P. H. Seeberger)
17. Kilogram-Scale Production of Synthetic Heparin Analogs (P. Trouilleux, P. Potier, P.-A. Driguez)
Protecting Group Strategies in Carbohydrate Chemistry
Anne G. Volbeda Gijs A. van der Marel and Jeroen D. C. Codée
Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
Carbohydrates are the most densely functionalized class of biopolymers in nature. Every monosaccharide features multiple contiguous stereocenters and bears multiple hydroxyl functionalities. These can, in turn, be decorated with sulfate groups, acyl esters, lactic acid esters and ethers, or phosphate moieties. Amine and carboxylate functions can also be present. Most often, the amine groups are acetylated, but different amide functions are also found, as well as N-sulfates and alkylated amines. The discrimination of the functional groups on a carbohydrate ring has been and continues to be one of the great challenges in synthetic carbohydrate chemistry [1-3].
This chapter describes the differences in the reactivity of the various functional groups on a carbohydrate ring and how to exploit these in the design of effective protecting group strategies. The protecting groups on a carbohydrate dictate the reactivity of the (mono)saccharide, and this chapter will describe how protecting group effects can be used to control stereoselective transformations (most importantly, glycosylation reactions) and reactivity-controlled one-pot synthesis strategies. Applications and strategies in automated synthesis are also highlighted.
1.1 Discriminating Different Functionalities on a Carbohydrate Ring
The main challenge in the functionalization of a carbohydrate (mono)saccharide is the discrimination of the different hydroxyl functionalities. The - often subtle - differences in reactivity can be capitalized upon to formulate effective protecting group strategies (see Scheme 1.1A). The primary alcohol functionality is generally the most reactive of the hydroxyl groups because of steric reasons (see Chapter 2). It can be site selectively addressed using bulky protecting groups such as silyl or trityl ethers. The anomeric hydroxyl group discerns itself from the other secondary hydroxyl groups in that it is part of a hemiacetal functionality (see Chapter 5). It can, therefore, be selectively modified using acetal chemistry, and acid-catalyzed acetal and mixed thioacetal formations are among the most used methods to start a protecting group manipulation sequence. Because it is part of a hemiacetal functionality, the anomeric hydroxyl group is also the most acidic alcohol on a carbohydrate ring, and it can be chemoselectively modified under basic conditions. Conversely, it is less reactive than the other secondary alcohol groups under acidic conditions. Axial secondary alcohols are generally slightly less reactive than the equatorial ones on a carbohydrate ring, and these reactivity differences can often be exploited in designing an efficient protecting group scheme (see Chapters 3 and 4). Finally, the position of a hydroxyl group on the carbohydrate ring and the nature of its neighboring substituents affect its reactivity. In this regard, the use of cyclic protecting groups that engage two hydroxyl groups in a cyclic context (see Chapter 11) has proven to be a very powerful tool . Benzylidene acetals and silylidene ketals can be used to mask C-4 C-6 diols, where isopropylidene groups and orthoesters are commonly employed to protect cis-hydroxyl groups in a five-membered ring constellation. Butane 2,3-bisacetals and the recently introduced o-xylylene groups can be used to protect vicinal diequatorial diols . To illustrate how the reactivity of various alcohol groups can be exploited, two examples are given in Scheme 1.1B,C. The first example shows a four-step reaction sequence that has been used to site selectively mask all groups of a glucosamine synthon 1. Thus, the nitrogen functionality in D-glucosamine can be chemoselectively protected with a trichloroacetyl group, by virtue of its higher nucleophilicity with respect to the alcohols present. Next, the primary alcohol at C-6 and the hydroxyl group at C-4 can be masked with a di-tert-butyl silylidene ketal. The selectivity of this transformation originates from the bulky nature of the protecting group and the fact that a stable trans-decalin system can be formed. Next, the anomeric hydroxyl group can be selectively addressed using basic conditions to install an imidate group. Finally, the remaining alcohol can be masked with a levulinoyl ester . In the second example, the different hydroxyls of D-mannose are discriminated using the following steps (Scheme 1.1C). First, all hydroxyl groups are acetylated, concomitantly locking the mannose monosaccharide in a pyranoside ring. Next, the anomeric thioacetal is installed under Lewis acidic conditions. After saponification of the four remaining acetyl groups (2), the alcohol groups are diversified through the installation of a benzylidene acetal  1 (3) and selective benzylation of the C2-OH using phase transfer conditions (4) . The selectivity in the latter transformation can be explained by taking into account the relative mild basic conditions (as opposed to the use of NaH in DMF) and the slightly higher acidity of the C2-OH because of its closer proximity to the anomeric center. Alternatively, the C3-OH can selectively be protected by exploiting the slightly higher nucleophilicity of this alcohol. Selective acylation is possible, as well as regioselective alkylation. To further enhance the reactivity difference between neighboring axial and equatorial hydroxyl groups, the use of stannylidene ketals presents a very effective approach . Thus, diol 3 can be transformed into a dibutylstannylidene ketal (5) using dibutin oxide, after which the tin ketal can react with an appropriate electrophile, such as para-methoxybenzyl chloride under the aegis of cesium fluoride and tetrabutyl ammonium bromide (6).
Scheme 1.1 (A) Relative reactivity of carbohydrate alcohols; (B) four-step reaction sequence to mask all functional groups in glucosamine; (a) Cl3CCOCl, Et3N, and MeOH; (b) (tBu)2Si(OTf)2, pyridine, and DMF, -40?°C (86% over 2 steps); (c) CF3C(=NPh)Cl, Cs2CO3, and acetone (98%); (d) LevOH, DIC, DMAP, and DCM (82%). (C) Site-selective modification of mannosyl hydroxyl groups; (e) Ac2O and pyridine; (f) PhSH, BF3·OEt2, and DCM (75% over 2 steps); (g) NaOMe and MeOH (100%); (h) HBF4·OEt2, PhCH(OMe)2, and DMF (60%); (i) Bu4NHSO4, BnBr, NaOH, and DCM (75%); (j) (i) Bu2SnO, toluene, and reflux; (ii) CsF, Bu4NBr, PMBCl, toluene, and reflux (94%).
Although the use of tin ketals, in stoichiometric and catalytic amounts, represents a very powerful means to discriminate alcohol functionalities, it requires the use of toxic tin species. To circumvent this drawback, Taylor and coworkers have introduced borinic acid catalysis to regioselectively protect glycosyl polyols [10, 11]. a-O-Methyl-fucopyranoside 7 can be regioselectively alkylated or acylated using a catalytic amount of diphenylborinic ethylamine ester 8 and benzyl bromide or benzoyl chloride (Scheme 1.2). The reaction proceeds via borinate intermediate 9 that reacts in a highly regioselective manner to protect the equatorial alcohol at C-3.
Scheme 1.2 Borinic acid catalysis to regioselectively protect alcohol functionalities: (a) 8; (b) BnBr, Ag2O, and MeCN, 40?°C, 48?h (94%); (c) BzCl, iPr2NEt, and MeCN (92%).
To streamline the introduction of protecting groups, the groups Hung [12-15] and Beau [16-18] have devised a strategy to provide fully orthogonal protected building blocks in a one-pot manner (see Chapter 7). A key to the strategy is the transformation of all hydroxyl groups into trimethylsilyl () ethers, which renders the carbohydrate 12 well soluble in an organic solvent, such as dichloromethane, even at a low temperature. As shown in Scheme 1.3, the next steps in Hung's strategy involve the selective TMSOTf-mediated formation of a C4-C6 acetal, ensuing the installation of a C2-C3 acetal and regioselective opening of the most reactive acetal (which is the acetal at C2-C3). This liberates the C2-O-TMS, which can be benzoylated to provide glucoside 13. Regioselective, reductive opening of the C4-C6 acetal can then give access to either the C4 (14) or the C6 alcohol 15. Using this strategy, the one-pot generation of a large variety of building blocks has been reported [12-15].
Scheme 1.3 One-pot protection of per-silylated thioglycoside to form different protected building blocks 13-15.
1.2 Strategies for an (Oligo)saccharide Synthesis Campaign
During an (oligo)saccharide synthesis campaign, different types of protecting groups can be discerned: those that will be removed during the assembly to allow for the manipulation of the unmasked alcohol, the temporary protecting groups; and those that are only to be removed at the very end of the assembly line, the permanent...