Synthesis of l-Hexoses - Chemical Reviews (ACS Publications)

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Synthesis of L‑Hexoses Tobias Gylling Frihed, Mikael Bols, and Christian Marcus Pedersen* Department of Chemistry, University of Copenhagen, DK-2100 Copenhagen, Denmark 7.2.2. Epimerization at C2, C3, and C4 by Other Methods 7.2.3. Preparation of All Eight 6-Deoxy- Lhexoses 7.2.4. Three-Component Epimerization 7.3. 6-Deoxy-L-sugars from Unsaturated Carbohydrates 7.3.1. Hydrogenation of Exocyclic Alkenes 7.3.2. From 6-Deoxy-L-glycals 7.3.3. From Other Unsaturated Carbohydrates 7.4. Addition to Carbohydrate C5 Aldehydes 7.5. Head-to-Tail Inversion 7.6. Rearrangement of 6-Deoxy-L-sugars 7.7. Deoxygenation of L-Hexoses 8. De Novo Syntheses of 6-Deoxy-L-hexoses 8.1. Diels−Alder Reaction 8.2. Enantioselective Aldol Reaction 8.3. Diastereoselective Alkene Dihydroxylation 9. Conclusion Author Information Corresponding Author Notes Biographies Acknowledgments Abbreviations References

CONTENTS 1. Introduction 1.1. Importance of L-Sugars 1.2. Occurrence of L-Hexoses and Their 6-DeoxyL-hexoses 1.3. Biomimetics 2. Historical Aspects 3. Synthesis of L-Aldohexoses from Carbohydrates 3.1. C5 Epimerizations 3.2. L-Sugars from Unsaturated Carbohydrates 3.3. Addition to Carbohydrate Aldehydes 3.4. Head-to-Tail Inversion 3.5. From Common L-Lactones 3.6. Rearrangement of L-Hexoses 3.7. C−H Activation of 6-Deoxy-L-sugars 4. De Novo Syntheses of L-Aldohexoses 4.1. Iterative Asymmetric Epoxidation 4.2. Diels−Alder Reaction 4.2.1. Hetero-Diels−Alder (HDA) Reaction 4.2.2. Cycloadditions of Furans 4.3. Enantioselective Aldol Reaction 4.4. Diastereoselective and Enantioselective Alkene Dihydroxylation 4.4.1. from Chain-Elongated Alkenes 4.4.2. From Easily Available Alkenes 4.5. Enzymatic Asymmetrization 5. Chemical Synthesis of 2-L-Ketohexoses 5.1. By Isomerization/Conversion of an Aldohexose 5.2. From Another Ketohexose by OH Inversion 5.3. By Chain Extension of a Shorter Aldose 6. Chemoenzymatic Synthesis of L-Hexoses 6.1. Oxidation of Alditols 6.2. Epimerization of Ketoses 6.3. Isomerization between Ketose and Aldose 6.4. Aldolase Reaction 7. Synthesis of 6-Deoxy-L-hexoses from Carbohydrates 7.1. C5 Epimerization 7.2. Other Epimerizations of 6-Deoxy-L-hexoses 7.2.1. Reduction of Carbonyl-Containing 6Deoxy-L-hexoses © XXXX American Chemical Society

A A B C D F F I K M O P P Q Q S S T V

AN AN AO AO AO AP AP AQ AQ AR AS AS AS AT AU AV AW AW AW AW AW AW AX

1. INTRODUCTION In this review we focus on the synthesis of compounds that are the rare antipodes of common hexoses. Therefore, we only cover L-aldohexoses, 2-keto-L-hexoses, and 6-deoxy-L-aldohexoses as they are the mirror images of common monosaccharides. We exclude coverage of, for example, 3-ketohexoses or other deoxyhexoses as the D-enantiomers in those cases are just as rare as the L-isomers and coverage in this text would have little meaning.

V V Z AF AF AF AG AI AJ AK AK AL AL

1.1. Importance of L-Sugars

The rare but biologically widespread L-hexoses and their corresponding 6-deoxy counterparts play important roles in nature.1 Although not as prevalent as their enantiomers, the Dhexoses, numerous significant biomolecules contain L-sugars. The L-sugars are commercially available but normally very expensive (Table 1). Therefore, syntheses of L-sugars from common carbohydrates have gained much attention throughout the history of carbohydrate chemistry. Several different approaches to synthesis of L-sugars from D-sugars have been suggested, of which the most prominent and interesting routes

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Received: February 23, 2015

AM A

DOI: 10.1021/acs.chemrev.5b00104 Chem. Rev. XXXX, XXX, XXX−XXX

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Table 1. Prices for Unfunctionalized L-Sugars6 L-sugar L-idose

(aq. solution) L-altrose L-talose L-allose L-galactose a

price per 10 g ($, USD)

L-sugar

price per 10 g (USD)

methodologies is the main topic, the review has been divided after reaction or method type and each of these subsections can therefore be used as a minireview. 1.2. Occurrence of L-Hexoses and Their 6-Deoxy-L-hexoses

15 800

L-gulose

473

11 550 9975 9500 3400

L-mannose

415 420 40 6

L-glucose a L-fucose L-rhamnose

a

As mentioned before, L-sugars are found in numerous important natural products, e.g., alginates 1, a highly anionic polysaccharide from the cell wall of brown algae, and some bacterial species consist of D-mannuronic acid and L-guluronic acid in various compositions (Figure 2).7 The acid functionalities in alginates can bind metals, thereby forming gels for multiple purposes in, e.g., healthcare (wound gels) and food industry (beer foam). The well-known potent antitumor antibiotic Bleomycin A2 2 produced by Streptomyces verticillus contains an L-gulose unit that has been shown to be critical for its activity.8−11 The antibiotic nucleoside Adenomycin contains an L-gulosamine and is active against Mycobacterium smegmatis.12 L-Gulose is also present in the main polar lipid of the thermophilic archaeobacteria Thermoplasma acidophilum and A. volcanium.13 The naturally occurring antibiotic capuramycin 3 contains an Ltalofuranosuronyl amide nucleoside.14−16 The extracellular polysaccharide of the anaerobic bacteria Butyrivibrio f ibrisolvens strain CF3 has been shown to contain L-altrose.17 L-Altruronic acid has been found both in the capsular polysaccharide of the Gram-positive bacteria Aerococcus viridans var. homari (structure 4) and in the Gram-negative Proteus mirabilis O10, a human opportunistic pathogen that causes urinary tract infections.18,19 The rare L-mannose has been found in various cell-wall polysaccharides of different bacteria.20−23 The capsular polysaccharides S-88 (structure 5) and S-130 from Sphingomonas both contain L-mannose and are used as gelling agents in the industry.24 Furthermore, p-nitrophenyl α-L-mannopyranoside can be used to measure the activity of commercial naringinase.25 The rare L-galactose has been isolated from the marine octocoral as an α-L-galactosyl saponin detected in red seaweeds and in glycoproteins from soft corals.26−28 Furthermore, L-galactose is a component of side chain A of rhamnogalacturonan-II 6 found in pectins mainly extracted from citrus fruits.29 Littoralisone 7 contains an L-glucoside and has been isolated from Verbena littoralis, which traditionally has been used in folk medicine.30,31 Littoralisone is demonstrated to be the active compound for

6-Deoxy-L-hexoses.

will be discussed.2−5 Tedious protecting group manipulations and thereby lengthy routes are often unavoidable using this approach. However, in some cases, the early installation of orthogonal protecting groups can be a great advantage for glycosylations and hence in the long term save time and material. Furthermore, the synthesis of the L-sugars is mostly performed before any donor functionality is installed at the anomeric position, which makes the methods less attractive for oligosaccharide synthesis. Some milestones in the synthesis of L-hexoses are highlighted in Figure 1. These are methods where one chemical strategy was utilized to prepare all eight L-hexoses. These approaches all demonstrate the utility of a certain synthetic method but often result in synthesis of unprotected L-sugars. Therefore, further manipulation of the L-hexoses may be necessary to turn the unfunctionalized L-sugars into suitable donors bearing orthogonal protecting groups. The subject of this review is to give a full overview of the development of L-hexose synthesis from the very beginning of carbohydrate chemistry to the end of 2014. The main focus is on the development in synthesis over the past 50 years, where the most significant advances in the methodologies have appeared. Interest in L-hexoses has changed significantly over the years. Initially, their synthesis was part of elucidating the structures of sugars and how they are connected stereochemically. Later, method development became more important, and today, interest also covers the need for natural product synthesis, where L-hexoses have turned out to be more important and abundant than originally believed. As the development in

Figure 1. Chronological evolution of the synthesis of all eight L-hexoses (or suggested methods). B


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Figure 2. Occurrence of some L-sugars in nature.

bacterial pathogen Mycobacterium avium has also been reported to contain both a 6-deoxy-4-O-sulfonato-L-taloside and a 3,4-diO-methyl-L-rhamnoside.44 L-Rhamnose (6-deoxy-L-mannose) and L-fucose (6-deoxy-L-galactose) are the only common 6deoxy-L-sugars widely distributed in nature. As an example, Lrhamnose is found in pectin along with D-galacturonic acid as the repeating disaccharide,29 whereas L-fucose is a component of sialyl-Lewis X. The uncommon 6-deoxy-L-altrose has been found in various lipopolysaccharides of pathogenic strains from the genus Yersinia. For instance, Yersinia enterocolitica serovars O:1.2a,3 and O:2a,2b,3 have a trisaccharide repeating unit 16 solely consisting of 6-deoxy-L-altrose.45,46

increasing NGF-induced neurite outgrowth from PC12D cells. LIduronic acid plays an important role as a component of the repeating unit of several mammalian glycosaminoglycans (GAG), i.e., heparin, heparan sulfate, and dermatan sulfate 8.32−35 The antibiotic aminoglycoside neomycin B contains a 2,6-diamino-2,6-dideoxy-L-idose unite and exerts its antibacterial effect by binding to a specific RNA sequence.36 6-Deoxy-L-hexoses are another class of naturally occurring Lsugars. Apoptolidin A 9, as an example, is a glycomacrolide containing an L-quinovose (6-deoxy-L-glucose), and this compound has been reported to induce apoptosis in several cancer cell lines (Figure 3).37 Likewise, lipopolysaccharide 10 from the Gram-negative pathogen Yersinia pseudotuberculosis has been identified as the major virulent factor and includes the rare 38 L-quinovose. Zorbamycin 11 belongs to the bleomycin family of antitumor antibiotics and is a glycopeptide comprising a 6deoxy-L-gulose unit.39 The rare 6-deoxy-L-idose has been reported to occur in the diterpene glycoside 12 isolated from Aster spathulifolius maxim.40 The tetracyclic triterpene Datiscoside C 13 isolated from the plant Datisca glomerata has been reported to comprise a 6-deoxy-L-alloside.41 The lipopolysaccharide of the Gram-negative bacteria Actinobacillus actinomycetemcomitans serotype c is reported to consist of a repeating disaccharide only comprising 6-deoxy-L-talose 14. This bacterium is associated with, e.g., periodontitis and endocarditis.42,43 The sulfated glycopeptidolipid 15 from the opportunistic

1.3. Biomimetics

The L-hexoses have also been used extensively in biomimetics. For instance, L-galactose has been investigated as sialyl-Lewis X (SLex) and Lewis X (Lex) mimetics,47−49 and the mirror image of a blood-type trisaccharide has been prepared.50 Since it was discovered that some fucosyltransferases can tolerate L-fucose with C6 modifications, a variety of substrates for these enzymes have been developed for various purposes.51,52 For instance, a fluorescently labeled 6-amino-6-deoxy-L-galactose has been used to monitor the activity of the fucosyltransferases,53,54 and incorporation of an azide functionality at C6 on L-fucose has been used as a chemical reporter for imaging fucosylated glycoproteins.55,56 Another topic in which L-sugars are used successfully is neoglycorandomization of drugs like betulinic acid C


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Figure 3. Occurrence of some 6-deoxy-L-hexoses in nature.

Scheme 1. Synthesis of α-Acrose (a mixture of stereoisomeric sugars) from Condensation of Simple Building Blocks

and chlorambucil where the attachment of L-sugars has improved the activity.57 Likewise, substitution of the trisaccharide of digitoxin to an L-mannose unit has been shown to improve its anticancer activity.58 Similar structure−activity relationship studies (SAR) have been reported on the antibiotic neomycin family using various L-hexoses and their amino analogues.36,59−61

2. HISTORICAL ASPECTS The first synthesis of L-sugars dates back to the very early days of carbohydrate chemistry even before the area was well established and put into system by Fischer. In the 1880s, Loew and Fischer independently synthesized a sugar-like compound from condensation of formaldehyde 17.62,63 A similar product was obtained from a mild oxidation of glycerol 18 or from “acrolein bromide” 19 when treated with Ba(OH)2.64,65 The synthesized material showed physical and chemical properties of natural sugars, and it was furthermore shown to be fermented by beer yeast to give ethanol. Fischer named this synthetic sugar “αacrose” (Scheme 1). It was however not realized, at that time, that the compound contained a mixture of D- and L-sugars. At the same time Kiliani worked on arabinose isolated from wood, and he was able to determine that this sugar did not follow the general trend for sugar composition, i.e., arabinose was found to be a pentose with the formula C5H10O5.66,67 Most importantly was that Kiliani

showed that HCN could be added to arabinose 20, giving a C6sugar 21 (Scheme 1). Despite synthesizing several C6 analogues of arabinose it was Fischer, and not Kiliani, who realized that these sugars, besides having the same physical and chemical properties, turned the planar polarized light in the exact opposite direction than the known “natural” sugars. Additionally, Fischer found that only the “natural” sugars could be fermented, whereas the one prepared from arabinose was not. Later it was found that the same sugar remained when fermenting α-acrose (only the Dsugars were fermented). Using Kiliani’s chain prolongation method followed by hydrolysis and reduction, using sodium amalgam (Scheme 2)68 Fischer was able to prepare the hexoses from arabinose (fructose, glucose, and mannose).69 Analyzing these products using the reaction with phenyl hydrazine and D


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of a parent monosaccharide. It was furthermore found that oxidative degradation led to (−)-tataric acid and hence confirmed the stereochemical relation between these classes of natural products.76 The same compound was prepared by Fischer from D-glucose, and logically Fischer applied his D,L system for the nomenclature and not anti for antipode as suggested by Votoček. On this basis Fischer suggested the compound to be called D-isorhamnose, since it was prepared from D-glucose.77 As it is also the antipode of the isorhamnose described above, the stereochemistry could now finally be confirmed for the “natural” rhamnose as being L. From the other available L-sugar, fucose, the next sugar to be synthesized, via the 2-OH epimerization, was obviously 6-deoxy-L-talose or “epifucose” as named by Votoček, who defended his proposed nomenclature.78−81 It was however not until 1948 that pure and crystalline 6-deoxy-L-talose could be synthesized and reliable analytical data obtained. The pure compounds were used to confirm that the natural product sarmentoside-A contained 6deoxy-L-talose.82 As the nomenclature rules were more or less settled and commonly agreed on, the next decades were devoted to fill out holes in the hexose “family tree”. The leading research group in synthesizing L-hexoses was led by Reichstein, who in 1933 could communicate his synthesis of ascorbic acid.83 In parallel to this work Haworth and collaborators independently reported an almost identical synthesis.84 The original approach was a chain prolongation of xylosone 25, prepared using the chemistry developed by Fischer, and Kiliani’s chain extension procedure to give 26/27, followed by acidic hydrolysis to give the ascorbic acid 28 (Scheme 3).85,86 The synthesis of L-ascorbinic acid was further developed by Reichstein, and already in 1934 the now well-known “Reichstein Procedure”, starting from D-glucose, appeared.87,88

Scheme 2. Initial Work by Kiliani Made It Possible for Fischer To Solve the Relative Stereochemistry of Sugars

comparing them with the compounds known from the α-acrose synthesis as well as the derivatives obtained from the natural sugars glucose and mannose, Fischer could establish that the Kiliani transformation of arabinose gave the antipode of mannose, i.e., its enantiomer. With access to these L-sugars Fischer immediately realized that this was a parallel to the observation on tartrates made by Pasteur. This was further supported by mixing the two kinds of mannitols (reduced mannose) in equivalent amounts, which gave a new third “compound” that was optical inactive but had the same properties as the reduced α-acrose. On the basis of these initial results Fischer proposed to classify the sugars into two classes, D and L, well aware that optical rotation could not be used for the classification, but at that time D (dextro) was most commonly found for sugars isolated from natural sources.70,71 The synthesis of L-glucose 23 and L-mannose 24 from L-arabinose using the Kiliani approach was the method of choice for the next 6 decades, where especially L-glucose was investigated for its biological role as the enantiomer of the naturally abundant D-glucose. First, in 1947 Sowden and Fischer published an improved method using nitromethane as the nucleophile instead of cyanide; this simplified the purification and improved efficiency of the synthesis.72 With the basis for analyzing and synthesizing carbohydrates settled and acknowledgment of their asymmetry the organization of structures could begin. As the D-sugars were found to be more prevalent in nature than their L-counterparts, the latter initially received less attention. Two L-sugars, L-rhamnose and L-fucose, were however accessible from natural resources and therefore investigated in the early years but without knowing the C5 stereochemistry. Due to the deoxy functionality the sugars were called methyl pentoses. From L-rhamnose Fischer prepared the L-rhamnonic acid, which the corresponding lactone could epimerize upon treatment with pyridine at high temperature and pressure in an autoclave. Reduction with sodium amalgam gave the “isorhamnose” (6deoxy-L-glucose).73 With several groups working on isolating sugars and solving their stereochemistry some dispute about the nomenclature appeared. One example is the work by Votoček, who as an example isolated “isorhodeose” and found it to be the antipode of Fischer’s isorhamnose (6-deoxy-L-glucose).74,75 This led him to propose a nomenclature that used epi and anti to name isomers

Scheme 3. First Synthesis of L-Ascorbinic Acid from LXylosone

With the structure and stereochemistry settled of ascorbinic acid the interest in L-sugars increased, and especially Reichstein synthesized several L-hexoses the following years. L-Sorbose-4methyl ether was prepared from D-glucose 3-methyl ether via the corresponding sorbitol derivative and microbial oxidation, which was found to be much slower than in the ascorbinic acid synthesis (without the 4-O-methyl).89 In connection with studying the biological activity of L-ascorbinic acid the chain-extended Lrhamno-ascorbinic acid was synthesized from L-rhamnosone, which was obtained from L-rhamnose using Fischer’s method.90 In 1935 Reichstein and Steiger could synthesize the, at the time unknown, L-psicose. The approach was again microbial oxidation but this time of allitol. The structure and stereochemistry was proven from synthesizing the corresponding L-allosazone and comparing the two.91 The last of the eight 2-keto-hexoses to be synthesized was L-tagatose 31, which was achieved in 1937 via Lgalactose 30, which in the same paper was synthesized from Dgalactose 29 by head-to-tail inversion (see section 7.5, Scheme 4).92,93 E


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followed by a reduction of the lactone to give L-talose.99 An almost identical procedure was used by Glatthaar and Reichstein for their synthesis.100 With the structural assignment of the sugars solved and all the main aldo-hexoses and keto-hexoses synthesized, the focus changed to L-sugar derivatives found in nature and their synthesis as part of the structural assignment. A few examples have already been mentioned above. Reichstein remained the leading scientist in this field and synthesized the 2-deoxy-L-rhamnose and 2deoxy-L-fucose in 1944 as they were expected to be found in Nature.101,102 Another example of natural product identification is Reichstein’s synthesis of 3-O-methyl-6-deoxy-L-glucose, which could confirm the structure of thevetose.103 Most of the chemistry employed in the first five decades of carbohydrate chemistry was based on the methods developed by Kiliani and Fischer in the late 19th century, but eventually the methods gradually changed to involve protective group chemistry and resemble the approaches used today, as such methods are more mass and mole efficient. After the second world war the main focus in L-hexose synthesis became simply efficient synthesis of these compound, and this is obviously main topic in this review.

Scheme 4. Synthesis of L-Tagatose from of Isomerization LGalactose (which was synthesized by head-to-tail inversion of D-galactose)

The related L-tagato-methylose (6-deoxy-L-tagatose) was synthesized directly from the natural occurring L-fucose and represents the first compound to be prepared from the 6-deoxy2-keto hexoses.94 As studies of ascorbinic acid synthesis and its derivatives were the main interest, L-sorbomethylose (6-deoxy-Lsorbose) 34 was a desired key intermediate. Several approaches were investigated; one, at the time novel and elegant, involved a di-tosylation of monoacetone-L-sorbose 32 followed by monosubstitution by iodide to give 33; Raney Ni hydrogenolysis and deprotection of the tosylate and acetonide afforded the product 34.95 The intermediate mono-acetone-6-deoxy-sorbose could be oxidized to the sorbosonic acid, which after acidic deprotection directly gave the 6-deoxy-L-ascorbinic acid (Scheme 5).96

3. SYNTHESIS OF L-ALDOHEXOSES FROM CARBOHYDRATES Efficient entries to L-sugars from D-sugars have been developed by sequential epimerization strategies, as depicted in Figure 4. The classical method uses direct C5 epimerization of furanosides. Other C5 epimerizations from constrained pentoses, under Mitsunobu condition, via oxidation/reduction, base-catalyzed C5 epimerization of uronic acids, radical-induced C5 epimerization, and C5 epimerization from 5,6-anhydro sugars have also been disclosed. Furthermore, L-sugars have been synthesized from unsaturated pyranosides, by addition of nucleophiles to C5 aldehydes, by head-to-tail inversion, and starting from common L-lactones.

Scheme 5. Synthesis of 6-Deoxy-L-sorbose by Deoxygenation of Protected L-Sorbose

Using the same deoxygenation approach 5-deoxy-L-xylose was prepared, and the sugar chain prolonged using Kiliani’s method. This gave a mixture of the 6-deoxy-L-iduronic acid and the 6deoxy-L-guluronic acid, where only the latter could be isolated and reduced by sodium amalgam to the 6-deoxy-L-gulose.97Last, in the 6-deoxy series 6-deoxy-L-idose 38 was finally synthesized in 1946 but from a different approach. 1,2-Isopropylidene-Dglucofuranoside 35 was 6-O-tosylated, and the remaining hydroxyl groups blocked by a benzylidene protection gave 36. Substitution of the tosylation with iodide followed by elimination to 37 and hydrogenation gave the protected 6-deoxy-L-idose, which was deprotected under acidic conditions to give the 6deoxy-L-idose 38 (Scheme 6).98 The last of the L-aldohexoses to be synthesized and analyzed was L-talose. This was accomplished independently by two research groups in 1938. Fukunaka and Kubota used Dgalacturonic acid isolated from citrus pectin acid. The Dgalacuronic acid was reduced by sodium amalgam to give the L-galactonic acid, which was isomerized by heating it in pyridine

3.1. C5 Epimerizations

C5 epimerization of furanosides constitutes one of the earliest approaches for synthesizing L-sugars. The starting material can be synthesized from D-glucose or D-mannose. After C5 epimerization this leads to L-idose104−110 or L-gulose,111,112 respectively. For instance, acetate-mediated double substitution of 5,6-di-Osulfonyl D-gluco or D-manno-furanosides 40 and 45 leads, after deprotection of 41 and 45, to the corresponding L-idopyranoside and L-gulo-furanosides 42 and 46 (Scheme 7a and 7b).106,111 Further elaboration of the L-idofuranosides into other L -sugars, like L -talose and L-gulose, have also been reported.108,113,114 In a similar approach L-talose was prepared from D-allofuranoside derivative.115,116 The D-allofuranoside derivative was available from D-glucose. Constrained glucuronolactone 47 synthesized from D-glucose has been used to prepare L-iduronic acids via C5 inversion (Scheme 8).117−119 Triflation of 47 followed by a pivaloatemediated substitution installed the ido configuration in which the

Scheme 6. Synthesis of L-Idomethylose (6-deoxy-L-idose) from D-Glucose

F


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Figure 4. Schematic representation of regioselective epimerization of D-sugars.

Scheme 7. Direct C5 Epimerization for the Synthesis of L-Idose and L-Gulose

Scheme 8. Epimerization of Constrained Glucuronolactone

Scheme 9. Synthesis of L-Sugars under Mitsunobu Conditions

benzyloxy lactames 56a−c were observed for the gluco (56a) and galacto (56b) cases. The observation of two compounds from either O- or N-alkylation was explained by the anions A and B, where B presumably is favored (Scheme 9). Hydrolysis of the N-benzyloxy imine 55a−c to the lactones 57a−c followed by DIBAL-H reduction gave the desired L-sugars 58a−c in excellent yields. The same method has also been applied for the preparation of 2,3;5,6-di-O-isopropylidene-L-gulofuranose and 122 L-ribofuranose starting from D-mannono-1,4-lactone. Later, Ikegami and co-workers also explored conditions favoring the Nbenzyloxy lactames 56a−c for the synthesis of L-iminosugars.121 Preparation of several L-aldono-1,4-lactones from D-aldose perpivalates and peracetates have been described.123 Here, 5-O-

lactone 49 was opened to the methyl ester followed by O3 benzylation. Hydrolysis and C6 methyl ester formation produced the methyl L-idofuranonate 51. Removal of the isopropylidene afforded the methyl L-idopyranuronate 52.118 Ikegami and co-workers reported C5 epimerization under Mitsunobu conditions for the synthesis of L-idose, L-altrose, and L-gulose from aldono-1,5-lactones of D-glucose, D-galactose, and 120,121 D-mannose, respectively (Scheme 9). The D-aldono-1,5lactones 53a−c were effectively opened to the δ-hydroxyalkoxamates 54a−c using the BnONH 2 −Me 3 Al complex. A Mitsunobu reaction using triphenylphosphine and diethyl azodicarboxylate (DEAD) led to the cyclized N-benzyloxy imine 55a−c in good to excellent yields. Minor yields of NG


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Scheme 10. C5 Epimerization via Oxidation and Reduction Applied for Synthesis of the Disaccharide in Bleomycin

Scheme 11. Intramolecular Tishchenko Reaction for C5 Epimerization

Scheme 12. Synthesis of 1,6-Anhydro L-Idose via the 5,6-Anhydro Sugar

transformed, by ozonolysis, into the desired disaccharide 65 containing the L-gulose unit. Iadonisi and co-workers employed a highly stereoselective intramolecular Tishchenko reaction using tBuOSmI2 on the hexo-5-uloses 67a−c obtained by Swern oxidation of 66a−c to invert C5 (Scheme 11).128 The reaction was applied for the synthesis of L-idose and L-altrose from D-glucose and D-galactose, respectively, via subsequent lactonization and reduction. When the same conditions were applied on the manno derivative C5 epimerization was however not observed. Base-catalyzed epimerization of D-uronic acids has been investigated as a direct method for preparing L-uronic acids.129−131 Unfortunately, a mixture of the D- and L-epimer is usually obtained, limiting the practicality. Radical-induced C5 epimerization of D-uronic acids has also been explored, especially for preparation of L-iduronic acid.132−135 Normally the methyl Duronate is treated with N-bromosuccinimide (NBS) to install a C5 bromide α to the methyl ester. Subsequent treatment with tributyltin hydride produces the methyl L-uronate in moderate yield along with various amounts of the D-uronate.132−134 Several examples of opening the 5,6-epoxide of D-furanosides to give the corresponding L-furanosides have been observed and used for the preparation of L-idose.136−143 Generally, the 5,6-diol is sulfonated followed by selective substitution of the primary C6 sulfonate group by acetate. Treatment with a sterically hindered base gives the 5,6-anhydro furanosides that can be reacted with any given O-nucleophile or aqueous acid to give the desired Lfuranoside. Hung explored a slightly modified route (Scheme 12) to synthesize 1,6-anhydro L-idose as an acceptor144−146 for the preparation of various biological relevant compounds.147−149 D-

mesyl-2,3,4,6-tetra-O-pivaloyl D-aldononitrile were refluxed under acidic condition to give the L-aldono-1,4-lactones. The inversion at C5 was believed to occur from a participating neighboring pivaloate followed by ring closure of the hydrolyzed anomeric nitrile. From this strategy the L-idono-1,4-lactone, the L-gulono-1,4-lactone, and the L-altrono-1,4-lactone were prepared. Lunau and Meier also explored C5 epimerization under Mitsunobu conditions of acyclic dithioacetals. The synthesis started from D-galactose and afforded the corresponding Laltrose.124 Although Mitsunobu inversion gave moderate to good yield (71%) the installation of the anomeric dithioacetal only gave moderate yield (58%). Oxidation of O5 followed by stereoselective reduction has also been employed for the synthesis of L-sugars. An early example by Kuzuhara and Fletcher converted 2,3,4,6-tetra-O-benzyl-N,Ndimethyl-D-gluconamide to its C5 epimer by oxidation and reduction to give the 2,3,4,6-tetra-O-benzyl-N,N-dimethyl-Lidonamide. The reduction was reported to give a low yield and a mixture of the D- and L-epimer. Subsequently, the amide was reduced to L-idose.125 Kobayashi and co-workers applied the oxidation/reduction method for the synthesis of L-gulose and the disaccharide of bleomycin 2.126,127 Swern oxidation of 60, synthesized by Wittig methylenation of lactol 59 followed by stereoselective reduction, resulted in the inverted alcohol 61 in good yield (Scheme 10). It was shown that L-selectride (LiBH(sec-Bu)3) was crucial for inducing the right stereoselectivity since both NaBH4 and DIBAL-H gave the undesired 127 D-manno-epimer. Protecting group manipulation followed by glycosylation with 63 gave compound 64, which could then be H


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Glucofuranoside 70 was selectively benzoylated followed by a C5 mesylation to give 71. Treatment with KOtBu followed by aqueous acid gave 1,6-anhydro L-idose 73 via the 5,6-anhydro Lfuranoside 72. Selective benzoylation afforded 74.

It was found that the selectivity depended not only on the borane reagent but also on the protecting group pattern, at least in the synthesis of L-gulose. Thus, exocyclic alkene 84 was prepared by treating 6-deoxy-6-iodo mannoside 83 with silver fluoride in pyridine (Scheme 14). Hydroboration catalyzed by Wilkinson’s catalyst was found to proceed smoothly using catecholborane followed by oxidative workup giving a selectivity of 50:1 in 82% yield of the desired L-guloside 85. Wei and co-workers investigated the epoxidation of 4deoxypentenosides followed by nucleophilic opening of the 4,5-anhydro sugars for the synthesis of L-sugars. 4-Deoxypentenoside 87α was produced from 86 by a two-step oxidation− decarboxylation elimination sequence (Scheme 15a).161,162 Epoxidation was accomplished under optimized conditions with dimethyldioxirane (DMDO), giving 88 as the major isomer (β/α 10:1) from the α-glycoside 87α (Scheme 15a). Epoxide 91 was formed as the major isomer (β/α 1:10) from the β-glycoside 87β (Scheme 15b). Ring opening could be accomplished with various nucleophiles, which upon further manipulation could be turned into the L-sugars. For instance, trans opening of the epoxide was preferred when 88 was treated with PhMe2SiCH2MgCl, giving 89, which could then be transformed into L-altroside 90 by a Fleming−Tamao oxidation (Scheme 15a).161 On the other hand, syn opening of the epoxide was preferred when 91 was treated with 2-furylzinc bromide, providing 92, presumably through an oxocarbenium ion intermediate. Ozonolysis of the furyl functionality resulted in 162 L-iduronic acid 93 (Scheme 15b). The method has also been used for synthesizing L-glycals and the mirror image of a bloodtype trisaccharide.50,163 Hung and co-workers explored the synthesis of various Lhexoses by stereoselective exocyclic hydroboration followed by regioselective epimerizations. Synthesis of the exocyclic alkene 96 was accomplished by ketal migration (5,6-OH → 3,5-OH) and substitution to give the primary bromide 95, which was eliminated by 1,8-diazabicyclo[5.4.0]undec7-ene (DBU) treatment (Scheme 16).164−166 Stereoselective hydroboration and oxidative workup gave the C5-epimerized L-idofuranoside 97. Acidic hydrolysis afforded the 1,6-anhydro L-idopyranose 98,167,168 which then functioned as the starting point for several other 1,6-anhydro L-glycopyranoses.165 Treatment with TFA/ Ac2O gave the fully peracetylated L-idopyranose 99. Regioselective O2 triflation followed by benzoylation afforded 100, which upon NaNO2 treatment produced 1,6-anhydro Lgulopyranose 101. Regioselective O3 benzylation was accomplished by TMSOTf-catalyzed Et3SiH reductive etherification of the per-trimethylsilylated 98, resulting in compound 102. Double triflation and NaNO2 substitution afforded the 1,6anhydro L-allopyranose 103, while regioselective O2 benzoylation followed by O4 triflation gave 1,6-anhydro L-altropyranose 105 after NaNO2 treatment.165 These compounds were used for synthesizing various biologically potent biomolecules containing 165 L-hexoses.

3.2. L-Sugars from Unsaturated Carbohydrates

Stereoselective hydroboration of exocyclic alkenes constitutes an attractive method for C5 epimerizing D -sugars to the corresponding L-sugars. These exocyclic alkenes (75, 78, 81) are easily prepared from the corresponding 6-deoxyhalo derivative by treatment with silver fluoride in pyridine. With the advent of the hydroboration methodology it was perceived to be useful here and obviously investigated.150,151 Unfortunately, addition of diborane to an exocyclic alkene only gave a 1:2.5 mixture of the methyl D-glucoside 77 and methyl L-idoside 76 (or methyl D-mannoside 80 and methyl L-guloside 79, 1:2), slightly favoring the L-isomer.152,153 Yields and stereoselectivities ranging from 11:1 to 1:8 (L-ido/D-glu) have been reported for the synthesis of L-idose as a monomer and dimers.36,154−159 Furthermore, it is a problem that the stereoselectivity and yield were dependent on the specific protecting group pattern which limits the practicality of this method. Other borane reagents have also been investigated, and it was found that 9-BBN gave good selectivity (9:1 L-ido(76)/D-glu(77)).157,160 A study on the effect of the stereochemistry on the pyranoside and the amount of borane employed revealed that the stereoselectivity could be increased for the preparation of methyl L-idoside 76 when 10 equiv of BH3·THF was used (Scheme 13).159 Interestingly, the Scheme 13. Hydroboration of Various Exocyclic Alkenes

stereoselectivity was much lower when α-5-enomannoside 78 was used (Scheme 13). In the case of the hydroboration of α-5enogalactoside 81 only the methyl D-galactoside 82 isomer was observed (Scheme 13). Unfortunately no explanation was given, but it appears that an axial α- or γ-substituent next to the alkene hampers attack of the borane from the top face (Re face). To increase the stereoselectivity of the hydroboration, Boger and Honda, in their total synthesis of bleomycin 2, explored addition of various hydroboration agents under metal catalysis.9

Scheme 14. Metal-Catalyzed Hydroboration of Exocyclic Alkenes for the Synthesis of L-Guloside

I


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Scheme 15. Synthesis of L-Hexoses from 4-Deoxypentenosides

Scheme 16. Synthesis of Various L-Hexoses via Exocyclic Hydroboration Followed by Regioselective Epimerization

Scheme 17. Synthesis of L-Altrose and L-Mannose

accomplished by oxidation with Cornforth’s reagent (pyridinium dichromate, PDC) and acetate enol ether formation of Lidofuranose 109. Palladium-catalyzed hydrogenation installed the manno configuration (110), which upon transesterification and acidic hydrolysis released the L-mannopyranose. Δ4-Uronates (α,β-unsaturated uronic acids) are easily prepared by basic treatment of O4 acyl-protected uronic acid and can be converted to L-iduronic acids and L-altruronic

L-Idofuranose 106 can be used as a starting material for the synthesis of L-mannose and L-altrose and was synthesized from 97 (see preparation in Scheme 16) by ketal migration (see Scheme 17).169 Epimerization of C4 to give L-altrofuranose 108 was affected first by DAST/pyridine-mediated elimination. Next, stereoselective endocyclic hydroboration and oxidative workup via enol ether 107 resulted in 108. Acidic hydrolysis produced the unprotected L-altropyranose. Synthesis of L-mannose was

J


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Scheme 18. Synthesis of L-Iduronic Acid from Δ4-Uronates

Scheme 19. Synthesis of L-Iduronic Acid Donors via Chelate-Controlled Cyanation

Scheme 20. Stereoselective Addition of (PhS)3CLi to C5 Aaldehyde

acids.170,171 Treatment of Δ4-uronates 111 and 112 with NBS in wet THF afforded the trans-diaxial bromohydrins 115 and 116 as the major products. These were transformed into the epoxide 117 and 118 by reaction with Ag2O (Scheme 18). Lewis-acidcatalyzed rearrangement of the epoxide to the ketone with concurrent C5 epimerization afforded the 4-oxo L-uronic acids 119 and 120. In the case of 1,1,3,3-tetraisopropylsiloxane-1,3diyl (TIPDS) protected 119 reduction under Luche’s condition (NaBH4/CeCl3)172 provided L-iduronic acid 121 after acetylation. When the benzyl-protected compound 120 was reduced under similar conditions, L-altruronic acid 92 was isolated after acetylation. The opposite selectivity observed by having different protecting groups could be explained by the influence of the TIPDS group to lock the conformation of 119 in a 4C1, whereas the benzyl-protected 90 was found in its 1C4 conformation. Therefore, reduction arose in both cases from an axial hydride attack.

rare L-ribose, which had to be synthesized from L-arabinose through its L-arabinal.174 In a similar method L-arabinose was converted to a mixture of L-glucose and L-mannose as described in the Historical Aspects above.175 More easily available aldehydes have been employed as starting material for synthesizing L-sugars. A well-studied method is the addition of nucleophiles to the C5 aldehyde that can be obtained by periodate cleavage of D-glucofuranosides (D-xylo-pentodialdo1,4-furanoside) which may afford the L-idofuranosides depending on the stereoselectivity of the reaction. This method has been used to prepare a mixture of unlabeled and 13C6-labeled Dglucose and L-idose.176−178 Gardiner and co-workers optimized the addition of KCN, employing MgCl2, giving 95% yield with a stereomeric excess of 90% for compound 124 (Scheme 19a).179 Nitrile hydration and regioselective acetylation provided the amide L-idopyranose 125. Treatment with amyl nitrite converted the amide to the acid, which could then be methylated to methyl 180 L-iduronate 126. The donor derivatives derived from 126 have been used in the synthesis of heparin-related dodecasaccharide (repeating GlcNAc-IdoA).181 Seeberger and co-workers have shown that iduronic acid donors 130 can be synthesized by chelate-controlled cyanation using TMSCN in the presence of MgBr2·OEt2 to acyclic aldehyde 127 derived from D-xylose (Scheme 19b).182,183 Subsequently, the nitrile was hydrolyzed in the presence of methanol to give methyl ester 129. Cyclization to

3.3. Addition to Carbohydrate Aldehydes

Homologation of short-chained carbohydrates has been used to synthesize L-sugars. An early report by Austin and Humoller described the addition of Ca(CN)2 to L-ribose, followed by hydrolysis, which gave a mixture of L-allono- and L-altrono-1,4lactone in 40% and 44% yield, respectively.173 Reduction with sodium amalgam in aqueous sulfuric acid yielded the L-allose (77%) and L-altrose (51%), respectively. The drawback of the procedure was the unselective cyanide addition and the use of the K


Chemical Reviews

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Scheme 21. Homologation via Addition of 2-(Trimethylsilyl)thiazole for the Synthesis of L-Gulose Derivative 139

Scheme 22. Homologation via Mukaiyama-Type Aldol Addition

Figure 5. Schematic presentation of the inversion of D-sugars into L-sugars by the head-to-tail method.

underwent addition with 2-(trimethylsilyl)thiazole to provide the L-gulo configuration 136 in a 95:5 diastereomeric ratio. The aldehyde-L-xylose diacetonide 135 was prepared in two steps through the corresponding diethyl dithioacetal 134. O2 benzylation followed by cleavage of the thiazole ring to the formyl group was accomplished in three steps affording 138 in which the isopropylidene was hydrolyzed, and peracetylation gave the fully protected L-gulose 139 in 70% from 137. Furthermore, epimerization of the free hydroxyl group in 136 by Swern oxidation and stereoselective reduction produced the compound with L-ido configuration. The L-idose could be liberated by the same thiazole cleavage sequence.189 Sowden and Fischer explored the addition of nitromethane to 2,4-di-O-benzylidene-L-xylose only to give 6-deoxy-6-nitro-Dsorbitol.190−192 Hydrolysis of the benzylidene protecting group was performed with dilute sulfuric acid. Conversion of the nitro group to the aldehyde by a Nef reaction was performed by the addition of the sodium salt of 6-deoxy-6-nitro-D-sorbitol to moderately concentrated sulfuric acid, which resulted in formation of L-gulose. The same method was applied for the synthesis of L-glucose and L-mannose starting from L-arabinose.72 Chain elongation with larger chain fragments also has been employed in the synthesis of L-hexoses. Seeberger and coworkers relied on the selective Mukaiyama-type aldol reaction that unified a silyl enol ether 141 and a dithioacetal-containing

give the thio L-ido donor 130 was accomplished by NIS-mediated cyclization. Bonnaffé and co-workers investigated numerous nucleophiles and discovered that addition of tris(phenylthio)methyllithium, (PhS)3CLi, exclusively gave the L-ido-configured thioorthoester 131 in high yield with no D-glucose product detected (Scheme 20).184−186 Cleavage of the thioorthoester was performed by exposure of the thioorthoester functionality to CuCl2/CuO/ MeOH to afford the furanose methyl ester 132, which could be converted into the pyranose 133 by TFA treatment. The method has been used to synthesize heparan sulfate fragments and iduronic acid building blocks for modular assembly of glycosaminoglycans.186,187 As mentioned in the Introduction chain elongation at the anomeric center of L-arabinose constitutes a method for the preparation of L -glucose. 188 To unprotected arabinose (phenyldimethylsilyl)methylmagnesium chloride (PhMe2SiCH2MgCl) was added which only resulted in one stereoisomer via 2,3-syn addition. This new anomeric center, masked as a C−Si bond, could be liberated by a Fleming−Tamao oxidation followed by oxidation of the resulting alcohol to the aldehyde, thereby giving rise to the L-glucose after debenzylation. Homologation of L-xylose by addition of 2-(trimethylsilyl)thiazole has been explored by Dondoni and co-workers (Scheme 21).189 It was found that aldehyde-L-xylose diacetonide 135 L


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Scheme 23. Synthesis of L-Glucose by the Oxidation/Reduction Method

Scheme 24. Synthesis of L-Sugars by a Direct Head-to-Tail Inversion

aldehyde 140 derived from L-arabinose (Scheme 22).193 A 1:1:1 mixture of D-glucuronic acid 142, L-iduronic acid 143, and Laltruronic acid 144 was obtained when BF3·OEt2 was used. LGalacturonic acid was not detected. Conversion of the compounds to their hexopyranosides was accomplished by O4 Fmoc protection and O5 desilylation followed by NIS-promoted cyclization to give the thioacetals 148−150. Application of other Lewis acids changed the selectivity in favor of the D-glucuronic acid.182,193

Swern conditions, but sulfur-containing byproducts compromised the following reduction. Functional group manipulation followed by Pt-catalyzed oxidation gave D-gulofuranosiduronic acid 153. Hydrolysis of 153 via 154 followed by Raney Nicatalyzed reduction resulted in the L-glucono-1,5-lactone 155 which was reduced to L-glucose. The conversion of D-glucose to L-gulose by the head-to-tail inversion has been carried out by Hecht and co-workers. The transformation was initiated by a Corey−Kim oxidation followed by N,N-dimethylhydrazone formation to give 157 (Scheme 24a).197 Next, deacetylation followed by N,N-dimethylhydrazone lactol reduction afforded the L-gulo configuration. Removal of the N,N-dimethylhydrazone was accomplished in three steps. First, N-methylation was followed by anion exchange to the tosylate 158, and then heating in the presence of TsOH afforded 1,6-anhydro L-gulose 159. A different route, but conceptually the same head-to-tail inversion method, for the synthesis of L-gulose has been reported starting from D-glucono-1,4-lactone.198 The galactitol derivative 161 was synthesized from 160 by removal of the isopropylidene groups, reduction of the lactol, and peracetylation of the remaining alcohols. Debenzylation using Adam’s catalyst gave 162, followed by a Dess−Martin oxidation of the “former” O6. Subsequent deacetylation and isopropylidenation afforded the diacetone-L-galactose 163 (Scheme 24b).199 This methodology has also been used to convert D-galactose to Lgalactose having a C6 aldehyde masked as its dithioacetal.200,201 The advantage of this approach is that the dithioacetal group can be installed at the anomeric position from the unprotected sugar followed by regioselective protection of the primary alcohol. Subsequent protection of remaining hydroxyl group, deprotection of the primary alcohol, oxidation, and further transformations afford L-galactose.

3.4. Head-to-Tail Inversion

Synthesis of L-sugars can also be performed by the head-to-tail inversion method. Since four D-hexoses have the 2-OH right in the Fischer projection, exchange of oxidation state between C1 and C6 will turn C2 into the new C5 with an L-configuration. Reduction of the anomeric C1 to an alcohol and oxidation of C6 to an aldehyde will, therefore, in the case of D-glucose, Dgalactose, D-allose, and D-gulose generate L-gulose, L-galactose, Lallose, and L-glucose, respectively. An early example utilized the available D-galacturonic acid, prepared from citrus pectic acid, for the synthesis of Lgalactose.194 The anomeric aldehyde was reduced followed by reduction of the resulting L-galactonic acid to L-galactose. The Lgalactonic acid was also prepared from galactitol also known as dulcitol. Furthermore, D-glucose has been converted to Lglucurone, which subsequently was transformed into L-glucose by a head-to-tail approach.195 Preparation of L-glucose was accomplished from D-glucose via D-gulofuranose. D-Gulofuranoside 152 was synthesized by oxidizing diacetone-D-glucose 94 to its enol acetate 151 using catalytic ruthenium tetroxide and potassium periodate followed by acetylation (Scheme 23).196 Enol acetate 151 was reduced quantitatively to D-gulofuranoside 152 by palladium-catalyzed hydrogenolysis. Enol acetate 151 could also be synthesized under M


Chemical Reviews

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Scheme 25. Head-to-Tail Inversion by C1 Addition Followed by C6 Decarboxylation

Scheme 26. Head-to-Tail Inversion by Wittig Elongation

Scheme 27. Synthesis L-Glucose by Head-to-Tail Inversion

orthogonal protected L-glucose acetate 169 as an anomeric mixture. Carbon extension by a Wittig reaction has been applied for the preparation L-galactose 173 and L-mannose 177 starting from Dgalactose or L-arabinose, respectively. In the case of the synthesis of L-galactose the C6 aldehyde 170 was extended by reaction with the ylide formed from methyltriphenylphosphonium bromide to produce terminal alkene 171 (Scheme 26a).205 Subsequent removal of the acetonides and reduction of the anomeric hemiacetal gave 172, and ozonolysis of the terminal alkene afforded L-galactose 173. Extension at the anomeric position of L-arabinose 174 with the same Wittig ylide has also been explored by Crich and Li (Scheme 26b).206 This alkene 175 was subjected to Sharpless dihydroxylation, resulting in a mixture of L-mannitol 176 and L-gulitol. Subsequent oxidation under Swern condition and removal of the isopropylidene group

A slightly different method of the head-to-tail inversion is addition of C-nucleophiles to C1 followed by C6 oxidation to the acid/ester. Subsequent decarboxylation of the C6 α-oxy carboxylic acid leads to a new hemiacetal with an inverted stereochemistry at the “new” C5. This method was first explored by Shiozaki, and later by van Boom and collaborators, for the synthesis of L-glucose from D-glucono-1,5-lactone.188,202 Recently, the concept has been rediscovered by Li and co-workers, who synthesized L-glucose, L-mannose, and L-galactose from Dglucose.203,204 Here, the β-C-glycoside 165 was prepared from Dglucosyl acetate 164 using Co(CO)8-catalyzed silyloxymethylation (Scheme 25). Exchange of the triethylsilyl protection group to the more stable tert-butyldiphenylsilyl group followed by benzylidene opening gave the primary alcohol 167. Oxidation mediated by TEMPO/BAIB produced the acid 168, which under palladium catalysis could be decarboxylated, resulting in the N


Chemical Reviews

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Scheme 28. Head-to-Tail Inversion Induced by the Pummerer Rearrangement

Scheme 29. L-Sugars from Common L-Lactones

3.5. From Common L-Lactones

afforded L-mannose derivative 177. The L-mannose derivative was converted to its thiomannoside and used in exploring βselective formation of L-rhamnosides (see Scheme 99). Large-scale synthesis of L-glucose from D-glucose using the extension of the reducing end followed by oxidative cleavage at the non-reducing end has been described.207,208 The easily available D-glucoheptonate 178, synthesized by cyanide addition to D-glucose,209 was isopropylidenated to give fully protected methyl ester 179 in 54% yield (Scheme 27).207 Subsequent regioselective removal of the terminal acetonide was accomplished in moderate yield. Reduction of the methyl ester 180 gave the triol 181 in 93% yield; the obtained vicinal diols were cleaved oxidatively by a silica-gel-supported periodate to form the diacetonide L-glucose 182, which could be deprotected to give L-glucose quantitatively. Head-to-tail inversion has also been completed taking advantage of a Pummerer rearrangement.210 Installation of a thioether at C6 can be carried out by reaction of the 6-OH with diphenyl disulfide in the presence of tributylphosphine. Reduction of the 6-deoxy-6-thiophenyl D-glucose 183 followed by peracetylation gave thioether 184, which could be oxidized to the sulfoxide 185 (Scheme 28). Here, the Pummerer rearrangement was induced by refluxing the compound with acetic anhydride in the presence of NaOAc, giving the thioacetal 186 as a C1 epimeric mixture. Treatment with a catalytic amount of NaOMe provided the deprotected L-gulose. The dithioacetal of 186 could be synthesized by reaction of 186 with thiophenol and BF3·OEt2. Conversion of D-galactose to L-galactose was also described using the same method. Starting from commercially available D-glucono-1,4-lactone Lipták and co-workers synthesized L-glucose by a head-to-tail inversion.211

A few L-lactones are commercially available at a reasonable cost and can be turned into highly valuable L-sugars. For instance, peracetylated L-galactose has been prepared by reduction of Lgalactono-1,4-lactone 187 followed by peracetylation (Scheme 29a).49,54,212,213 The starting material, L-galactono-1,4-lactone, is a byproduct from the sugar beet industry and is therefore inexpensive and commercially available.214 L-Ascorbic acid can be transformed to L-gulono-1,4-lactone and therefore constitutes a potential starting material for the synthesis of L-gulose. Palladium-catalyzed hydrogenation of L-ascorbic acid 28 resulted in unprotected L-gulono-1,4-lactone, which could be isopropylidenated to give 190 (Scheme 29b).215 Reduction of the lactone followed by acid treatment converted the lactol to the 1,6anhydro L-gulose 191. This compound was used in the synthesis of alginate oligosaccharide. The Codée and van der Marel group utilized the same L-gulono-1,4-lactone as starting material for the synthesis of L-guluronic acid alginates.216 L-Gulono-1,4-lactone 192 was converted to the isopropylidenated lactol 193 in two steps followed by hydrolysis and peracetylation (Scheme 29c). Next, the peracetylated L-gulose was transformed into its anomeric bromide followed by treatment with PhSH under phase-transfer conditions giving the thio-L-guloside 194. This served as a starting material for the preparation of armed donors and the methyl thio-L-guloronate. L-Talonic lactone has also been prepared starting from ascorbic acid by hydrogenation of the double bond using a rhodium catalyst.217 From the natural occurring quebrachitol (2-O-methyl-Linositol) Ogawa and collaborators showed that a lactone could be prepared by a regioselective Bayer−Villiger reaction.218 This lactone was used to prepare an L-galactose derivative. O


Chemical Reviews

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3.6. Rearrangement of L-Hexoses

was applied by Bols and co-workers for the preparation of methyl

́ to undergo epimerization Aldoses have been shown by Bilik reaction catalyzed by molybdate ions under acidic conditions.219,220 The reaction leads to an equilibrium of epimeric aldoses in which the predominant epimer is the one which possesses a trans relationship of the hydroxyl groups at C2 and C3 (D-manno/D-gluco 25:75). This method has been utilized for the epimerization of L-mannose to L-glucose.221 L-Glucose could be crystallized in 66% yield after a 2-fold epimerization using molybdic acid in water. The mechanism of the epimerization was deduced by using labeled and deoxygenated compound, and it was found that a dimolybdate-aldose complex 195 was formed (Scheme 30).222 In this complex, rearrangement can occur

L-galactoside 202 and methyl L-mannoside 205 (Scheme 31a and 229

31b). Initially, the free 4-OH (198 or 203) was silylated using diethylsilane catalyzed by iridium followed by C−H activation with the same catalyst to afford oxasilolane 200 and 204.230 Subsequent Fleming−Tamao oxidation and acetylation produced the methyl L-galactoside 202 and methyl L-mannoside 205 in excellent yield over four steps (67% and 82%).231−233 As described in this review, various methods have been explored for the preparation of L-hexoses. These methods mostly address the synthesis of unprotected sugars. However, before these sugars can be utilized in oligosaccharide and glycoconjugate synthesis extensive functionalization is often necessary. Therefore, it is highly desirable to be able to synthesize all eight Lhexoses with orthogonal protecting groups and an anomeric thio donor functionality.234 In order to synthesize all eight L-sugars via the C−H activation procedure, access to all eight 6-deoxy-Lhexoses as their thio hexopyranosides was achieved by Bols and co-workers from the inexpensive and commercially available Lfucose and L-rhamnose (see Schemes 85−87).235 With all 6deoxy-L-hexoses in hand the four-step C−H sequence was used to prepare all eight L-hexoses as their thioglycoside 206−214 (Table 2).234 It was found that the initial Fleming−Tamao oxidation (conditions A: 30% H2O2, KHCO3) needed to be optimized since the protodesilylated compound (acetylated 6deoxy-L-sugar) was a major byproduct. This could be avoided by removing all protic source by changing to an urea-hydrogen peroxide complex (UHP) in DMF and lowering the reaction time to avoid oxidation of the anomeric thioacetal (conditions B and C: UHP, KHCO3, or K2CO3, 3 or 1 h). With the optimized condition in hand (condition C) the remaining L-hexoses 206− 214 could be prepared in good to excellent yield via the four-step C−H activation procedure (Table 2). The four-step procedure was also applicable on a gram scale, giving the thiomannopyranoside 206 in 53% yield over four steps (85% per step), thereby emphasizing the utility and scalability of the method.234 The protodesilylated product can be recycled in the C−H activation procedure after deacetylation, thus limiting the waste of precious building blocks. Taking into account that the byproduct can be reused in the C−H activation procedure

Scheme 30. Mechanism for the Epimerization of Aldoses by Dimolybdate

through a transition state 196. Bond formation between C1 and C3 produces the C2 epimer 197, while bond formation between C2 and C3 regenerates the starting aldose. Besides catalyzing the bond breaking and formation, the molybdate complex assures the stereospecificity of the rearrangement. Furthermore, microwave irradiation has been shown to accelerate the reaction markedly from hours to minutes with improved yield.223 3.7. C−H Activation of 6-Deoxy-L-sugars

The only two easily available 6-deoxy-L-sugars (L-rhamnose and L-fucose) constitute an alternative entrance to the preparation of 224 L-hexoses via C−H activation of the primary C6−H bond. However, activation of the inherently unreactive primary C−H bond in the presence of multiple functional groups that are found in carbohydrates is a challenge. Recently, Simmons and Hartwig reported a procedure for site-selective functionalization of primary methyl groups that requires an iridium catalyst and a free γ-hydroxyl as a directing group.225−228 This methodology

Scheme 31. Four-Step C−H Activation Sequence for the Synthesis of Methyl L-Mannoside and Methyl L-Galactoside

P


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Table 2. Synthesis of All Eight Thio L-Hexopyranosides via the Four-Step C−H Activation Sequence

a Conditions: (A) 30% H2O2 (10 equiv), KHCO3 (2.5 equiv), THF/MeOH (1:1), 50 °C, 15−18 h. (B) UHP (30 equiv), KHCO3 (5 equiv), KF (3 equiv), DMF, 50 °C, 3 h. (C) condition B, with K2CO3 as the base and 1 h reaction time. bIsolated product after column chromatography on silica gel. cod = 1,5-cyclooctadiene, DMAP = 4-dimethylaminopyridine, Me4Phen = 3,4,7,8-tetramethyl-1,10-phenanthroline, UHP = urea-hydrogen peroxide.

products via catalyst-controlled induction, and (3) use of small quantities of the catalyst. One the other hand, the de novo approaches are not always stereoselective, lowering the yield and requiring (often tedious) purification. Furthermore, synthesis of L-sugars by de novo methods often gives rise to unprotected sugars that require subsequent functionalization for use in glycosylations.

after 4-O-deacetylation, the protocol results in a yield of 84% (over four steps!) based on recovered starting material. The CH activation is selective for the methyl group in the γ-position and can be performed on densely functionalized thioglycosides, which are one of the most important types of glycosyl donors in glycosylation. The method distinguishes itself from other preparation methods for L-sugars in its ability to produce the Lhexoses as their thioglycosyl donors ready for glycosylation.

4.1. Iterative Asymmetric Epoxidation

In the seminal work by Masamune, Sharpless, and co-workers all eight L-hexoses were synthesized through iterative asymmetric epoxidation of allylic alcohols.236,237 One achiral allylic alcohol, (E)-4-diphenylmethoxybut-2-en-1-ol 215 was used to synthesize all eight L-sugars. Sharpless asymmetric epoxidation of 215 was performed with Ti(OiPr)4, (+)-tartrate, and tert-butyl hydroperoxide to give epoxide 216. The following Payne rearrangement and nucleophilic opening resulted in the thioether 218. Here, NaOH is shifting the equilibrium between the internal

4. DE NOVO SYNTHESES OF L-ALDOHEXOSES Synthesis of L-sugars by de novo approaches has attracted much attention since Masamune, Sharpless, and co-workers (1983) prepared all eight L-hexoses through asymmetric epoxidation.236,237 Several other approaches have been disclosed which the will be described here.4,238 The advantages of de novo synthesis are (1) use of inexpensive and available starting materials, (2) conversion of achiral substrates into chiral Q


Chemical Reviews

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Scheme 32. Synthesis of Key Intermediate 221

Scheme 33. Synthesis of Four L-Hexose Precursors 230−233

Scheme 34. Synthesis of All Eight L-Hexoses

R


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electron demand in which the reaction primarily occurs between the electron-rich diene (HOMOdiene) and the electron-deficient dienophile (LUMOdienophile). Cycloaddition between electrondeficient α,β-unsaturated carbonyl compounds and alkenes is considered to be predominantly controlled by an inverse electron demand (LUMOdiene−HOMOdienophile interaction). Another obstacle in the asymmetric HDA cycloaddition is the control of stereoselectivity. Control of the absolute configuration of the product is obtained by (1) use of a diene or dienophile with a chiral auxiliary or (2) use of a chiral catalyst. The first reported synthesis of fully oxygenated L-hexoses was achieved by Danishefsky and Bednarski. Here, Danishefsky’s diene 237 was reacted with benzaldehyde catalyzed by the Lewis acid Eu(hfc)3 (hfc = 3-(heptafluoropropylhydroxymethylene)camphorate) giving silyl enol ether 238 and its enantiomer in a 25:1 mixture (Scheme 35).242 Further treatment with TFA afforded the enone 239. Installation of an α-hydroxy functionality was performed by reaction of enone 239 with manganese(III) acetate producing 240. Subsequent Luche reduction172 and acetylation gave the glucal 241, which could be dihydroxylated under Upjohn conditions (OsO4/NMO).243 Conversion of the phenyl group in 242 to a hydroxymethylene was accomplished by ozonolysis followed by oxidative treatment with hydrogen peroxide. Reduction of the L-glucuronic acid was achieved with borane and acetylation, resulting in the isolation of peracetylated Lglucose 243. Later, an improved catalyst consisting of a chiral (salen)chromium(III) complex for preparing 239 was reported by Jacobsen and co-workers.244 Use of the catalyst resulted in greater enantiomeric selectivity and higher yields. An example of controlling the absolute configuration by a chiral auxiliary for the synthesis of an ethyl L-mannoside was disclosed by Tietze and co-workers.245,246 Here, an oxazolidinone attached to an enone 245 was utilized to induce the stereoselectivity when reacting with cis-alkene 245 (Scheme 36). Four stereoisomers were observed derived from the endo and exo products and their corresponding isomers. When the cycloaddition was performed at low temperature and catalyzed by TMSOTf, excellent endo/exo (32:1) selectivity was observed in favor of the desired enantiomer 246 (246/ent-246 5:1). Removal of the oxazolidinone was performed by reduction to the primary alcohol 247 followed by acetylation, hydroboration, and oxidative workup which gave the L-mannoside 248. The synthesis of all eight L-hexoses has not been achieved using the asymmetric HDA reaction. As seen with the examples above, excessive post-HDA manipulation is necessary. Instead, some deoxygenated L-sugars are easily prepared by similar methods (vide supra), as seen for the synthesis of 4-deoxy-Lglucoside and 2-deoxy-L-guloside.247,248

epoxide 216 and the terminal 217. Isopropylidenation followed by oxidation of the sulfide to the sulfoxide 220 set the stage for the Pummerer rearrangement which gave the thioacetal 221 as a starting point for preparation of all eight L-sugars (Scheme 32). Reduction of the thioacetal to the aldehyde was achieved using DIBAL-H (giving 222), whereas α-epimerization to give aldehyde 223 was accomplished with K2CO3 in methanol. Wittig olefination followed by reduction of the introduced aldehyde resulted in an excellent yield and high stereoselectivity resulting in the allylic alcohols 224 and 225. A second Sharpless asymmetric epoxidation was accomplished under similar conditions as described above only varying the (+)/(−)-tartrate to give the different epoxides 226−229. Further manipulation was performed by the usual Payne rearrangement and isopropylidenation affording 230−234 (Scheme 33). To obtain all eight unprotected L-hexoses the sulfides were oxidized to their corresponding sulfoxides, and a subsequent Pummerer rearrangement afforded the thioacetals. These thioacetals were either subjected to a DIBAL-H-mediated hydrolysis or reacted with K 2 CO 3 and methanol with concomitant α-epimerization to afford two new aldehydes. Subsequent hydrolysis and hydrogenation gave all eight Lhexoses in varying amounts (Scheme 34). In the case of deprotection to the L-altrose a mixture of L-altrose and the 1,6anhydro-β-L-altropyranose was observed. Although this seminal work was a major achievement in the synthesis of L-sugars, the practical use is limited due to incomplete stereo- and regioselectivity and in some cases low yields. On the other hand, this work set the stage for further research on how to synthesize L-hexoses from non-carbohydrate sources. 4.2. Diels−Alder Reaction

4.2.1. Hetero-Diels−Alder (HDA) Reaction. A highly explored subject for the synthesis of carbohydrate derivatives is the hetero-Diels−Alder (HDA) cycloaddition.239 This method has been utilized for preparing various carbohydrate derivatives of both enantiomers, but only a few studies have managed to synthesize fully oxygenated L-hexoses.240,241 Generally, formation of the pyranose moiety can be achieved by two different approaches: (1) reaction of aldehydes/ketones with a diene or (2) cycloaddition of α,β-unsaturated carbonyls with alkenes (Figure 6). The first method is an example of HDA with normal

Figure 6. Approaches for synthesizing pyranoses by HDA cycloaddition.

Scheme 35. Asymmetric HDA Cycloaddition Using a Chiral Catalyst for the Synthesis of L-Glucose

S


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Scheme 36. Asymmetric HDA Cycloaddition Using a Chiral Auxiliary for the Synthesis of L-Mannoside

Scheme 37. Schematic Representation of Suggested and Accomplished Synthesis of L-Sugars from 7-Oxonorbornenyl Derivatives

Scheme 38. Synthesis of Enantiomerically Pure 7-Oxabicyclo[2.2.1]heptane-2-one

Scheme 39. Synthesis of L-Allose from 7-Oxabicyclo[2.2.1]heptane-2-one

derivatives were used extensively in the synthesis of carbohydrates and their derivatives.251,252 Enantiomerically pure 7-oxonorbornenyl derivatives 250 and 254 were used as a starting point for various L-sugars. They were synthesized from the cycloaddition of furan with 1-cyanovinyl (1′S)/(1′R)-camphanate 249/253, which gave a mixture of isomers from which the desired enantiomer could be crystallized (Scheme 38).253 Dihydroxylation of the alkene catalyzed by OsO4 and subsequent isopropylidenation afforded compounds 251 and 255 only as the exo isomer.254 Saponification of 251 and 255 followed by treatment with formalin (used to displace the equilibrium implying the corresponding cyanohydrines) gave ketones (−)-252 and (+)-252.

A mixture of D- and L-mannose has been prepared by a thermal/hyperbaric hetero-Diels−Alder reaction.249 Likewise, a mixture of both D- and L-gulose has been prepared via multicomponent enyne cross metathesis−hetero-Diels−Alder reaction utilizing trimethylsilylacetylene, ethylvinyl ether, and ethyl glycoxalate in the presence of Grubbs’ second-generation catalyst.250 4.2.2. Cycloadditions of Furans. The applications of 7oxonorbornenyl derivatives were explored by Vogel and coworkers for the synthesis of various L-sugars. The method relied on introducing various patterns of vicinal diol at the alkene followed by conversion to L-sugars by a number of manipulations (Scheme 37).251,252 Furthermore, these 7-oxonorbornenyl T


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Scheme 40. Synthesis of L-Talose from 7-Oxabicyclo[2.2.1]heptane-2-one

Scheme 41. Suggested Synthesis of L-Galactose and L-Altrose

Scheme 42. Suggested Synthesis of L-Gulose and L-Idose

was 78% over those three steps, which were carried out in an onepot fashion. Acid-catalyzed Fischer glycosylation with methanol followed by concomitant reduction of the methyl ester and removal of the O5 acyl protection group gave methyl furanoside 262. Subsequent acidic hydrolysis afforded L-allose. Starting from ketone (+)-252 the α-bromo ketone 264 was obtained via the silyl enol ether 263 (Scheme 40). Subsequent regioselective Bayer−Villiger oxidation with mCPBA gave uronolactone 265. Again, the oxygen inserted between the bridgehead C1 center and the carbonyl. Methanolysis in the

The enantiomerically pure ketones (−)-252 and (+)-252 served as the starting point for the synthesis of some L-sugars. Silyl enol ether formation (256) from the corresponding ketone was epoxidized stereospecifically to 257 on the exo face using mCPBA (Scheme 39).255 The intermediate hemiketal 257 was heated to form α-acyloxy ketone 258. Then, ketone 258 underwent regioselective Bayer−Villiger oxidation with Oinsertion between the bridgehead center C1 and the carbonyl group giving the uronolactone 259. Rearrangement of the εlactone to the methyl L-furanuronate 260 was accomplished by treatment with methanol in the presence of K2CO3. The yield U


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Scheme 43. Synthesis of L-Hexoses via Organocatalyzed Iterative Aldol Reaction

conditions for the subsequent diastereoselective Mukaiyama aldol reaction with 286. Later, the synthesis of L-allose, only employing L-proline or hydroxy-L-proline for both condensation steps, was disclosed by Córdova and co-workers.263−265 Only conditions for the preparation of three L-hexoses (L-gluco, Lmanno, and L-allo) have been disclosed. A potential synthetic route to all eight L-hexoses should in principle be possible via an iterative use of protected glycolaldehydes utilizing the prolinecatalyzed aldol reaction.266 The asymmetric organocatalyzed aldol reaction has been used in the synthesis of both natural and artificial carbohydrates.267 For instance, in the synthesis of littoralisone 7 (Figure 2) Mangion and MacMillan took advantage of the proline-catalyzed asymmetric aldol reaction for preparing the properly protected Lglucose precursor.31 Homologation of properly protected L-threose with chiral γalkoxy allylic stannanes with BF3·OEt2 has been investigated by Marshall and co-workers for the preparation L-iduronic acid.268 Subsequently, the C6 acid was elaborated by ozonolysis of the resulting allylic ether followed by functional group manipulation and oxidation of C1 to the aldehyde to give L-iduronic ester. Unfortunately, the crucial aldol reaction gave rise to a 2:1 mixture at C4, thereby hampering the utility of this method. In a later study Marshall and Hinkle reported much higher enantioselectivity for the crucial aldol reaction with chiral γ-alkoxy allylic stannanes with InCl3.269 This method was used for the preparation of two compounds which were suggested to be precursors for the synthesis of L-talose and L-gulose. The group of Davies has explored the preparation of D-hexoses (D-galactose, D-idose, and D-talose) and 6-deoxy-D-hexoses (Dfucose, 6-deoxy-D-idose, and 6-deoxy-D-talose) via an iterative syn glycolate aldol reaction using Evans chiral oxazolidinone auxiliary.270,271 This methodology could be used for the preparation of the L-hexoses and 6-deoxy-L-hexoses, but this has not been done so far.

presence of K2CO3 followed by reduction afforded 267, which was transformed into L-talose upon treatment with dilute acid. The rigid structure of the 7-oxonorbonenyl derivative is ideal for introducing two different oxy functionalities at the alkene. This was carried out by converting the ketone 268, synthesized by an cycloaddition,253,256 to an acetal followed by epoxidation of the alkene functionality to give 269 (Scheme 41a).257 Opening of the oxirane with the superacid, fluorosulfuric acid, resulted in migration of a benzyloxy group, thereby forming a 1,2-trans diol 271. The same pathway should be feasible for ketone 272, giving rise to dihydoxylated ketone 275 (Scheme 41b). Vogel suggested this route to compounds 271 and 275 as starting material for the synthesis of L-galactose and L-altrose using the route described in Schemes 40 and 39, respectively (Scheme 41c).251,252 Finally, Vogel also suggested the preparation of L-gulose and Lidose by manipulation and opening of the 7-oxabicyclo[2.2.1]heptane-2-one derivative.251,252 The synthesis comprised of an addition of PhSeCl to the alkene in the presence of AgOAc giving compound 277 (Scheme 42a).258 Methanolysis followed by treatment with aqueous formalin afforded 278, which was protected as its MOM ether 278. This selenide 279 underwent a seleno-Pummerer rearrangement when oxidized with mCPBA and treated with acetic anhydride and NaOAc to produce 280 and 281 in 60% and 13% yield, respectively. Removal of the selenide was accomplished with stannane-mediated reduction of the protected cis diol 280 to furnish 282. It was suggested that treatment with DBU in methanol would lead to the inverted trans diol 283. Furthermore, Vogel also suggested that these two compounds 282 and 283 could serve as starting materials for the synthesis of L-gulose and L-idose via the route used in Schemes 39 and 40 (Scheme 42b).251,252 4.3. Enantioselective Aldol Reaction

Recent progress in enantioselective organocatalyzed aldol reactions, utilizing small chiral molecules or simple amino acids, has led to the synthesis of several L-hexoses.259 An early report by Mukaiyama and Stevens described the enantioselective synthesis of L-pentose derivatives from protected dihydroxyacetone and methyl pyruvate using N-ethylpiperidine as the catalyst.260 Later MacMillan and Northrup showed that Lglucose, L-mannose, and L-allose could be prepared easily in two steps (Scheme 43).261,262 The first step consisted of a stereoselective α-oxyaldehyde dimerization of 284 catalyzed by L-proline. Interestingly, the initial proline-catalyzed aldol reaction stopped at the stage of the four-carbon L-tetrose 285. This building block 285 served as a starting point for synthesis of the three L-hexoses by varying the Lewis acid and the reaction

4.4. Diastereoselective and Enantioselective Alkene Dihydroxylation

Catalytic asymmetric dihydroxylation of alkenes constitutes potentially a powerful method to prepare oxygenated chiral centers. The asymmetric dihydroxylation developed by Sharpless and co-workers for synthesizing 1,2-diols from olefins is an extraordinary example of this methodology.272 4.4.1. from Chain-Elongated Alkenes. An early example by Mukaiyama and co-workers explored the synthesis of a protected L-talono-γ-lactone starting from 4-O-benzyl-2,3-Oisopropylidene-L-threose by carbon extension via a Wittig V


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Scheme 44. Stereoselective Synthesis of α,β-Unsaturated Esters

Scheme 45. Asymmetric Dihydroxylation of E-Alkenes To Give Four L-Hexoses

reaction and cis dihydroxylation of the resulting α,β-unsaturated γ-lactone using KMnO4.273 Also, Vandewalle and collaborators explored the preparation of all eight L-hexoses as their Llactones.274 L-Erythrose was used as the starting material and extended by a Wittig reaction to afford either the Z- or the Eisomer. Subsequent, dihydroxylation of the α,β-unsaturated ester under various conditions produced all L-hexoses as their lactones. Unfortunately, the dihydroxylation was not very selective for all reactions. In a similar method Kim and collaborators reported the synthesis of L-galactose from a precursor 290 derived from Lascorbic acid.275 Shortly afterward Sasaki and co-workers showed that the same precursor 290, utilizing similar chemistry, could be used for the synthesis of all eight L-hexoses.276,277 The precursor 290 was prepared in three steps from L-ascorbic acid 28,278,279 and the hydroxy group in 290 could be inverted by a Mitsunobu

reaction to give 291 (Scheme 44).277 Both compounds 290 and 291 were benzylated, reduced to the primary alcohol, and oxidized by a Swern oxidation affording 296 and 297. In the route by Kim and co-workers the TBS-protected α-hydroxy ester was directly converted to the aldehyde with DIBAL-H, thereby avoiding an additional synthetic step.275 With these two aldehydes 296 and 297 in hand a Horner−Wadsworth− Emmons olefination was performed to give the α,β-unsaturated esters 298 and 300 with high stereoselectivity for the Econfiguration. Applying the Still−Gennari modifications, the selectivity could be directed to favor the Z-alkenes 299 and 301. The synthesis of the E- and Z-γ-alkoxy-α,β-unsaturated esters 298−301 has also been achieved by hydrogenative coupling of acetylene to glyceraldehyde (scheme not shown).280 The addition of two molecules of acetylene went through a W


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Scheme 46. Asymmetric Dihydroxylation of Z-Alkenes To Give Four L-Hexoses

Scheme 47. Synthesis of Two Precursors for the Preparation of L-Hexoses via a Three-Chain Homologation

rhodacyclopentadiene281 ligated by either enantiomer of MeOBIPHEP with high diastereoselectivity. Both epimers were benzylated followed by oxidative periodate cleavage of the terminal alkene to give the cis-enal. Conversions of the enals to the Z-α,β-unsaturated esters was achieved by exposure to manganese oxide in the presence of sodium cyanide and the relevant alcohols (MeOH of EtOH) as solvent. Isomerization of the Z-alkene 299 and 301 to the E-unsaturated ester 298 and 300 was accomplished by treatment with a catalytic amount of trimethylphospine. Stereoselective osmium-catalyzed trans dihydroxylation272 of the (E)-γ-alkoxy-α,β-unsaturated esters 298 and 300 was performed in the presence of a chiral quinine ligand (either (DHQD)2PHAL or (DHQ)2PHAL) affording the vicinal diols with high facial selectivity (Scheme 45).276,277 The two ligands gave opposite selectivity. The diols were isopropylidenated affording four different esters 302−305. Reduction with DIBALH followed by hydrolysis of the isopropylidene and peracetylation gave the fully protected L-hexoses: L-galacto 306, L-ido 307, L-gluco 308, and L-altro 309. Regarding the synthesis of the remaining four L-hexoses, Lgulose, L-talose, L-allose, and L-mannose, the same procedure was used on the (Z)-γ-alkoxy-α,β-unsaturated esters 299 and 301 (Scheme 46). Although the asymmetric cis dihydroxylation272 of

the (Z)-alkene gave lower yield and was less selective, the synthesis of the remaining L-hexoses 314−317 was achieved in good yield. A three-carbon homologation reagent consisting of the protected (5,6-dihydro-1,4-dithiin-2-yl)methanol 318 was discovered for the synthesis of all eight L-sugars. In the initial studies, addition of the lithiated carbanion of 318 to L-glyceraldehyde 319 gave a disappointing diastereo mixture (anti/syn 2:3).282−284 This problem was solved by employing the methyl 284 L-glycerate ketone 320 (Scheme 47). Stereoselective reduction was accomplished using NaBH4, which gave the syn-321 in 98% with high selectivity. Inversion of syn-321 to the anti-321 was achieved under Mitsunobu conditions. These two compounds set the stage for the synthesis of all eight L-hexoses. anti-321 was used in the synthesis of the four L-hexoses that have an equatorial C4 substituent. Initially, the unprotected alcohol was benzylated followed by removal of the pmethoxybenzyl group by 1 equiv of DDQ and PCC-mediated (pyridinium chloroformate) oxidation to the aldehyde 322 (Scheme 48a).282 Treatment with acid in methanol afforded the 2,3-unsaturated glycoside 323, which was acetylated and reduced with Raney nickel to give compound 324. Dihydroxylation of the 2,3-alkene was accomplished under Upjohn conditions, which gave the cis-diols 325 (L-mannoside).243 On the other hand, X


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Scheme 48. Synthesis of Four L-Hexoses (L-manno, L-altro, L-gluco, and L-allo) by Various Dihydroxylation Methods

Scheme 49. Synthesis of Four L-Hexoses (L-gulo, L-talo, L-ido, and L-galacto) by Various Dihydroxylation Methods

to the trans-diol 326 (L-altroside) was accomplished by treatment with perchloric acid. When the anti-321 was treated

treatment with in-situ-generated methyl(trifluoromethyl)dioxirane (TFDO) gave the epoxide. Opening of the epoxide Y


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Scheme 50. Synthesis of L-Galacto via Allylic C−H Oxidation and Dihydroxylation

Scheme 51. Synthesis of a Levoglucosenone-Type Precursor

alkene 345 (Scheme 49b). Epoxidation of the alkene was achieved by TFDO followed by opening to the methyl α-Lgalactoside 348 by treatment with TMSOTf in methanol. Asymmetric dihydroxylation of allylic alcohols has been found to be highly stereoselective and therefore been used for the synthesis of orthogonally protected L-galactose. The synthesis was initiated by epoxidation of (Z)-2-butene-1,4-diol 349 to give meso-epoxide 350. Then, a cobalt-catalyzed desymmetrizing Payne rearrangement of meso-epoxide 350 and subsequent isopropylidenation afforded the terminal epoxide 351. Regioselective opening of the terminal position with vinylcuprate followed by benzylation gave the protected homoallylic alcohol 352. Then a crucial palladium-catalyzed allylic C−H oxidation in the presence of p-anisic acid afforded allylic ester 353. Asymmetric dihydroxylation272 proceeded smoothly with high stereoselectivity (>20:1) to give 354, which was silylated followed by ester removal with DIBAL-H. Oxidation of the resulting primary alcohol to the aldehyde under Swern conditions and removal of the isopropylidene with Zn(NO3)2· 6H2O afforded the orthogonally protected L-galactose 355. 4.4.2. From Easily Available Alkenes. In an early report by Achmatowicz and collaborators furfural was realized to function as a hexose precursor.286,287 Ring expansion was accomplished under oxidative conditions to afford pyranosides with an enone moiety ready for manipulation to afford methyl L-glucopyranoside. In the search for cheap and available starting materials for the synthesis of L-hexoses, Ogasawara and collaborators discovered that a levoglucosenone type of compound could be used for the synthesis of all eight L-sugars.288,289 The precursors 356 and 357 were prepared from furfural by a Horner−Wadsworth−Emmons reaction. This was followed by reduction of the resulting α,βunsaturated ester and protection of the allylic alcohol by silylation or naphthylmethylation (Scheme 51).288 The crucial asymmetric dihydroxylation was performed under Sharpless osmium-catalyzed conditions272 giving the diol 358 and 359. Oxidative ring expansion was accomplished with mCPBA,

with 2 equiv of DDQ a domino reaction yielding the 1,6-anhydro compound 327 was observed (Scheme 48b).283 It was suggested that the 2 equiv of DDQ triggered the domino reaction by initial PMB removal followed by oxidation to the aldehyde and removal of the isopropylidene leading to the formation of the pyranose and finally ring closure to the 1,6-anhydro compound 327. Treatment with Raney nickel gave the 2,3-alkene 328, which was syn-dihydroxylated with OsO4 to afford 329. Subsequent acetal ring opening in the presence of TMSOTf and MeOH provided the methyl α-L-alloside 330. The same 2,3-alkene 328 was used to synthesize methyl α-L-glucoside 333 by epoxidation to give 1,6:2,3-dianhydro pyranoside 331 from in-situ-formed TFDO. Opening to the trans-dihydroxylated compound 332 with KOH and further reaction with methanol in the presence of TMSOTf gave the methyl L-glucoside 333. Regarding the four remaining L-hexoses (L-gulo, L-talo, L-ido, and L-galacto), with an axial C4 substituent, compound syn-321 was used. Again, the free alcohol was protected either as a benzyl group or as an acetyl group (Scheme 49a).284 Subsequent DDQ treatment in the presence of methanol and acetylation led to cyclized 2,3-unsaturated glycoside 335 and 336, which could be desulfurizated by reaction with Raney nickel affording 337 and 338. This alkene set the stage for various dihydroxylations leading to different L-hexoses. Syn dihydroxylation of the α-face was performed under Upjohn conditions243 and produced the methyl L-guloside 339. Methyl L-taloside 340 was syn dihydroxylated at the β-face by first removing the C4 acetyl group followed by osmium-catalyzed dihydroxylation in the presence of TMEDA. The opposite stereoselectivity of the syn dihydroxylation was explained by the directing effect of the hydrogen bond formation between the axial 4-OH and the OsO4/TMEDA complex.285 Installation of the trans diaxial diols was achieved by epoxidation with in-situ-formed TFDO, which could be opened to the methyl α-L-idoside 342. Synthesis of the trans diequatorial diol in methyl α-L-galactoside 348 was accomplished by the before mentioned DDQ-mediated conversion to 1,6-anhydro 344 and desulfurization to give 2,3Z


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Scheme 52. Syntheses of Three L-Hexoses from Levoglucosenone 360 and 361

Scheme 53. Synthesis of Three Intermediates 378, 382, and 384 from Levoglucosenone 361

inspired by the Achmatowicz procedure.286,287 Acid-catalyzed cyclization afforded the levoglucosenone 360 and 361. Manipulation of the enone moiety of the precursor led to the synthesis of all eight L-hexoses. Reduction of the enone functionality in 360 under Luche condition172 afforded the allylic ether after benzylation of 360 (Scheme 52a). Dihydroxylation under Upjohn conditions243 and benzylation of the resulting diol yielded compound 363. Transformation of the primary alcohol into the iodide 364 was

accomplished by desilylation, mesylation, and substitution with lithium iodide. Treatment with zinc in acetic acid gave hemiacetal 365, which was subjected to a Fischer glycosylation with benzyl alcohol. This afforded the terminal alkene 366. Ozonolysis of the terminal alkene and subsequent reduction of the aldehyde intermediate gave the primary alcohol 367. This compound was converted to the unprotected L-gulose by hydrogenolysis catalyzed by Pearlman’s catalyst. When the hemiacetal 365 was converted to its lactone 368 by treatment with tetrapropylamAA


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Scheme 54. Synthesis of the Remaining Five L-Hexoses from the Three Intermediates 378, 382, and 384

monium perruthenate (TPAP), α-epimerization of the axial to the equatorial substituent was accomplished under basic conditions. Subsequently, reduction of the lactone 369 and Fischer glycosylation with benzyl alcohol afforded the terminal alkene 370. Again, ozonolysis and NaBH4-mediated reduction followed by hydrogenolysis gave the unprotected L-idose. Trans diaxial dihydroxylation of the enone functionality of the naphthylmethyl protected levoglucosenone 361 was accomplished by epoxidation. Subsequently, reduction of the ketone and benzoylation produced epoxide 372 (Scheme 52b). Then, the epoxide was opened in the presence of BF3·OEt2 to the trans diol followed by debenzoylation and benzylation of the resulting triol. Selective removal of the naphthylmethyl ether under hydrogenolysis, mesylation, and iodide substitution yielded the iodide 373. Iodide 373 was transformed into the terminal alkene 374 as described above followed by ozonolysis/reduction to the primary alcohol 375. Deprotection under hydrogenolysis afforded the unprotected L-galactose. In the synthesis of the remaining five L-hexoses (L-gluco, L-talo, L-manno, L-altro, and L-allo) Ogasawara and co-workers synthesized three intermediates from the common naphthylmethyl-protected levoglucosenone 361 (Scheme 53).289 Reduction of the enone under Luche’s conditions172 furnished the allylic alcohol 376. Epimerization of the alcohol via Mitsunobu inversion and subsequent hydrolysis resulted in the epimerized allylic alcohol 377. Acylation of the alcohol and dihydroxylation under Upjohn conditions243 followed by deacylation and benzylation of the resulting triol afforded the first intermediate

378. When the mesylated allylic alcohol generated from 377 was treated with aqueous CaCO3 a regio- and diastereoselective SN2′ rearrangement arose to afford the isomeric allylic alcohol 379. Then oxidation with PCC afforded enone 380. Reduction of the enone unit under Luche’s conditions172 followed by benzylation generated the allylic ether 381. This compound was dihydroxylated under Upjohn conditions,243 and benzylation of the resulting diol afforded the intermediate 382. Exposure of the enone 380 to sodium hypochlorite followed by reduction and benzylation of the resulting alcohol produced the epoxide 383. Opening of the epoxide to the trans diaxial alcohol was accomplished under the influence of BF3·OEt2 followed by hydrolysis and benzylation of the generated triol giving intermediate 384. With the three intermediates in hand, manipulation to produce the five remaining L-hexoses was performed (Scheme 54).289 The initial procedures were the same for transforming the naphthylmethyl-protected primary alcohol 385a−c into their corresponding terminal alkenes 386a−c as described above. Transformation of the lactol 386b to the lactone 387b was accomplished by oxidation with TPAP and NMO which allowed C2 epimerization by DABCO treatment followed by DIBAL-H reduction to the lactol 388b. Fischer glycosylation with benzyl alcohol followed by ozonolysis and reductive workup furnished the unprotected L-glucose (derived from the b series) after palladium-catalyzed hydrogenolysis. For the preparation of the unprotected L-talose the lactol 386a was reduced to its diol followed by benzylation. Subsequent dihydroxylation of the AB


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Scheme 55. Synthesis of Starting Material for the Preparation of L- and D-Hexoses from Furfural

Scheme 56. Synthesis of Three D-Hexoses via Oxidative Ring Expansion and Dihydroxylation

Scheme 57. L-Hexoses from a Synthetic Equivalent of a Dihydroxycycloheaxadiene

mannoside 398. Epimerization of the hydroxy group in 397 was accomplished under Mitsunobu conditions followed by unmasking the alcohol to give 399. The protected D-talose 400 isomer was selectively produced upon treatment with OsO4 and TMEDA,285 whereas Upjohn conditions243 afforded the Dgulose isomer 401. As suggested by the authors, the three enantiomer L-hexoses can be synthesized under similar conditions using ent-393.290,291 In fact, O’Doherty and coworkers synthesized oligomers of L-hexoses by the route described. Furthermore, a palladium-catalyzed glycosylation step on the enone functionality was incorporated.293−295 Postfunctionalization of the enone moiety allowed the synthesis of the oligomeric L-mannosides. Substrate-controlled synthesis leading to all eight L-hexoses from a chiral equivalent of cis-1,4-dihydroxycyclohexane-2,5diene was disclosed by Ogasawara and co-workers.292 The starting material 402 was synthesized by a cycloaddition of cyclopentadiene and benzoquinone followed by stereoselective reduction and asymmetrization by chemoenzymatic296−298 or chemical299 methods (Scheme 57). Further manipulation led to the highly constrained bromo ether 403 in which one double bond is masked due to the norbornyl moiety. The other alkene can be stereoselectively functionalized due to the inherent convex-face selectivity. In the study four L-hexoses and four Dhexoses were prepared. Starting from allylic ether 403 stereoselective dihydroxylation to afford either trans or cis diols was performed by stereoselective

terminal alkene under Upjohn conditions furnished the diol which could then be cleaved by treatment with sodium periodate to aldehyde 389a. Removal of the benzyl groups by hydrogenolysis afforded L-talose (derived from the a series). This method is equivalent to the head-to-tail inversion as previously described. The preparations of the three remaining L-hexoses (Lmanno, L-altro, and L-allo) started by a Fischer glycosylation of 386a−c with benzyl alcohol giving 390a−c. Subsequently, the terminal alkenes 390a−c were converted into their primary alcohols 391a−c by ozonolysis followed by reductive workup. Palladium-catalyzed hydrogenolysis of the benzyl ethers resulted in the unprotected L-altrose (derived from the a series, Scheme 54), L-mannose (derived from the b series, Scheme 54), and Lallose (derived from the c series, Scheme 54). Later work by O’Doherty and collaborators also explored asymmetric osmium-catalyzed dihydroxylation272 of vinylfuran 392 prepared by a Peterson olefination of furfural (Scheme 55).290,291 Depending on the asymmetric dihydroxylation both enantiomers 393 were obtained in good yield and high enantiomeric excess. These could then be used to synthesize some of both the D- and the L-hexoses. In the synthesis of three D-hexoses the diol 393 was protected at the primary alcohol followed by oxidative ring expansion inspired by Achmatowicz.286,287 This resulted in enone 394 and 395 after anomeric protection (Scheme 56).290,291 Luche reduction172,292 afforded the allylic alcohol 396 and 397 which could be syn-dihydroxylated under Upjohn conditions giving DAC


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Scheme 58. Preparation of Four Cyclohex-2-enol Intermediates

Scheme 59. Synthesis of Four L-Hexoses from Cyclohex-2-enol Intermediates

epoxide opening (compound 405 and 407) or osmium-catalyzed dihydroxylation (compound 408 and 410) (Scheme 58). All bromo ethers (405 (first step), 407 (first step), 403 (second step), and 410 (first step)) were transformed into the alkene by

reductive cleavage using zinc/acetic acid. Unmasking the alkene by a retro-Diels−Alder reaction to elaborate the cyclopentadiene and the desired polyoxygenated cyclohexene was performed by refluxing the compounds in diphenyl ether. Regioselective AD


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Scheme 60. Asymmetric Dihydroxylation Approach from Dienoate

Scheme 61. Synthesis of Precusor 445 from Cycloheptadiene

issues regarding regioselectivity (in which double bond reacts first), enantioselectivity (facial selectivity of the first dihydroxylation), and double diastereoselectivity. When subjecting the (2E,4E)-dienoate 430 to the first osmium-catalyzed dihydroxylation with (DHQ)PHAL as a ligand, diol 431 was isolated in high yields and with excellent enantiomeric excess (Scheme 60a).301 The regioselectivity could be explained in terms of electron density if the π-system in which the most electron-rich double bond reacted first. The second dihydroxylation with (DHQH)PHAL and higher catalyst loading afforded the Lgalacto-γ-lactone 432 after acid-mediated lactonization. Synthesis of the L-galacto-δ-lactone 434 could be accomplished by introducing an O4 protecting group and perform the same dihydroxylation (Scheme 60b).302 When the starting material was changed to the (2Z,4E)-dienoate 436 a surprising dihydroxylation with concomitant lactonization to 437 was observed (Scheme 60c).303 Subsequent silylation was crucial to the diastereoselectivity of the following dihydroxylation under Upjohn conditions. With the silyl group absent, a 5:1 dr was observed, but this was drastically enhanced to 10:1 when silyl protected to afford the L-talo-γ-lactone 438.

removal of one protecting group gave the four cyclohex-2-ene intermediates 414−417 (conduritols300). For the synthesis of the four L-hexoses a standard procedure starting from the p-methoxybenzyl-protected cyclohexenes was utilized.292 To afford the four different tetrols, epimerization of the unprotected hydroxy group was performed either by a Mitsunobu inversion or by stereoselective reduction of the corresponding ketone affording 418−421 (Scheme 59). Subsequent ozonolysis and reductive workup resulted in four glycitols 422−425. Upon exposure of the PMB group to DDQ, the rearrangement afforded a 1,3-dioxolane whose primary alcohol could be oxidized to the aldehyde 426−429. Hydrogenolysis catalyzed by Pearlman’s catalyst resulted in the unprotected L-gulose, L-idose, L-altrose, and L-talose. The enantiomers of the four cyclohex-2-enols 414−417 can be prepared from the enantiomer of 403, thereby enabling the synthesis of the remaining L-hexoses.297,298 Iterative dihydroxylation of dienoates constituted an attractive route to L-hexo-γ- and δ-lactones as illustrated by O’Doherty and co-workers.301−303 This concept of bis-dihydroxylation appeared to be ideal for synthesizing carbohydrates, but there were some AE


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Scheme 62. Synthesis of Peracetylated L-Glucose 450 from Cycloheptene 445

Scheme 63. Base-Catalyzed Isomerization of L-Galactose to L-Tagatose

4.5. Enzymatic Asymmetrization

each of these general strategies in turn. Method number 1 has been used to prepare L-sorbose and L-tagatose, method number 2 has been used for L-fructose, L-psicose, and L-tagatose, while method 3 has been used for preparation of L-fructose and Ltagatose.

Preparation of hexoses via de novo asymmetric approaches can also be accomplished by the use of biocatalysis instead of conventional catalysis. For instance, this has been explored by Johnson and co-workers for the synthesis of L-glucose starting from cycloheptadiene 439 (Scheme 61).304,305 The approach started by a highly stereoselective palladium-catalyzed Bäckvall oxidation of diene 439 prepared from cycloheptatriene to give the Cs-symmetric triol diacetate 440.306 Subsequent protecting group manipulation of the resulting diol in 441 was followed by an enzymatic desymmetrization using Amano P-30 lipase in isoprenyl acetate for 5 days to produce monoacetate 442. The remaining alcohol was protected followed by removal of the acetyl group and PDC oxidation to afford the enone 443. αHydroxylation was accomplished by a stereoselective Rubottom oxidation to give enone 444 followed by stereoselective DIBALH reduction and isopropylidenation affording the fully protected alkene 445.307−309 The alkene 445 was dihydroxylated under Upjohn conditions followed by isopropylidenation giving 446 (Scheme 62). Then the BOM protecting group was removed followed by mesylation of the resulting hydroxyl group to give 447. Desilylation and concomitant elimination resulted in enone 448 after Swern oxidation. Subsequently, the ketone was reduced followed by ozonolysis and reductive workup affording triol 449. The peracetylated L-glucose 450 was liberated after periodate cleavage, removal of the isopropylidene groups, and peracetylation.

5.1. By Isomerization/Conversion of an Aldohexose

The intuitively most obvious and direct method to prepare a ketose from an aldose is by base-catalyzed 1,2-isomerization. However, it is not necessarily so practical for an L-ketose because the required starting material is an L-aldose and thus not readily available. Nevertheless, it has been used by Glatthaar and Reichstein to prepare L-tagatose (31) from L-galactose (30, Scheme 63). L-Galactose was obtained from D-galactose by intermediacy of D-galacturonic acid and L-galactonic acid. The isomerization was conducted for 5 h in boiling pyridine, which led to a 5% yield of 31 with 82% 30 being recovered.92 The equilibrium was probably not reached as Morgenlie and collaborators have shown in a recent paper that addition of aluminum oxide speeds up the isomerization and that a 2:1 ratio of 30 and 31 could be obtained after 2 h. They also showed that Lgulose (451) is converted to a 5:1 mixture of L-sorbose (452) and 451 by these conditions. No attempt to purify 452 was made.310 Byproducts, such as epimeric aldoses, are formed in these reactions, which obviously will limit the potential yield of pure ketose. From old work it is known that isomerization in base can continue beyond 1,2-isomerization and that D-glucose can isomerize all the way to sorbose, but the sorbose will be racemic.311 A much more useful isomerization for L-ketohexose synthesis is a 1,5-isomerization of the carbonyl group as this will allow synthesis of L-sorbose (452) and L-tagatose (31) from the cheap aldoses D-glucose and D-galactose, respectively. The translocation of the carbonyl group in this manner can be done by the Meerwein−Pondorf−Verley type of transformation. Nicotra and co-workers showed that 2,3,4,6-tetra-O-benzyl-D-glucose (453) could be transformed into 1,3,4,5-tetra-O-benzyl-Lsorbose (454) in 94% yield by reaction with magnesium ditert-butoxide. In this remarkable reaction the C1 aldehyde is reduced while oxidizing the C5 alcohol, so it is obviously

5. CHEMICAL SYNTHESIS OF 2-L-KETOHEXOSES Chemical synthesis of L-ketohexoses was started by Emil Fischer who synthesized L-fructose.69 Since then there has been an Lketohexose synthesis on average every 5 years, so the literature is very limited for all 4 stereoisomers. Basically L-ketohexoxes have been made by three different methods: (1) From an aldohexose by isomerization of the carbonyl group either directly in one step or through multistep conversion involving reduction and oxidation, (2) from another ketohexose by configurational inversion of one or more OH groups, or (3) from a shorter aldose or aldonic acid by chain extension. In the following we will cover AF


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reversible. However, it occurs in dichloromethane at 40 °C, and only 2% of 453 is present when the equilibrium is reached (Scheme 64, top).312 Later the same reaction has been

In a related synthesis the 1,2-acetonide of 458, 463, was the starting material. Selective benzoylation at the primary OH to 464 allowed further protection of the 3- and 4-OH to give 465. Oxidation and deprotection of 465 gave 452 (Scheme 65).317 A more straightforward and efficient route from D-glucose to Lsorbose was published in 1967 by Rabinsohn and Fletcher. Starting from 453 reduction with LiAlH4 gave 466, which was selectively protected with a trityl group to give 467. Oxidation of the 5-OH to a ketone followed by removal of the trityl group gave 454, which could be hydrogenolyzed to L-sorbose (Scheme 66).318 Recently, this synthesis was repeated claiming slightly higher yields.319 L-Tagatose (31) has been made from 1,5-anhydro-D-galactitol (468, Scheme 67), which itself can be readily made from Dgalactose (30). Reaction of 468 with dimethoxypropane and acid gave a 1:1 mixture of the 3,4-O-isopropylidene-2,6-di-Omethoxypropyl derivative and the 3,4-O-isopropylidene-2,6-diO-methoxypropyl derivative which upon mild hydrolysis and benzylation gave 469 (Scheme 67). Treatment of 469 with potassium tert-butoxide in DMSO afforded enol ether 470, which is equivalent to a glycal of L-tagatose or L-sorbose. Epoxidation and simultaneous methanolysis using m-chloroperbenzoic acid in methanol gave the methyl glycoside 471. Hydrogenolysis of the benzyl ethers and acidic hydrolysis gave 31 in a very good overall yield (Scheme 67).320

Scheme 64. One-Step Rearrangement of D-Glucose and DGalactose into L-Sorbose and L-Tagatose

performed with preoxidized samarium iodide. If air was bubbled through samarium iodide until disappearance of the blue color, 453 was added, and the mixture refluxed for 4 h in tetrahydrofuran (THF) 61% yield of 454 was obtained. Similarly, 2,3,4,6-tetra-O-benzyl-D-galactose (455) could be converted into 1,3,4,5-tetra-O-benzyl-L-tagatose (456) in 81% yield (Scheme 64, bottom).313 If THF was exchanged with tetrahydropyran yields could be improved presumably due to the higher reflux temperature. Now 454 was obtained in 92% yield, and 456 was obtained in 88% yield (Scheme 64).314 1,5-Isomerization has also been observed on unprotected Dglucose when treated with a titanium β-zeolite. Reflux of Dglucose with the zeolite in water for 2 h gave up to 12% conversion to L-sorbose (452). Eight percent D-fructose was also observed, so 1,2-isomerization is occurring simultaneously.315 The equivalent of the 1,5-isomerization of D-glucose to Lsorbose can also be formed in a multistep process where the aldehyde is reduced and protected and the C5 alcohol is oxidized. Starting from D-glucitol (458), which obviously is obtained from D-glucose by hydrogenation, protection with acetaldehyde to the triethylidene acetal 459 followed by selective acidic hydrolysis of 5-ring acetal gave 460 that upon selective benzoylation gave 461. Oxidation of 461 and deprotection led to L-sorbose (452, Scheme 65).316 The yields in this synthesis are not impressive and perhaps to some extent caused by the stereoisomerism in the protection groups.

5.2. From Another Ketohexose by OH Inversion

This methodology relies on the fact that L-sorbose is commercially available and inexpensive because it is an intermediate in the ascorbic acid synthesis (see section 6). Therefore, a popular route to especially L-fructose but also occasionally L-psicose and L-tagatose is to invert one or more OH groups in L-sorbose. A good synthesis of L-fructose (475) from L-sorbose (452) was reported by Chen and Whistler (Scheme 68a).321 L-Sorbose (452) was protected as the diisopropylidene derivative 472, which was formed in over 80% yield. Mesylation of the 3-OH and selective hydrolysis of the 6-ring isopropylidine group gave 473. Treatment of 473 with base gave 474, which was deprotected to give 475.321 This synthesis (Scheme 68) has subsequently been used by Shi and co-workers. They reported that they could perform the first two steps of the synthesis in 40−60% yield and conduct the last 3 steps in one pot and obtain 85% yield.322 Bach and Höfer also employed the synthesis with modifications that allowed them to obtain 475 from 452 in a 19% overall yield.323 Finally, Zhao and Shi proposed further improvements in terms of

Scheme 65. Multistep Conversion of Sorbitol to L-Sorbose

AG


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Scheme 66. Fletcher’s Synthesis of L-Sorbose

Scheme 67. Synthesis of L-Tagatose from 1,5-Anhydro-D-galactitol

Scheme 68. Whistler’s and Bemiller’s Syntheses of L-Fructose from L-Sorbose

Scheme 69. Synthesis of L-Psicose from L-Sorbose by Inversion of the 4-OH Group

sorbopyranoside, which was protected as 1,3-O-benzylidene acetal 480. Selective tosylation gave only the 5-O tosylate, which was used as a protection group. Oxidation of 481 using DMSO/ P2O5 followed by reduction with sodium borohydride led to clean epimerization of 4-OH and gave 482. Deprotection using LiAlH4 to remove the tosylate and acid hydrolysis to remove the benzylidene and methoxy groups gave L-psicose (479).326 Subsequently, a very related synthesis of L-psico derivatives was reported. Using essentially the synthetic method as outlined in Scheme 69 5-O-benzyl and 5-O-methyl derivatives of 479 were made.327

changes in solvents and reaction times, but the sequence of reactions and intermediates is still the same.324 An alternative route from L-sorbose to L-fructose has been reported by Gizaw and BeMiller.325 In that synthesis 452 was converted to the pyranosidic 1,2-O-isopropylidene derivative 476, which could be selectively tosylated at the 3-OH under phase-transfer conditions to give 477 (Scheme 68b). Treatment of 477 with NaOH gave a 3,4-epoxide that upon further base treatment was opened at the 4 position to give 478. Deprotection of 478 gave L-fructose.325 L-Psicose (479) has also been made from L-sorbose (Scheme 69). In this case L-sorbose is first converted to the α-methyl AH


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Scheme 70. Synthesis of L-Tagatose Derivatives 487 from L-Sorbose (452)

Scheme 71. Synthesis of L-Fructose by Chain Extension of L-Arabinose

Scheme 72. Synthesis of L-Fructose by Chain Extension of L-Arabinoic Acid (a) or L-Arabonolactone (b)

Scheme 73. Synthesis of L-Tagatose from L-Threose (a) and Snthesis of L-Fructose by Aldol Condensation (b)

(31) can also been made from L-sorbose (452).328 In this case it is the 3-OH of 452 that has to be epimerized (Scheme 70). L-Sorbose was tetraacetylated to form 483 which was reacted with dimethyl pyrocarbonate and base to form a 2-Omethylcarbonate. Treatment of the later with HCl gas gave the glycosyl chloride 484. Treatment of 484 with Hg(CN)2 afforded elimination and formation of a 2,3-acyloxyglycal 485. Reaction of 485 with mercury acetate in methanol gave mercury derivative L-Tagatose

486 that was reduced with NaBH4 to give the acetylated methyl glycoside of L-tagatose 487. Obviously 487 can be converted to 31 by acidic hydrolysis, though it was not carried out.328 5.3. By Chain Extension of a Shorter Aldose

Chain extension has been a very important route to rare sugars since Emil Fischer’s era, and it is also a route that has been used to prepare L-ketohexoses. It is particularly obvious that L-fructose may be prepared in this way as it would be derived from LAI


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Scheme 74. Microbial Synthesis of 1-Deoxy-L-fructose

Scheme 75. Synthesis of All the L-Ketoses and Two L-Aldoses by Microbial Oxidation

with furyl lithium in the presence of ZnBr2, which gave 498 with 97:3 diastereoselectivity. Reaction with bromine in methanol gave oxidative addition of two molecules of methanol over the furan via an Achmatowicz rearrangement. Subsequent rearrangement of the protection groups in weak acid, ozonolysis, reduction, and acetonide protection gave 499, which was deprotected to give 31.332 Finally, L-fructose (475) has been made in remarkably good yield by a simple base-catalyzed aldol condensation of Lglyceraldehyde (500) and dihydroxyacetone (501). The reaction was conducted in water with a basic ion-exchange resin as the catalyst and led after 5 min to a 91% yield of mixed L-ketones with an L-fructose content of about 70%. Upon treatment of the mixture with acetone and acid and separation a 49% yield of Lfructose acetonide 502 was obtained (Scheme 73).333 As Lfructose can be obtained by hydrolysis of 502 this is obviously one of the simplest and best yielding routes to L-fructose.

arabinose 20, which is the only readily available L-pentose as outlined in the Historical Aspects section. A very direct synthesis was reported by Matsumoto and co-workers using a benzoin condensation between 2,3,4,5-tetra-O-acetyl-L-arabinose (488), available from L-arabinose through the dithioacetal, and formaldehyde catalyzed by benzothiazolium bromide (Scheme 71). From 488 the L-fructose derivative 489 was formed in high yield and then deprotected with Ba(OH)2 to give 475 in 72% yield overall yield from 20.329 The synthesis of L-fructose (475) is perhaps more logically carried out from L-arabinoic acid, the oxidation product of Larabinose, as addition of a nucleophile should lead to the correct oxidation state at C-2. Wolfrom and Thompson made the Larabonyl acid chloride 491 from L-arabinoate 490 and reacted it with diazomethane to form a diazoketone 492. Acidic decomposition of 492 gave the fructose derivative 493, which was saponified to 475 (Scheme 72a).330 A related synthesis was reported by Bessiére and Morin.331 They started from 3,4-O-isopropylidine-L-arabinose (494) and oxidized it to the corresponding lactone which was benzylated to give 495. Addition of iodomethyllithium gave 496. Hydrolysis and deprotection gave 475 (Scheme 72b). L-Tagatose (31) has been made by addition of two carbons to a tetrose (Scheme 73a). The L-threose derivate 497 was reacted

6. CHEMOENZYMATIC SYNTHESIS OF L-HEXOSES Enzymatic- and microbial-assisted synthesis of L-sugars can be quite powerful and efficient. These methods are by no means new in the application to synthesis of L-sugars as even the Reichstein synthesis of vitamin C relied on a microbial oxidation AJ


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Scheme 76. Enzymatic Epimerization of Ketoses

Scheme 77. Isomerization of Ketoses to Aldoses

of D-glucitol to L-sorbose as outlined in the Historical Aspects.87 However, recently these methods have experienced resurgence, and several recent reviews cover some of the latest developments.334,335 In this text we will obviously not dwell on material that has been covered so well by others but concentrate on presenting an overview over uncovered recent work. Also, work where no actual preparation of the pure hexose was performed is omitted. The methods that have been used for biosynthetic preparation of L-hexoses are as follows. (1) Enzymatic or microbial oxidation of an alditol into an L-aldose or L-ketose. The alditol may be derived from a D-hexose when the oxidation is selective for C-5 or C-6. (2) Enzymatic isomerization/epimerization at C-3 of a ketohexose. In this manner, one L-ketohexose may be transformed into another. (3) Enzymatic isomerization of an L-aldose into an L-ketose and vice versa. (4) Synthesis of an L-ketose from dihydroxyacetonephosphate and L-glyceraldehyd using an aldolase. In the following we will cover these methodologies in turn. It should be mentioned here that a combination of 1−3 has been used by Ken Izumori to devise a strategy for synthesis of the 24 stereoisomeric hexoses.334

(508) (Scheme 75).87 There is considerable literature on the latter process as it is the first step of a two-step biotechnological process for preparation of vitamin C from 508.341−344 Many smart developments such as immobilized organisms,345−349 thermoresistant strains,350 fed-batch methods,351−355 continuous fermentation,356 computer-coupled substrate feeding,357 and using oxygen vectors358 have been reported. Yields are frequently over 90%,359 but byproducts such as D-fructose and D-mannitol can be formed,360 and rates can be limited.361 Aldoses can also be made by oxidation of alditols. A recombinant E. coli was used to oxidize D-glucitol (508) and galactitol (506) at C-6 giving L-gulose (159) and L-galactose (30), respectively.362 L-Glucose (159) and L-galactose (20) have also been made by using galactose oxidase to transform 506 and 363 D-glucitol 508, respectively. 6.2. Epimerization of Ketoses D-Tagatose

3-epimerase is a promiscuous enzyme, which catalyzes the epimerization of a range of ketoses including Lisomers. Izumori and Fleet carried out several epimerizations of deoxyketoses with this enzyme. 1-Deoxy-L-fructose (505) was converted into a 3:1 mixture of 505 and 1-deoxy-L-psicose (509, Scheme 76a).364 Similarly, 6-deoxy-L-fructose (510) was converted into a 1:1 mixture of 510 and 6-deoxy-L-psicose (511) by the enzyme (Scheme 76b). The epimers were separated using chromatography on an ion-exchange column on calcium form. Itoh and Izumori have shown that L-fructose (475) can be made in a similar manner by isomerization of L-psicose (479) and that L-tagatose (31) can be made from L-sorbose (452, Scheme 76c and 76d).365

6.1. Oxidation of Alditols

This strategy for L-hexose synthesis has recently been demonstrated quite effectively by Fleet and Izumori. Hydrogenation of L-rhamnose (503) using Raney nickel catalysis gave the 6-deoxy-L-mannitol (504), and subsequent microbial oxidation at C-5 led to 1-deoxy-L-fructose (505, Scheme 74).335,336 The overall yield of the two steps was 74%. Other Lketoses have been synthesized in this manner such as L-tagatose (31) by microbial oxidation of galactitol (506),337,338 L-fructose (475) from L-mannitol (176),339 L-psicose (479) from allitol (507),340 and obviously L-sorbose (452) by oxidation of sorbitol AK


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Scheme 78. Synthesis of Ketoses Using Aldose

6.3. Isomerization between Ketose and Aldose

7. SYNTHESIS OF 6-DEOXY-L-HEXOSES FROM CARBOHYDRATES The deoxy-L-sugars constitute a class of carbohydrates widely distributed in nature (see Figure 3). Many of these deoxy sugars are known as component of natural products where they confer unique biological properties on the natural substance. Therefore, the synthesis of deoxy and dideoxy sugars has been extensively explored and reviewed.379−383 In the following section we wish to focus on the various methods used for the preparation 6-deoxy-Lhexoses.

L-Talose (512) can be made by isomerization of L-tagatose (31) using L-rhamnose isomerase (Scheme 77).366 The thermodymanic equilibrium is heavily in favor of the ketose, so the final ratio between 31 and 512 was 9:1. Nevertheless, the isomers could be separated using chromatography on an ion-exchange column on calcium form, and a 7% yield of crystalline L-talose (512) was obtained on a gram scale.367 A recombinant Lrhamnose isomerase has been used to convert L-tagatose (31) to L-galactose (30), the C2 epimer of L-talose (512). This enzyme transforms the tagatose into an epimeric mixture of 30 and 512, and at equilibrium the ratio of 31:30:512 was 6:3:1. It was possible to get 26% pure L-galactose (30) by the process (Scheme 77a).368 L-Glucose (23) can be made by isomerization of L-fructose (475) using D-arabinose isomerase present in a mutant strain of Klebsiella pneumonia. In this manner L-glucose (23) could be made in 35% yield from L-fructose (475).369 L-Fructose (475) has itself been made from L-mannose (24) using isomerases present in cell-free extracts of Aerobacter aerogenes (Scheme 77b). This isomerization led to a 2:3 ratio of 24 to 475, and L-fructose (475) could be isolated.370 Isomerization of L-fructose (475) to a mixture of 475 and L-glucose (23) has also been performed using 371 L-fucose isomerase, and 23 was isolated in 29% yield. In a similar fashion, L-fucose has been made by isomerization of Lfuculose using fucose isomerase. This reaction gives a 9:1 equilibrium mixture in favor of L-fucose.372

7.1. C5 Epimerization

As described earlier epimerization of C5 in the D-sugar series results in the corresponding L-sugars (Figure 4). This methodology has also been applied for the preparation of 6-deoxy-Lsugars. An early example from Reichstein and Meyer and Baker and co-workers prepared 5,6-anhydro-L-idofuranose from Dglucose and opens the epoxide to afford 6-deoxy-L-idose.109,384 Another early example reported the SN2 displacement of an O5 tosylate in methyl 6-deoxy-D-allofuranoside 517 with benzoate to produce the methyl 6-deoxy-L-talofuranoside 518 (Scheme 79a).385 The starting material was prepared from 2,3-Oisopropylidene-L-rhamnose.386 This method has also been used Scheme 79. Synthesis of 6-Deoxy-L-sugars via C5 Epimerization

6.4. Aldolase Reaction L-Ketohexoses

can be obtained by an aldolase-catalyzed reaction between dihydroxyacetone and L-glyceraldehyde.373 L-Fructose (475) was prepared by Wong’s group using rhamnulose-1phosphate aldolase-catalyzed condensation of dihydroxyacetone phosphate (513) and L-glyceraldehyde (514) followed by dephosphatation with acid phosphatase (Scheme 78a).373 This gave a 37% yield. Later the method has been modified to allow preparation of L-fructose (475) and L-fructose from the racemic 514374 or from dihydroxyacetone.375 Wang and collaborators used L-fuculose-1-phosphate aldolase to synthesize L-fructose (475) and L-tagatose (31) from 513 and 514. The two ketoses were subsequently separated (Scheme 78b).376 L-Sorbose (452) can be made when rabbit fructose-1,6phosphate aldolase is used to condensate L-glyceraldehyde (514) and dihydroxyacetone phosphate (513).377 The yield was 28% (Scheme 78b).378 AL


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7.2. Other Epimerizations of 6-Deoxy-L-hexoses

to prepare a 6-deoxy-L-gulofuranoside derivative from Dmannose.112 Rearrangement of 4-brosylated 6-deoxy-D-mannopyranoside 519 into a mixture (7:1) of a ring contracted of 6deoxy-D-talofuranoside 520a and 6-deoxy-L-allofuranoside 520b (Scheme 79b) has also been described.387 Formation of the 6deoxy-D-talofuranoside 520a resulted from inversion at C4, while the 6-deoxy-L-allofuranoside 520b was formed via inversion at both C4 and C5. Starting from 3-O-methyl-D-galactofuranose 521 inversion at C5 afforded the 3-O-methyl-L-altropyranose 525, also known as L-vallarose and found as a cardiac glycoside (Scheme 79c).388 The 5,6-anhydro furanoside 523 was prepared by regioselective benzoylation, mesylation of the remaining hydroxyl group to give 522, followed by formation of the epoxide by treatment with NaOMe. The epoxide was opened with LiAlH4, which afforded the 6-deoxy-L-altrofuranoside 524. Subsequent acidic hydrolysis and peracetylation afforded 3-Omethyl-6-deoxy-L-altropyranoside 525. A similar approach via 5,6-anhydro-1,2-O-isopropylidene-3-O-methyl-β-L-mannofuranose has been explored for the preparation of 3-O-methyl Lrhamnose (L-acofriose), a sugar found in certain cardiac glycosides.389 Lunau and Meier explored C5 epimerization under Mitsunobu conditions of acyclic dithioacetals. The synthesis started from Dfucose derivative 526 and afforded the corresponding 6-deoxy-Laltrose 530.124 Although the crucial Mitsunobu inversion from 527 to 528 gave a good yield (61%), installation of the anomeric dithioacetal (527) only a gave low yield (28%), thereby limiting the utility of this procedure.

Since both L-fucose and L-rhamnose (6-deoxy-L-galactose and 6deoxy-L-mannose) are commercially available these sugars have been applied as the starting point for various other 6-deoxy-Lhexoses via different epimerization methods. These methods will be discussed below. 7.2.1. Reduction of Carbonyl-Containing 6-Deoxy-Lhexoses. Stereoselective reduction of 6-deoxy-L-hexoses having a carbonyl group in the 2, 3, or 4 position (6-deoxy-L-ulosides) is a well-studied method for epimerization at the given carbon. This is accomplished by oxidation of the unprotected hydroxyl group followed by (stereoselective) reduction. Often the reduction is very selective due to (non)chelation to α-neighboring groups and 1,3-diaxial interactions.235,390,391 Following this route Collins and Overend prepared 6-deoxy-L-taloside 533 (Scheme 81a). First, the free hydroxyl 531 was oxidized to the 2-uloside 532 followed by stereoselective hydrogenation using Adams’ catalyst which after hydrolysis and peracetylation afforded 6deoxy-L-taloside 533.392,393 In a search for a good method for the preparation of the difficult β-L-rhamnosides, Lichtenthaler and co-workers found that 2-ulosyl bromides like 535 gave excellent β-selectivity for both isopropanol (e.g., to 536) and sugar acceptors upon activation with silver carbonate (Scheme 81b).394−396 The 2-ulosyl bromide 535 was prepared by treatment of the acyloxy-L-rhamnal 534 with N-bromosuccinimide (NBS). The reduction of the uloside 536 was affected by NaBH4, giving rise to the axial anomer 537 with high stereoselectivity. Interestingly, the selectivity was influenced by the protecting group at the 3-O position as a 3-O-benzoyl group, instead of a 3-O-benzyl group, gave a selectivity that dropped to 3:1. Preparation of labeled (2-2H)-L-rhamnosides has also been reported using sodium borodeuteride in methanol-d4 for the reduction of 2-uloside.397 Here, it was found that the anomeric group needed to be equatorial. For the total synthesis of the natural product Apoptolidin 9 (Figure 3), a glycosylated macrolide, 6-deoxy-L-glucose was needed. This compound was independently prepared by the groups of Nicolaou and Koert (Scheme 81c).398−401 Starting from L-rhamnose the 3-O-methylated L-rhamnoside 538 was prepared. The remaining 2-hydroxyl group was oxidized under Swern condition affording the 2-uloside 539. Stereoselective reduction with NaBH4 afforded the 6-deoxy-L-glucoside 540. The selectivity was explained by the hydride attacking from the opposite side of the bulky and axial anomeric substituent.399 A

Scheme 80. Synthesis of 6-Deoxy-L-altroside via Head-to-Tail Inversion

Scheme 81. Stereoselective Reduction of 2-Ulosides

AM


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side.421 Hasegawa and co-workers also explored the preparation of various 6-deoxy-L-hexoses from L-fucose and L-rhamnose via substitutions of the corresponding triflate.422 The substitution was affected by reacting 3-O-triflate L-fucoside 549 with CsOAc in the presence of crown ether, affording 6-deoxy-L-guloside 550 (Scheme 83b). In a similar approach, 6-deoxy-L-taloside was prepared from methyl thio-α-L-rhamnoside and 6-deoxy-Lglucoside was synthesized from the corresponding methyl thioβ-L-fucoside.422 A 6-deoxy-L-guloside with an anomeric phenyl thioacetal has also been prepared by the same approach.235 Other groups have also reported the preparation of 6-deoxy-L-glucoside via nucleophilic displacement of triflates from L-fucoside.55,423 LFucofuranoside has been synthesized by replacement of a 3-Omesylate of a 6-deoxy-L-gulofuranoside derivative with sodium benzoate.424 Opening of anhydro sugars with oxygen nucleophiles also leads to inversion of the stereocenter. Furthermore, these opening are, according to the Fürst−Plattner rule, very selective for the 1,2-trans diaxial products.425 An early report utilizing this methodology has been reported for the preparation of 6-deoxy-Lidose from either methyl 3,4- or 2,3-anhydro-6-deoxy-α-Ltaloside but with low yield.426 Preparation of 6-deoxy- L-altrose was also explored starting from L-rhamnoside 551 in which the benzylidene was opened selectively with NBS to give 552 (Scheme 84).427 Subsequently, epoxide formation to give 553 was affected with NaOMe, which after treatment with a second portion of NaOMe afforded the methyl 3-O-methyl-6-deoxy-α-Laltroside 554. Hydrolysis of this glycoside produced the 3-Omethyl-6-deoxy-L-altrose, also known as L-vallarose, a constituent of cardiac glycosides. 7.2.3. Preparation of All Eight 6-Deoxy-L-hexoses. From the commercially available L-fucose and L-rhamnose all eight 6deoxy-L-hexoses as their thioglycosides have been prepared as described by Bols and co-workers.235 In this study various epimerization methods, as described above, were explored in order to synthesize all of the desired 6-deoxy-L-hexoses. Initially, the unprotected phenyl 1-thio-L-glycosides 555 and 566 were prepared according to standard procedures.428−430 Starting from L-fucoside 555, 6-deoxy-L-glucoside 558 was prepared by regioselective protection of the 2,3-trans diol with a butane1,2-diacetal to give 556 followed by epimerization using the Mitsunobu reaction and removal of acyl group in 557 (Scheme 85).431,432 Preparation of 6-deoxy-L-guloside 563 and 6-deoxy-L-alloside 565 was performed by orthoester formation followed by benzoylation of the remaining 2-hydroxyl group (Scheme 86).235 Subsequent opening of the orthoester afforded the alcohol 560. Inversion of this hydroxyl was realized by triflation and substitution with CsOAc in the presence of crown ether to give the fully acylated 6-deoxy-L-guloside 561. In order to invert the 4-hydroxyl group the acyl groups were removed and the 2,3cis diols were isopropylidenated to give 563. Next, epimerization was performed by oxidation under Swern condition and

disaccharide containing 6-deoxy-L-glucose has also been synthesized from the corresponding 3-O-benzoyl 2-uloside by stereoselective reduction.402 Stereoselective reduction of 3-ulosides has been used to prepare 6-deoxy-L-altrosides.235,403−406 For instance, L-rhamnoside 541 was oxidized to 3-uloside 542 followed by stereoselective reduction with NaBH4 to give 543 having an axial C3 substituent (Scheme 82a).403 A highly explored method for the Scheme 82. Stereoselective Reduction of 3- And 4-Ulosides

synthesis of 6-deoxy-L-taloside is the stereoselective reduction of 2,3-isopropylidene 4-oxo-L-rhamnoside.235,393,407−416 This method was, for instance, used by oxidizing the free hydroxyl in 544 with Cornforth reagents followed by stereoselective reduction of 545 to give the 6-deoxy-L-taloside 546 (Scheme 82b).409 Deuterium has also been introduced by the reduction with NaBD4.408 7.2.2. Epimerization at C2, C3, and C4 by Other Methods. The inversion of hydroxyl groups has also been investigated as a means for synthesizing rare 6-deoxy-L-hexoses. This can be accomplished by nucleophilic displacement of sulfonates with inversion of stereochemistry.417−419 In an early report by Jones and Nicholson 2-O-tosyl-L-fucoside 547 was heated in aqueous hydrochloric acid resulting in the formation of 6-deoxy-L-taloside 548 (Scheme 83a).420 Methyl 2,5-di-OScheme 83. Preparation of 6-Deoxy-L-hexoses by Substitution

methyl-α-L-rhamnofuranoside has also been converted by treatment with sodium benzoate to afford the L-altrofuranoScheme 84. Openings of 6-Deoxy Anhydro-L-hexoses

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concomitant installation of orthogonal protecting groups.433 The reaction is general for cyclic triols (or tetrols) with continuous hydroxyl groups in a cis−trans sequence. The reaction proceeds with inversion of the central C atom of the cis−trans triol unit. This epimerization results in the formation of a carbamoyl protecting group and a newly formed acetal with inversion of configuration of the central C atom. The method utilizing chloral/dicyclocarbodiimide (DCC) has been used for the synthesis of methyl 6-deoxy-L-altroside 579 starting from methyl L-rhamnoside 578 (Scheme 88a) and a dimer using DCC and a perfluorinated dialdehyde.434,435 Starting from thiofucoside 555 6-deoxy-L-guloside 580 was prepared (Scheme 88b).235 The carbamate could easily be deprotected with NaOMe, but removal of the trichloroethylidene acetal proved more difficult in the presence of the thioacetate. Thus, dehalogenation using Bu3SnH/1,1′-azobis(cyclohexanecarbonitrile) (ABCN) resulted in partial removal of the anomeric thioacetate. 6-Deoxy-Lgulosides in the form of methyl 6-deoxy-L-guloside and 6-deoxy436−438 L-gulosyl azide have been prepared by the same method.

Scheme 85. Synthesis of Protected 6-Deoxy-L-galacto- and 6Deoxy-L-glucoside from Thio L-Fucoside

stereoselective reduction with L-selectride which produced the desired 565. From L-rhamnoside 566 the 6-deoxy-L-taloside 569 was prepared by regioselective isopropylidenation to give 567 followed by Swern oxidation (568) and stereoselective reduction with NaBH4 (569, Scheme 87).235 The remaining 6-deoxy-Laltroside 575 and 6-deoxy-L-idoside 577 were also synthesized from 6-deoxy-L-rhamnoside 566 (Scheme 87b).235 The synthesis began with the regioselective orthoester formation and silylation of the remaining 4-hydroxyl group to give 570. Then the orthoester was opened to alcohol 571, which was epimerized by oxidation and stereoselective (only isomer) reduction with Lselectride with concomitant benzoyl migration to produce 6deoxy-L-altroside 573. Interestingly, the selectivity was highly dependent on temperature and choice of reducing agent. Reduction with NaBH4 at room temperature afforded a 4:1 mixture, whereas this changed to 12:1 at −78 °C in favor of the 6deoxy-L-altroside 573. Then the benzoyl was removed with EtMgBr, and the remaining hydroxyl groups were benzylated followed by desilylation to give 6-deoxy-L-altroside 575. The subsequent inversion was realized by a Mitsunobu reaction and deacylation to give the 6-deoxy-L-idoside 577. All eight 6-deoxy-L-hexoses with an anomeric thioacetal were used for the preparation of all eight L-hexoses via C−H activation of the primary methyl at C6 (see Table 2).234 7.2.4. Three-Component Epimerization. A highly attractive three-component reaction has been developed by Miethchen and co-workers which ensures both epimerization and

7.3. 6-Deoxy-L-sugars from Unsaturated Carbohydrates

7.3.1. Hydrogenation of Exocyclic Alkenes. Stereoselective reduction of exocyclic alkenes constitutes an entry to the preparation of 6-deoxy-L-hexoses. The 5-enoglucosides are easily prepared from the corresponding 6-deoxyhalo hexoses. Metal-catalyzed hydrogenation of the exocyclic alkene delivers the 6-deoxy sugars, mostly favoring an equatorial C6 substituent (Re face attack). This method has been explored by various groups for the preparation of 6-deoxy-L-idoside 583 (Scheme 89a) as well as a disaccharide derivative.439−443 Several metal catalysts including palladium on carbon, Raney nickel, and Adam’s catalyst (PtO2) in various solvents have been screened with different results.439,442 The same method has been applied for the synthesis of L-fucoside 586 starting from D-altrose (Scheme 89b); both gave a mixture of L-fucoside 586 and its C5 epimer 6-deoxy-D-altroside (4.4:1).444,445 Starting from a Dmannose derivative 587 or D-allose derivative 590, 6-deoxy-Lguloside 589 and 6-deoxy-L-taloside 592 were prepared (Scheme 89c and 89d).446 The final stereoselective hydrogenations were dependent on the metal catalyst where it was found the Raney nickel produced the best result for the preparation of 6-deoxy-Lguloside 589 and palladium on carbon was the best for 6-deoxy-Ltaloside 592.

Scheme 86. Preparation of Protected 6-Deoxy-L-gulo- and 6-Deoxy-L-alloside from Thio L-Fucoside

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Scheme 87. Preparation of 6-Deoxy-L-talo-, 6-Deoxy-L-altro-, and 6-Deoxy-L-idoside from Thio L-Rhamnoside

protecting group manipulation, and dihydroxylation under Upjohn condition (Scheme 92a).450−452 Later, the hexose was converted to the trichloroacetimidate donor and used for the synthesis of the potent antitumor agent calicheamicin. The 2,3unsaturated hexose 605, prepared by a Ferrier rearrangement (Scheme 92b), was deacetylated followed by inversion of the 4OH under Mitsunobu conditions (Scheme 92b).453 Subsequent dihydroxylation of the allylic alkene 608 with osmium tetroxide afforded a 2:1 mixture of 6-deoxy-L-taloside 609 and 6-deoxy-Lguloside 610. Steroidal aglycones, like 5α-cholestan-3β-ol, have also been used in the Ferrier rearrangement, giving compound 612 (Scheme 92c).454 Subsequent halohydrin formation was effectuated by reaction with N-bromosuccinimide (NBS), water, and an acid scavenger. Conversion of the axial bromo substituent in 613 into an equatorial hydroxyl group was performed by an intramolecular substitution first by treatment with ethyl (chloroformyl)acetate to give 614 followed by reaction with NaH in HMPA affording 615. Deacylation produced the unprotected 6-deoxy-L-alloside 616. The same procedure has also been used for the preparation of an analogue of the cardiac glycoside orbicuside A.455 Epoxidation of 6-deoxy-L-glycals followed by opening of the epoxide has been shown to lead to the preparation of 6-deoxy-Lglycosides. The epoxidation has been accomplished with DMDO, methyltrioxorhenium/urea hydrogen peroxide complex, or RuCl3/CeCl3/NaIO4 (Scheme 93).456−460 Opening of the epoxide in situ or afterward with various nucleophiles resulted in 6-deoxy-L-glucosides 619 having different anomeric functionalities (methyl, uridine diphosphate, dibutyl phosphate, and acetate). 7.3.3. From Other Unsaturated Carbohydrates. Epoxide ring opening of the epoxypyranoside 88 (prepared from alkene, see Scheme 15) with 13C-labeled methylmagnesium iodide afforded the 6-deoxy-L-altroside 620 with complete regio- and stereoselectivity (Scheme 94).161

Scheme 88. Three-Component Reaction for the Synthesis of 6-Deoxy-L-hexoses

The highly constrained exocyclic alkene 593 (for preparation, see Scheme 16) has been stereoselectively reduced using palladium on carbon to give 6-deoxy-L-idofuranoside 594 (Scheme 90).3,60,164,447 This pyranoside was liberated by acidic treatment followed by peracetylation to give 6-deoxy-Lidopyranoside 595. Epimerization of C3 was accomplished by oxidation and stereoselective reduction of compound 597 derived from 596 by removal of the 3,5-isopropylidene and regioselective silylation to give 598. 7.3.2. From 6-Deoxy-L-glycals. The Lewis-acid-catalyzed Ferrier rearrangement of 6-deoxy-L-glycals represents an entry to the preparation of 6-deoxy-L-hexoses after functionalization of the 2,3-unsaturated glycoside (Scheme 91).448,449 Furthermore, an anomeric aglycone is installed as well during the allylic shift. The 6-deoxy-L-glycals from either L-rhamnose or L-fucose (Lrhamnal or L-fucal) are commercially available or easily prepared by treatment of their 6-deoxy-L-glycosyl bromide with zinc in acetic acid. From L-rhamnal diacetate 601 the L-rhamnoside 602 has been prepared by a Ferrier rearrangement with benzyl alcohol, AP


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Scheme 89. Stereoselective Reduction of 5-Enoglycosides

Scheme 90. Stereoselective Hydrogenation of Exocyclic Alkene and Regioselective Epimerization

Scheme 91. Ferrier Rearrangement of 6-Deoxy-L-glycals

7.4. Addition to Carbohydrate C5 Aldehydes

endocyclic oxygen was blocked by one molecule of Me3Al. Preparation of 6-deoxy-L-talo derivatives has also been explored, but the addition was less stereoselective.464,465

Stereoselective addition of methyl metallic reagents to C5 aldehydes has been shown to afford 6-deoxy-L-sugars. This method was used by Wolfrom and Hanessian for the preparation of 6-deoxy-L-idose 622 starting from D-glucose (Scheme 95a).461 The high stereoselectivity was proposed to derive from a chelation between the methyl Grignard reagent to the endocyclic oxygen and the C5 carbonyl in 93. High stereoselectivity was also encountered for the preparation of L-fucosides (Scheme 95b).462,463 The C5 aldehyde was prepared from methyl α-Darabinofuranoside tribenzoate. When the aldehyde 624 was subjected to methylmagnesium iodide/zinc chloride high stereoselectivity was observed in favor of the L-fucoside 625. On the other hand, when trimethylaluminum in hexane was used the opposite stereoisomer 623 was produced (96% de, 6-deoxyD-allofuranoside). The high stereoselectivity was explained by chelation of the methyl Grignard reagent to the endocyclic oxygen to produce L-fucofuranoside 625. The opposite stereomer was explained to arise from nonchelation in which the

7.5. Head-to-Tail Inversion

The interesting head-to-tail approach for the formation of 6deoxy-L-hexoses takes advantage of the selective removal of dithioacetal groups using the Mozingo reaction with Raney nickel (reductive desulfurization).466,467 This results in the conversion of the anomeric carbon to the new C6. Selective oxidation of the primary alcohol affords the new anomeric center, thereby completing the head-to-tail inversion. This method has been used for the formation of 6-deoxy-L-glucose from D-glucoD-guloheptose 626 (Scheme 96a) and L-fucose from D-galactose (Scheme 97b).468,469 The preparation of 6-deoxy-L-gulose via a head-to-tail approach using reductive desulfurization has been reported by Ireland and Wilcox (Scheme 97c).470 In their approach D-glucurono-6,3-lactone 631 was converted into 632 via dithioacetal formation and isopropylidenation. Next, reductive desulfurization was affected by Raney nickel, and the AQ


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Scheme 92. Preparation of 6-Deoxy-L-glycosides from L-Rhamnal

corresponding L-fucofuranoside by replacement of a 3-Omesylate with sodium benzoate (scheme not shown).424 In a recent report by Izumori, Fleet, and co-workers L-ascorbic acid was used as starting material for the preparation of L-fucose (Scheme 97).471 First, hydrogenation and isopropylidenation afforded lactone 190, which underwent a stereoselective addition of methyllithium (93% de) followed by reduction of the hemiacetal to give 635. Next, selective manipulation of the isopropylidene protecting groups produced diol 637 via fully protected lactol 636. Then L-fucose was liberated via periodate cleavage and removal of the remaining isopropylidene groups.

Scheme 93. Opening of Epoxides Derived from L-Rhamnals

Scheme 94. Synthesis of L-Fucoside from 4-Deoxypentenoside

7.6. Rearrangement of 6-Deoxy-L-sugars

As for the rearrangement of the aldoses (Scheme 30) 6-deoxy-Laldoses also undergoes epimerization catalyzed by molybdate ions. Exposing L-fucose to molybdic acid in water resulted in a 4:1 mixture of L-fucose and 6-deoxy-L-talose (Scheme 98).472 From this mixture the 6-deoxy-L-talose could be isolated. The opposite reaction has been used to convert 4-2H-labeled 6-deoxy-L-talose into L-[4-2H]-fucose.408 Microwave irradiation has been shown to accelerate the reaction drastically.473 The same method has

remaining hydroxyl group was silylated to give 633. The 6-deoxyL-gulose was liberated by reduction of the lactone and subsequent acidic hydrolysis. A similar method starting from Dglucurono-6,3-lactone 631 has been used for the preparation of 6-deoxy-L-gulofuranoside, which also could be converted to the Scheme 95. Addition of Methyl Metallic Reagents to C5 Aldehyde

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Scheme 96. Synthesis of 6-Deoxy-L-hexoses via Head-to-Tail Inversion

Scheme 97. Synthesis of L-Fucose from L-Ascorbic Acid via a Head-to-Tail Approach

of neighboring group participation, and shielding of the βface.480,481 Working in the D-manno series, Crich and co-workers discovered that a 4,6-O-benzylidene protecting group was βdirecting under preactivation conditions due to the influence of the benzylidene.482−486 When donor 642 was subjected to preactivation condition followed by the addition of acceptor 643 to the β-linkages, 644 was observed as the only isomer. Subsequent desulfurization with Raney nickel afforded the β-Lrhamnoside 645 (Scheme 99b). Although this method gave high yield and was highly β-selective the donor is nontrivial to synthesize and needs to be prepared by substitution of the primary hydroxyl group with a thiol in L-mannose followed by benzylidene formation.

Scheme 98. Epimerization of L-Fucose Catalyzed by Molybdate Ions

been utilized to epimerize L-rhamnose to a mixture of Lrhamnose and 6-deoxy-L-glucose (1:1.5 heating, 1:2.3 MW irradiation).473−477 7.7. Deoxygenation of L-Hexoses

From L-hexose derivatives their 6-deoxy counterparts can easily be obtained by dehalogenation, deoxygenation, or desulfurization. This method has been explored extensively in the D-series but should also be possible in the L-series where a few examples have been reported.478 Dehalogenation of 6-bromo-6-deoxy-Lgalactoside 640, prepared by opening of the benzylidene 639 with NBS, was accomplished by palladium-catalyzed hydrogenation to give peracetylated L-fucose after acetylation (Scheme 99a).479 In a search for a good approach for the synthesis of β-Lrhamnosides Crich and Li explored 4-O-6-S-cyanobenzylideneprotected 6-thiorhamnosyl thioglycoside 642 in glycosylation under preactivation conditions.206 The β-rhamnosides are considered one of the most difficult glycosidic linkages to prepare due to an unfavorable anomeric effect, the Δ2 effect, lack

8. DE NOVO SYNTHESES OF 6-DEOXY-L-HEXOSES 8.1. Diels−Alder Reaction

An early report by David and co-workers explored the formation of disaccharides via cycloaddition of butyl glyoxylate with a chiral-protected dienyl ether of glucose (Scheme 100).487 In order to install the diene moiety on diacetone glucose 94 the 3hydroxyl group was converted to the phosphonium ion 647 via (methylthio)methyl ether 646. Subsequent Wittig olefination with acrolein produced a separable mixture of trans and cis diene 648. Cycloaddition between tert-butyl glyoxylate and trans diene 648 afforded a mixture of four stereoisomers which could be AS


Chemical Reviews

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Scheme 99. Dehalogenation and Desulfurization of L-Hexoses

Scheme 100. Preparation of the Disaccharide Precursor via Hetero-Diels−Alder Reaction

Scheme 101. Completion of the Disaccharide Containing L-Fucose

converted into α-D-649 and α-L-649 under acidic conditions. Subsequently, the ester in L-649 was reduced to the alcohol 650. Precursor 650 was deoxygenated in three steps to give 651 followed by epoxidation (Scheme 101).488 Subsequently, the epoxide was opened to the allylic alcohol 653 by treatment with DBU and trimethylsilyl iodide. Inversion of the allylic alcohol by oxidation and stereoselective reduction afforded allylic alcohol 654, which underwent dihydroxylation to give disaccharide 655 containing the L-fuco unit. Although this procedure is interesting from an academic point of view, the route has some flaws. One could hope that the D-glucofuranose would induce much greater selectivity in the hetero-Diels−Alder reaction, but this is not the case. Furthermore, the formation of the diene gave rise to a mixture of trans and cis dienes in which only the trans diene could be used. On the other hand, this method constituted an

early example of hetero-Diels−Alder reaction for the preparation of L-sugars. Danishefsky and co-workers also explored a cycloaddition reaction as a means for generating L-fucose (Scheme 102).489 In their approach a mixture of dienes 656 was reacted with acetaldehyde catalyzed by zinc chloride which after treatment with TFA afforded of mixture of enone 657 and 658. Subsequent stereoselective reduction under Luche’s conditions generated Lfucal 659 in which the benzoyl group was exchanged with acetyl groups. To complete the synthesis, L-fucal 660 was treated with mCPBA in the presence of methanol, which after acetylation afforded a mixture of α- and β-methyl L-fucoside 661. 8.2. Enantioselective Aldol Reaction

An elegant asymmetric synthesis of 6-deoxy-L-talose from achiral starting materials has been disclosed by Mukaiyama and coAT


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Scheme 102. Diels−Alder Reaction for the Synthesis of LFucoside

Scheme 104. Methodology for the Preparation of 6-Deoxy-Lhexoses Starting from 2-Acetylfuran

workers.490,491 The method was based on the cross-aldolization of enoxysilane 662 and crotonaldehyde in the presence of the chiral inducer, diamine 663 (Scheme 103a). Both high

protection of the emerging alcohol produce the allylic alcohol 676 in which the double bond can be manipulated to afford the 6deoxy-L-hexose. The described method was used to prepare L-rhamnose by stereoselective reduction of enone 678 and protection of the resulting alcohol to give 679 (Scheme 105a).494 Subsequent dihydroxylation under Upjohn condition afforded L-rhamnoside 680. The group of O’Doherty has shown that enone 681 with an anomeric tert-butyl carbonate protecting group could be glycosylated with benzyl alcohol catalyzed by Pd(0) followed by epoxidation to give 682 (Scheme 105b).495 Stereoselective reduction under Luche’s conditions followed by opening of the 2,3-anhydro-L-hexose 683 with Sc(OTf)3 in AcOH produced the 6-deoxy-L-altroside 684. Wharton and Bohlen disclosed a rearrangement of epoxy ketones to their allylic alcohols by treatment with hydrazine.496 This rearrangement was utilized by O’Doherty and co-workers to convert epoxy ketone 685 to allylic alcohol 686 (Scheme 105c).497 Subsequently, the resulting alcohol was inverted by oxidation and stereoselective reduction followed by dihydroxylation with a chiral ligand ((DHQD)2DPP) to produce 6-deoxy-L-alloside 688 as the major product (>10:1, 6-deoxy-L-allo/L-fuco). The L-fucoside could be favored by silylation (TBS) of the 2-hydroxyl group and performing the dihydroxylation under Upjohn conditions (OsO4/NMO, 1:7, 6-deoxy-L-allo/L-fuco, 95%). Wharton rearrangement has also been explored for the preparation of 6deoxy-L-idose 691 or L-rhamnose 692 (Scheme 105d).498 Epoxidation of the allylic alcohol with mCPBA afforded the 3,4-anhydro hexose 690. The condition for the epoxide opening was used to prepare either 6-deoxy-L-idose 691 or L-rhamnose 692. 6-Deoxy-L-idose 691 (6-deoxy-L-ido/L-fuco 99:1) was favored when opening the epoxide with Sc(OTf)3 in AcOH, whereas L-rhamnose 692 was favored by treatment with NaOH (6-deoxy-L-ido/L-fuco 1:5). This methodology was also explored for the preparation of L-idose or L-mannose but gave either low yield or low selectivity.498 The great advantage of the approach described above is the possibility to perform a palladium-catalyzed glycosylation on the anomeric tert-butyl carbonate enone 681 (see Scheme 105b). This methodology has been explored extensively by O’Doherty and co-workers for oligosaccharide synthesis, natural product preparation, and structure−activity relation studies.499−504 The method enables iterative glycosylation and thereby a quick assembling of highly complex oligosaccharides (Scheme 106).499 13 C-Labeled L-fucose in the C-1 and C-2 position has been prepared based on homologation of chiron 695 (Scheme 107).505 Elongation to the α,β-unsaturated ester 697 was performed with a labeled Wittig ylide on the corresponding aldehyde derived from the reduction of 695 to the alcohol 696 and subsequent oxidation with Dess−Martin periodinane

Scheme 103. Preparation of 6-Deoxy-L-hexoses via Asymmetric Aldol Reaction

diastereoselectivity (anti/syn > 98:2) and enantioselectivity (>97% ee for anti aldol) were observed. Subsequent dihydroxylation with moderate facial selectivity afforded aldonolactone 665 and 666 (78:28) from which 6-deoxy-L-talose 667 was prepared by reduction of δ-lactone 666 and debenzylation. Applying an analogous approach, Kobayashi and Kawasuji synthesized L-fucose starting from silyl ketene acetal 668 and crotonaldehyde (Scheme 103b).492 8.3. Diastereoselective Alkene Dihydroxylation

A highly attractive method for the preparation of 6-deoxy-Lhexoses (and L-hexoses, see Scheme 55) have been developed by O’Doherty and co-workers.238 Asymmetric transfer hydrogenation (developed by Noyori) of 2-acetylfuran 673 provides the (S)-furan alcohol 674 (Scheme 104).493 This furan derivative can be oxidized in an Achmatowicz rearrangement often deploying N-bromosuccinimide in the presence of simple alcohols or di-tert-butyl dicarbonate ((Boc)2O) to give enone 675.286,287 A similar approach has been applied by O’Doherty on 1-(2′-furyl)-2-tert-butyldimethylsilanyloxyethan-1S-ol. Subsequent stereoselective reduction of the enone moiety and AU


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Scheme 105. Preparation of Various 6-Deoxy-L-hexoses by Manipulation of Enones 678 and 681

Scheme 106. De Novo Synthesis of Disaccharide Containing L-Rhamnose

Scheme 107. Preparation of Labeled L-Fucose by Dihydroxylation

Scheme 108. Preparation of 6-Deoxy-L-glycopyranosides via Hydroalkoxylation of Allene and Ring-Closing Metathesis

the 2,3-unsaturated pyranoside 704 in excellent yield (Scheme 108). Both anomers could be prepared depending on the ligand 705. In principle, this allylic ether can be dihydroxylated, as shown previously, to give various 6-deoxy-L-glycopyranosides.

(DMP). The following Sharpless dihydroxylation afforded ethyl L-fuconate 698 as the only enantiomer which could be converted to the 1,4-lactone and silylated to give 699. Subsequent DIBALH reduction with and conversion of the furanoside to pyranoside yielded the peracetylated L-fucose 701 with C-1 and C-2 labeled. A newly developed method for the preparation of cyclic acetals was recently disclosed by Rhee and collaborators.506 In their method the acyclic acetal was formed by a Pd-catalyzed asymmetric intermolecular hydroaloxylation between alcohol 702 and allene 703 which after ring-closing metathesis provided

9. CONCLUSION This review has discussed the synthesis of L-hexoses using all the methods available to chemists. Despite the fact that L-hexoses have played a very important role in the initial years of carbohydrate chemistry and hence have ben early investigated, AV


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they have remained a niche in organic chemistry and therefore much less studied than the corresponding D-sugars. The limited natural abundance of the L-sugars has, from the beginning, forced chemists to be creative, and as described through the review, many elegant solutions have been developed for synthesizing Lsugars. It is however still the classic methods developed before World War II that dominate the overall picture. With access to new methods in organic synthesis developed over the last decades, there seems to be a slight change in terms of which methods are most attractive. As we described L-sugars can, for example, now be prepared from achiral starting material by using enantioselective reactions or from the abundant 6-deoxy-Lhexoses from C−H activation. Both these approaches allow protective group manipulation along the way, and the glycosyl donors are often prepared directly. These advantages have become more and more important as the focus has moved to oligosaccharide synthesis and away from structure determination, which was a main interest in the first many decades of Lhexose synthesis. It is clearly seen from this review that the Lsugars with industrial or biological interest have received the most attention, whereas others have rarely been prepared and their chemistry less developed. We think that in the coming years the more rare sugars will receive more attention, both as synthetic targets and as mimetics in biological studies. Access to the new methods mentioned in the review and above will pave the way for this development. This review gives an overview of the first 130 years of L-sugar synthesis and provides a platform for finding the best methods for a given target but also information about the areas where methods need to be improved in the future.

reagents. His current research interest is carbohydrate chemistry in general, total synthesis, organosilicon chemistry, and alkyne metathesis.

Mikael Bols was born in 1961 in Copenhagen, Denmark. He received his M.Sc. (1985) and Ph.D. (1988) degrees from the Technical University of Denmark under the Supervision of Professor Inge Lundt. After a Postdoctoral stay in 1988−1989 at Queen’s University, Canada, with Professor Walter Szarek he joined Leo Pharmaceutical Products, where he was a research chemist from 1989to 1991. He then returned to an assistant professorship at the Technical University of Denmark. In 1994 he did a sabbatical stay at Columbia University in Professor Gilbert Stork’s group. In 1995 he went to Aarhus University, where in 2000 he became a Full Professor. Finally, in 2007 he assumed his present position as Head of the Chemistry Department of the University of Copenhagen. His research interests are polar organic molecules and artificial enzymes.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

Christian Marcus Pedersen received his Ph.D. degree in 2007 from Aarhus University under the supervision of Prof. Mikael Bols. During his Ph.D. studies he was a visiting scientist at the University of Illinois at Chicago (UIC) performing research with Professor David Crich. Postdoctoral studies were carried out at University of Konstanz with Professor Richard R. Schmidt, working on the total synthesis of lipoteichoic acid from Streptococcus pneumoniae. He is currently associate professor at the University of Copenhagen, where he is working on the total syntheses of lipoteichoic acids and in various fields of organic chemistry.

Tobias G. Frihed received his Ph.D. degree in Chemistry from the University of Copenhagen (Denmark) in 2014 from the group of Prof. Mikael Bols working with various aspects of carbohydrate chemistry. His Ph.D. studies have focused on understanding the mechanism and effects in β-mannosylations and detecting reactive intermediates in glycosylations. Furthermore, he has applied the hot topic of C−H activation with carbohydrate chemistry for the preparation of the rare but biologically important L-sugars. During his Ph.D. studies he was a visiting scientist in the group of Keith A. Woerpel, New York University, for half a year working with the synthesis of new silylene transfer

ACKNOWLEDGMENTS The Lundbeck Foundation is acknowledged for financial support. ABBREVIATIONS ABCN 1,1′-azobis(cyclohexanecarbonitrile) Ac acetyl AW


Chemical Reviews AIBN BAIB 9-BBN Bn Boc BOM BSP Bu Bz CSA bs cod DABCO DAST DBU DCC DDQ DEAD DHQ DHQD DIAD DIBAL DIPEA DIPF DMAP DMDO DMF DMP DMSO DTBMP Et Fmoc HAD hfc HMPA HOMO KHMDS LUMO mCPBA Me Me4Phen MOM Ms Nap NBS NIS NMO PCC PDC PHAL Piv PMB Pr pyr SAR TBAI TBDPS TBS TEMPO Tf TFA TFAA TFDO

Review

THF TIPDS TIPS TMEDA TMS TMSEt TPAP Ts TTBP UDP UHP

2,2′-azobiisobutyronitrile diacetoxy iodobenzene 9-borabicyclo[3.3.1]nonane benzyl tert-butoxycarbonyl benzyloxy methyl 1-benzenesulfinyl piperidine butyl benzoyl 10-camphorsulfonic acid p-bromobenzenesulfonyl 1,5-cyclooctadiene 1,4-diazabicyclo[2,2,2]octane (diethylamino)sulfur trifluoride 1,8-diazabicyclo[5.4.0]undec-7-ene 1,3-dicyclohexylcarbodiimide 2,3-dichloro-5,6-dicyano-1,4-benzoquinone diethyl azodicarboxylate dihydroquinine dihydroquinidine diisopropyl azodicarboxylate diisobutylaluminum N,N-diisopropylethylamine diisopropylformamide 4-dimethylaminopyridine 2,2-dimethyldioxirane dimethylformamide Dess−Martin periodinane dimethyl sulfoxide 2,6-di-tert-butyl-4-methylpyridine ethyl 9-fluorenylmethyloxycarbonyl hetero-Diels−Alder 3-(heptafluoropropylhydroxymethylene)camphorate hexamethylphosphoramide highest occupied molecular orbital potassium bis(trimethylsilyl)amide lowest unoccupied molecular orbital m-chloroperoxybenzoic acid methyl 3,4,7,8-tetramethyl-1,10-phenanthroline methoxy methyl methylsulfonyl naphthyl N-bromosuccinimide N-iodosuccinimide 4-methylmorpholine N-oxide pyridinium chlorochromate pyridinium dichromate phthalazine pivaloyl p-methoxybenzyl propyl pyridine structure−activity relationship tetrabutylammonium iodide tert-butyldiphenylsilyl tert-butyldimethylsilyl 2,2,6,6-tetramethyl-1-piperidinyloxy trifluoromethanesulfonic trifluoroacetic acid trifluoroacetic anhydride methyl(trifluoromethyl)dioxirane

tetrahydrofuran 1,1,3,3-tetraisopropyl-1,3-diyl triisopropylsilyl N,N,N′,N′-tetramethylethylenediamine trimethylsilyl trimethylethylidene tetra-N-propylammonium perruthenate 4-toluenesulfonyl 2,4,6-tri-tert-butylpyrimidine uridine diphosphate urea-hydrogen peroxide complex

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