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Tetrahedron report 1124 Regioselective acylation, alkylation, silylation and glycosylation of monosaccharides Janice Lawandi y , Sylvain Rocheleau y , Nicolas Moitessier * Department of Chemistry, McGill University, 801 Sherbrooke St. W., Montr eal, Qu ebec H3A 0B8, Canada article info Article history: Received 19 May 2016 Available online 5 August 2016 Keywords: Regioselectivity Glycosylation Carbohydrates Acylation Natural products Contents 1. Introduction ..................................................................................................................... 6284 1.1. Biosynthesis of polysaccharides .............................................................................................. 6284 1.2. Polysaccharides and other biopolymers ............................................... ........................................ 6284 1.3. This review ................................................................................................................ 6284 2. Selective methods to functionalize sugars based on the intrinsic reactivity of the hydroxyls ......................... ..................... 6285 2.1. In the 60s and 70s: relative reactivity and hydrogen bond network .............................................................. 6285 2.2. 4-Dimethylaminopyridine- (DMAP)-catalyzed acylation of alcohols ................................. ............................. 6286 2.3. Catalysis using other bases or activating agents ................................................................................ 6288 2.4. The influence of the hydrogen bond network .................................................................................. 6288 2.5. The role of the acylating agent ............................................................................................... 6290 2.6. Selective silylation ......................................................................................................... 6290 2.7. Glycosylation on minimally protected acceptors ................................................................................ 6291 2.8. Hydrogen-bond and regioselectivity ........................................................................................... 6292 3. Extrinsic methods which internally deliver the reagent ............................................................................... 6292 3.1. DMAP-based catalysts ....................................................................................................... 6292 3.2. Peptidic catalysts ........................................................................................................... 6293 3.3. Metal catalysis .......................................................... .................................................. 6294 4. Extrinsic methods which pre-activate the sugar .............................................. ....................................... 6295 4.1. Organotin derivatives ........................................................................................................ 6295 4.1.1. Acylation via stannyl ether derivatives ................................................................................. 6295 4.1.2. Acylation and alkylation via stannylene acetals ......................................................................... 6295 4.1.3. Glycosylation via stannylene acetals ................................................................................... 6297 4.2. Organoboron derivatives ...................................................... .............................................. 6297 4.2.1. Boronic derivatives .................................................................................................. 6297 4.2.2. Borinate derivatives ................................................................................................. 6298 4.3. Chiral catalysts ............................................................................................................. 6300 4.4. Salt additives .............................................................................................................. 6301 * Corresponding author. Fax: þ1 514 398 3797; e-mail address: [email protected] (N. Moitessier). y These two authors contributed equally to this manuscript. Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet Tetrahedron 72 (2016) 6283e6319 http://dx.doi.org/10.1016/j.tet.2016.08.019 0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

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    Tetrahedron 72 (2016) 6283e6319

    Contents lists avai

    Tetrahedron

    journal homepage: www.elsevier .com/locate/ tet

    Tetrahedron report 1124

    Regioselective acylation, alkylation, silylation and glycosylation ofmonosaccharides

    Janice Lawandi y, Sylvain Rocheleau y, Nicolas Moitessier *

    Department of Chemistry, McGill University, 801 Sherbrooke St. W., Montr�eal, Qu�ebec H3A 0B8, Canada

    a r t i c l e i n f o

    Article history:Received 19 May 2016Available online 5 August 2016

    Keywords:RegioselectivityGlycosylationCarbohydratesAcylationNatural products

    * Corresponding author. Fax: þ1 514 398 3797; e-my These two authors contributed equally to this ma

    http://dx.doi.org/10.1016/j.tet.2016.08.0190040-4020/� 2016 Elsevier Ltd. All rights reserved.

    Contents

    1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62841.1. Biosynthesis of polysaccharides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62841.2. Polysaccharides and other biopolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62841.3. This review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6284

    2. Selective methods to functionalize sugars based on the intrinsic reactivity of the hydroxyls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62852.1. In the 60’s and 70’s: relative reactivity and hydrogen bond network . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62852.2. 4-Dimethylaminopyridine- (DMAP)-catalyzed acylation of alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62862.3. Catalysis using other bases or activating agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62882.4. The influence of the hydrogen bond network . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62882.5. The role of the acylating agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62902.6. Selective silylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62902.7. Glycosylation on minimally protected acceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62912.8. Hydrogen-bond and regioselectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6292

    3. Extrinsic methods which internally deliver the reagent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62923.1. DMAP-based catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62923.2. Peptidic catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62933.3. Metal catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6294

    4. Extrinsic methods which pre-activate the sugar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62954.1. Organotin derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6295

    4.1.1. Acylation via stannyl ether derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62954.1.2. Acylation and alkylation via stannylene acetals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62954.1.3. Glycosylation via stannylene acetals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6297

    4.2. Organoboron derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62974.2.1. Boronic derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62974.2.2. Borinate derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6298

    4.3. Chiral catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63004.4. Salt additives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6301

    ail address: [email protected] (N. Moitessier).nuscript.

    mailto:[email protected]://crossmark.crossref.org/dialog/?doi=10.1016/j.tet.2016.08.019&domain=pdfwww.sciencedirect.com/science/journal/00404020http://www.elsevier.com/locate/tethttp://dx.doi.org/10.1016/j.tet.2016.08.019http://dx.doi.org/10.1016/j.tet.2016.08.019http://dx.doi.org/10.1016/j.tet.2016.08.019

  • J. Lawandi et al. / Tetrahedron 72 (2016) 6283e63196284

    4.5. The role of the acylating agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63054.6. Brønsted base and Brønsted acid catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63064.7. Directing-protecting groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6307

    5. Labile protecting groups and tethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63085.1. Labile transient protecting groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63085.2. Tethering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6310

    6. Methods for selective deprotection of sugars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63106.1. Selective removal of an acyl group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63106.2. Selective cleavage of 4,6-O-benzylidenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63116.3. Selective removal of benzyls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63136.4. Selective deprotection of silyl groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6314

    7. Tandem methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63158. Conclusions and prospect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6315

    Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6316References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6316Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6319

    1. Introduction

    1.1. Biosynthesis of polysaccharides

    Many organisms use sugars as building blocks for more complexstructures in nature such as cellulose in plants and chitin in crus-taceans. To construct these large polysaccharides from carbohy-drates, these organisms use powerful enzymes which performcoupling reactions on these sugar building blocks. The enzymesbuild polysaccharides in an efficient process that yields a largeamount of the desired product quickly, with minimal energy wasteand without generating undesired side products such as unwantedregio- and stereoisomers. As synthetic chemists, we wonder howwe could perform such efficient reactions when Nature’s seeminglysimple building blocks are actually quite complex because of thenumber of stereocenters and functional groups (i.e., hydroxylgroups) with similar reactivity.

    1.2. Polysaccharides and other biopolymers

    Polysaccharides, proteins, and nucleic acids are biopolymerswhich can be prepared by assembling simple building blocks to-gether (i.e., monosaccharides, amino acids, and nucleotide, re-spectively). Thus, high yielding, scalable, and automated syntheticmethods and strategies have been the focus of synthetic chemistsfor decades. As a result, with the aid of automated synthesizers,amino acids can easily be assembled into polypeptides and evenproteins. Similarly, nucleic acids oligomers can be made in justa few hours. On the other hand, automated polysaccharide pro-duction is far less common and the coupling of carbohydrate unitsinto polysaccharides is nowhere near the level of automation ofpeptide synthesizers. In fact, given the complexity of carbohydratechemistry, carbohydrates remain largely under-explored inchemistry.

    A withstanding challenge in carbohydrate chemistry is regio-selective monofunctionalization, in addition to stereoselectivity(specifically, how to control whether a or b anomers form). Unlikepeptide synthesis, polysaccharide synthesis is all but straightfor-ward as polysaccharides are often branched, while peptides andproteins are almost all linear. Furthermore, polysaccharides aremade of saccharide units which featuremultiple hydroxyl groups ofsimilar reactivity, while peptides are made of amino acids whichfeature orthogonal groups (amines and carboxylic acids) that caneasily be targeted, through the use of orthogonal protecting groups.For example, amino acids can be converted into carbamate-protected (e.g., Boc, Fmoc, Cbz) amino esters (e.g., methyl ester,benzyl ester). Then, chemoselective deprotection enables their

    coupling into peptides or proteins. In contrast, selective protectionof secondary hydroxyl groups of carbohydrate building blocks issignificantly more challenging. Chemists commonly use a series ofprotection and deprotection steps in processes that are wasteful,costly, time consuming and that, in the end, yield little product.

    Another major breakthrough that benefited peptide synthesiswas the development of solid-phase synthesis where: 1) an excessof reagent drives the reaction forward and 2) the purification pro-cess is reduced to simple washing and filtration steps. Again, forpolysaccharides, solid support synthesis will never be as easy aslong as the problem of regioselectivity is not resolved. One pro-posed solution is to use enzymes (i.e., glycosyltransferases) toperform selective glycosylation reactions, but enzymes are verysubstrate specific and their application to large industrial scale isoften difficult.

    1.3. This review

    Herein, we review the existing chemical methods that are usedto selectively functionalize various carbohydrates or even carbo-hydrates on large natural products, with the end goal being to usecarbohydrates as chiral sources and/or building blocks for poly-saccharide synthesis or to deliver natural product analogues. Al-though our focus is largely on hexopyranosides, many of themethods reviewed here have been successfully applied to furano-sides. Rather than listing all the reported methods, we have orga-nized these methods according to whether they take advantage ofthe intrinsic reactivity of the hydroxyls of sugars, or whether ex-trinsic factors are used to overcome the innate reactivity of thehydroxyls. Related methods using masking reagents or tethers arealso described. To complete this review, selective deprotection willalso be discussed.

    Although several biochemical approaches using enzymes toselectively manipulate carbohydrates exist (see e.g.,1e3), we willrestrict our analysis to chemical methods. In addition, wewill focuson the secondary and primary alcohols. Therefore, we will notdiscuss methods that differentiate the anomeric positions over theother hydroxyl groups. For some examples of these, the reader isreferred to a review from Hanessian and Lou4 and to recentexamples.5e7 Catalytic methods for regioselective carbohydratefunctionalization have also been reviewed.8e10 In this current re-port, we attempt to cover the whole field, from catalysis usingmetal ions to boronic acids as transient protecting groups. How-ever, we do not expect to cover the literature evenly as somemethods, such as the use of tin reagents, have been extensivelystudied.

  • Scheme 2. Benzoylation of methyl 6-deoxy-a-D-mannopyranoside.

    J. Lawandi et al. / Tetrahedron 72 (2016) 6283e6319 6285

    2. Selective methods to functionalize sugars based on theintrinsic reactivity of the hydroxyls

    2.1. In the 60’s and 70’s: relative reactivity and hydrogen bondnetwork

    To better understand how one could perform a reaction selec-tively on a sugar, Williams and Richardson first attempted to rankthe secondary hydroxyls of three sugars (methyl a-D-glucopyr-anoside (1), methyl a-D-mannopyranoside (2) and methyl a-D-gal-actopyranoside (3), Fig. 1) according to how reactive each hydroxylwas under benzoylation conditions (Scheme 1).11,12

    Fig. 1. Position numbering of methyl a-D-glucopyranoside (1), a-D-mannopyranoside(2), a-D-galactopyranoside (3) and methyl b-D-glucopyranoside (4).

    Scheme 1. Benzoylation of methyl a-D-glucopyranoside (1).

    Fig. 2. Intramolecular hydrogen bond network of various monosaccharides de-termined by IR (in DCM or CCl4 solutions) and NMR in CDCl3 (solutions).

    By benzoylating each sugar with an excess of benzoyl chloride inpyridine and carefully isolating and analyzing the di- and tri-benzoylated products from the mixture (such as 5 and 6 inScheme 1), Williams and Richardson established that the primaryhydroxyl at position 6 of each of the sugars reacted first (likelybecause this position is the most accessible of them all) and ob-served the following reactivity trends for the secondary hydroxyls:2-OH>3-OH>4-OH for the glucopyranoside, 3-OH>2-OH>4-OHfor the mannopyranoside, and finally 2-OH, 3-OH>4-OH for thegalactopyranoside. They proposed that intramolecular hydrogen-bonding possibly influenced the reactivity of each hydroxyl.While the adjacent anomeric position may contribute an extrahydrogen bond to the 2-OH, thereby increasing the reactivity of the2-OH of the glucopyranoside, the 2-OH is axial in the mannopyr-anoside, rendering it less reactive than the 3-OH. Intramolecularhydrogen bonding is unlikely in pyridine, the basic solvent used fortheir benzoylation experiments. Interestingly, they observed simi-lar reactivity when they ran their experiments in carbon tetra-chloride, a solvent that cannot provide any hydrogen bonding(unlike pyridine), thereby promoting the intramolecular co-operative hydrogen bonding network of the sugar.

    In a second part to the study of hydroxyl reactivity,13 Williamsand Richardson examined how reactive the secondary hydroxylswould be under similar benzoylation conditions, but when theprimary hydroxyl was eliminated from each sugar system; in otherwords, the 6-OH was replaced with a 6-H (7, Scheme 2).

    Again, the 4-OH did not react under the benzoylation conditionsused, while the 2-OH and 3-OH of methyl 6-deoxy-a-D-man-nopyranoside were benzoylated (8). They concluded that the

    hydroxyl (or rather the benzoylated hydroxyl since this position isbenzoylated rapidly) at position 6 is not to blame for the ‘non-re-activity’ of the 4-OH. They also confirmed the previous results,namely that the 4-OH was the least reactive. A few years later,Kondo et al. also confirmed that the order of reactivity of the sec-ondary hydroxyls of methyl 6-deoxy-a- and b-D-glucopyranosideswas the same as the order that Williams and Richardson previouslyobserved for methyl a- and b-D-glucopyranosides.14

    This ground-breaking work demonstrated that the hydroxyls ofdifferent sugars have different intrinsic reactivity patterns that varydepending on the sugar explored. In a more exhaustive experi-mental study, Vasella and co-workers investigated the differenthydrogen bonds in a variety of carbohydrate units in either a orb configuration and proposed hydrogen bond networks for severalhexopyranoside derivatives (Fig. 2).15

  • J. Lawandi et al. / Tetrahedron 72 (2016) 6283e63196286

    Researchers also studied regioselective monomethylation re-actions, comparing several methods. For example, Handa andMontgomery investigated the regioselectivity of a-D-mannopyr-anoside partial methylation under a variety of conditions(Scheme 3),16 while Ovodov and Evtushenko carried out a similarstudy on methyl b-D-xylopyranoside (Scheme 4).17

    Fig. 3. Mechanism of DMAP catalysis using acylating agents such as acetic anhydrideor acetyl chloride.

    Scheme 3. Regioselective methylation methods of D-mannose under conditions pre-viously reported by Haworth and Mache,18 Kuhn and Trischmann,19 and Hakomori.20

    Scheme 4. Comparison of different regioselective methylation methods of methyl b-D-xylopyranoside using conditions previously reported.19,21e23

    Scheme 5. Regioselective glycosylation of a monoprotected glucose unit in the totalsynthesis of sialyl LewisX.

    These studies revealed that the selectivity is highly dependenton the conditions (methylating agent and base) and substrate usedwith Haworth and Hakamori’s conditions leading to either similarselectivities with methyl a-D-mannopyranoside (Scheme 3) or verydifferent selectivities with methyl b-D-xylopyranoside (Scheme 4).It is likely that the relative acidities of the hydroxyl groups inmethyl b-D-xylopyranoside is a major factor controlling theselectivity.

    These studies set the stage for future work that could revealwhether extrinsic factors, such as the sterics of the reagent, alsoinfluence the products formed. Furthermore, other studies wereneeded to provide an easy method to selectively react at one hy-droxyl over all the other hydroxyls. Such a method would greatlysimplify the number of steps a chemist is required to performwhenattempting to react at a specific position of a sugar, thereby re-ducing the amount of waste generated, the amount of time nec-essary, and the financial resources required to perform suchreactions.

    This difference in intrinsic reactivity of the secondary hydroxylgroups has been exploited to synthesize polysaccharides withoutusing so many protecting groups. For example, the fourth buildingblock of the sialyl LewisX tetrasaccharide was introduced onto

    a partially protected trisaccharide through a regio- and stereo-differentiated glycosylation (Scheme 5).24

    2.2. 4-Dimethylaminopyridine- (DMAP)-catalyzed acylationof alcohols

    Several methods take advantage of the innate reactivity of thehydroxyl groups in order to regioselectively functionalize a sugar.One of the largely used catalysts for carbohydrate acylation isDMAP. In fact, DMAP and chiral DMAP derivatives are now quitecommonly used as catalysts (catalytically or stoichiometrically) inmany reactions, including peptide bond formation,25 the Mor-itaeBayliseHillman reaction,26 and Michael addition.27 For carbo-hydrate chemists, DMAP-catalyzed acylation of alcohols representsan essential tool to functionalize sugars. In 1901, Verley and Bolsingreported the first procedure for acylation of hydroxyls using aceticanhydride and pyridine.28 This reliable procedure is widely used,even today, for acetylation of carbohydrates. However, it was notuntil the late 60’s that H€ofle and Steglich discovered that DMAP and4-pyrrolidinopyridine catalyzed the acylation reaction, not onlyspeeding up the reaction but also rendering this new set of con-ditions applicable to large-scale synthesis.29 Fersht and Jencksoriginally proposed a mechanism for DMAP-catalyzed acylation in1970 (Fig. 3).30

    DMAP and 4-pyrrolidinopyridine catalyze acylation reactionsbetter than other bases due to their greater nucleophilicity. Thenitrogen is acylated, forming N-acylpyridinium salts, which exist asion pairs where the charge renders the N-acylpyridinium highly

  • J. Lawandi et al. / Tetrahedron 72 (2016) 6283e6319 6287

    electrophilic. The mechanism of nucleophilic catalysis of 4-dialkylaminopyridines was further studied experimentally31 andcomputationally when, more recently, Zipse and co-workers per-formed a more detailed computational study of DMAP-catalyzedacetylation of alcohols.32 They not only confirmed the mechanismin Fig. 3, but also determined that the hydroxyl that is acetylated ismost likely deprotonated by the acetate counterion generated, andnot DMAP or other bases used (such as triethylamine).32

    Given the versatility of DMAP, Kurahashi, Mizutani and Yoshidaacetylated unprotected carbohydrates using DMAP. They acetylatedoctyl b-D-glucopyranoside (28, Scheme 6), as well as the a-anomer(30, Scheme 6), in order to rank the hydroxyls according to theirrelative reactivity.33

    Scheme 6. DMAP-catalyzed acetylation of octyl a/b-D-glucopyranoside.

    Scheme 8. Regioselective pivaloylation of 1-C-(4,6-O-benzylidene-b-D-glucopyranosylacetone in presence of DMAP-Et3N.

    Unlike the uncatalyzed acylation reactions performed with anexcess of acylating agent mentioned above, the 6-OH hardly reac-ted for both the a- and b-D-glucopyranosides (28 and 30) whena limiting amount of the acylating agent was added to the reactionin Scheme 6. Clearly then, the 6-OH was not the most reactiveposition on the sugar under catalytic conditions, even though it wasthe least sterically hindered. Furthermore, the hydroxyls at position2 of the glucopyranosides hardly reacted, if at all. The main posi-tions that did react on each of the glucopyranosides were the 3-OHand the 4-OH, which reacted fairly equally for the b-stereoisomer,while the 4-OH was three times more reactive for the a-stereo-isomer (Scheme 6). Clearly, the stereochemistry at the anomericposition affected the reactivity of the hydroxyls and the outcome ofacylation. Recall, researchers previously found that position 4 to benearly unreactive in the absence of DMAP (Scheme 1). Upon com-paring the reactions in Scheme 6 with Scheme 1, we find that theacylating agent also differed: in Scheme 1, the reagent is an acylchloride, while in Scheme 6, the reagent is an anhydride, demon-strating that the reactivity may also depend on the acylating agentused (the role of the acylating agent is further discussed below).

    When the acylating reagents were bulky, the observed regio-selective acylation of 6-O-protected octyl b-D-glucopyranosides 32and 34 by DMAP catalysis was complete (Scheme 7).34

    Scheme 7. DMAP-catalyzed acylation of octyl a/b-D-glucopyranoside functionalized atposition 6.

    Applying the same conditions to octyl a- and octyl b-D-man-nopyranosides and octyl a- and octyl b-D-galactopyranosidesallowed the authors to better understand the effect of the stereo-chemistry of the hydroxyls at positions 2 and 4 on the relative re-activity of the hydroxyls. In these cases, the stereochemistry of theanomeric position did not affect the order of reactivity of the hy-droxyls, which was determined as 4-OH>6-OH>3-OH>2-OH forthe mannopyranosides, and as 6-OH>4-OHz3-OH>2-OH for thegalactopyranosides.33

    Using both DMAP and triethylamine, Fang et al. studied theregioselective monoacylation of 1-C-(4,6-O-benzylidene-b-D-glu-copyranosyl) acetone.35 While both monoacylated and diacylatedproducts were formed in solution, the 3-O-acyl products formedpredominantly. Fang et al. tried nine different aliphatic or aromaticacylating agents (including acetyl, benzoyl and pivaloyl chloride) inthree different solvents (i.e., DCM, THF, and MeCN). They observedthe following general trend: higher steric hindrance or strongelectron-withdrawing groups from the acylating agent favored the3-O-acylation. Typical yields varied between 80% and 98% ona 330 mg scale and their best result was obtained for the piv-aloylation reaction performed in DCM specifically (Scheme 8).

    To rationalize the observed regioselectivity, Fang et al. de-termined the energy profile of the reaction using a semi-empiricalmethod (PM6), comparing the 2-O- with the 3-O-acylation mech-anisms. These calculations suggested that the rate limiting stepwasthe acylation of 2-OH or 3-OH with the DMAP-activated acylatingagent (Fig. 4). The computed energy of activation of both reactionmechanism pathways differed, favoring the reaction at position 3.

    Fig. 4. Possible explanation of the regioselectivity observed for the acylation of 1-C-(4,6-O-benzylidene-b-D-glucopyranosyl) acetone.

    Fang et al. also investigated the effect of the intramolecularhydrogen-bond network by 1H NMR spectroscopy. First, they ob-served that 2-OH formed hydrogen-bonds either with the aglyconecarbonyl or with 3-OH. They also noticed that 3-OH hydrogen-bonds only with 2-OH (not with the benzylidene O-4). This hy-drogen bond network (3-OH hydrogen bonded to 2-OH itself hy-drogen bondedwith the carbonyl), renders 3-OHmore nucleophilicand consequently more prone to acylation than 2-OH. With this

  • Scheme 11. Regioselective acylation using benzoic acid, DMAP and BOP-Cl.

    J. Lawandi et al. / Tetrahedron 72 (2016) 6283e63196288

    information they proposed models to rationalize the regiose-lectivity (Fig. 4a,b).

    With all of these studies pointing to cooperative intramolecularhydrogen bond networks, many computational and experimentalstudies did not call these hydrogen bonds into question, choosing tofocus more on the geometric features of the carbohydrates ratherthan the nature of the interaction.36 However, in 2002 and 2006,Klein reported computational investigations using high levelmethods such as MP2/6-31þG(d). These calculations suggestedthat the interactions between adjacent hydroxyl groups are nothydrogen bonds.37,38 A more recent independent study by Sillaet al., using a different set of computational methods, confirmedthat the interactions between adjacent hydroxyl groups are nothydrogen bonds,39 but rather ‘hydroxyl interactions’, as proposed byCorchado and co-workers.40 However, to be consistent with theliterature in this field, we will continue to name these interactionshydrogen bonds, understanding that they are not true hydrogenbonds.

    2.3. Catalysis using other bases or activating agents

    Using triethylamine and either acetic or benzoic anhydride,Hung and co-workers showed that various glucopyranosides, suchas 9, could be selectively functionalized at position 2 when an ex-cess (9.0 equiv) of triethylamine was used (Scheme 9).41 As anexample of this high regioselectivity, when benzoylating 9, theregioisomer 39awas the only observed product. Interestingly, theyobtained an almost random mono-functionalization of the sugarswhen pyridine was used instead of triethylamine.

    Scheme 9. Regioselective acylation of position 2 over position 3 of 4,6-O-benzylidenemethyl a-D-glucopyranoside.

    Using benzyl chloroformate, Mor�ere et al. mono-functionalizedseveral sugars.42 Combining two bases, namely DMAP and DABCO,they selectively installed a benzyloxycarbonyl in high yields andregioselectivities. In fact, they were able to install a benzylox-ycarbonyl group at position 2 of 6-O-(4-methoxytrityl) methyl a-D-glucopyranoside (40) (80% yield of 41, Scheme 10) and 6-O-(4-methoxytrityl) methyl a-D-galactopyranoside (74% yield), and se-lectively at position 3 (and not position 2) of 6-O-(4-methoxytrityl)methyl a-D-mannopyranoside (85% yield). Again for the man-nopyranoside, the equatorial position 3 was more reactive com-pared to the axial 2-OH. Interestingly, when the b-isomer of theglucopyranosidewas subjected to the same conditions, a mixture ofproducts, functionalized at either position 2 or 3, was obtained (31%and 43%, respectively), further demonstrating the influence of theorientation of the anomeric position. The reactivity pattern fromMor�ere mirrored that from Williams and Richardson with benzoylchloride (Scheme 1 and Scheme 2).

    In the same vein, Procopio and colleagues selectively acylatedposition 2 of 6-O-trityl methyl a-D-glucopyranoside (42), yielding

    Scheme 10. Combination of bases to selectively functionalize methyl a-D-glucopyranoside.

    43a as the major isomer (73%). They used a combination of BOP-Cland DMAPwhich, along with the desired acid, most likely first formthe mixed anhydride of BOP-Cl with that acid (Scheme 11).43

    However, the necessary control experiments were not performedto determine, firstly, whether the acyl pyridinium formed from thereaction of DMAP with the mixed anhydride, and secondly,whether a symmetric anhydride formed from the reaction of themixed anhydride with another equivalent of the acid.

    2.4. The influence of the hydrogen bond network

    In explaining the results of their acylation experiments, Wil-liams and Richardson mentioned the influence of the intra-molecular hydrogen bond network.11,12 In fact, several groups haveinvestigated this intramolecular hydrogen bond network experi-mentally and computationally to better understand the order ofreactivity of the hydroxyls on sugars.44e51 Surprisingly, Williamsand Richardson performed their experiments in pyridine, a solventthat is able to hydrogen bond with the sugar, a fact which rendersthis inference of the intramolecular hydrogen bond networkseemingly less plausible. However, a few groups have discoveredthat even in hydrogen bonding solvents, although it may beweakened, the intramolecular hydrogen bond network still ex-ists,46,50,51 supporting Williams and Richardson’s theory that theinternal hydrogen bond network influences acetylation reactions ofsugars, even when the reactions are performed in pyridine.

    From 1H NMR studies, Davies found that for methyl a-D-gluco-pyranoside (1), only one intramolecular hydrogen bond existedbetween the hydroxyls at position 4 and 6, while for the a-anomerof glucose (47), glucose has an extensive hydrogen bond network,as in Fig. 5.46 Brewster et al. rationalized the reactivity of the hy-droxyls of glucose by determining the acidities of the hydroxyls ofa-D-glucopyranose (and b-maltose).47 To do this, they performedcomputational calculations using a semi-empirical method (AM1).From their calculations, Brewster determined that the 6-OH is theleast acidic along with the following order of acidity: 1-OH>4-OH>3-OH>2-OH>6-OH. This would explain why Kurahashi, Miz-utani and Yoshida observed very little acylation of position 6 in

    Fig. 5. Davies proposed intramolecular hydrogen bond networks of methyl a-D-glu-copyranoside (1) and the a-anomer of glucose (47).

  • J. Lawandi et al. / Tetrahedron 72 (2016) 6283e6319 6289

    their experiments, even though this primary OH was free(Scheme 6). On the other hand, position 6-OH sometimes seems themost reactive towards alkylation and acylation because it is theleast hindered position and therefore more accessible to electro-philes. Thus, if more than an equivalent of acylating agent was usedon an unprotected pyranoside, researchers (such as Williams andRichardson) observed di-acylation, the 6-OH being one of the po-sitions acylated.

    In the late 90’s, Kurahashi, Mizutani and Yoshida proposed thatthe internal hydrogen bond network of octyl a-D-glucopyranoside(Fig. 6) could account for the reactivity patterns which they ob-served experimentally in Scheme 6.33 For example, even thoughposition 6 was the most accessible position from a steric point ofview, the 6-OH was the least acylated position because this flexibleprimary hydroxyl does not hydrogen bond well. On the other hand,position 4 was preferentially acylated because the positive chargecan be thoroughly delocalized through the hydrogen bond network(as in Fig. 6a). Kurahashi, Mizutani, and Yoshida also performedsemi-empirical calculations (PM3) to quantify the proton affinitiesof the hydroxyl groups of monosaccharides, finding that the re-activity trend parallels the proton affinities, in other words, posi-tion 4 has a higher proton affinity than the 3-OH and 2-OH. Themeasured proton affinities mirror the hydroxyl nucleophilicity inthis case.33

    Fig. 6. Kurahashi Muzutani and Yoshida proposed the hydrogen bond network of octyla-D-glucopyranoside 30 supports DMAP-catalyzed acylation of the 4-OH (a) over the 3-OH (b), the 2-OH (c) and the 6-OH (d).

    Scheme 12. Modulating hydroxyl group acidity for regioselective tosylation andacetylation.

    Scheme 13. Example of regioselective glycosylation of a partially unprotected

    In 2008, Pakulski attributed the results from the mannosylationexperiments to the hydrogen bond network of the mannopyrano-sides used (48e480 and 49e4900 in Fig. 7).52 In fact, allyl 6-O-TBDPSb-D-mannopyranoside should be capable of an extra hydrogenbond, between the 2-OH and the anomeric O-allyl (4900) because

    Fig. 7. Some possible hydrogen bonds that could explain why the 2-OH of allyl 6-O-TBDPS b-D-mannopyranoside (shown in 49e4900) reacts more than in the a-form(48e480).

    these two groups are in a cis-configuration, and therefore closeenough to interact. The 2-OH could therefore have a slightly morenegative charge in the b-form than in the a-form, rendering itslightly more nucleophilic in the b-form. As a result, mixturescontaining mostly products mannosylated at position 3, but alsosome at position 2, were observed.

    Wang et al. explored the impact of the hydrogen bond networkon hydroxyl group acidity.53 Once more, they postulated that theintramolecular hydrogen bond network with (a configuration) orwithout (b configuration) the anomeric oxygen modulates of theacidity of 2-OH and 3-OH. This change in acidity would, in turn,explain the reversal of selectivity observed when acetylating 9 andits anomer 11 (Scheme 12). They also observed a reversal of se-lectivity when tosylating the glucoside 11 and thioglucoside 51.Once more this could be attributed to a change in the hydrogenbond network.

    Simple bases, such as NaH or tBuOK, enabled the regioselectiveglycosylation of a number of pyranosides (Scheme 13).54,55 asWanget al. above, Matwiejuk and Thiem postulated that regioselectivityoriginated from the difference in acidity of the hydroxyl groups.56

    glucopyranoside.

    To assess this hypothesis, they carried out spectrophotometry ex-periments to measure the relative acidities (Ke) of these hydroxylgroups. They observed that these acidities were related to theintramolecular hydrogen bonds and stereochemistry of the carbo-hydrate. For example, compound 53 featuring two interacting ad-jacent hydroxyl groups had a Ke value of 171 (Scheme 13). Incontrast, the 3-O and 2-O-methylated analogs of 53 had botha single free hydroxyl group, with Ke values of 10.6 and 14.2,respectively.

    As discussed above, the 6-OH is characterized by its lower in-trinsic reactivity than the secondary hydroxyl groups but a higheraccessibility. Using the latter, Smiljanic et al. achieved regiose-lective glycosylation at the primary 6-OH over secondary alcohols.

  • J. Lawandi et al. / Tetrahedron 72 (2016) 6283e63196290

    As an example, they synthesized a trisaccharide by reacting a glu-copyranoside, 56, unprotected at position 6 and 3, with a mannosedonor (Scheme 14) leading to the regioisomer 58 then to the finaltrisaccharide 59.57

    Scheme 14. Regioselective glycosylation using TMSOTf to obtain a single di-ortrisaccharide.

    Fig. 8. Detailed mechanism of DMAP-catalyzed acylation illustrating the role of thecounterion (X�) or base.

    Fig. 9. Acetate counterion can direct acylation to secondary hydroxyls of glucopyr-anoside 28.

    Fig. 10. Silyl protection of 1,2-, 1,3- and 1,4-diols.

    Scheme 15. Selective protection of hydroxyl groups in deoxynucleosides using al-kylsilyl reagents.

    From these efforts, we can clearly see that the hydrogen bondnetwork influences hydroxyl groups’ acidity and outcome of re-actions (whether simple acylation reactions or more complex gly-cosylations) performed on unprotected or partially protectedsugars.

    The complex nature of these hydrogen bond networks is furtheramplified in larger systems (e.g., disaccharides and poly-saccharides) such as sucrose inwhich acidity can be unusually high.This is beyond the scope of this report which focuses on mono-saccharides but it is worth mentioning the highly regioselectiveglycosylation on a secondary alcohol of sucrose, which featureseight free hydroxyl groups including two primary alcohols, byMiller and co-workers.58

    2.5. The role of the acylating agent

    Many of the methods presented thus far differ, not only throughthe use of a variety of catalysts or additives, but also through theacylating agent used. In fact, only a few research groups addressedthe role of the acylating agent when selectively protecting sugars,and yet the following examples clearly illustrate that the acylatingagent used influences the selectivity of the reaction and thereforethe products formed. Kattnig and Albert researched themechanismof DMAP-catalysis, investigating specifically the influence of dif-ferent acylating agents and bases on DMAP catalyzed acylationreactions.59

    Homogeneous acylation with acetyl chloride, pyridine (asa base) and DMAP (as a catalyst) are faster than those with aceticanhydride under the same conditions. The reverse is true for het-erogeneous acylation with acetic anhydride and potassium car-bonate (as a base) which are faster than that using acetyl chlorideunder the same conditions. Updating Fig. 3, which illustrated theproposed mechanism for DMAP-catalyzed acylation, to include thebase used for these reactions and the deprotonation step, we obtainFig. 8. Kattnig and Albert further investigated the influence ofpyridinium ion pair formed, which Guibe-Jampel, Le Corre, andWakselman began to examine in 1979.60

    If the base is ‘unavailable’ to deprotonate the nucleophile YeH,like when using insoluble potassium carbonate, the counterion(either acetate or chloride provided by the acylating agent) may act

    as the base. If the counterion is a chloride or a cyanide, deproto-nation can only occur at one position, most likely the most acces-sible position 6. On the other hand, if the counterion is an acetateion, the acetate oxygens can hydrogen bond to position 6 and po-sition 3 or 4. In this way, deprotonating a secondary hydroxyl, ateither position 3 or 4, is possible and the electrophile can add ontoa secondary hydroxyl, while acylation of the primary position issuppressed (Fig. 9).

    2.6. Selective silylation

    Although acylation has been themajor focus to date, researchershave also looked into the silylation of sugars. A wide variety of silylether derivatives of carbohydrates can be formed for the protectionof hydroxyls, and, more importantly, 1,2- and 1,3-diols.61 For in-stance, Corey explored di-iso-propylsilyl and di-tert-butylsilyl di-triflates to protect 1,2-, 1,3-, and 1,4-diols (Fig. 10).62

    Acyclic silyl ethers have also been popular. In the 70’s, Ogilvieet al. and Chaudhary et al. selectively targeted primary alcoholsover secondary alcohols using imidazole or DMAP as a base/catalystas shown with deoxynucleotides (Scheme 15)63 and simple diols(Scheme 16).64

  • Scheme 16. Silylation of primary alcohols in the presence of secondary alcohols.

    Scheme 19. Regioselective silylation of galactopyranosides.

    J. Lawandi et al. / Tetrahedron 72 (2016) 6283e6319 6291

    When multiple secondary hydroxyl groups are present, regio-selective silylation is significantly more challenging. TheMiethchengroup applied branched oligosilyl triflates with silyl spacers (as in70) as protecting groups for some fructopyranose sugars (69),leaving only one secondary hydroxyl available (Scheme 17) forfurther functionalization.65

    Scheme 17. A one-step protection of two positions of a fructopyranoside.

    Scheme 20. Glycosylation of allyl 2-acetamido-6-O-TBDPS-2-deoxy-b-D-glucopyrano-side with a galactose trichloroacetimidate derivative.

    Arias-Per�ez and Santos disilylated methyl and allyl a-D-man-nopyranosides, at various temperatures, to establish the order ofreactivity of the secondary hydroxyls from the disilylated productsobserved.66 At low temperatures, mainly the 3,6-disilylated prod-uct formed, while at higher temperatures, the 2,6-disilylatedproduct was predominant. From this data, Arias-Per�ez and Santosnot only derived the order of reactivity of the secondary hydroxyls(3-OH>2-OH>4-OH), but also that at higher temperatures, the silylgroup migrated from position 3 to position 2. In fact, they couldmanipulate which position the TBDPS group migrated to usingdifferent bases: stronger bases like n-butyl lithium forced migra-tion of the TBDPS from position 3 of 71a to position 4, which is lesshindered than position 2 (kinetic conditions yielding 71b), whilesofter imidazole base (longer reaction times and higher tempera-tures) promoted migration from position 3 of 71a to position 2 (thethermodynamic product 71c) (Scheme 18).

    Halmos et al. investigated the regioselective silylation of gal-actopyranosides using conditions similar to those used for the

    Scheme 18. Controlled TBDPS migration.

    nucleotides described above.67 The b configuration enabled thesilylation at positions 2 and 6 mostly. However, they observedsilylation at positions 3 and 4 when they used the a anomer(Scheme 19).

    2.7. Glycosylation on minimally protected acceptors

    A few groups have glycosylated minimally protected acceptorsin order to determine if long synthetic routes of protection anddeprotection were actually necessary (Schemes 5 and 14). The Roygroup synthesized N-acetyl-lactosamine derivatives (such as 77),finding that a 6-O-TBDPS allyl b-D-glucopyranoside acceptor (75)could be selectively glycosylated with 76 at position 4 withoutprotecting any of the other positions of the sugar (Scheme 20).68

    Similarly, the Pakulski group investigated the mannosylation(i.e., glycosylation using a mannose-based donor) of 6-O-TBDPSbenzyl a-D-mannopyranoside and allyl a- and b-D-mannopyrano-side (80).52 They observed that the a-D-mannopyranosides could beselectively glycosylated 78 with the trichloroacetimidate 79 atposition 3, when the 2-, 3-, and 4-OHs were unprotected (Scheme21).

    Scheme 21. Mannosylation of allyl 6-O-TBDPS-a-D-mannopyranoside.

    Their best results were obtained for allyl 6-O-TBDPS-a-D-man-nopyranoside (78) when they used either BF3$OEt2 (70% yield ofglycosylation at position 3) or with TMSOTf (56% yield of glyco-sylation at position 3). Interestingly, for allyl 6-O-TBDPS-b-D-

  • Scheme 23. Acylation catalyzed by tri-pseudo-peptide containing DMAP.

    J. Lawandi et al. / Tetrahedron 72 (2016) 6283e63196292

    mannopyranoside, Pakulski and co-workers observed a mixture ofdisaccharides containing a much larger amount of product man-nosylated at position 2. Furthermore, for benzyl 6-O-TBDPS-a-D-mannopyranoside, the yields were also significantly lower, al-though they were able to selectively mannosylate the acceptor atposition 3 using TMSOTf (34% yield).

    2.8. Hydrogen-bond and regioselectivity

    All of these studies highlight the complex nature of the hydro-gen bond network and its impact on the regioselectivity of varioustransformations. First of all, the hydrogen bond network modulatesthe acidity of the different hydroxyl groups involved. More hydro-gen bonded is an oxygen of a hydroxyl group, more acidic it is. Asa result, in presence of a base, the most acidic group is the mostreactive as it is the first to be converted into a more reactive alk-oxide. However, under neutral conditions, it is the least reactive asits lone pairs is interacting with surrounding hydrogen bond donorgroups and is consequently less nucleophilic. These studies alsorevealed that the most accessible group (i.e., position 6 of gluco-pyranoside) is not necessarily the first to react. The hydrogen bondnetwork can also be modulated by the presence of acids (Fig. 9). Asa result, glycopyranosides can be differently functionalized underdifferent conditions (e.g., with or without a base) knowing its in-trinsic hydrogen bond network.

    3. Extrinsic methods which internally deliver the reagent

    Some researchers have chosen to emulate enzyme active sitescreating compounds or peptides capable of hydrogen-bonding withthe sugar substrates, reacting with the reagents and internallydelivering the reagents to a specific position.

    3.1. DMAP-based catalysts

    Kurahashi, Mizutani, and Yoshida continued their work onDMAP-catalyzed acylation, using DMAP analogues with acid moi-eties (81aee) capable of hydrogen bonding with the sugars(Scheme 22). In this case, they found that the 6-OH was the mostreactive for the octyl a- and octyl b-D-glucopyranosides and gal-actopyranosides. The 4- and 6-OH positions of the mannopyrano-sides reacted equally. Interestingly, while di-acylation waspreviously inevitable, as in Scheme 1, Kurahashi, Mizutani, andYoshida have developed a method which avoids this issue.69

    Scheme 22. Acetylation catalyzed by DMAP analogues.

    In the quest for more efficient catalysts for acylation of sugars,Kawabata and colleagues incorporated DMAP analogues into shortdi- and tri-peptides (such as 83a/b, Scheme 23). Initially, the cata-lysts were used to enantioselectively acylate meso-1,2- and 1,3-diols.70,71 These catalysts and others were also applied to selec-tive acylation of sugars. Kawabata hypothesized that the catalystscan wrap around the sugar being acylated, directly delivering theacyl group to a specific position: only the 4-OH is selectively acyl-ated (Scheme 23). Once again, the intrinsic reactivity of the sugarhas been manipulated, and the reactivity (or rather the accessibil-ity) of position-6 was quenched and the acyl group was deliveredvery specifically.72,73 Recently, the Kawabata group used this samecatalyst with other anhydrides, for example bearing an amino acid,successfully installing a N-Cbz-phenylalanine at position 4 of octylb-D-glucopyranoside (28).74

    The same group developed other analogous catalysts featuringDMAP (e.g., 85, Scheme 24), also demonstrating that changing theacylating agent from the anhydride to the acyl chloride allowedthem to switch from acylating the position 4-OH to the position 6-OH due to kinetic effects.75 To rationalize the observed regiose-lectivity, they proposed a complex in which the DMAP-containingchiral catalyst is participating in two hydrogen bonds (with 2-OHand 6-OH) with the carbohydrate unit. In this complex, only 4-OH is available for functionalization and is properly positioned toreact with the DMAP-like activated dimethyl acetate (Fig. 11).

    Applying thismethod, the Kawabata group usedmembers of thiscatalyst series to prepare a fully orthogonally protected glucopyr-anoside derived from 2876 and to prepare monoacylated natural

    Scheme 24. Acylation catalyzed by tetra-peptide containing DMAP.

  • Fig. 13. Natural products synthesized using Kawabata’s regioselective glucoseacylation.

    Scheme 25. Regioselective benzoylation of position 2 over position 3 of 4,6-O-ben-zylidene methyl a-D-glucopyranoside 9 using a cage.

    Fig. 11. Proposed complex for the regioselective acylation of octyl b-D-glucopyranoside28 in presence of 83a.

    J. Lawandi et al. / Tetrahedron 72 (2016) 6283e6319 6293

    products such as monoacylated digitoxin77 and acylated LanatosideC (Fig. 12).78 In the latter case, the complete reversal of selectivityobserved when going from DMAP to 83b is striking. They furtherapplied their innovative regioselective strategy to the total syn-thesis of two ellagitannins (strictinin and euginiin) from un-protected glucose.79 In the first step of the synthesis, theyperformed a direct and highly stereoselective (b/a¼99:1) glycosyl-ation of glucose with gallic acid trimethoxymethyl ether. In thesecond synthetic step, Kawabata and co-workers optimized a one-pot regioselective diacylation. First, they performed a regiose-lective 4-O-galloylation, followed by a 6-O-galloylation with theirpreviously reported catalyst leading to 90, an intermediate in thesynthesis of ellagitannins (Fig. 13). In the same vein, the total syn-theses of strictinin and euginiin were performed in 5 and 6 stepswith 21% and 18% overall yields, respectively, a significantly moreefficient approach than those previously reported.80e82 Catalysts ofthe same family were also instrumental in the late stages of mul-tifidoside AeC syntheses (Fig. 13).83 Although our focus is on car-bohydrates, it is worth mentioning that the Kawabata groupsuccessfully applied this class of catalysts to the regioselective ac-ylation of acyclic diols. For example, 1,7-heptan-diol was mono-acylated in 92% yield with only 3% of diacylated product. In contrast,when the Kawabata group performed the reactionwith DMAP, theyobtained a 71% yield and very poor regioselectivity (45:26).84 Thesemultiple applications to natural product synthesis and/or func-tionalization highlight the potential of Kawabata’s catalysts.

    Fig. 12. Complete regioselective monoacylation of digitoxin at position 4000 .

    L€uning reported a very innovative method using pyridine-containing cages such as 92 (Scheme 25).85 They postulated thatthe pyridine forms a hydrogen bond with a single alcohol. Appliedto methyl 4,6-O-benzylidene a-D-glucopyranoside, this molecularrecognition process selectively activated 2-OHwhich, when reactedwith benzoic anhydride, provided a single benzoylated product.

    3.2. Peptidic catalysts

    While the Kawabata group devised DMAP-containingpeptidic catalysts to perform selective acylation reactions, Millerpioneered the use of peptides. Miller constructed and screeneda series of longer peptides to catalyze acetylation reactions.86 Ofthe series, peptide 94 was particularly noteworthy as it favoredacetylation at position 3 over position 4 (97:3) of a glucosaminesubstrate (93), whereas the same substrate was acetylated at po-sition 4 in the absence of the peptide catalyst (Scheme 26). Fur-thermore, when the catalyst was absent, the Miller grouprecovered a significant portion of di-acetylated product from the

    Scheme 26. Selective acetylation of position 3 over position 4 of a glucosamine sub-strate 93, catalyzed by peptide 94.

  • J. Lawandi et al. / Tetrahedron 72 (2016) 6283e63196294

    mixture, while in the presence of the catalyst, di-acetylation wasnot observed.

    On the other hand, when peptide 96 was used as catalyst, thesecondary hydroxyl at position 4 of 28 was acetylated pre-dominantly, while the primary hydroxyl reacted to a lesser extent,and finally positions 3 and 2 reacted about equally (Scheme 27).Recall that some of the intrinsic reactivity studies discussed aboveshowed that 4-OH was the least reactive.

    Scheme 27. Optimized acylation catalyzed by a short peptide.

    Fig. 14. Regioselective lipidation of unprotected vancomycin using different methylhistidine-containing short peptides.

    This peptide-catalyzed strategy was extended to regioselectiveBartoneMcCombie deoxygenation.87 This was achieved by regio-selective installation of the xanthate which can be then reactedunder radical conditions to provide deoxysugars as illustrated inScheme 28. In this report, Miller and co-workers identified twodifferent peptides, 97 and 98, leading to opposite regioselectivityfurther demonstrating the potential of this method.

    Scheme 28. Regioselective deoxygenation using peptidic catalysts.

    Scheme 29. Chiral diamine (104) catalyzed acylation of methyl-6-O-TBDPS-b-D-glu-copyranoside (103).

    More recently, Miller and co-workers successfully achievedthe regioselective functionalization of fully unprotected Vanco-mycin using decanoic anhydride as acylating agent (Fig. 14).88

    Using different methyl histidine-containing short peptides

    (102aec), they were able to reach a certain level a regioselectivityon given positions over other reacting groups including phenols,secondary alcohols, primary alcohol, carboxylic acid, primary andsecondary amines (101aec). More importantly, as shown inFig. 14, Miller and co-workers identified peptides to regiose-lectively acylate alternatively at each of the three positions. Theyobtained 24e38% yield over 2 steps (w10e30 mg of each com-pound), allowing them to follow up with some biological testingof these products.

    Instead of using peptides, the Vasella group selectively ben-zoylated methyl 6-O-TBDPS-b-D-glucopyranoside (103), in thepresence of a chiral diamine (104).89 Although they gave little ex-planation to the regioselectivity they observed, they inferred thatthe hydrogen bond network of the sugar may influence the out-come of the reaction (Scheme 29).90

    3.3. Metal catalysis

    Schlaf and co-workers devised a fairly unique approach, relyingon the activation of silane reagents through silane alcoholysis andcatalyzed by palladium nanoparticle.91 Applied to methyl a-D-glu-copyranoside, this approach led to the 3,6-O disilyl product, 106b,as the major isomer (Scheme 30). Interestingly, this approach is

  • Scheme 30. Regioselective disilylation using palladium nanoparticle-catalyzed silanealcoholysis.

    Scheme 32. Stannyl ethers promote regioselective acylation.

    J. Lawandi et al. / Tetrahedron 72 (2016) 6283e6319 6295

    complementary to that of Halmos et al. which yielded primarily the3,6-O disilylated product (Scheme 19).67 Unfortunately, the un-known structure of the surface of the nanoparticles made therationalization of the regioselectivity difficult.

    Three years later, the same group devised another silane alco-holysis method using homogeneous catalysts. They obtainedregioselectively trisilylated hexopyranosides when they added over3 equiv of silane to the reaction mixture in presence of an un-charged rhodium (Scheme 31).92 They also reported regiose-lectivity patterns similar to the disilylation reaction observed withpalladium nanoparticles when 2.3 equiv of silane were used inpresence of Ir(I).

    Scheme 31. Regioselective di- or trisilylation using iridium or rhodium-based homo-geneous catalysts.

    Scheme 33. Selective benzoylation via a stannylene acetal intermediate.

    Fig. 15. Stannylene acetal of methyl a-D-glucopyranoside (112) compared to methyl b-D-glucopyranoside (113).

    4. Extrinsic methods which pre-activate the sugar

    Researchers have developed many methods to pre-activatesugars with organotin or organoboron derivatives, or metal salts,prior to performing the reaction of interest.

    4.1. Organotin derivatives

    Although David and Hanessian and more recently Dong et al.reviewed many of the applications of organotin derivatives of var-ious sugars,93,94 a few among them are worth mentioning here.Interestingly, although tin derivatives are highly toxic making thempoor candidates for industrial use, there is still a fair amount ofwork focusing on their use in carbohydrate chemistry.

    4.1.1. Acylation via stannyl ether derivatives. Nearly forty years ago,Ogawa and Matsui prepared stannyl ethers of methyl a-D-gluco-pyranoside (1), mannopyranoside (2) and methyl b-D-galactopyr-anoside (3), as well as methyl b-D-galactopyranoside (72), whichthey benzoylated.95,96

    Interestingly, when they treated the methyl a-D-glucopyrano-side (1) with bis(tributyltin) oxide, Ogawa andMatsui hypothesizedthat stannyl ethers would form at positions 2 and 6 (108 inScheme 32). Subsequent benzoylation occurred at positions 2 and 6

    of methyl a-D-glucopyranoside (109, 82% yield). When treated inthe sameway, benzoylation occurred at positions 3 and 6 of methyla-D-mannopyranoside (2) (90% yield) and methyl b-D-galactopyr-anoside (72, 95% yield). On the other hand, benzoylation of methyla-D-galactopyranoside (3) actually yielded four products, theproduct mono-benzoylated at position 6, di-benzoylated at posi-tions 2 and 6, and positions 3 and 6, and finally the tri-benzoylatedproduct at positions 2, 3, and 6 (yields of 21, 10, 20, and 41%, re-spectively). The postulated formation of pentacoordinated tincomplexes such as 108 was later experimentally supported usingSn119 NMR.97

    4.1.2. Acylation and alkylation via stannylene acetals. When con-ventional acylation methods failed to be regioselective and fol-lowing preliminary work on regioselective tosylation ofnucleosides using tin-containing reagents,98,99 Munavu, andSzmant turned to dibutylstannylene acetals to selectively func-tionalize partially-protected methyl a/b-D-hexopyranosidesugars.100 Acylation occurred exclusively at position 2 for the a-D-glucopyranoside 9, but was non selective for the b-anomer (11)(Scheme 33).

    The stannylene acetal of 4,6-O-benzylidene methyl a-D-gluco-pyranoside formed at positions 2 and 3, most likely because theanomeric methoxy could stabilize the tin acetal (Fig. 15). On theother hand, when the stereochemistry of the starting sugar doesnot allow for stabilization of the stannylene acetal, acylation wasnon-selective, as for the 4,6-O-benzylidene of methyl b-D-

  • Scheme 36. Selective oxidation at position 3 of a 3,4-stannylene acetal ofa galactopyranoside.

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    glucopyranoside (113) and methyl a-D-mannopyranoside (notshown). The models shown in Fig. 15 may be oversimplified as di-mers may also form (see below).

    The importance of the anomeric center was further demon-stratedwhenMunavu and Szmant acylated the unprotectedmethyla- and b-D-glucopyranosides under the same conditions: they iso-lated the 2-O-acylated product of the a-isomer (as expected fromthe previous experiments), while the b-isomer, lacking the possibleanomeric stabilization of the 2,3-stannylene acetal, reacted at po-sition 6, the primary alcohol (80% yield of 6-O benzoylatedproduct).100

    In a further exploration of stannylene acetals, Nashed andAnderson compared the reactivity of axial hydroxyls with equato-rial hydroxyls of stannylene acetals of partially protected gal-actopyranoside and mannopyranoside.101 As expected, they foundthat the equatorial hydroxyls were more reactive: the 3-O of thegalactopyranoside 114 reacted selectively to benzoylation(Scheme 34), and the equatorial 3-O of the mannopyranoside wasmost reactive and predominantly alkylated over the axial 2-O-position.102

    Scheme 34. Stannylene acetal 115 for regioselective acylation of a partially protectedgalactopyranoside 114.

    Scheme 37. Selective benzoylation of position 3 of a galactopyranoside anda glucopyranoside.

    Nashed and Anderson found that the conditions developed tobenzoylate the equatorial position of the galactopyranoside actu-ally yielded the mannopyranoside benzoylated selectively at theaxial position 2 (118a, Scheme 35).101 They also developed condi-tions to selectively benzoylate the equatorial hydroxyl at position3.101 This same strategy was applied to methylation and allylationof the same substrate.102 Thus, unlike Munavu and Szmant,100

    Nashed and Anderson found optimal conditions for functionaliz-ing either the equatorial hydroxyl at position 3 or the axial hy-droxyl, at position 2 (Scheme 35).

    Scheme 35. Stannylene acetal for regioselective acylation of a partially protectedmannopyranoside.

    Scheme 38. Selective alkylation of position 3 of a galactopyranoside.

    David and Thieffry also successfully used stannylene acetals notonly to selectively acylate sugars, but also to oxidize a 2,6-O-di-benzoyl-a-D-galactopyranoside (119) at position 4 and

    a 4,6-O-benzylidene-b-D-galactopyranoside (122) at position 3(Scheme 36).103

    David and Thieffry applied benzoylation conditions to galacto-and glucopyranosides protected at positions 2 and 6 (119 and 126,respectively). In both cases, although position 4 should be activatedby the stannylene acetal, position 4 was less reactive and thusbenzoylation was occurring predominantly at position 3(Scheme 37).

    As shown by Heidecke and Lindhorst, the use of stannylidenesacetal also enabled the regioselective alkylation of unprotectedmethyl a-D-pyranosides (e.g., from galactose, xylose, fucose andmannose) at position 3. This application allowed the preparation ofcarbohydrate derivatives that can be further functionalized throughhydrolysis of the phthalimide into a primary amine (Scheme 38).104

    Martinelli et al. reported the regioselective tosylation of methyla-D-xylopyranoside (Scheme 39)105 and compared their observa-tions to those from Tsuda et al.106

    Martinelli et al. attempted to rationalize the observed regiose-lectivity: they first considered the conformation of the a-xyloside

  • Scheme 39. Catalytic and regioselective tosylation of xylosides catalyzed by dibutyltinoxide and a base. Scheme 41. Glycosylation of a galactopyranoside acceptor via a stannylene acetal

    intermediate.

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    as a tin complex. There is an equilibrium between the 2 possible tincomplexes (with the xylopyranoside adopting either the 4C1 or the1C4 conformation), and one complex is less favorable because ofdiaxial interactions (Scheme 40). While tin complexes form dimerswith diols, the addition of TsCl likely induces a rearrangement intoa new intermediate, which then reacts at O-2 (the most availableand reactive oxygen). An equivalent of base is used to selectivelydeprotonate the alcohol and regenerate dibutyltin oxide for a sec-ond catalytic cycle. One equivalent of base is required to completethe reaction and the rate of the reaction depends on the pKa of thebase (the more basic, the faster). In this reaction, Martinelli et al.demonstrated that the alkyl ligands and the nature of the nucleo-phile can have a major impact on the regioselectivity of thereactions.

    Scheme 40. Proposed explanation of the observed regioselectivity of the tosylationreaction: a) Favored 1,2-stannylidene complex 4C1 versus 1C4, b) Formation andbreaking of tin complex dimer.

    Scheme 42. Regioselective (1/6)-glycosylation using an excess of Bu2SnO.

    4.1.3. Glycosylation via stannylene acetals. Several groups have alsoused this type of chemistry to perform regioselective glyco-sylations.107e109 For example, the Kaji group explored the use ofstannylene acetals to selectively glycosylate sugars. In fact, startingwith a sugar protected at position 6 (either with a trityl or TBSgroup), glycosylation occurred at position 3. On the other hand, for

    sugars with a free primary hydroxyl at position 6 (as in 72), theacetal formed between positions 4 and 6, and glycosylation oc-curred selectively at position 6 (140, Scheme 41).110

    Madsen and co-workers also achieved tin oxide-mediatedregioselective glycosylation of a variety of monosaccharides withan excess of Bu2SnO (e.g., glucose, galactose and mannose,Scheme 42).111 In over 11 examples, they observed poor (23%) toexcellent (85%) yields with nomention of the regioselectivity or thestereoselectivity. The major limitation of this research is that theglycosylation is restricted to 1/6 glycosides only.

    The Kaji group later developed a new method to switch fromglycosylation at position 6 to position 3 of the glycosyl acceptor,without having to protect position 6 of the acceptor (144) prior tothe reaction, simply by adding TBAF to the reaction mixture.112

    Most likely, the 3,4-stannylene acetal, formed initially, quickly re-acts with the fluoride source forming 145a, releasing the position 3alkoxide (145b) which is more reactive and easily glycosylated(Scheme 43). Thus, without TBAF, glycosylation occurs at position 6of the acceptor, but with TBAF, glycosylation occurs at position 3.

    Dong and co-workers further exploited this activation withhalides, using stoichiometric amounts of organotin reagents acti-vated by tetrabutylammonium halides (i.e., F, Cl, Br and I) on un-protected sugars in order to perform regioselective mono- anddibenzylation (Scheme 44).113 As previously proposed by Kaji, theauthors hypothesize that the halide anion further activates the tinreagent, which correlates with increased reaction rates.

    More recently, Namazi, and Sharifzadeh used this organotin-based chemistry to install an acrylate and a methacrylate at posi-tion 2 of methyl 4,6-O-benzylidene-a-D-glucopyranoside (49% yieldwith acryloyl chloride and 45% with methacryloyl chloride) and ofmethyl 4,6-O-benzylidene-a-D-galactopyranoside (45% yield withacryloyl chloride and 58% with methacryloyl chloride).114

    4.2. Organoboron derivatives

    4.2.1. Boronic derivatives. Given that sugars readily form com-plexes with boronates,115e118 the Aoyama group investigated how

  • Scheme 44. Regioselective mono- and dibenzylation of methyl-b-D-galacto- and glu-copyranoside using bromide ions activated tin reagent.

    Scheme 43. TBAF mediated glycosylation of a 3,4-O-stannylene acetal yields a 3-O-glycoside.

    Scheme 46. Regioselective benzoylation of cis-diol using the ethanolamine ester ofdiphenylborinic acid.

    Scheme 47. Regioselective benzoylation of methyl 6-(tert-butyldimethylsilyloxy)-a-D-galactopyranoside using the ethanolamine ester of diphenylborinic acid.

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    to utilize those complexes to selectively alkylate119 and glycosy-late120 sugars. In their initial studies, the Aoyama group selectivelyalkylated fucopyranosides at position 3, going through a 3,4-boronate intermediate. More recently, they applied these sameboronate intermediates to glycosylations (Scheme 45).120

    Scheme 45. A peracetylated bromide glycosyl donor reacts with an activated 3,4-boronate of a fucopyranoside.

    Scheme 48. Regioselective benzylation and tosylation of 6-(tert-butyldimethylsily-loxy)-a-D-galactopyranosides using the ethanolamine ester of diphenylborinic acid.

    From the boronic activation of various sugars, they observedthat some sugars were glycosylated at position 3 (such as methyl 6-O-trityl-a-D-galactopyranoside in a 91% yield, methyl a-D-man-nopyranoside in a 32% yield, and methyl a-L-fucoside 150 in a 93%yield, Scheme 45). Unfortunately, this method was hardly applica-ble to other sugars, which were glycosylated at position 6 (like bothmethyl a- and octyl b-D-glucopyranosides in 24% and 35% yields,respectively). In most cases, yields were lower because tri-saccharides are formed when both positions 3 and 6 are glycosy-lated. In fact, the only high yields they reported were with fucoside150 (Scheme 45), which lacks a hydroxyl at position 6, and thegalactopyranoside they used, in which the hydroxyl at position 6was protected.120

    4.2.2. Borinate derivatives. Taylor and co-workers proposed a veryoriginal and efficient way to either perform monofunctionalizationor glycosylation of cis-diols, using borinic acids for molecular rec-ognition of diols (Scheme 46).121 In 2011, they reported a regiose-lective activation of equatorial over axial hydroxyl groups,exploited in regioselective benzoylations.9

    Through the screening of boron-containing catalysts, Taylor andco-workers identified conditions to regioselectively benzoylatea 1:1 mixture of 1,2-diol with a good yield (70%) and a good cis/trans ratio (11:1) (Scheme 46). With these catalyst-controlledconditions in hand, they benzoylated other cis-diols, includingcarbohydrates as shown in Scheme 47.

    One of the most interesting applications was the regioselectivebenzylation of a 6-OTBS protected methyl galactoside, with goodyield and excellent regioselectivity (Scheme 48).

    In a subsequent paper, Taylor and co-workers succeeded toregioselectively install a benzyl, a naphthylmethyl, a 4-bromobenzyl, and a benzyloxymethyl protecting group on differ-ent carbohydrate units, such as a 6-OTBS-protected methyl gal-actopyranoside and 6-OTBS-protected methylmannopyranoside.122

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    Using very similar conditions, they were also able to performregioselective glycosylation of 6-O-protected derivatives carbohy-drates such as 157 (Scheme 49).123

    Scheme 51. Catalyst-controlled regioselective glycosylation of digitoxin.

    Scheme 49. Formation of regio- and stereoselective b-glycosidic linkage activated viaa tetracoordinated borinate complex.

    In 2012, Taylor and co-workers reported regioselective sulfo-nylations (i.e., tosylation, Scheme 48), the application of theirmethodology to more substrates (e.g., 1,3-diols and different car-bohydrates units) and explored the mechanism through competi-tion and kinetics experiments. They rationalized the observedregioselectivity through the formation of charged tetracoordinatedborinate complexes with the cis-diols, a complex which cannotform with trans-diols (Scheme 50). Using pairs of diols (primary vssecondary, syn vs anti, and diols of different lengths) and the cat-alyst 152, they observed that syn equatorial hydroxyl groups weremore reactive than axial or primary ones. This showed that theborinic acid used as catalyst formed a borinate intermediate withthe carbohydrate during the course of the reaction. Using 1H NMRspectroscopy, they measured the rate of reaction of TsCl with theactivated carbohydrate. They determined that the reaction of theborinate was the turnover-limiting step of the catalytic cycle.Moreover, introducing either electron-withdrawing or electron-donating groups on the borinic acid decreased the rate of the re-action. DFT calculations of the Mulliken charges on an ethyleneglycol model showed a correlation with the catalytic activity.124

    Taylor and co-workers also expanded their methodology to in-

    Scheme 50. Mechanistic model of regioselective acylation/alkylation: formation ofcharged tetracoordinated borinate complexes.

    Scheme 52. Formation of regio- and stereoselective b-deoxyglycosidic linkage througha tetracoordinated borinate complex.

    clude regioselective silylation reactions (e.g., tert-butyldimethylsi-lylation), studying the effect of different boronic acids and differentLewis bases (Fig. 16).125 The combination of boronic acids and Lewisbases led to boronate complexes which are equivalent to borinatecomplexes (Fig. 16).

    Fig. 16. Different mechanisms of diol activation by: a) borinic acids b) boronic ester/Lewis base co-catalyst, proposed by Taylor et al.

    That same year, Taylor applied their borinic-ester catalyzedfunctionalization method to synthesize six digitoxin derivatives(differing by the glycosyl donor used), glycosylated at a single of thefive free hydroxyl positions in good isolated yields (51e77%) withgood regioselectivity (values not mentioned, Scheme 51).126 It is

    worth recalling that digitoxin has been previously regioselectivelyacylated using Kawabata’s methodology (Fig. 12).

    More recently, Taylor et al. formed b-2-deoxyglycosidic linkages

    between a fully protected ‘disarmed’ glycosyl donor and a 6-O-silylated glycosyl acceptor with good yields, good stereoselectivity,and excellent regioselectivity with glycosylation occurring at po-sition 3 only (Scheme 52).127

    In 2015, the same group exploited their borinic-ester catalyzedmethod in two key steps of the total synthesis of a natural penta-saccharide derived from a Saponin, originally extracted from Sper-gularia ramosa a South American herbaceous plant.128 Glycosylationbetween acetobromofucose (171) andmethyl 6-O-p-methoxyphenyla-L-arabinopyranoside (170), acetobromoglucose (149) and n-pen-tenyl a-L-rhamnopyranoside (173) provided the disaccharides with49% and 81% yield, respectively (Scheme 53). The first disaccharidewas obtained in a 4.4:1.0 regioisomer ratio, while only oneregioisomer was isolated for the second disaccharide. The authorsperformed the reactions on aw1 g and aw50mg scale, respectively.After a second glycosylation step, the authors obtained the targetedtrisaccharide, in a 98%yield fromthe seconddisaccharide usingmoreclassical conditions on a w4 g scale.

  • Scheme 53. Key glycosylation steps used in the total synthesis of a natural penta-saccharide derived from a Saponin.

    Scheme 55. Regioselective silylation of a 6-O-protected nucleoside.

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    Taylor et al. performed additional glycosylation steps to finallyobtain the pentasaccharide under classical conditions in a yieldranging between 17% and 85% yield.

    Using borinic acid for catalytically-controlled activation of cis-diols is an elegant solution to address the problem of regiose-lectivity encountered in carbohydrate synthesis. Unfortunately,these methods only work with cis-diols or axial-equatorial-equatorial triols and are therefore not applicable to glucopyrano-sides which feature only trans-diols.

    4.3. Chiral catalysts

    Given the success of histidine-containing peptides, researcherscontinued the work with much simpler methyl imidazole de-rivatives. In 2013, Tan and co-workers reported newchiral catalysts,specifically 178 (Scheme 54). In contrast to other catalysts (e.g.,104)

    Scheme 54. Regioselective functionalization of methyl 6-O-tert-butyldimethylsilyl-a-D-mannopyranoside using a chiral catalyst from methyl imidazole derivative.

    which only activates the acylating agent,178makes a covalent bondwith the carbohydrate unit. After optimizing the reaction condi-tions, they were able to regioselectively monofunctionalize (i.e.,silylation, acetylation and sulfonylation) a 6-O-TBS protectedmethyl mannoside at position 2. The monofunctionalization stepwas regiospecific (Scheme 54).129

    Interestingly, using a pseudo-enantiomer of the catalyst led tothe reversed regioselectivity, favoring position 2 instead. We canexplain this reversal whenwe consider the intrinsic reactivity of C3(over C2 and C4) and the preferred position for the catalyst due toa different structural match between the stereocenters of theauxiliaries and carbohydrates. Tan and co-workers applied similarreaction conditions to other triols: methyl a-L-rhamnose, methyl b-L-arabinose, 1,6-anhydro-b-D-galactose, and other galactose de-rivatives. Overall, the yields varied from 61% to 98%, and theregioselectivity was at least 80:20 over the 3 different positionsdepending on the configuration of the sugar and the catalyst used.Monofunctionalization reactions were initially performed onw3e30 mg, then scaled up to w60e230 mg and, in a few cases, toa 1.2 g scale.

    Tan and co-workers also applied the same strategy on ribonu-cleosides, and they observed high regioselectivities in many cases(98:2) (Scheme 55).130 Once more, using the enantiomer of the cat-alyst led to the opposite regioselectivity. Among the 18 examplesstudied, the regioselectivity was greater than 85:15 (except for thecontrol catalyst) and the isolated yields varied between 71% and 93%.

    As amechanism of activation, they proposed the transacetalationof a first axial hydroxyl group onto the oxazolidine ring, with dis-placement of a molecule of methanol. Then, the second equatorialhydroxyl groupof thediol canbeactivated throughan intramolecularhydrogen bond with the nitrogen of the imidazole ring (Fig. 17).

    Fig. 17. Proposed intermediates for the regioselective monofunctionalization of methyla-D-mannopyranoside.

  • Scheme 58. Acetylation using zinc(II) chloride.

    Fig. 18. Mechanism of the regioselective benzoylation of methyl a-D-glucoside 1through a complex with lanthanum(III) and BzMP.

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    4.4. Salt additives

    Many researchers have selectively functionalized sugars by firstadding salts to the reaction mixture, prior to adding the function-alizing agent. Initially, Avela, Melander, and Holmbom formedcopper(II) chelates of various sugars to observe if the chelate wouldinfluence the outcome of alkylation (Scheme 56).131,132

    Scheme 56. Sodium hydride with or without copper(II) salt for selective methylationof 4,6-O-benzylidene-methyl-a-D-glucopyranoside to copper(II).

    Scheme 59. Selective benzoylation in the presence of nickel(II) chloride.

    Scheme 60. Selective benzoylation in the presence of copper(II) chloride.

    In fact, if only 1 equiv of sodium hydride was used, Avela and co-workers found that position 2 reacted to alkylation, yielding mainly187a (Scheme 56). If an excess of sodium hydride was used, 9reacted at positions 2 and 3, yielding 187c. On the other hand, if themono-sodium alkoxide of 9 reacted with copper(II) chloride priorto functionalization, position 3 reacted predominantly, yielding187b, with less reaction at position 2 ‘blocked’ by the copper ion(Scheme 56). Although the authors did not infer this from theirresults, perhaps the hydrogen bond network of the sugar may playa role in that position 2 seems to be the most acidic, leading tocopper blocking the 2-O from alkylation.

    Similarly, Eby and Schuerch133 formed dianions of various a-D-hexopyranoside starting materials with 2 equiv of sodium hydride,and then used a copper(II) salt, namely copper(II) chloride, tochelate the dianion, deactivating it prior to alkylation (using eithermethyl, benzyl, or allyl iodide). In this way, Eby and Schuerchalkylated a number of different sugars, protected at various posi-tions (Scheme 57).

    Scheme 57. Selective alkylation in the presence of copper(II) chloride.

    Scheme 61. Optimized conditions to acylate a sugar using copper(II) acetylacetonate.

    For example, when positions 4 and 6 were protected as a ben-zylidene (as in Scheme 57), alkylation occurred preferentially atposition 3 of the sugar (66e95% yield of mainly 188b), agreeingwith Avela’s results. When positions 2 and 3 were benzylated, al-kylation occurred at position 4 (51e100% yield). They later con-tinued with selective alkylation and acylation reactions, findingthat copper salts (as opposed to mercury salts) eliminated anydisubstitution reactions, favoring mono-functionalization of thestarting materials.134

    In 1990, Hanessian and Kagotani proposed the use of zinc saltsand acetylated various methyl a-D-hexopyranosides (including 1).As with copper(II) salts, the regioselectivity observed was highlydependent on the presence of zinc(II) chloride (Scheme 58).135

    More recently, Gangadharmath and Demchenko136 comparedchloride salts of zinc, platinum, and nickel to observe their impacton the benzoylation of sugars. They found that the nickel(II) chlo-ride salt yielded the most selective benzoylation of 9 (Scheme 59)and benzylation.

    Osborn also selectively acylated and alkylated 4,6-O-benzyli-dene-a- and b-D-gluco- and galactopyranosides (such as 190) atposition 3, first forming the copper(II) chelate prior to furtherfunctionalization (Scheme 60).137 They even successfully appliedthis chemistry to selectively glycosylate these sugars, again at po-sition 3.138

    The Osborn group continued to optimize their reaction condi-tions to functionalize sugars in the presence of copper(II), screeningother copper sources. In fact, while copper(II) chloride requiresa first step deprotonating the sugar so that the copper(II) canstrongly interact with the sugar, other copper sources, like cop-per(II) acetylacetonate (Cu(acac)2), interact strongly with the sugarwithout the need for deprotonating. Thus, they optimized condi-tions to selectively acetylate 190 with no need for basic treatment(Scheme 61).139

  • J. Lawandi et al. / Tetrahedron 72 (2016) 6283e63196302

    In 2012, Evtushenko used copper trifluoroacetate salts to acylatea variety of carbohydrates with good to excellent yields and regio-selectivities (Scheme62).140 The regioselectivity appeared as directlyrelated to the configuration of each sugar. The major compound was2-OBz for a-rhamnose and a-fucose; 6-OTr for a-glucose, a-galac-tose, and a-mannose; 3-OBz for b-rhamnose, b-fucose, and b-galac-tose; and 4-OBz for b-xylose and b-arabinose configurations.Evtushenko proposed specific coordination modes to rationalize theobserved regioselectivity (Fig. 19). In these complexes, the carbohy-drates are anionic and complex with the copper ion.

    Scheme 62. Use of copper trifluoroacetate in regioselective benzoylation.

    Fig. 19. Proposed coordination of copper(II) trifluoroacetate and a) methyl a-rham-noside b) methyl b-rhamnoside c) benzyl b-xyloside configuration.

    Scheme 63. Regioselective benzoylation of 4,6-O-benzylidene mannosides usingCuCl2-(R/S)-PhBOX.

    Scheme 64. Selective monoacetylation of methyl a-L-rhamnopyranoside with mo-lybdenum(V) chloride.

    In 2015, they also extended the scope to 4,6-O-benzylidenes.141

    Once more, they proposed regioselective coordination with copperto explain the observed regioselectivities (Fig. 20).

    Fig. 20. Proposed coordination of copper(II) trifluoroacetate with 4,6-O-benzylidene ofa) methyl a-glucoside b) methyl b-galactoside c) and d) methyl a-mannoside. PMP:para-mehoxyphenyl.

    The Miller group exploited chiral copper complexes to performregioselective monofunctionalization of glycosides (Scheme 63).Applied to several substrates and electrophiles, the methodologyenabled conversions that are nearly quantitative in most cases withreasonable to excellent regioselectivities between 1:>99 (2-OBz)and 15:1 (3-OBz). Applied to mannoside 15, they observed thatinversion of the stereochemistry of the copper complex modulatedthe regioselectivity, the best results they obtained were for thebenzoylation of methyl 4,6-O-benzylidene-a-D-mannopyrano-side.142 This work was followed by Dong’s report using similarconditions (Cu(OTf)2 (S,S)-Ph-PyBox).

    Though they focused their investigation on tin and copper,Evtushenko and co-workers also considered other metals. For ex-ample, they investigated molybdenum(V) chloride as a catalyst forselective acylation of deoxyhexoses such as 203 (Scheme 64).143

    They subsequently investigated other molybdenum salts such asMoO2(acac)2. With this metal complex, Evtushenko’s group re-ported the regioselective benzoylation of a number of glycopyr-anosides (Scheme 65).144 The sugar units were restricted to galacto-or mannopyranoside derivatives, either 6-deoxy (rhamnosides,fucosides, or arabinosides) or 6-O-protected. By complexing car-bohydrates with molybdenum, they were able to preferentiallyactivate the equatorial hydroxyl group over the axial one, in 1,2-cisdiols (not applicable to glucose derivatives). Benzoylation reactionswere performed with excellent 1H NMR yields (83%e97%) and ex-cellent regioselectivity (2-/3-/4-OBz ratios ranging from 5:83:0 to1:90:2).

    Scheme 65. Regioselective benzoylation of methyl 6-triphenylmethyl-a-D-man-nopyranoside via a metal complex with molybdenum.

  • J. Lawandi et al. / Tetrahedron 72 (2016) 6283e6319 6303

    Last year, the Evtushenko group published the regioselectivebenzoylation of 4,6-O-benzylidenes of gluco-, galacto-, and man-nosides (Scheme 66).141 In presence of MoO2(acac)2, the Evtush-enko group isolated 3-O-benzoates when starting from gluco- andmannosides, while they obtained 2-O-benzoates from galactosides.Interestingly, under the copper conditions previously reported, allsubstrates showed 3-O-benzoate selectivity.

    Scheme 66. Regioselective benzoylation of 4,6-O-benzylidene mannosides in presenceof MoO2(acac)2 or Cu(CF3COO)2.

    Scheme 69. Regioselective methylation of methyl fucoside using SnCl2 anddiazomethane.

    The Kluger group looked at the use of lanthanum ion in theregioselective benzoylation of methyl a-D-glucopyranoside 1(Scheme 67). Sodium benzoyl methyl phosphate (BzMP) was se-lected as the benzoylating reagent.145e148 Lanthanides enhance thereactivity of the hydroxyl groups and of the BzMP. This complexpositions both partners and enables an internal delivery of thebenzoyl group to a specific position. Furthermore, they used mag-nesium ion as a scavenger in the monobenzoylation reaction,chelating the phosphate leaving group from BzMP, leaving La(III)free to react in another catalytic cycle.142 Interestingly, they per-formed a series of benzoylation experiments using a larger metalion, where the selectivity at position 2 was enhanced.143

    Scheme 67. Selective functionalization of methyl a-D-glucopyranoside with lantha-num salts.

    Scheme 70. Stepwise protection of methyl a-D-glucopyranoside (1) with catalytic di-methyl tin(IV) chloride.

    Although this approach was promising, the Kluger group re-

    ported yields ranging from 14% to 34%, with a 2-/6-OBz selectivityof 2.8:1.0 to 1.0:1.6. Other conditions they tested led to di- andtribenzoylation dependent on how the complex formed betweenthe diol and the lanthanide ion.

    Kartha et al. used silver carbonate, a well-established promoterin KoenigseKnorr glycosylations, to induce regioselective alkyl-ations.149 With this method, they were able to regioselectively in-stall a para-methoxy benzyl group at position 6, a primary alcohol,of different galactosides on a w200 mg scale with high yields(91e94%) (Scheme 68). Silver oxide was also previously assessed asshown in Scheme 12.

    Scheme 68. Regioselective alkylation of octyl b-D-galactopyra