Amino-functionalized iminocyclitols: synthetic glycomimetics of medicinal interest

Abstract

Carbohydrate mimetics play vital roles in various cell-mediated processes due to their structural resemblance to natural sugars but properties quite distinct from them. This unique combination has made them attractive targets for synthesis, exploring their biological applications, and understanding their structure–activity relationship at molecular levels, that would eventually help in the development of novel small molecule drugs. Iminosugars, also termed iminocyclitols and, often erroneously azasugars, constitute the most attractive glycomimetics as they find significant applications as drug candidates. Examples of iminocyclitol based marketed drugs include Miglustat and Miglitol. Continued research in this area has led to the discovery that synthetic analogues obtained through replacement of one or more of the hydroxyl groups of naturally occurring iminocyclitols with amino functionalities, termed as amino-iminocyclitols, display profound effects on their biological activities, in terms of both selectivity and specificity. Such molecules are expected to be potential lead against viral infections, osteoarthritis, tuberculosis, diabetes, bacterial infections, lysosomal storage disorders etc. due to which chemistry and biology of amino-iminocyclitols have emerged as a fertile area for research. This review covers all the available synthesis of various amino-iminocyclitols and their biological activities. The structure–activity relationship of these molecules with various glycosidases would provide opportunities for the design and development of novel molecules with improved inhibition properties and spur further research towards carbohydrate based drug discovery.

---

Vimal Kant Harit

Vimal Kant Harit graduated in Pharmacy and obtained his M.S. in medicinal chemistry with a gold medal from National Institute of Pharmaceutical Education and Research (NIPER), Raebareli in 2010. Subsequently he worked as research associate in Jubilant, Chemsys (CRO) for a brief period before taking up the DST-INSPIRE research fellowship, in 2012, to pursue his PhD program under the supervision of Prof. N. G Ramesh, Department of chemistry, IIT-Delhi. He has been working in the area of synthetic organic chemistry with special focus towards the construction of carbocyclic and heterocyclic frameworks of biological interest.

Namakkal G. Ramesh

N. G. Ramesh received his PhD degree from the Indian Institute of Technology Madras, Chennai under the supervision of Prof. K. K. Balasubramanian. He was a postdoctoral fellow at Bar-Ilan University, Israel (Prof. Alfred Hassner) and at University of Nijmegen, The Netherlands (Prof. Binne Zwanenburg). He also spent a couple of years as a JSPS postdoctoral fellow at Osaka University, Japan (Prof. Yasuyuki Kita). He joined the Department of Chemistry, Indian Institute of Technology Delhi, India in 2000 where he is currently a full professor. His areas of research include synthetic organic chemistry, carbohydrate chemistry and asymmetric synthesis.

---

1. Introduction

Glycosidases (glycoside hydrolases) are enzymes that catalyze the hydrolysis of oligo- and/or polysaccharides by facilitating the attack of a water molecule at the anomeric carbon of the sugars.¹ Since hydrolysis of the glycosidic bonds is a ubiquitous biological process, inhibitors of glycosidases have many potential applications including their use as drugs, agrochemicals and therapeutic agents.² For instance, α-glucosidase plays an important role in controlling blood glucose level in human and in the transport of glucose in insects and fungi.³ Hence inhibitors of α-glucosidase have been used for the treatment of type II diabetes⁴ and as insecticides as well.⁵ As glycosidases are involved in the trimming of complex glycans present in the surface of cells and viruses, inhibitors of these enzymes can disrupt the biosynthesis of carbohydrates thereby interfering in various cell-mediated processes such as cell–cell recognition, cell–virus recognition etc.⁶ This forms the basic principle of inhibitor based drugs for the treatment of various diseases such as diabetes,⁷ tumor metastasis,⁸ viral infections⁹ (including HIV, hepatitis B and C virus) and lysosomal storage disorders¹⁰ (such as Gaucher's disease, Fabry's disease, etc.). Carbohydrate and carbohydrate mimic (glycomimetic) based inhibitors of glycoconjugate processing enzymes are expected to play important roles against such diseases and disorders due to their structural resemblance to naturally occurring carbohydrates and their ability to mimic the oxo-carbenium ion transition state that offer unparalleled advantages over other classes of inhibitors.¹¹ Among them, several reversible inhibitors that are able to block glycoconjugate formations/functions have emerged as versatile tools for biochemists and cell biologists, especially for those in quest for the development of novel and new therapeutic agents.² Compounds of this class are already in the market as pharmaceuticals against type-II diabetes such as Miglitol 5,¹² while a few others such as Zanamivir 1,¹³ Tamiflu 2,¹⁴ etc. exhibit promising anti-infective properties. In addition, drugs of this class are used for the treatment of Gaucher's disease (Zavesca 4 (ref. 15)), epilepsy (Topamax 3 (ref. 16)), osteoarthritis (Orthovisc 6 (ref. 17)) and thrombosis (Fragmin 7, Fraxiparin 8)¹⁸ (Fig. 1).¹⁷

Fig. 1 Prominent examples of glycomimetic based drugs (trade names are given in parenthesis).

Glycomimetic-derived inhibitors of glycoconjugate processing enzymes generally belong to three major classes: iminosugars, thiosugars and carbaglycosylamines (aminocyclitols) where the ring oxygen atom of naturally occurring carbohydrates has been replaced by nitrogen, sulphur and carbon atoms respectively (Fig. 2). Among them, naturally occurring iminocyclitols, also termed iminosugars or, erroneously, azasugars^19a and their synthetic counterparts have received immense attention in the last four decades as selective inhibitors of glycosidases.^19b–d The NH group being isoelectronic with oxygen, enables iminosugars to mimic the structure, conformation and chirality of their carbohydrate counterparts but at the same time, retain their stability against further processing. Hence, they possess the ability of blocking the activities of glycoconjugate processing enzymes, due to which such compounds and their derivatives have found enormous therapeutic potential against many diseases. The isolation of first azasugar nojirimycin (NJ) 9, in 1966, by Inouye et al.²⁰ and its identification as a powerful inhibitor of α- and β-glucosidases, spurred research in this area resulting in subsequent isolation of a number of iminocyclitols of varied ring sizes and functionalities, mainly from plant sources. Many of them have been found to be highly selective inhibitors of different glycosidases.

Fig. 2 General classes of inhibitors of glycoconjugate processing enzymes based on their structures.

1.1 Piperidines

Nojirimycin 9, though a stronger inhibitor of α and β-glucosidase, being a hemiaminal, was found to be unstable under physiological condition. 1-Deoxynojirimycin (DNJ) 10 which is void of the anomeric hydroxyl group was isolated from the roots of mulberry trees (Moracae) in 1976 and was found to be more stable than NJ 9.²¹ A number of N-alkylated polyhydroxylated piperidines were also isolated from natural sources. N-Methyl DNJ 11, the first naturally occurring N-alkylated derivative of DNJ 10, was isolated from the leaves and roots of mulberry tree (Moracae) in 1994.²² N-Methyl-1-deoxy-mannojirimycin 14 was isolated in 2001 from Angylocalyx pynaertii (Fig. 3).²³ D-Galactonojirimycin (also called as D-galactostatin) 15 (ref. 24) was isolated in 1988 from Streptomyces lydicus. 1-Deoxy-D-mannojirimycin (DMJ) 12 was isolated from Lonchocarpus sericeus, in 1979 prior to the isolation of its unstable oxygenated parent compound D-mannojirimycin 13 (ref. 25) from Streptomyces lavandulae in 1984.²⁶ D-Altro-DNJ 17 and L-gulo-DNJ 18 [from A. pynaertii (Leguminosae) 2001] and allo-DNJ 16 [from Connarus ferruginens (Combretaceae) 2005] were isolated by Asano and co-workers.²⁷ In 2000, same authors have also isolated 1-deoxyadenophorine 19 from Adenophorea radix.²⁸ Fagomine 20 (Fagopyrum esculentum, 1974) and its epimers 3-epi-fagomine 21 and 3,4-diepi-fagomine 22 (Xanthocercis zambesiaca, 1997) have also been found in natural sources (Fig. 3).²⁹

Fig. 3 Naturally occurring six-membered iminocyclitols.

1.2 Pyrrolidines

2,5-Dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP) 23 and other five membered iminocyclitols mimic the flattened half-chair conformation of the oxo-carbenium ion transition state involved during the glycosidic hydrolysis.^19,30 DMDP was isolated from the leaves of Derris elliptica, and the seeds of Lonchocarpus sericeus.³⁰ 2-Hydroxymethyl-3-hydroxypyrrolidine (CYB-3) 24 was isolated from Castanospermum australe in 1985.³¹ 1,4-Dideoxy-1,4-imino-D-arabinitol (DAB-1) 25, a structurally related compound to DMDP 23, was isolated in 1985 from two types of leguminose plants.³² In 2000, 2-hydroxymethyl-3,4-dihydroxy-5-methylpyrrolidine (6-deoxy-DMDP) 26 was isolated from seeds of the Angylocalyx pynaerii.³³ In 1991, 2,5-dideoxy-2,5-imino-D-glucitol (DGDP) 27, a C-2 epimer of DMDP 23, was first synthesized. Subsequently, in 2005, DGDP 27, was also isolated from the Thai traditional medicine “Non tai yak” (Stemona tuberosa).³⁴ 3,4-Dihydroxy-5-hydroxymethyl-1-pyrroline 28 (nectrisine) was isolated from Nectria lucida in 1988.³⁵ 2,5-Dideoxy-2,5-imino-D-glycero-D-manno-heptitol, 29 a homologue of DMDP 23, was initially synthesized by Wong and co-workers prior to its isolation from Hyacinthoides nonscripta in 1997 (Fig. 4).³⁶

Fig. 4 Examples of naturally occurring pyrrolidine iminocyclitols.

1.3 Indolizidines

Indolizidines are bicyclic ring systems possessing piperidine and pyrrolidine rings fused together with a nitrogen atom at the ring junction (Fig. 5). They include swainsonine 30 which was isolated from plants of the genus Swainsona in 1979 and in 1982, from the plants of Astralagus spp. and Oxytropis spp.³⁷ Castanospermine 31 is a polyhydroxylated indolizidine in which the hydroxyl groups of its piperidine moiety resemble that of glucose in the pyranose form. It was isolated from Castanospermum australe in 1981.³⁸ Later, 6-epi-castanospermine 32 and 6,7-di-epi-castanospermine 33 were also isolated from the same source.³⁹ Lentiginosine 34, the least hydroxylated naturally occurring indolizidine derivative was isolated from Astragalus lentiginosus in 1990.⁴⁰ Very recently, in 2010, (−)-steviamine 35 was isolated from Stevia rebaudiana (Asteraceae) by Fleet and co-workers (Fig. 5).⁴¹ (−)-Steviamine 35 is the only naturally occurring indolizidine alkaloid that possesses a methyl group in one of the rings.

Fig. 5 Examples of naturally occurring polyhydroxylated indolizidine alkaloids.

1.4 Pyrrolizidines

Pyrrolizidine derivatives are fused pyrrolidine bicyclic ring systems and they have been shown to exhibit several inhibitory properties (Fig. 6). Casuarine 36, the most oxygenated bicyclic iminosugar reported so far from natural sources, was isolated from Casuarina equisetifolia in 1994.⁴² Alexine 37 was isolated from Alexa spp. in 1988.⁴³ Australine 38, which is regarded as a ring-contracted form of castanospermine 31, resembles DMDP 23. 1-epi-Australine 39 was isolated from Castanospermum australe in 1990. Pochonicine 40 is a new polyhydroxylated pyrrolizidine alkaloid, isolated from a solid fermentation culture of the fungal strain Pochonia suchlasporia var. suchlasporia TAMA 87.⁴⁴ Hyacinthacine-A₁ 41 and hyacinthacine-A₂ 42 were isolated from Muscari armeniacum in 2000.⁴⁵ Hyacinthacine-B₁ 43 and hyacinthacine-B₂ 44 were isolated from Scilla campanulata in 1999. In the same year, hyacinthacine-C₁ 45 was isolated from Hyacinthoides nonscripta (Fig. 6).

Fig. 6 Examples of naturally occurring polyhydroxylated pyrrolizidine alkaloids.

While the six membered azasugar (for instance DNJ 10) closely resembles the ground state of the parent sugar D-glucose (46) in an unexpected chair conformation, the five-membered ring of pyrrolidine iminosugars (for instance DMDP 23) is assumed to mimic the half-chair conformation involved in the transition state.⁴⁶ This has prompted the search for novel analogues that mimic the transition state more closely both electronically and structurally, with the aim of developing new potent and selective inhibitors (Fig. 7).

Fig. 7 Structures of D-glucose and some synthetically modified iminosugars.

Since the successful discovery of synthetically modified six-membered azasugar based drugs such as Miglustat® 4 (ref. 47) and Miglitol® 5 (ref. 48) (Fig. 1), there has been an upsurge in research related to the synthetic modifications of naturally occurring azasugars. Two types of modifications are found to be the most common, (i) introduction of a lipophilic group on the ring nitrogen of naturally occurring iminocyclitols and (ii) replacement of one or more of the their hydroxyl groups by amino functionalities, termed as amino-modified iminocyclitols (e.g., 47 and 48). While greater emphasis has been given in the last four decades towards the synthesis and biological studies of amino-modified six-membered azasugars and their analogues,⁴⁹ those towards five-membered iminocyclitols have been relatively limited.⁵⁰ In 2007, the first structural basis of the inhibition of benzamido-modified five-membered iminocyclitol 49 with β-glucosidase was established through single crystal X-ray analysis of the enzyme–inhibitor complex,⁵¹ wherein it was shown that the amide side chain binds to the enzyme through two polar contacts. Wong, in 2006, identified acetamido derivatives of five-membered iminocyclitols (e.g., 48) as novel structures for antivirals and osteoarthritis.⁵² These articles provided further impetus towards research related to the synthesis of amino-modified five-membered iminocyclitols and their analogues.

Even though chemistry and biology of amino-modified iminocyclitols have been briefly discussed in various reviews on iminosugars,⁵³ a dedicated review on these derivatives is missing. Given the biological significance of amino-modified iminocyclitols not only as highly selective (and in many cases specific) inhibitors of various glycosidases but also as potent drug candidates and the vast number of publications that have appeared in the last four decades, an exclusive review on this topic is timely and would be beneficial to researchers working in this interdisciplinary area of glycobiology. In this review, all available syntheses of amino-modified five-, six- and seven-membered as well bicyclic iminocylitols are covered along with their glycosidase inhibition activities given in the form of a table. For the sake of conciseness, glycosylamine-like amino-iminocyclitol derivatives, bearing a gem-diamine functionality, are not covered in this review. Readers interested in this particular type of glycomimetics can find useful information in the given selected ref. 54.

2. Amino-modified five-membered iminocyclitols

In the area of polyhydroxypyrrolidines, all the synthetic modifications reported so far have been directed towards replacing one of the side chain hydroxyl groups with an amino derivative. Strategies reported in literature for the synthesis of amino-substituted dihydroxymethyl dihydroxypyrrolidine (ADMDP) 47 and its stereo-analogues can be broadly classified into three categories:

1. Chemo-enzymatic synthesis.

2. Asymmetric synthesis.

3. Chiral pool strategy.

a. Non-carbohydrate based synthesis.

b. Carbohydrate based approaches.

While most of the methodologies rely on carbohydrate precursors, mainly due to their ready availability with chiral integrity, other approaches are much less represented.

2.1 Chemo-enzymatic synthesis

The only chemo-enzymatic approach towards the synthesis of amino-modified polyhydroxypyrrolidine available as of today is due to Wong and co-workers.⁵⁵ The key step in their synthesis was the aldol condensation of optically active (S)-2-azido-3-acetamidopropanal 50, synthesized from cinnamaldehyde, with dihydroxyacetone phosphate (DHAP) 51 in presence of FDP-aldolase to get the corresponding phosphate ester 52, which on cleavage with acid phosphatase gave the trihydroxy ketone 53. Upon hydrogenation in the presence of Pd/C, compound 53 underwent a facile reduction of the azido group along with concomitant reductive amination to give N-acetyl ADMDP 48, in one-pot. Following a similar synthetic sequence, 2-epi-N-acetyl ADMDP 55 (Scheme 1), was also obtained in 3 steps from 54. Through their chemoenzymatic strategy, they have also reported the synthesis of iminocyclitol sulfates 56 and 57 as new drug candidates for osteoarthritis⁵⁶ (Fig. 8).

Scheme 1 Wong's synthesis of N-acetyl ADMDP 48 and 2-epi-N-acetyl ADMDP 55.

Fig. 8 Iminocyclitol sulfates 56 and 57 synthesized by Wong.

2.2 Asymmetric synthesis

An asymmetric synthesis of 1,2,5-trideoxy-1-amino-2,5-imino-D-glucitol [(+)-ADGDP] 63 was reported by Davies et al.⁵⁷ α,β-Unsaturated ester 58 (ref. 58) was converted in a few steps to the allyl alcohol 59, as an optically pure stereoisomer, the key intermediate in their synthesis. Intramolecular iodoamination followed by displacement of the iodo group using sodium azide gave the corresponding pyrrolidine 60 and piperidine 61 along with recovery of starting material 59. HF·pyridine mediated deprotection of the silyl ether of 60 followed by Pd(OH)₂ catalyzed hydrogenation afforded L-ADGDP 63 as its bishydrochloride salt (Scheme 2).

Scheme 2 Davies' asymmetric synthesis of (+)-ADGDP 63.

2.3 Chiral pool strategy

2.3.1 Non-carbohydrate based synthesis. Vogel and co-workers⁵⁹ developed a methodology for the synthesis of amino substituted polyhydroxypyrrolidines (−)-69 and (−)-70 starting from an optically active lactam. Their synthesis relied on the conversion of the free primary hydroxyl group of polyhydroxypyrrolidines (−)-66 and (−)-67 into an amino group via oxidation followed by reductive amination reaction. For this, following the procedure reported by Ikota and co-workers,⁶⁰ the semi-protected lactam 64 was converted to the allylic alcohol 65 as a mixture of inseparable diastereoisomers. Alcohol 65 was further transformed to the polyhydroxypyrrolidines 66 and 67 in four steps. The primary hydroxyl group of the major diastereomer (−)-66 was oxidized under Swern condition and the resulting aldehyde was subjected to reductive amination to generate the protected amino-modified polyhydroxylated pyrrolidine (−)-68. Concomitant deprotection of trityl, Boc and isopropylidene groups was achieved in a single step using CF₃COOH to get N-benzyl derivative (−)-69 in quantitative yield. On the other hand, N-debenzylation of (−)-68 by Pd(OH)₂ catalyzed hydrogenation followed by acidic hydrolysis delivered the parent (2S,3S,4R,5R)-2-(aminomethyl)-5-(hydroxymethyl)pyrrolidine-3,4-diol (−)-70 (Scheme 3).

Scheme 3 Vogel's synthesis of amino functionalized polyhydroxypyrrolidines.

They also meticulously utilized the free hydroxyl group of compound (−)-66, for the synthesis of (+)-69 and (+)-70, the enantiomers of (−)-69 and (−)-70. Protection of the free hydroxyl group of (−)-66 as its TBS ether, followed by cleavage of the trityl group under basic condition released the hydroxyl group at C-6 position to get compound (+)-71, which was then converted into (+)-69 following the same synthetic sequence used for the synthesis of (−)-69. Debenzylation of (+)-72 through catalytic hydrogenation in presence of 10% Pd(OH)₂ followed by deprotection of the TBS, isopropylidene and Boc groups under acidic condition delivered (+)-70 (Scheme 4).

Scheme 4 Synthesis of amino functionalized polyhydroxypyrrolidines.

Using the same strategy as described above, the synthesis of benzylaminomethyl and aminomethyl derivatives of polyhydroxypyrrolidine, (+)-73 and (+)-74, was also accomplished (Scheme 5).

Scheme 5 Synthesis of amino functionalized polyhydroxypyrrolidines (+)-73 and (+)-74.

Jäger and co-workers⁶¹ utilized a Henry reaction to construct iminopolyols and amino derivatives of iminocyclitols. Henry reaction of optically active nitro compound 75 (ref. 62) to 76 proceeded with high diastereoselectivity to give hexitol 77 as the major product. Hydrogenation of compound 77 was followed by Cbz protection of resulting amine. Mesylation of its primary hydroxy group gave compound 78, which on intramolecular reductive aminocyclization afforded dihydroxy pyrrolidine 79. Acid catalyzed deprotection gave the amino-polyhydroxypyrrolidine 80. Protection of the ring nitrogen of 79 as its Cbz derivative and subsequent N-Boc deprotection, acetylation of resulting primary amine and Cbz deprotection resulted in the formation of acetamido derivative 81 (Scheme 6).

Scheme 6 Jäger's synthesis of iminocyclitol hydrochloride 80 and acetamido derivative 81.

2.3.2 Carbohydrate based approaches. Mignani and co-workers,⁶³ in 1996, reported the synthesis of polyhydroxypyrrolidine, piperidine and azepane based non-peptide mimics of somatostatin/sandostatin®. Their synthesis started from amino heterocyclization of 1,2,5,6-di-anhydro-3,4-di-O-benzyl-D-mannitol with tryptamine⁶⁴ which provided the key intermediates 83 and 84. N-Boc protection of indole nitrogen of 83, protection of primary hydroxyl group as its TBS ether followed by mesylation of the resulting secondary hydroxyl group delivered 86. When compound 86 was treated with N-Boc-1,6-hexyldiamine followed by acid mediated deprotection, pyrrolidine 87 was obtained through an aziridinium ion as the intermediate⁶⁵ (Scheme 7).

Scheme 7 Mignani's synthesis of somatostatin/sandostatin analogues.

The first carbohydrate based synthesis of N-acetylamino-polyhydroxypyrrolidine 96 was reported by Kang et al.,⁶⁶ in 1997, starting from 2,3-O-isopropylidene-L-threitol 88. Oxidation of both the primary hydroxyl groups of 88 with Dess–Martin periodinane (DMP), followed by double Wittig olefination reaction and subsequent cleavage of the isopropylidene group gave the diene 89. The key step in their synthesis was double iodoamination of diene 89 to get the bicyclic compound 90. Thus, the treatment of optically active diene 89 with CCl₃CN in the presence of DBU followed by in situ iodocyclization with IBr gave the bicyclic compound 90 as a mixture of stereoisomers with a de of 90%. After complete hydrolysis of 90 with methanolic hydrochloric acid, the resulting C₂-symmetric iodo-hydroxy ammonium chloride 91 was cyclized using sodium bicarbonate in presence of Boc₂O at 50 °C to get a 4 : 2:1 : 2 mixture of piperidines 92 and 93, and pyrrolidines 94 and 95 respectively. When compound 94 was heated at 70 °C with silver acetate in a 2 : 1 mixture of DMF and acetic acid, it was converted to oxazolidinone 95. Both carbamate groups in 95 were hydrolyzed by refluxing it in aqueous barium hydroxide and the unmasked primary amino group was chemoselectively acetylated in situ at 0 °C using p-nitrophenyl acetate to obtain N-acetylamino-polyhydroxypyrrolidine 96 (Scheme 8).

Scheme 8 Kang's synthesis of N-acetylamino-polyhydroxypyrrolidine 96.

Later in the same year, synthesis of ADMDP 47 was reported by Stütz and co-workers.⁶⁷ They have carried out the synthesis of C-1 amino-modified five-membered iminocyclitols through Amadori rearrangement of compound 98 with dibenzylamine as the key step. The required starting material, namely 5-azido-5-deoxy-D-glucofuranose 98, was synthesized from D-glucofuranurono-3,6-lactone 97, in seven steps, following a literature procedure⁶⁸ (Scheme 8). Azido alcohol 98 underwent a facile Amadori rearrangement with benzylamine, at 40 °C, in presence of an acid to give the D-fructopyranose derivative 99 with the incorporation of the aminomethyl group at C-1 position. The driving force for such a rearrangement is the relief of ring strain experienced by the five-membered ring. The pyranose derivative 99 was successively transformed into the ADMDP 47 in one step through catalytic hydrogenation in presence of Pd(OH)₂ (Scheme 9).

Scheme 9 Stütz's synthesis of ADMDP 47 and its C-1-N-modified analogues.

The authors have also prepared a library of C-1 amino-modified derivatives such as 100 and 101 (Scheme 9) with a view of identifying better inhibitors than the parent compound ADMDP 47. Different functional groups were introduced at C-1 nitrogen atom through the coupling of the side chain amine with a variety of carboxylic acids mediated by HBTU and Et₃N⁶⁹ or by its reaction with various sulfonyl chlorides.

Through a similar synthetic sequence, they have also accomplished the synthesis of 6-amino-2,5,6-trideoxy-2,5-imino-D-glucitol (ADGDP) 104 from 5-azido-5-deoxy-L-idofuranoside 102, through 1-aminodeoxy derivative of L-sorbopyranose 103 as the intermediate (Scheme 10).⁷⁰

Scheme 10 Stütz's synthesis of ADGDP 104.

The Amadori rearrangement strategy was later, in 2006, followed by Wong and coworkers.⁷¹ en route to their synthesis of a library of amino-modified iminocyclitols, in their quest for identifying potent inhibitors for N-acetyl-β-hexosaminidase. The library of compounds was synthesized by treating a mixture of iminocyclitol 47, a carboxylic acid, diisopropylethyl amine and HBTU in DMSO in a 96-well microtiter plate and shaken for 5 h to make amide derivatives 48 and 105–111. Without purification, the compounds were tested for their inhibition against various glycosidases considering that the amide formation was complete. Some of the potent inhibitors (48 and 105–111) are depicted in Scheme 11.

Scheme 11 Wong's derivatisation of ADMDP 47.

Reynolds et al.⁷² reported the synthesis of two stereoisomers of 1-(hydroxymethyl)propyl derivatives of aminomethyl polyhydroxypyrrolidines, 118 and 121, from polyhydroxypyrrolidine 114 through “protection-functional group transformation-deprotection” strategy. Compound 114 in turn was prepared from 5-keto-D-fructose 112, through reductive amination with benzylamine to get 113 and N-deprotection. Initial protection of the ring nitrogen of 114 with benzyl chloroformate yielded the N-Cbz derivative 115. 3,4-cis-Hydroxyl groups of 115 were then protected as their isopropylidene derivative and the free primary hydroxyl group of 116 was then converted into amino derivative 118 through standard steps. In a similar manner, compound 116 was also converted to another polyhydroxypyrrolidine stereoisomer, namely 121, through intermediates 119 and 120 (Scheme 12).

Scheme 12 Reynolds's synthesis of 1-(hydroxymethyl)propyl derivatives of aminomethyl polyhydroxypyrrolidines, 118 and 121.

Wong and co-workers⁷³ also developed an elegant chiron approach to the synthesis of N-acetyl ADMDP 48 and its analogues via ring opening-intramolecular cyclization of a carbohydrate derived amino epoxide as the key step. The required starting material 123 was synthesized from the protected pentose 122, in about ten steps. Staüdinger reduction of the azido functionality of 123 was accompanied by an in situ regioselective intramolecular epoxide opening in an 5-exo-tet fashion to give the protected iminosugar 124. Boc protection of the ring nitrogen of 124 to 125 followed by oxidative cleavage of the vicinal diol using Pb(OAc)₄ provided the aldehyde 126. Through a sequence of standard reactions involving three steps, aldehyde 126 was transformed into a mixture of the protected azidomethyl polyhydroxypyrrolidine 128 (major) and the bicyclic carbamate 127 (minor). Subsequent reduction of the azido group in 128 to amine and its acetylation provided acetamido derivative 129. Debenzylation and N-Boc deprotection gave 2-acetamidomethyl polyhydroxypyrrolidine 48. Compound 129 was also converted into C-1 N-alkyl derivatives 132 and 133 via Boc deprotection followed by reductive amination reaction with formaldehyde and butyraldehyde to get 130 and 131 respectively. Catalytic hydrogenation of 130 and 131 afforded the N-alkylated 2-acetamido polyhydroxypyrrolidines 132 and 133 respectively.

As the N-alkylation of the ring nitrogen often resulted in decreased inhibitory activity at the molecular level, although increased hydrophobicity is advantageous for penetrating the cell membrane, Wong and co-workers have decided to do functionalization at C-1 of DMDP 23.⁷⁴ Hence, they prepared (2S,3R,4S,5R)-N-butyloxycarbonyl-(3,4-dibenzyloxy-5-benzyloxymethyl)-pyrrolidine-2-carbaldehyde 134 having an aldehyde group at C-1, following the procedure similar to the preparation of its C-4 epimer 126. Subsequently, they carried out reductive amination reaction of 134 with a variety of alkyl amines to get the protected polyhydroxypyrrolidines 135. Deprotection of the benzyl and Boc groups was accomplished through hydrogenolysis under acidic conditions to get N-substituted derivatives represented by 136 (Scheme 13).

Scheme 13 Wong's approach to the synthesis of N-acetyl and N-alkyl ADMDP analogues.

On a similar line, the same research group⁷⁵ have also reported the synthesis of ADMDP 47, through selective conversion of one of the hydroxyl groups of polyhydroxypyrrolidine 138. Also, their previously synthesized core structure 48 was coupled with different aromatic aldehydes via reductive amination with NaBH₃CN to get analogues of ADMDP substituted at the ring nitrogen (142–146) (Scheme 14).

Scheme 14 Wong's synthesis of ADMDP 47, and its derivatives.

Duréault and co-workers⁷⁶ reported the synthesis of ADGDP 104 and its acetyl derivative 96 through double nucleophilic ring opening of C₂-symmetric bis-aziridine 150 derived from 3,4-di-O-benzyl-D-mannitol 147. The tetrol 147 was transformed into the corresponding diazidodiol 149 via primary ditosylate 148. Conversion of the diazide 149 to amino group under Staudinger condition in presence of (Boc)₂O resulted in concomitant intramolecular double cyclization reaction and Boc protection leading to a mixture of products in which, N-Boc bis-aziridine 150 was the major product. Acetic acid mediated ring opening of one of the aziridine rings⁷⁷ at the primary carbon followed by an intramolecular 5-exo-tet heterocyclization yielded mainly pyrrolidine 151. Deprotection of the benzyl and acetyl groups of 151 under Birch condition followed by TFA mediated N-Boc cleavage delivered the parent ADGDP 104. Alternatively, TFA mediated Boc deprotection followed by acetylation of the amino group and final deprotection of the hydroxyl groups using Na/liq. NH₃ gave rise to the acetyl derivative 96 (Scheme 15).

Scheme 15 Duréault's synthesis of 6-amino-2,5,6-trideoxy-2,5-imino-D-glucitol 104 and its acetyl derivative 96.

Jeanneret and co-workers,⁷⁸ in 2005, synthesized substituted pyrrolidine-3,4-diol derivatives for assay against commercially available glycosidases, glioblastoma and melanoma cells (both associated with tumour). Their synthesis started with protected carbaldehyde 152,⁷⁹ which was subjected to reductive amination with phenyl glycinol derivatives to get the amino-pyrrolidine derivatives 153. Acid catalyzed deprotection delivered compounds 154–157. In a similar way, substrate 158 (ref. 80) was converted to 161 in three steps by Swern oxidation, reaction with aminoalcohol 159 to get 160 and acid-promoted removal of the protecting groups. The carbaldehyde 152 was also modified to compound 164 over a few steps involving condensation with Boc-protected aminoester 163, readily available from Boc-protected aminoalcohol 162 (Scheme 16).

Scheme 16 Jeanneret's synthesis of amino-substituted polyhydroxypyrrolidine derivatives.

Overkleeft and co-workers⁸¹ developed a novel tandem Staudinger/aza-Wittig/Ugi (SAWU-3CR) strategy for the synthesis of amino-substituted polyhydroxypyrrolidines. 4-Azidopentanal 166, which was synthesized from hemiacetal 165 in six steps, was subjected to SAWU-3CR process by treating it with trimethylphosphine in methanol to get 167 followed by addition of an isocyanide and a carboxylic acid to get the polyhydroxypyrrolidine 168 as a single stereoisomer. The generality of the reaction was established through the synthesis of a library of such molecules with varying R¹ and R² substituents. Later in 2008, they⁸² have also studied the effect of different Lewis acids on the diastereoselectivity of Ugi three-Component reaction. They have further proved that the diastereoselectivity of SAWU-3CR multicomponent reaction was based on kinetic control determined at the stage of attack of the isocyanide at the iminium ion⁸³ (Scheme 17).

Scheme 17 Overkleeft's tandem Staudinger/aza-Wittig/Ugi (SAWU-3CR) approach for the synthesis of amino-substituted polyhydroxypyrrolidines.

On a similar line, Furman and co-workers,⁸⁴ recently reported the synthesis of polyhydroxypiperidine and pyrrolidine peptidomimetics through one-pot sequential lactam reduction followed by Ugi–Joullié reaction. Sugar derived pyrrolidine lactam 169 was reduced with Schwartz's reagent to imine 170 and without isolation it was subjected to the Joullié–Ugi reaction along with trifluoroacetic acid and an aliphatic or aromatic isocyanide to get peptidomimetics 171. These trifluoroacetamides were further hydrolyzed with sodium hydroxide to get pyrrolidine amides 172. A collection of such pyrrolidine peptidomimetics was synthesized starting from different lactams (Scheme 18).

Scheme 18 Furman's synthesis of polyhydroxypiperidine and pyrrolidine peptidomimetics.

Goti and co-workers⁸⁵ developed a strategy for the synthesis of ADMDP 47·HCl and L-ADGDP 63·HCl involving nucleophilic addition of cyanide to sugar derived nitrone 174 as the key step. The starting nitrone 174 was prepared from D-arabinose 173 in four steps following literature procedures⁸⁶ and converted to the corresponding α-cyano hydroxylamine 175 by treating it with trimethylsilyl cyanide in methanol. Oxidation of the N-hydroxyl function of compound 175 to vinyl nitrone 176 with manganese(IV) oxide, followed by stereoselective reduction of the iminium ion intermediate with sodium borohydride resulted in the epimerization of the stereo-centre at C-2 carbon. When compounds 175 and 176 were subjected to hydrogenolysis in presence of HCl using MeOH as a solvent, the corresponding D-ADMDP derivatives 47 and L-ADGDP 63 were obtained as their hydrochloride salts (Scheme 19).

Scheme 19 Goti's synthesis of ADMDP 47·HCl and 63·HCl.

Cheng⁸⁷ followed a similar strategy of Goti to synthesize L-ADGDP 63 (Scheme 20) and the authors have also reported the synthesis of another stereoisomer of ADMDP 47, by inverting the configuration at C-2 carbon bearing the nitrile group of 175 through an elimination-reduction to get 178 followed by another-reduction process to get 179 and 180.

Scheme 20 Cheng's synthesis of ADMDP 63.

Later in 2013,^88a they extended their strategy to make scaffolds of amino-DMDP 74 by utilizing general and flexible transformations on five-membered cyclic nitrones. They further coupled the free amine with structurally diverse acids (Scheme 21) to get the corresponding amides 175 and 176 and assayed them against different glycosidases. Recently, they have also reported some amides of compound 74 as pharmacological chaperones for treatment of Fabry disease.^88b

Scheme 21 Cheng's synthesis of amide derivatives of amino-polyhydroxypyrrolidine 74.

Nhein et al.,⁸⁹ in 2009, have developed a strategy to synthesize polyhydroxyamino proline starting from D-ribose,⁹⁰ which was converted into the azido hemiacetal 178. Exposure of 178 to HCOONH₃Bn in presence of Ti(OiPr)₄ and TMSCN, resulted in the formation of a mixture of the acyclic α-aminonitriles 179 and 180. Cyclization to pyrrolidines was carried out with methanesulfonyl chloride and the major isomer 181 was subsequently transformed into polyhydroxyamino proline 182 (Scheme 22).

Scheme 22 Nhein's synthesis of polyhydroxyamino proline 182.

Postel and co-workers⁹¹ reported the synthesis of C-1 aminocyclopropyl polyhydroxylated pyrrolidine 187 through cyclopropanation of the C-1 cyano group of 185 as the key step. Compound 185 was synthesized from 183 via the acyclic intermediate 184, using the same strategy as that of Nhein et al.⁸⁹ Cyanopyrrolidine 185 was then transformed into cyclopropyl pyrrolidine 186 by reacting it with methyltitanium triisopropoxide mediated aminocyclopropanation in presence of EtMgBr. Deprotection of the benzyl groups under standard condition afforded the final 2-aminocyclopropyl pyrrolidine 187 possessing L-ido configuration (Scheme 23).

Scheme 23 Postel's synthesis of C-1 aminocyclopropyl polyhydroxylated pyrrolidine 187.

Following this procedure, they have also prepared two more cyclopropyl amino-methyl polyhydroxypyrrolidines 188 and ent-188, starting from the corresponding protected aldopentoses. Later in 2012, they⁹² further reported the synthesis of pyrrolidine based iminocyclitols 187, 188, 189, 190 by utilizing same strategy for assay against different glycosidases and found that one of their molecules 189 (Fig. 9) is a selective inhibitor of α-L-fucosidase from human placenta.

Fig. 9 Postel's pyrrolidine based iminocyclitols.

In 2010, Ramesh and co-workers,⁹³ reported a novel and a concise approach towards the synthesis of new stereoisomers of amino-modified five membered iminocyclitols. Their synthesis started from diamine 191,⁹⁴ which was transformed into protected amino-substituted iminocyclitol 192 in two steps, through LiAlH₄ mediated reductive ring opening followed by an intramolecular Mitsunobu cyclization. Global deprotection of 192 under Birch condition afforded parent amino-substituted iminocyclitol 193 which on acetylation using acetic anhydride afforded the acetyl derivative 194. On the other hand, Na–Hg mediated chemoselective detosylation of the tertiary tosylamide group followed by catalytic hydrogenation delivered the N-tosyl derivative 195. Base mediated reaction of compound 192 with alkyl halides followed by stepwise deprotection of various protecting groups delivered 198 and 199 in good yields. Glycosidase inhibitory activities revealed that compounds 198 and 199 display selectivity against α-galactosidase (Scheme 24).

Scheme 24 Ramesh's synthesis of amino-modified five membered iminocyclitols 194, 195, 198 and 199.

Subsequently, the authors have provided a molecular basis for the affinity and specificity of these iminocyclitols with various glycosidases through docking studies and MD simulations. They have observed a good correlation between the experimental findings and theoretical calculations and such combined studies prove to be a reliable tool for the identification of novel iminocycltiols for various drug targets.^93b

In 2011, Timmer and co-workers⁹⁵ demonstrated that a combination of a diastereoselective two-step one-pot Vasella/Strecker reaction⁹⁶ and an iodine-promoted carbamate annulation methodology, developed by them, allowed the synthesis of aminoiminohexitols possesing L-ido, D-manno, D-gluco, D-galacto, D-talo, and L-altro configurations starting from readily available D-arabinose 173 and D-ribose.⁹⁷ In order to prepare iminocyclitols having D-gluco, D-manno and L-ido configurations (104, 47, and 193 respectively), D-arabinose was used as the starting material, which was first converted into benzyl protected 5-iodo methylglycoside 200 in five steps following literature procedures.⁹⁸ Subsequent treatment of the iodide 200 with activated zinc in EtOH, according to the conditions of Vasella,⁹⁶ gave the corresponding aldehyde 201, which on further reaction with NH₄OH in presence of TMSCN delivered a diastereomeric mixture of syn- and anti-α-aminonitrile 202 in 9 : 1 (syn/anti) diastereoselectivity. The major isomer syn-202 was exposed to iodine and an excess of NaHCO₃ in THF–H₂O to get the 4,5-cis carbamate 203 in excellent diastereoselectivity (dr > 95 : 5). Hydrogenation of the carbamate 203 with Pd(OH)₂/C in the presence of 2.0 M HCl then produced the deprotected cyclic carbamate 204 which upon hydrolysis gave the known L-ido-aminoiminohexitol 193 as its hydrochloride salt. Using a similar strategy, two more strereoisomers of polyhydroxypyrrolidines 47 and 104 were obtained from anti-202 (Scheme 25).

Scheme 25 Timmer's synthesis of aminoiminohexitols.

Use of D-ribose⁹⁹ in the above synthetic sequence led to the synthesis of aminoiminocyclitols possessing D-talo 205, D-galacto 206 and L-altro 207 configurations (Scheme 26).

Scheme 26 Timmer's synthesis of amino-iminocyclitols 205–207.

With a view of investigating Fleet's “mirror image postulate”, Timmer and co-workers⁹⁹ in 2013, synthesized a number of potential glycosidase inhibitors. Through a study of inhibition properties of these compounds, authors concluded that Fleet's mirror image principle¹⁰⁰ appeared to have some success in predicting the α-fucosidase activity of C-2 substituted polyhydroxypyrrolidines.

Ayers et al.,¹⁰¹ in 2014, reported the synthesis of polyhydroxylated prolinamides and assayed their activity against β-N-acetylhexosaminidase. Their synthesis started with known glucuronolactone 208, which was converted to the azido derivative 209 following literature procedure.¹⁰² Conversion of the free hydroxyl group of 209 into its triflate was followed by catalytic hydrogenation to get the unstable bicyclic lactone 211, that readily underwent ring opening in presence of methylamine to form the protected prolinamide derivative 212. Catalytic hydrogenation of 212 in presence of 10% Pd–C afforded L-gulo prolinamide 213. On the other hand, methylamine mediated ring opening of lactone 215, obtained from 210 via alcohol 214 following a literature procedure,¹⁰² afforded an inseperable mixture of open-chain amides 216 and 217. Reduction of the azide through catalytic hydrogenation followed by Boc protection of the resulting amine gave protected prolinamide derivatives 218 and 219, which were subsequently transformed to prolinamide 220 through acid catalyzed hydrogenation. Utilizing a similar strategy, authors have prepared sixteen isomers of prolinamides including 222 from azido-glucuronolactone 221 and carried out their inhibition studies against β-N-acetylhexosaminidase (Scheme 27).

Scheme 27 Ayers's synthesis of polyhydroxylated prolinamides.

Blériot and co-workers,¹⁰³ in 2015, reported the synthesis of novel polyhydroxylated pyrrolidines with an acetamido moiety through a ring-contraction strategy and carried out their assay against N-acetyl-D-glucosaminidase. Their synthetic strategy started from azidoazepane 223, which after replacement of the Boc protecting group into benzyl group to get 224 and further exposure to trifluoroacetic anhydride underwent a facile ring contraction to give azido polyhydroxypyrrolidine 225. While catalytic hydrogenation of 225 in presence of HCl delivered the bis-HCl salt 228, Staudinger reduction followed by acetylation of the resulting amine to 226 and subsequent debenzylation delivered 227. In a similar way, authors have reported the formation of a diastereomer of 227, namely 230, starting from azidoazepane 229 (Scheme 28).

Scheme 28 Blériot's ring-contraction approach to the synthesis of polyhydroxylated pyrrolidines.

3. Six membered amino-modified iminocyclitols

In the area of six-membered iminocyclitols, synthetic modifications have been mainly focused on replacing the hydroxyl groups at C-2 and C-6 positions of DNJ 10 and its stereo-analogues by an amino functionality. The methodologies adapted for such synthetic analogues can be broadly classified as follows:

1. Chemo-enzymatic synthesis.

2. Asymmetric synthesis.

3. Carbohydrate based synthesis.

3.1 Chemoenzymatic synthesis

3.1.1 Synthesis of 2-amino and 2-acetamido-1,2-dideoxy nojirimycin and its stereo-analogues. Wong and co-workers,¹⁰⁴ in 1991, reported a chemoenzymatic approach to the synthesis of 2-acetamido-1,2-dideoxymannojirimycin 237, 2-acetamido-1,2-dideoxynojirimycin 238 and other deoxyhexoses. Their synthesis started with optically pure (+)-231, which was converted to aziridine 232 (ref. 105) and subsequently acetylated to get 233. Sodium azide mediated nucleophilic opening of aziridine 233 in presence of ZnCl₂ provided 234. After acidic hydrolysis of the ketal, the resulting aldehyde was condensed with one equivalent of dihydroxyacetone phosphate (DHAP) in the presence of FDP aldolase at pH 6.5 to get the azidoketone 235. Subsequently, phosphatase was used for the removal of the phosphate group to 236. Reductive amination through catalytic hydrogenation then provided 2-acetamido-1,2-dideoxymannojirimycin 237. 2-Acetamido-1,2-dideoxynojirimycin 238 was prepared through the same procedure starting from (−)-231 (Scheme 29).

Scheme 29 Wong's chemoenzymatic synthesis of 2-acetamido-1,2-dideoxymannojirimycin 237 and 2-acetamido-1,2-dideoxynojirimycin 238.

Later,¹⁰⁶ in 1998, they also developed a chemoenzymatic strategy for the synthesis of a library of iminocyclitol derivatives in search of new and selective fucosidase inhibitors. They started their synthesis from readily available cyclic imine 241, which was synthesized in a chemoenzymatic fashion from the phosphate ester and azide precursors 239 and 240.¹⁰⁷ Cyclic imine 241 was treated with KCN to get nitrile 242. Platinum oxide catalyzed hydrogenation provided the primary amine 243, that was protected as its Cbz derivative. After bisacetonide formation, deprotection of the Cbz group by palladium catalyzed hydrogenation afforded 244. Coupling of amine 244 with Cbz-protected glycine or protected serine in presence of HOBt/EDC afforded the corresponding amides which were deprotected to get compounds 245–247 (Scheme 30).

Scheme 30 Wong's chemoenzymatic synthesis of iminocyclitol derivatives as fucosidase inhibitors.

3.2 Asymmetric synthesis

Recently Davies and co-workers¹⁰⁸ reported an asymmetric synthesis of 2-amino-1,2-dideoxymannojirimycin (−)-ADMJ 256 and 2-amino-1,2-dideoxyallonojirimycin (+)-ADANJ 257. They started their synthesis from previously reported allyl alcohol 59,⁵⁷ which was treated with I₂ and NaHCO₃ in acetonitrile followed by addition of TsNCO to get a mixture of compounds 248–250. Methanolysis of the crude reaction mixture in presence of K₂CO₃ provided compounds 251–253. Utilizing the same strategy, they also obtained compound 255 from amine 254.¹⁰⁹ Final deprotection of compounds 251 and 255 was carried out in 3 steps to get (−)-ADMJ 256 and (+)-ADANJ 257 respectively (Scheme 31).

Scheme 31 Davies' asymmetric synthesis of (−)-ADMJ and (+)-ADANJ.

3.2.1 Synthesis of 2-acetamido-1,2-dideoxynojirimycin derivatives. Giannis¹¹⁰ and co-workers, in 2004, reported an asymmetric synthesis of 2-acetamido-1,2-dideoxymannojirimycin 237 and its 1-N-substituted derivatives. Sharpless asymmetric epoxidation of dienol 258 using L-(+)-DIPT afforded the epoxide 259. Primary hydroxyl group at C-1 of 259 was converted to benzoylcarbamate 260 using benzoylisocyanate. Regioselective intramolecular epoxide ring opening under mild basic condition also led to migration of the benzoyl group to afford oxazolidinone 261. N-Allylation of compound 261 followed by intramolecular RCM resulted in the formation of the bicyclic derivative 262. The benzoyl group of 262 was removed to 263 and replaced with a benzyl group to get 264. Asymmetric dihydroxylation using (DHQD)₂Phal delivered the diol 265 with complete diastereoselectivity. Reaction of 265 with dibutyltin oxide and treatment of the resulting dibutyltin ketal with benzyl bromide delivered compound 266. Oxidation of the alcohol 266 followed by reductive amination with p-methoxybenzylamine followed by acetylation and subsequent deprotection of all the groups afforded 2-acetamido-1,2-dideoxymannojirimycin 237. Authors have also introduced substituents at the ring nitrogen through reductive amination with butyraldehyde and phenylacetaldehyde before the deprotection step. Final deprotection delivered N-functionalized-2-acetamido-1,2-dideoxymannojirimycin analogues 273 and 274 (Scheme 32).

Scheme 32 Giannis's synthesis of 2-acetamido-1,2-dideoxymannojirimycin and its 1-N-substituted derivatives.

Riera and co-workers,¹¹¹ in 2013, reported the synthesis of 2-acetamido-1,2-dideoxy-D-allonojirimycin (DAJNAc) and they found out that one of their new iminosugars is a better competitive inhibitor of β-N-acetylglucosaminidase (human placenta) than the D-gluco (DNJNAc) and D-galacto (DGJNAc) stereoisomers. Their approach started with a key optically active bicyclic precursor 263. Protection of the hydroxyl group of 263 as its carbonate followed by palladium catalyzed allylic substitution with phthalimide as the nucleophile proceeded smoothly to give a single regio- and stereoisomer 275. The phthalimido group was deprotected with hydrazine and the resulting free amine was acetylated using Ac₂O and pyridine to get 276. Sharpless asymmetric dihydroxylation of 276 resulted in a mixture of two diastereomeric cis-diols 277 and 278 in a diastereomeric ratio of 4 : 1. Final hydrolysis of the oxazolidinone ring of 277 and 278 was carried out by refluxing them in 6 M NaOH to get the iminosugars DAJNAc 279 and DGJNAc 280 respectively (Scheme 33).

Scheme 33 Riera's synthesis of DAJNAc, and DGJNAc.

The authors^112a have also utilized compound 265, reported in Scheme 32, for the synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) 238 and ureido-DNJNAc derivatives. cis-Diol 265 was converted to its cyclic sulfate using SOCl₂. Ring opening of the cyclic sulfate with sodium azide gave a 2 : 1 mixture of azido alcohols 282 and 283. Azido alcohol 282 was then converted to DNJNAc 238 in five steps, via intermediates 284–286, using standard protocols. In a similar way, diastereomer 283 was converted to 287 (Scheme 34).

Scheme 34 Riera's synthesis of DNJNAc 238 and its regioisomer 287.

Towards the direction of target ureido-DNJNAc derivatives 291, azidoalcohol 282 was subjected to the cleavage of the oxazolidinone ring by refluxing it with sodium hydroxide which was followed by protection of the ring nitrogen as its Boc derivative to give 288. Palladium catalyzed hydrogenation and subsequent acetylation provided the tetracetate 289. TFA mediated deprotection of N-Boc followed by reaction of the ring nitrogen with different isocyanates afforded the corresponding urea adducts 290. Exposure of 290 to ammonia resulted in chemoselective O-deacetylation to give the target ureido-DNJNAc derivatives 291a–291d. All these new compounds were assayed against commercial β-N-acetylglucosaminidases (Scheme 35).

Scheme 35 Riera's synthesis of ureido-DNJNAc derivatives.

Recently, the same research group^112b has disclosed a new synthetic route to get DAJNAc derivatives as hexosaminidase inhibitors. They started their synthesis from previously reported oxazolidinone 276.¹¹¹ Base mediated hydrolysis of oxazolidinone followed by Boc protection provided compound 292. Acetylation of primary hydroxyl group and asymmetric dihydroxylation afforded diol 293. The free hydroxyl groups of 293 were protected as their acetates. Subsequent N-Boc deprotection using TFA followed by reaction of the resulting amine with derivatives of isothiocyanates provided thioureas 294a–294d. These thiourea derivatives were deprotected using NH₃/MeOH to get N-thioureido derivatives 295a–295d and corresponding 2-iminothiazolidines 296a–296d (Scheme 36).

Scheme 36 Riera's synthesis of DAJNAc-thiourea and bicyclic 2-iminothiazolidine derivatives.

3.3. Carbohydrate based synthesis

3.3.1 Synthesis of 2-amino and 2-azido-1,2-dideoxynojirimycin derivatives. Hasegawa et al.¹¹³ reported a carbohydrate based synthesis of acetamido derivative of 1-deoxynojirimycin sulfonic acid and its C-5 epimer. Their synthesis started with methyl 2-acetamido-3,6-di-O-benzoyl-2-deoxy-5-O-mesyl-β-D-glucofuranoside 298,¹¹⁴ which was obtained in four steps from known methyl 2-acetamido-2-deoxy-5,6-O-isopropylidene-β-D-glucofuranoside 297.¹¹⁵ Mesylate 298 was converted into diol 299 in three steps. Tritylation of the primary hydroxyl group of 299 and mesylation of the secondary hydroxyl group yielded compound 300, which was taken forward towards the azido derivative 301 in four steps. Acetolytic cleavage of the glycosidic bond of 301 led to 302, in which all the acetate groups were replaced by THP in a two step process to get 303. Catalytic hydrogenation of the azide to the amine 304 was followed by treatment with sulfur dioxide which resulted in the formation of 2-acetamido derivative of 1-deoxynojirimycin sulfonic acid 305. Through inversion of the C-5 hydroxyl group of 297 and following the same strategy as above, the authors have as well reported the synthesis of 308, the C-5 epimer of 305, through intermediates 306 and 307 (Scheme 37).

Scheme 37 Hasegawa's synthesis of acetamido derivative of 1-deoxynojirimycin sulfonic acid and its C-5 epimer.

Fleet et al.,¹¹⁶ in 1986, reported the first synthesis of 2-acetamido-1,5-imino-1,2,5-trideoxy-D-glucitol 238 and 2-acetamido-1,5-imino-1,2,5-trideoxy-D-mannitol 237 and studied their glycosidase inhibition activities. They started their synthesis from a benzyloxycarbonyl protected bicyclic amine 309.¹¹⁷ The free hydroxyl group of 309 was converted into epimeric azides 310 and 311 through its triflate. Azido group of 310 was reduced with sodium hydrogen telluride and the resulting amine was acetylated to get 312. Exposure of 312 to TFA in water led to the hydrolysis of the glucosidic bond and the resulting hemiacetal was then reduced to get compound 313. Catalytic hydrogenation of 313 in presence of Pd/C and AcOH led to the deprotection of both the benzyl and Cbz groups to afford 2-acetamido-2-deoxy-DNJ 238. In a similar way, 2-acetamido-1,2-dideoxy mannojirimycin 237 was obtained from epimeric azide 311 (Scheme 38).

Scheme 38 Fleet's synthesis of 2-acetamido-1,5-imino-1,2,5-trideoxy-D-mannitol 238 and 2-acetamido-1,5-imino-1,2,5-trideoxy-D-glucitol 237.

Bӧshagen's approach¹¹⁸ to 2-acetamido-2-deoxy-DNJ 238 involved the displacement of C-2 hydroxyl group of DNJ 10 with an azide, through a double-inversion procedure. DNJ 10 was benzylated at the endocyclic nitrogen and treated with isopropenyl methyl ether to get the monoisopropylidene derivative 314. The resulting diol was converted to olefin 315, which on dihydroxylation with OsO₄ in presence of NMO gave the manno-configured diol 316. Chemoselective benzylation of C-3 hydroxyl group of 316 was carried out using dibutyltin oxide-benzyl bromide. Esterification of the free hydroxyl group at C-2 of 317 with triflic anhydride and subsequent displacement of the resulting triflate with lithium azide delivered the 2-azido derivative 318. Reduction of azido group followed by its acetylation provided 2-acetamido derivative 319. Hydrogenation of the benzyl groups and acidic hydrolysis of the isopropylidene acetal finally delivered 2-acetamido-2-deoxy-DNJ 238 (Scheme 39).

Scheme 39 Bӧsahagen's synthesis of 2-acetamido-2-deoxy-DNJ.

Legler and co-workers,¹¹⁹ in 1989, reported a ten step synthesis of 2-acetamido-2-deoxynojirimycin 330 and 2-acetamido-1,2-dideoxy-DNJ 238 and studied their glycosidase inhibition activities. N-Acetyl-D-glucosamine 320 was converted to 2-acetamido-3-O-benzyl-6-O-trityl-β-D-glucofuranosides 321 and 322 in a few steps. Free hydroxyl group of 321 was then oxidized to ketone and its subsequent treatment with hydroxylamine gave oxime 323. It was then reduced with RANEY® nickel to 5-amino furanoside 325. TFA mediated detritylation afforded methyl furanoside 327 which was subjected to Pd(OH)₂ catalyzed hydrogenation followed by anomeric demethylation to get 2-acetamido-2-deoxynojirimycin 330. On the other hand, benzyl furanoside 328, obtained from 322 through intermediates 324 and 326, when subjected to Pd(OH)₂ catalyzed hydrogenation delivered 2-acetamido-1,2-dideoxynojirimycin 238 (Scheme 40).

Scheme 40 Lagler's synthesis of 2-acetamido-2-deoxynojirimycin and 2-acetamido-2-dideoxy-DNJ.

Schueller and Heiker,¹²⁰ in 1990, reported the first synthesis of 2-acetamido-1,2,5-trideoxy-1,5-imino-O-galactitol 339 from DNJ 10, which was readily converted to N-benzyl-1,5-dideoxy-1,5-imino-4,6-O-isopropylidene-D-mannitol 316 (Scheme 39). N-Debenzylation of diol 316 through catalytic hydrogenation and protection of the endocyclic nitrogen as its Cbz derivative afforded carbamate 331. Treatment of 331 with thionyl chloride and TEA gave a diastereomeric mixture of cyclic sulfates 332. Lithium azide mediated ring opening of 332 proceeded in a highly regioselective fashion to deliver 333 as the major product along with a minor amount of its regioisomer 335. The free hydroxyl group of 333 was protected as its benzyl ether 334 and subsequent acidic hydrolysis cleaved the isopropylidene acetal to give diol 336. Selective protection of the C-6 hydroxyl group was carried out by converting it into its carbamate 337. Inversion of the C-4 hydroxyl group was then accomplished in three steps through mesylation, nucleophilic substitution with lithium benzoate and subsequent hydrolysis. Final deprotection of the carbamate furnished the target molecule 339 (Scheme 41).

Scheme 41 Schueller's synthesis of 2-acetamido-1,2,5-trideoxy-1,5-imino-O-galactitol.

Hasegawa and co-workers,¹²¹ in 1991, reported a synthesis of N-acetylhexosamine analogues 238 and 350–352 from DNJ 10 which was converted into epoxides 340 and 341, through literature known steps that include N-Boc protection, 4,6-benzylidenation and intramolecular epoxide formation. The epoxides 340 and 341 were treated with sodium azide to get 342 in (59%), 344 (31%), 346 (58%) and 348 (22%) respectively. Selective reduction of their azido groups followed by acetylation led to the N-acetyl derivatives 343, 345, 347 and 349 respectively. Final Boc deprotection was carried out with TFA to get 2-N-acetylhexosamine derivatives 238, 350, 351 and 352 (Scheme 42).

Scheme 42 Hasegawa's synthesis of N-acetylhexosamine analogues.

They also utilized compound 10 towards the synthesis of 2-N-acetylmannosamine analogue 237 through selective inversion at C-2 position followed by deprotection as described by them for compound 351 (Scheme 43).

Scheme 43 Hasegwa's synthesis of 2-N-acetylmannosamine 237.

Compound 342 was used by the authors for the synthesis of galactosamine analogue 339 as well. Two step conversion of azido group of 342 to the corresponding acetamido derivative was followed by catalytic hydrogenation to get 355. Selective protection of the primary hydroxyl group as its trityl ether and through an oxidation–reduction process, the stereochemistry at C-4 carbon was inverted to get 356, which was then taken through a few deprotection steps to get the final compound 339 (Scheme 43 and 44).

Scheme 44 Hasegawa's synthesis of 2-acetamido-1,2,5-trideoxy-1,5-imino-O-galactitol.

Furneaux et al.,¹²² in 1993, reported the synthesis of 2-acetamido-1,2-dideoxynojirimycin 238 from readily available N-acetyl-D-glucosamine 320 (Scheme 39). Treatment of 320 with iron(III) chloride in acetone provided the oxazoline 357, which without purification was subjected to sequential acidic methanolysis and hydrolysis to get triol 358. Chemoselective oxidation of C-5 secondary hydroxyl group was performed using Bu₂SnO and bromine, which was then subjected to acid hydrolysis to obtain keto aldehyde 359. Reductive amination of 359 with benzhydrylamine hydrochloride in presence of sodium cyanoborohydride afforded N-substituted iminosugar 360. Benzhydril group was then deprotected by catalytic hydrogenation to the title azasugar 238. Alternatively, target compound 238 was also achieved directly from 359 in one step using ammonium acetate as the nitrogen source (Scheme 45).

Scheme 45 Furneaux's synthesis of 2-acetamido-1,2-dideoxynojirimycin.

In 1995, Khanna et al.¹²³ followed an almost similar strategy as that of Hasegawa¹²¹ and reported the synthesis of 3-amino-1,3-dideoxynojirimycin 366, starting from compound 10. They protected endocyclic nitrogen of 10 as its Cbz carbamate 361, which was followed by benzylidene protection and regioselective tosylation to get compound 362. Epoxidation to 363, followed by ring opening with NaN₃ provided two regioisomers 364a and 364b. The free hydroxyl group of 364b was oxidized using DMSO and TFAA, which was then epimerized at C-2 position by stereoselective reduction of the ketone of 365 with DIBAL-H. Catalytic hydrogenation of the azido group and deprotection of Cbz in one step followed by benzylidene deprotection was carried out with TFA/H₂O to get 3-amino-1,3-dideoxynojirimycin 366 (Scheme 46).

Scheme 46 Khanna's synthesis of 3-amino-1,3-dideoxynojirimycin 366.

In a similar way, authors have also reported the synthesis of 2,3-diamino-1,2,3-trideoxy nojirimycin 370 from 364a through intermediates 367–369 (Scheme 47) as depicted in Schemes 46 and 47.

Scheme 47 Khanna's synthesis of 2,3-diamino-1,2,3-trideoxynojirimycin 370.

Shin's¹²⁴ approach towards the synthesis of protected 2-amino-1,2-dideoxymannojirimycin relied on a late stage introduction of azido group on to a partially protected 1-deoxynojirimycin 372, which in turn was synthesized from diacetone glucose 371 in a few steps. When compound 372 was subjected to benzoylation reaction, bis-benzoylated regioisomers 373 and 374 were obtained in a 1 : 1 ratio. Exposure of the mixture to mesyl chloride gave the regioisomeric mesyl derivatives 375 and 376 respectively, which were subjected to substitution reaction by azide in DMSO. Under this condition, only compound 375 underwent substitution reaction to give protected 2-azido-mannojirimycin derivative 377. Mesylate 376 did not react and was completely recovered. Catalytic hydrogenation of 377 led to the reduction of azido and deprotection of N-nitrobenzyl carbamate functionality to afford 378 (Scheme 48).

Scheme 48 Shin's synthesis of protected 2-amino-1,2-dideoxynojirimycin.

A novel approach to 2-acetamido-1-2-dideoxynojirimycin 238 from 6,6′-diazido sucrose 379 was reported by Stütz and co-workers.¹²⁵ The known disaccharide 379 was first benzylated to the corresponding per-O-benzyl derivative 380. Acidic hydrolysis of 380 provided a 1 : 1 mixture of 6-azido-D-glucopyranose 381 and 6-azido-D-fructofuranose 382. Controlled hydrogenation of the azido group of 382 with RANEY® nickel was followed by concomitant intramolecular reductive amination and subsequent protection as its Cbz derivative to get 383. The free hydroxyl group of 383 was then converted to the azido derivative 384 with inversion of configuration through the displacement of the corresponding triflate. Staudinger reduction of the azide to the amine, subsequent N-acetylation and final O-debenzylation through catalytic hydrogenation provided 2-acetamido-1,2-dideoxynojirimycin 238 (Scheme 49).

Scheme 49 Stütz's synthesis of 2-acetamido-1-2-dideoxynojirimycin.

Mignani and co-workers⁶³ previously described the synthesis of polyhydroxypyrrolidine based non-peptide mimics (Scheme 7). In the same article,⁶³ they also reported the synthesis of polyhydroxypiperidine based somatostatin/sandostatin analogues 386 and 388. Aminopiperidine 386 was synthesized from intermediate 85 (Scheme 7) through TBS protection of both of hydroxyl groups. The primary hydroxyl group was then selectively deprotected by treating it with acetic acid/water. It was then mesylated to compound 385 and subjected to nucleophilic substitution with N-Boc-1,6-hexyldiamine which was followed by acid catalyzed deprotection to get the piperdine 386. The other regioisomer 388 was synthesized from 85 by treating it first with TBSCl to protect primary hydroxy group. Mitsunobu inversion of secondary hydroxyl group with HN₃ provided azido compound 387 which was reduced through catalytic hydrogenation and the resulting amine was treated with 6-bromo-N-Boc-hexylamine. Subsequent acidic hydrolysis provided piperidine analogue 388 (Scheme 50).

Scheme 50 Mignani's synthesis of piperidine based somatostatin/sandostatin analogues.

Vasella¹²⁶ and co-workers, in 1998, reported the synthesis of 2-acetamido-1,2-dideoxynojirimycin 238 starting from lactone 389, involving lactam 391 as the intermediate. Their synthesis started with commercially available N-acetyl glucosamine 320 (Scheme 40), which was converted into lactone 389 in three steps. Ammonolysis of the lactone afforded the hydroxy amide 390, which upon oxidation followed by reductive amination resulted in the formation of aminoacetyl lactam 391. Benzyl groups of 391 were then deprotected through catalytic hydrogenation to get the parent 2-acetamido-5-amino-3,4,6-trihydroxy-2,5-dideoxy-D-glucono-1,5-lactam 392. Reduction of the lactam 392 with BF₃·Et₂O and NaBH₄ delivered the 2-acetamido-1,2-dideoxynojirimycin 238 (Scheme 51).

Scheme 51 Vasella's synthesis of 2-acetamido-1,2-dideoxynojirimycin.

Following the procedure of Vasella, Lin and co-workers¹²⁷ further elaborated the utility of protected 2-acetamido nojirimycin 393 by incorporating a variety of functional groups on ring nitrogen and synthesized compounds 396–400, with a view of identifying potent and selective inhibitors against N-acetyl-β-hexosaminidase (Scheme 52).

Scheme 52 Lin's synthesis of N-substituted 2-acetamido-1,2-dideoxynojirimycin.

Further utility of compound 238 was demonstrated by Mobashery and co-workers¹²⁸ who reported the synthesis of iminosaccharides 238·HCl and 401–403 containing 2-acetamido group and studied their inhibitory activities against purified recombinant NagZ of Pseudomonas aeruginosa and the lytic transglycosylase MItB of E. coli, which are involved in bacterial cell wall recycling¹²⁹ (Fig. 10).

Fig. 10 Mobashery's 2-acetamidonojirimycin based iminosaccharides.

Stütz¹³⁰ and co-workers, in 2009, reported a synthesis of 2-acetamido-1,2-dideoxynojirimycin 238 and its lysine derivatives. The lysine derivatives displayed improved inhibition against β-N-acetylglucosaminidase from Streptomyces plicatus as compared to previously described compounds.¹³¹ Reductive amination of uloside 404 in presence of protected lysine or chain extended amide using Pd(OH)₂/C as a catalyst afforded 405 and 407 respectively. Boc removal of 405 and 407, and subsequent treatment with dansyl chloride afforded the dansyl derivatives 406 and 408 respectively (Scheme 53).

Scheme 53 Stütz's synthesis of lysine derivatives of 2-acetamido-1,2-dideoxynojirimycin.

Wrodnigg and co-workers,¹³² in 2010, reported the synthesis of fluorous iminoalditols as new inhibitors for glycosidases and pharmacological chaperones. They reported an amino modified piperidine based fluorous iminocyclitol 410, through Pd/C catalyzed hydrogenation of GlcNAc-derived ulososide 404 in presence of fluorous amine 409 (Scheme 54).

Scheme 54 Wrodnigg's synthesis of fluorous iminoalditol.

Fleet and co-workers,¹³³ in 2010, reported the synthesis of 2-acetamido-1,2-dideoxy-D-galactonojirimycin DGJNAc 280 as the first potent competitive sub-micromolar inhibitor of α-N-acetyl-galactosaminidases. They started their synthesis from a commercially available D-glucuronolactone derived acetonide 411,¹³⁴ which on esterification with triflic anhydride followed by substitution with sodium azide gave compound 412. The azido lactone was reduced to the lactol using DIBAL-H and subsequently with NaBH₄ to get the diol 413. Protection of the primary hydroxyl group as its TBS ether followed by inversion of stereochemistry of C-3 hydroxyl group through an oxidation–reduction sequence gave 415 which was protected as its benzyl ether 416. Compound 418 was obtained from 416 via the methyl furanoside 417 through standard protocols. The key step in their synthesis was the displacement of ditriflate 418 with benzylamine to get the bridged bicyclic intermediate 419, which on exposure to BF₃·Et₂O in acetic anhydride resulted in the ring cleavage to afford a 4 : 1 mixture of epimers of compound 420. Reductive removal of the methoxy group gave the diacetate 421. Rapid reduction of the azido group using zinc powder in presence of copper(II) sulfate in acetic acid–acetic anhydride medium resulted in concomitant acylation as well to deliver the tri-acetate 422. Final two step deprotection of the acetyl and benzyl groups afforded DGJNAc 280 (Scheme 55).

Scheme 55 Fleet's synthesis of 2-acetamido-1,2-dideoxy-D-galactonojirimycin (DGJNAc).

Using a similar strategy, later in 2012,¹³⁵ the authors have reported the synthesis of DNJAc 238 and DGJNAc 280 along with their enantiomers ent-238 and 428 and the N-alkylated derivatives 424–427 and 429, 430, respectively, and studied the effect of N-alkylation on hexosaminidase inhibition (Fig. 11).

Fig. 11 Structures of N-alkylated derivatives of DNJAc and DGJNAc synthesized by Fleet.

Stubbs et al.¹³⁶ reported an elegant synthesis of a series of N-acyl analogues of 2-amino-1,2-dideoxynojirimycin 238 and 437–441 and assayed them against β-glucosaminidase NagZ, an enzyme involved in regulating the induction of AmpC expression, which is associated with the action of antibiotic resistant enzyme.¹³⁷ Their synthesis started with readily available 2-amino methyl glucoside 431 (ref. 138) which was subjected to azido transfer reaction¹³⁹ to get the azido triol 432. Primary hydroxyl group of triol 432 was converted to the corresponding iodide and the remaining hydroxyl groups were acetylated to get 433. Subsequent exposure to DBU resulted in a facile dehydrohalogenation to give olefin 434. Staudinger reduction followed by acylation with various anhydrides provided a series of amides 435. Epoxidation of the double bond of 435 with 3-chloroperbenzoic acid in presence of BnOH gave the ulososides, which were then deacylated with sodium methoxide to get the triol 436. Pd(OH)₂ catalyzed hydrogenolysis in presence of ammonium acetate then provided the desired iminosugars 238 and 437–441 (Scheme 56).

Scheme 56 Stubbs' synthesis of N-acyl analogues of 2-amino-1,2-dideoxynojirimycin.

3.3.2 Synthesis of 6-amino- and 6-azido-1,6-dideoxynojirimycin derivatives. Hoornaert and co-workers,^140a in 1995, reported the first synthesis of 6-azido and 6-amino analogues of 1-deoxynojirimycin. Their synthesis started with N-Boc derivative of 1-amino-1-deoxy-D-glucitol 442. Upon treatment with acetone, 2,2-dimethoxypropane and p-toluenesulfonic acid, compound 442 provided an inseparable mixture of diacetonides 443 and 445. Their free hydroxyl group were acetylated to get the acetates 444 and 446, which were then treated with pyridinium p-toluenesulfonate in aqueous methanol, resulting in the selective deacetylation of the terminal acetonide group to give products 447 and 448. Sulfonylation of diol 447 followed by treatment with sodium azide in DMF delivered the desired azido compound 449, which on exposure to trimethylsilyliodide resulted in Boc deprotection and subsequent deacetylation to afford epoxide 450. Upon refluxing in MeOH in presence of silica epoxide 450 underwent a stereo- and regioselective intramolecular opening to afford protected 6-azido deoxynojirimycin 451. Deprotection of 451 to the final compounds 452 and 453 was then achieved using standard procedures (Scheme 57).

Scheme 57 Hoornaert's synthesis of 6-azido and 6-amino analogues of 1-deoxynojirimycin.

Using an almost similar protocol,^140b compound 445 was transformed to protected 6-amino-1,6-dideoxy-L-gulonojirimycin 455 via azide 454. Alternatively, conversion of the primary hydroxyl group of 454 to the corresponding bromide followed by reductive cyclization also yielded 455. Final deprotection under acidic condition provided 6-amino-1,6-dideoxynojirimycin 456·2HCl. Authors have also utilized compound 455 as a convenient starting material for the synthesis of 2-fluoro- and 2-azido analogues of 1-deoxnojirimycin 458 and 461 respectively (Scheme 58).

Scheme 58 Hoornaert's synthesis of 6-amino-1,6-dideoxy-L-gulonojirimycin and its analogues.

Vasella and Peer,¹⁴¹ in 1999, reported the synthesis of a novel amino-modified six-membered iminocyclitol 465, which was found to be a very strong inhibitor of bovine epididymis α-L-fucosidase. For this purpose, they have synthesized L-fuconitrone 463 in about 12 steps starting from allyl glycoside 462. AlMe₂Cl promoted addition of TMSCN to nitrone 463 followed by desilylation in presence of TsOH and MeOH, predominantly, gave the nitrile 464. Deprotection of the TMS group was carried out using TsOH and H₂O. Reduction of the cyanide group and debenzylation were carried out in a single step through catalytic hydrogenation over Pd/C in MeOH/HCl to get bis-hydrochloride salt 465 (Scheme 59).

Scheme 59 Vasella's synthesis of amino-modified six-membered iminocyclitol 465.

Compernolle's approach¹⁴² to protected 6-azido- and 6-amino-1,6-dideoxymannojirimycin involves the nucleophilic ring opening of an aziridine derived from commercially available 1-amino-1-deoxyglucitol 466 as the key step. Nucleophilic ring opening of aziridine 468, obtained from mesylate 467, with NaN₃ or benzylamine proceeded from the less hindered side to afford the azido amine 469 or diamine 470. Selective hydrolysis of the terminal isopropylidene group to 471, followed by an intramolecular Mitsunobu reaction provided the protected 6-azido and 6-amino-1,6-dideoxy mannojirimycin 472 and 473 respectively (Scheme 60). Later,¹⁴³ in 2000, they also reported an alternate synthesis for 6-azido- and 6-amino-1,6-dideoxynojirimycin 451 and 452.

Scheme 60 Compernolle's synthesis of protected 6-azido and 6-amino-1,6-dideoxymannojirimycin.

Noort and co-workers¹⁴⁴ designed a synthesis of 2-acetamidomethyl derivatives of isofagomine and assayed their biological activities against human spleen lysosomal β-hexosaminidase. They observed that 1-N-imino-2-acetamidomethyl derivative 482 is a selective inhibitor with a K_i of 2.4 μM. Their synthesis started with Cerny epoxide 474 (ref. 145) which was treated with vinylmagnesium bromide to get 475 in a regioselective fashion. Oxidative cleavage of the double bond followed by reduction of the resulting aldehyde and benzyl protection of the obtained alcohol gave 476. Conversion of compound 476 to lactone 477 was accomplished in four steps. Lactone 477 was then transformed to lactam 478 following the method originally described by Vasella,¹⁴⁶ Pandit,¹⁴⁷ and them.¹⁴⁸ Deprotection of the TBS group followed by its mesylation and subsequent reaction with sodium azide provided azido lactam 479. Staudinger reduction of azido group of 479, acetylation of the resulting amine and further catalytic hydrogenation afforded iminosugar lactam 480. Towards the synthesis of isofagomine derivative 482, lactam 479 was reduced with BH₃·DMS and the ring nitrogen was protected as its benzyl derivative, to get 481. Conversion of 481 to 482 was achieved in five steps (Scheme 61).

Scheme 61 Noort's synthesis of 2-acetamidomethyl derivatives of isofagomine.

Xiao and co-workers,¹⁴⁹ in 2007, reported a rapid synthesis of iminosugar derivatives in a microtiter plate and carried out their in situ screening against cancer cell lines. Their synthesis to make protected iminocyclitols started with galactose 483 which was converted to compounds 484 and 485 according to the previously reported procedure.¹⁵⁰ Compounds 484 and 485 were individually oxidized with PCC and the resulting aldehydes were condensed with hydroxyl amine which was followed by palladium catalyzed hydrogenation to get final iminocyclitols 486 and 487. They were coupled with different aliphatic and aromatic acids to make a library of amides in microtiter plate. Without purification they performed in situ screening against two tumor cell lines, human cervical carcinoma cell line HeLa and leukaemia cell line HL-60 (Scheme 62).

Scheme 62 Xiao's synthesis of iminosugar derivatives.

A novel intramolecular azide–alkene cycloaddition reaction based methodology was developed by Zhou and Murphy¹⁵¹ for the synthesis of azido substituted 1-deoxynojirimycin derivative 492. They started their synthesis from D-glucono-δ-lactone 488 which was converted to diol 489 through literature known procedure.¹⁵² Primary hydroxyl group of 489 was mesylated and subsequently substituted with an azido group. The secondary hydroxyl group was then protected as its benzyl ether. Acid catalyzed cleavage of the terminal isopropylidene group followed by oxidative cleavage of the resulting diol delivered the aldehyde, which on Wittig reaction afforded substrate 491 required for azide–alkene cycloaddition reaction. Interestingly, compound 491 was converted to 492 through a one-pot procedure involving 3 steps viz. [3 + 2] cycloaddition, elimination of N₂ to give a cyclopropane and subsequent ring opening by sodium azide (Scheme 63).

Scheme 63 Murphy's synthesis of azido substituted 1-deoxynojirimycin derivative.

Estévez and co-workers,¹⁵³ in 2009, developed a new route for the synthesis of 6-amino-1,6-dideoxynojirimycin 453·2HCl from a glucose derived ketone 493.¹⁵⁴ Henry reaction of ketone 493 with nitromethane provided C-5 nitromethyl-α-D-glucofuranose 494 and its epimer 495, as a mixture, in a ratio of 58 : 42. This epimeric mixture was subjected to hydrogenation using RANEY®-Ni as a catalyst to get a 1 : 1.5 mixture of the D-gluco derivative 496 and the L-ido derivative 497. During this process, migration of benzoyl group from oxygen to nitrogen atom was also observed. NaIO₄ mediated oxidative cleavage of the mixture of diols 496 and 497 provided ketone 498, which underwent hydrolysis of the acetal group upon treatment with TFA. Subsequent reaction with diphenylmethylamine afforded an iminium salt 499. Sodium cyanoborohydride mediated reduction of 499 provided a mixture of epimers 501 (major) and 500 (minor). Final deprotection of 501 with palladium catalyzed hydrogenation in the presence of HCOONH₄ followed by acid treatment afforded 6-amino-1,6-dideoxynojirimycin 453 (Scheme 57) as its bishydrochloride salt (Scheme 64).

Scheme 64 Estévez's synthesis of 6-amino-1,6-dideoxynojirimycin.

Tamayo et al.,¹⁵⁵ in 2010, reported a concise synthesis of 6-amino-1,6-dideoxynojirimycin 453·2HCl and 6-amino-1,6-dideoxy-L-talonojirimycin 506·HCl from a commercially available cheap material, namely, 2,3-O-isopropylidene-1,6-di-O-p-toluenesulfonyl-α-L-sorbofuranose 502. Lithium azide mediated transformation of ditosylate 502 into diazide 503, was followed by deprotection of the acetonide group with trifluoro acetic acid to get the triol 504. Without isolation, the triol 504 was hydrogenated in presence of Pd/C to get 6-amino-1,6-dideoxynojirimycin as its bishydrochloride salt 453. In order to get 6-amino-1,6-dideoxy-L-talonojirimycin 506, inversion of stereochemistry at C-3 position was carried out through an oxidation–reduction process that resulted in the formation of compound 505. Using an identical synthetic sequence as described above, compound 505 was converted into 506 (Scheme 65).

Scheme 65 Tamayo's synthesis of 6-amino-1,6-dideoxynojirimycin and 6-amino-1,6-dideoxy-L-talonojirimycin.

Our group,¹⁵⁶ in 2013, reported a glycal based approach towards the synthesis of 6-amino-1,6-dideoxy-L-gulonojirimycin 511. Tri-O-benzyl-D-glucal 507 was converted into the diamino alcohol 508 in two steps.^93,94 TBS protection of the hydroxyl group of 508 was followed by debenzylation through catalytic hydrogenation to get the triol 509. Intramolecular Mitsunobu reaction of 509 proceeded in a highly chemoselective manner to give protected 6-amino-1,6-dideoxy-L-gulonojirimycin. One pot N-detosylation and debenzylation under Birch condition was followed by a chemoselective aceylation at the side chain nitrogen to get the 6-acetamido-1,6-dideoxygulonojirimycin 511. Compound 511 was found to be a selective inhibitor of β-N-acetylhexosaminidase (Scheme 66).

Scheme 66 Ramesh's synthesis of 6-amino-1,6-dideoxy-1-gulonojirimycin.

Soengas and Silva,¹⁵⁷ in 2013, developed an indium catalyzed aza-Henry type reaction to construct various sugar derived diamines and exploited this strategy for a concise synthesis of 6-amino-1,6-dideoxynojirimycin 453·2HCl. Sugar derived imine 512, on treatment with α-bromonitromethane, in presence of 10 equiv. of zinc and catalytic amount of indium (0.12 equiv.), underwent a smooth aza-Henry type reaction to afford the nitro derivative 513 in a diastereomeric ratio of 4 : 1. SmI₂ mediated reduction of the nitro group of the major diastereomer to 514, followed by its protection with CbzCl delivered the protected diamine 515. Deprotection of the p-methoxybenzyl group using CAN, acidic hydrolysis of the isopropylidene group and catalytic hydrogenation gave 6-amino-1,6-dideoxynojirimycin which was isolated as its bishydrochloride salt 453·2HCl (Scheme 67).

Scheme 67 Silva's synthesis of synthesis of 6-amino-1,6-dideoxynojirimycin 451·2HCl.

Cardona and co-workers¹⁵⁸ reported the synthesis of 6-amino-1,6-dideoxy-L-gulonojirimcin 523 and its N-benzyl derivative 522, starting from protected sugar derived aldehyde 518, which in turn was synthesized in three steps from protected D-mannose 517.¹⁵⁹ The aldehyde 518 was subjected to Strecker reaction with benzylamine in presence of TMSCN to get products 519a and 519b in a diastereomeric ratio of 86 : 14. Ambersep® 900-OH ion exchange resin mediated deprotection of anomeric acetyl group of the major isomer 519a and then intramolecular reductive amination of the resulting hemiacetal with NaBH₃CN at room temperature provided 2-amido-piperidine azasugar 520. The amide group of 520 was successfully reduced with lithium aluminium hydride to the corresponding amine 521. Acetonide group was then deprotected under acidic condition to get the N-benzyl derivative of 6-amino-1,6-dideoxy-L-gulonojirimycin 522. On the other hand, Pd/C catalyzed hydrogenation of 521 in methanolic HCl followed by treating the residue with Dowex 50WX8 gave the parent compound 523 (Scheme 68).

Scheme 68 Cardona's synthesis of 6-amino-1,6-dideoxy-L-gulonojirimcin and its N-benzyl derivative.

Taking a clue from Overkleeft's Staudinger/aza-Wittig/ugi three component sequence,⁸¹ Wrodnigg and co-workers,¹⁶⁰ in 2014, developed a new Staudinger/aza-Wittig/Strecker (SAWS) multicomponent reaction sequence to get C-1-cyano iminoalditols. When 5-azido-5-deoxy-D-xylose 524, easily accessible from D-xylose, was subjected to Staudinger reaction with trimethylphosphine followed by addition of sodium cyanide, the expected 1-C-cyano-1,5-dideoxy-1,5-imino-D-xylitol 527 was obtained. The cyano group of 527 was reduced under platinum catalyzed hydrogenation to get 1-C-aminomethyl-1,5-dideoxy-1,5-imino-D-xylitol (DIX) 528, which was further functionalized with dansyl chloride to get dansyl substituted fluorescent DIX derivative 529 (Scheme 69).

Scheme 69 Wrodnigg's multicomponent reaction strategy to iminoalditols.

3.3.3 Miscellaneous synthesis of amino-modified deoxynojirimycin derivatives. Duréault et al.¹⁶¹ developed a synthesis of an azido-amino derivative of polyhydroxypiperidine 532 starting from D-mannitol derived bisaziridine precursor 530, which was reported by them earlier.¹⁶² Heating the tosyl substituted bisaziridine with NaN₃ in DMF led to the piperidine derivative 532 through the transient intermediate 531. This approach was later used by them for the synthesis of differently substituted piperidines as well¹⁶³ (Scheme 70).

Scheme 70 Duréault's synthesis of 2,6-diamino substituted polyhydroxypiperidine.

Chakraborty and Jayaprakash,¹⁶⁴ in 1997, reported a stereoselective synthesis of 1,7-diamino-1,2,6,7-tetradeoxy-2,6-imino-D-glycero-D-ido-heptitol 538 involving an intramolecular 6-exo-tet opening of a terminal aziridine as the key step. Their synthesis started with methyl 6-deoxy-6-azido-2,3,4-tri-O-benzyl-D-glucopyranoside 533 which was easily obtained from methyl α-D-glucopyranoside.¹⁶⁵ Acidic hydrolysis followed by reduction with NaBH₄ afforded diol 534 which was then refluxed with Ph₃P. Under this condition, the incipient amine formed by the reduction of the azido group displaced the adjacent hydroxyl group to form the aziridine directly, that was protected as its Boc derivative 535. The aldehyde group obtained by the oxidation of 535 using DMP, was subjected to Strecker reaction with benzylamine in presence of TMSCN to provide the cyano amine 536. DIPEA mediated intramolecular aziridine ring opening provided 537, which when subjected to catalytic hydrogenation resulted in the formation of the required novel diamino polyhydroxypiperidine 538 (Scheme 71).

Scheme 71 Chakraborty's synthesis of 1,7-diamino-1,2,6,7-tetradeoxy-2,6-imino-D-glycero-D-ido-heptitol.

Wong and co-workers,¹⁶⁶ in 2003, reported the synthesis of amino-substituted fuconojirimycin analogue 543 from L-gulono-1,4-lactone 539 through a modified procedure developed by Fleet.¹⁶⁷ Lactone 539 was converted into azido lactone 540 through literature known procedure.¹⁶⁸ Addition of MeLi to lactone 540 and reductive amination of resulting hemiacetal provided the piperidine derivative 541. N-Boc protection of 541 was followed by TBAF mediated deprotection of TBS group to release the primary alcohol. Intermolecular Mitsunobu reaction with TMSN₃ provided the azido derivative 542 that was converted to 543 using standard protocols. Compound 543 was then used for subsequent diversity oriented reaction with a variety of carboxylic acids in presence of HBTU and DIEA to generate about sixty derivatives of amide 544. Amongst them, compounds 545 and 546 were found to be the most potent inhibitors of α-L-fucosidase with K_i values in nM range (Scheme 72).

Scheme 72 Wong's synthesis of amino-substituted fuconojirimycin analogues.

Nicotra and co-workers,¹⁶⁹ in 2004, developed a method for the synthesis of iminosugar scaffolds to generate a library of inhibitors against glycosidases. In the process, they also reported the synthesis of azido-piperidine derivatives 554 and 555. They planned their synthesis to obtain a methylenecarboxylic acid appendage at C-1 so that it can be further derivatized and their route allowed the synthesis of both α-and β-glycosides, in both D and L series of sugars as well. They started their synthesis from 2,3,4,6-tetra-O-benzyl-D-glucopyranose 547 and converted it into a aldehyde 548.¹⁷⁰ Ethoxycarbonyl-methylene triphenylphosphorane treatment on aldehyde 548 afforded 549, which underwent smooth Michael addition with allylamine to give the amino ester as a mixture of diastereomers 550a and 550b in a ratio of 2 : 1. Construction of the piperidine ring was achieved through intramolecular reductive amination of amino ketones 551a and 551b to (552a and 552b, respectively), which were obtained in a few steps from 550a and 550b respectively. Desilylation of 552a to 553, mesylation of the resulting hydroxyl group and displacement with NaN₃ provided the azido-piperidine derivative 554. In a similar way, diastereomer 555 was obtained from 552b (Scheme 73).

Scheme 73 Nicotra's synthesis of iminosugar scaffolds as glycosidases inhibitors.

Overkleeft and co-workers¹⁷¹ extended their SAWU-3CR process⁸¹ to generate highly functionalized, enantiomerically pure pipecolic acid amides. Their synthesis started with carbohydrate derived partially protected 5-azido-D-ribofuranoside 558, which in turn was obtained from pentose 556 in four steps that include tosylation of the primary hydroxyl group, benzoylation of the hemiacetal to 557, substitution of the tosyl group with sodium azide and final debenzoylation. Staudinger reaction of 558 with trimethylphosphine in MeOH was followed by reaction of the resulting imine with Boc-Ala-OH and cyclohexyl isocyanide at −78 °C to get 560, through the transient cyclic imine 559, as a single stereoisomer through SAWU-3CR. The general applicability of the SAWU-3CR was demonstrated through the synthesis of a small library of molecules (Scheme 74).

Scheme 74 Overkleeft's synthesis of pipecolic acid amides, through SAWU-3CR.

Moravcová and co-workers¹⁷² reported an elegant synthesis of 3-acetamido-1,3,5-trideoxy-1,5-imino-D-glucitol 569 and 3-acetamido-1,3,5,6-tetradeoxy-1,5-imino-D-glucitol 568 starting from methyl β-D-glucopyranoside 561.¹⁷³ NaIO₄ mediated oxidative cleavage of 561 to 562 and treatment of the resulting dialdehyde with nitromethane provided a mixture of three nitropyranosides of which 563 was the major product. Pd/C catalyzed hydrogenation of nitro group to amine and subsequent acetylation provided peracetylated 3-acetamido-3-deoxy-D-glucopyranoside 564. Chromium trioxide mediated oxidative cleavage of 564 provided the keto ester in which the keto group was converted to the corresponding oxime 565. Pd/C catalyzed hydrogenation of 565 was accomplished by a concomitant intramolecular cyclization to give a mixture of two lactams 566 and 567 in a ratio of 3 : 1. LiAlH₄ reduction of lactams 566 and 567 provided the 3-acetamido derivatives 568 and 569 respectively (Scheme 75).

Scheme 75 Moravcová's synthesis of 3-acetamido-1,3,5-trideoxy-1,5-imino-D-glucitol and 3-acetamido-1,3,5,6-tetradeoxy-1,5-imino-D-glucitol.

Blériot and co-workers¹⁷⁴ reported a flexible strategy to prepare six-membered D- and L-iminosugars from easily available 6-azido-6-deoxy-2,3,4-tri-O-benzyl-D-glucopyranose precursor 570 and their methodology involves a highly diastereoselective tandem ring enlargement/alkylation and a stereocontrolled ring contraction reaction. Through this strategy, they were able to introduce structural diversity at both C-1 and C-6 position of the iminosugars. Their initial attempts to obtain azepane 571 through the reaction of azido glucopyranose 570 with PPh₃ failed. Interestingly, the reaction could be realized using a polymer-bound triphenylphosphine, however, it resulted in the formation of the N,O-acetal 572, formed through the intramolecular nucleophilic addition of the free hydroxyl group of 571 to the imine. Exposure of the bicyclic N,O-hemiacetal to a large excess of allylmagnesium bromide led to the isolation of allylazepane 573 as the major product. N-Benzylation of 573 to 574 followed by mesylation of the free hydroxyl group using MsCl in presence of Et₃N furnished chlorinated six-membered iminosugar C-glycoside 575. The reaction proceeds through an initial formation of the mesylate, which was displaced by the ring nitrogen atom to form a transient fused piperidine-aziridinium intermediate. Regioselective opening of this intermediate by the released chloride ion then gave the six-membered iminosugar 575. The isomeric seven-membered derivative 576 was not observed in this case. On the other hand, when the reaction was carried out under Mitsunobu condition with diphenylphosphoryl azide (dppa), a mixture of azido derivatives of six-membered and seven-membered iminocyclitols 577 and 578 was obtained (Scheme 76).

Scheme 76 Blériot's synthesis of six and seven-membered D- and L-iminosugars.

Posakony et al.,¹⁷⁵ applied Vasella's strategy¹²⁶ on allyl glycoside 579 to synthesize lactam 580, and carried out selective phosphorylation at C-6 position to get 581, for evaluation as catalytic cofactors of the glmS ribozyme, a bacterial gene-regulating RNA that controls cell wall biosynthesis (Scheme 77).

Scheme 77 Posakony's synthesis of C-6 phosphorylated iminosugar lactam.

Wong and co-workers,¹⁷⁶ in 2014, reported the first synthesis of iminosugar C-glycosides of α-D-GlcNAc-1-phosphate 592, iminosugar phosphonate and its elongated phosphate analogues. They also performed bacterial transglycolase inhibition, which is a key enzyme for bacterial cell wall formation. They synthesized amino modified iminocyclitol 589 as an intermediate enroute to their targeted iminosugar phosphates. Their synthesis started with GlcNAc 582, which was prepared¹⁷⁷ and subjected to Wittig reaction to get olefin 583. Oxidation of 583 under Swern condition delivered the corresponding ketone 584, which was found to exist in its hemiaminal form 584. Reductive amination of hemiaminal with an excess of sodium cyanoborohydride and ammonium acetate provided a mixture of diaminoheptenitols 586 and 587 in a diastereomeric ratio of 2 : 1. Diaminoheptenitol 586 was subjected to NIS mediated intramolecular iodoamination reaction that delivered exclusively the α-anomer 588. Displacement of the iodo group of 588 using silver acetate followed by hydrolysis afforded C-2 acetamido analogue of homonojirimycin (HNJ) 589 as the major product. Azido group was also introduced by replacing the iodo group of iodoamine 588 to have the corresponding azido azasugar 590 as well. Similarly, diaminoheptenitol 587 was allowed to react with NIS to afford L-ido-iodoamine 591. Iodoiminosugars 588 and 591 were also used for the synthesis of iminosugar phosphonates for assaying their biological activities (Scheme 78).

Scheme 78 Wong's synthesis of iminosugar C-glycosides, iminosugar phosphonate and its elongated phosphate analogues.

Cardona and co-workers,¹⁵⁸ in 2014, reported the synthesis of 4-amino-polyhydroxy piperidine type iminosugar from readily available D-mannose and studied their glycosidase inhibition activities. They started their synthesis from a D-mannose derived aldehyde 593 (ref. 178) and converted it to a piperidone derivative 594.¹⁷⁹ Reductive amination of the keto group of 594 with various amines provided 4-amino-substituted piperidine derivatives 595–597. When the reductive amination was carried out with sodium cyanoborohydride, the results were not encouraging, resulting in low yields of the products along with unwanted side products. On the other hand, catalytic hydrogenation in presence of Pd(OH)₂/C was not only smooth, affording the expected products in better yields, but was also highly stereoselective. Subsequent treatment of compounds 595–597 with methanolic HCl cleaved the acetonide protection as well as the Boc group to give new N-alkylamino piperidines 598–600 respectively. 5-Amino piperidine 601 was also synthesized through global deprotection of 595 by palladium catalyzed hydrogenation in acidic medium (Scheme 79).

Scheme 79 Cardona's synthesis of 4-amino-polyhydroxypiperidines.

Sollogoub and co-workers¹⁸⁰ developed a synthesis of 1,2-cis-homoiminoazasugars derived from GlcNAc and GalNAc by utilizing a β-amino alcohol skeletal rearrangement as the key step and they studied their enzyme inhibition activities against various glycosidases. Their synthesis started with a commercially available D-arabinofuranose derivative 602. Wittig olefination of 602 with methyltriphenylphosphonium bromide in presence of BuLi was followed by a Mitsunobu inversion of the hydroxyl group to get 603. Conversion of the hydroxyl group of 603 as its triflate was followed by its displacement using allylamine. Boc protection of the amine then led to the diene 604 which was subjected to ring closing metathesis in the presence of Grubbs' first-generation catalyst to get azacycloheptene 605. Osmium tetroxide catalyzed dihydroxylation followed by acetonide protection of the resulting cis-diol provided a diastereomeric mixture of 606 and 607 in a ratio of 5 : 3. Boc and isopropylidine groups of 606 were deprotected together in one-step using TFA and subsequent chemoselective N-benzylation gave diol 608. Intermolecular Mitsunobu reaction of diol 608 in presence of AcOH afforded the desired piperidine 609 as the major product. Mitsunobu reaction of 609 with diphenyl phosphoryl azide (dppa) afforded azidopiperidine 612 with retention of stereochemistry. They hypothesized anchimeric assistance of endocyclic nitrogen to displace free OH at C-2 to generate the transient bicycle intermediate 611 which was opened up by the azide from α-face to give 2-azidopiperidine 612 possessing α-D-gluco configuration. Compound 612 was deprotected over four steps involving Staudinger reduction of azide to amine followed by its conventional N-acetylation. O-Deacetylation followed by palladium catalyzed hydrogenation in acidic medium afforded target α-HNJNAc 613 (Scheme 80).

Scheme 80 Sollogoub's synthesis of 1,2-cis-homoiminoazasugars.

Later in the same year, Blériot et al.¹⁸¹ also reported the synthesis of 1,2-trans-2-acetamido-2-deoxyhomoiminosugars as mimics of β-D-GlcNAc and α-D-ManNAc. They started their synthesis from previously reported azacycloheptene 605 (Scheme 80).¹⁸⁰ cis-Dihydroxylation of the double bond of azacycloheptene was followed by the conversion of the resulting diol to the cyclic sulfates 614 and 615. NaN₃ mediated ring opening of the cyclic sulfate 615 led to a regioisomeric mixture of azido alcohols 616 and 617. Deprotection of Boc group of the major diastereomer 616 and subsequent treatment with BnBr gave the benzyl derivative 618. Exposure of 618 to TFAA followed by treatment with aq. NaOH led to ring contraction to give the piperidine derivative 619, which was taken further towards deprotection to get the final compound 1,2-trans-2-acetamido-2-deoxy homonojirimycin 621. In a similar way cyclic sulfate 614 provided 1,2-trans-2-acetamido-2-deoxy homonojirimycin 622 (Scheme 81).

Scheme 81 Blériot's synthesis of 1,2-trans-2-acetamido-2-deoxyhomoiminosugars.

By employing same reaction sequence, authors have also reported the synthesis of α-homo-2-acetamido-1,2-dideoxy-galactonojirimycin (α-HGJNAc) 623 from L-ribose, possessing opposite stereochemistry at C-3 (Scheme 82).¹⁸⁰

Scheme 82 Blériot's synthesis α-homo-2-acetamido-1,2-dideoxy-galactonojirimycin (α-HGJNAc).

4. Amino polyhydroxyazepanes

Polyhydroxyazepanes are seven-membered polyhydroxylated heterocyclic compounds containing an endocyclic ring nitrogen atom. In contrast to their five- and six-membered counterparts, polyhydroxyazepanes, such as 624, are conformationally flexible. Due to this, they can adopt appropriate conformation to be best accommodated within the active site of glycosidases resulting in enhanced inhibition.¹⁸² Further studies have revealed that replacement of one or more of the hydroxyl groups of polyhydroxyazepanes with an amino group increases their inhibitory activities.¹⁸³ Compounds 625 and 626 are representative examples of such synthetic modifications. While 625 is a selective inhibitor of NagZ,¹⁸³ 626 is a strong inhibitor of N-acetylglucosaminidases.^182a Molecular basis for inhibition with glycoside hydrolases reveals that amino-azepane 626 binds 140 times more tightly to O-GluNAcase than the hydrolyzed product GlcNAc itself.¹⁸⁴ Moreover, amino-azepane core in the fungal metabolite (−)-balanol 627, plays a crucial role in its inhibition against protein kinase.¹⁸⁵ These findings have prompted a spurt in research related to the synthesis of amino-azepanes (Fig. 12).¹⁸⁶

Fig. 12 Examples of seven-membered iminocyclitols.

The methodologies reported for such synthetic analogues can be broadly classified as follows:

1. Chemo-enzymatic synthesis.

2. Carbohydrate based synthesis.

4.1 Chemoenzymatic synthesis

In 2009, Wang and co-workers^186b exploited their chemoenzymatic approach to the synthesis of amino-polyhydroxyazepanes. Chemoselective oxidation of the C-6 primary hydroxyl group of 628 and 629 (ref. 187) afforded the corresponding aldehydes 630 and 631. Conversion of these aldehydes to their respective oximes using hydroxylamine followed by catalytic hydrogenation provided the amino-polyhydroxyazepanes 632 and 633 (Scheme 83).

Scheme 83 Wang's chemoenzymatic synthesis of amino-polyhydroxyazepanes.

4.2 Synthesis based on chiral pool strategy

4.2.1 Carbohydrate based synthesis. With the theoretical support which indicated that the energy minimized structure of 638 has an excellent overlap with the mannosyl cation, Farr et al.,¹⁸⁸ designed and synthesized it as a potential inhibitor of α-mannosidase. Their synthesis started with the known azido alcohol 634,¹⁸⁹ which was converted to the azidoamine 635 in four steps. Oxidative cleavage of its benzyloxy group using NaIO₄ and RuO₂ followed by hydrolysis of the resulting benzoate with NaOMe in methanol provided azidohemiacetal 636 which was subjected to catalytic hydrogenation to get the bicyclic amino compound 637. Sodium cyanoborohydride mediated reduction of 637 followed by its treatment with HCl gas gave 638 (Scheme 84).

Scheme 84 Farr's synthesis of amino-polyhydroxyazepane 638.

Mignani and co-workers,⁶³ in 1996, reported the synthesis of polyhydroxyazepane based non-peptide mimics of somatostatin/sandostatin analogues. Their synthesis started with N-Boc protection of compound 84 (reported in Scheme 7). Mitsunobu reaction of one of the hydroxyl groups of 639 with hydrazoic acid provided azido compound 640 along with mixture of corresponding azidomethyl piperidine. The azido group of 640 was reduced using catalytic hydrogenation and subsequently its treatment with 6-bromo-N-Boc-hexylamine and HCl afforded azepane 641 (Scheme 85).

Scheme 85 Mignani's synthesis of azepane based somatostatin/sandostatin analogues.

Wong and co-workers,¹⁹⁰ in 1996, reported an elegant synthesis of aminoacetyl derivative of polyhydroxyazepanes 644. They started their synthesis from easily available N-acetyl glucosamine 642 which was converted to azido compound 643 in three steps. Catalytic hydrogenation of compound 643 afforded aminoacetyl derivative of polyhydroxyazepane 644 directly (Scheme 86).

Scheme 86 Wong's chemical synthesis of N-acetyl polyhydroxyaminoazepanes 644.

Bleriot et al.,^186a in 2005, reported the synthesis of a variety of 2-amino and 3-amino-polyhydroxyazepanes. Their strategy started with oxidation of known azacycloheptene 645 with m-cpba which provided a diastereomeric mixture of epoxides 646 and 647 in a ratio of 3 : 5. Nucleophilic ring opening of epoxide 646 with NaN₃ afforded a regioisomeric mixture of azidoalcohols 648 and 649 again in a ratio of 1 : 1.6, which were converted to the corresponding aminopolyhydroxyazepanes 652 and 653, respectively, through catalytic hydrogenation. Following a similar strategy, epoxide 647 was also converted to azepanes 650 and 651. Authors have also synthesized four more stereoisomers of aminopolyhydroxyazepanes 654–657, starting from azepane 645 (Scheme 87).

Scheme 87 Bleriot's synthesis of synthesis of 2-amino and 3-amino-deoxy-polyhydroxyazepanes.

Braga and co-workers,¹⁹¹ in 2008, reported the synthesis of trihydroxylated aminoazepane from protected D-glucitol 658 employing intramolecular ring opening of epoxide as the key step. The primary hydroxyl group of known diacetonide 658 (ref. 192) was tosylated and the secondary hydroxyl group was protected as its benzyl ether to get 659. Diazide 661 was synthesized from 659 following deprotection to 660 and substitution strategy, which when treated with triphenylphosphine in acetonitrile followed by addition of water delivered the aminoazepane 662 (Scheme 88).

Scheme 88 Braga's synthesis of trihydroxylated aminoazepanes.

Blériot et al.¹⁸¹ reported a synthesis of polyhydroxyaminoazepanes starting from previously reported azacycloheptene 605 (Scheme 80) which was subjected to Shi epoxidation to get α-epoxide 663 and β-epoxide 664. The epoxides 663 and 664 produced a mixture of ring opened products 616, 617 and 665, 666 on treatment with sodium azide. All azido alcohols were deprotected by treating them with TFA which was followed by palladium catalyzed hydrogenation to get aminoazepanes 667–670 respectively (Scheme 89).

Scheme 89 Blériot's synthesis of polyhydroxyaminoazepanes.

In 2009, the same authors also reported the synthesis and biological evaluation of acetamido tri- and tetra-hydroxyazepanes.^182a They started their synthesis from an azepane intermediate 672, which was obtained from azido-methylpyranoside 671 over 3 steps.¹⁹³ The free hydroxyl group of azepane 672 was mesylated and then substituted with sodium azide to get compound 673. Staudinger reduction in presence of Ac₂O followed by catalytic hydrogenation afforded acetamido trihydroxyazepane 626. The free hydroxyl group of compound 672 was subjected to Mitsunobu inversion to get 674 and following the same sequence as described for 626, acetamido trihydroxyazepane 676 was also synthesized through intermediate 674 and 675 (Scheme 90).

Scheme 90 Blériot's synthesis of acetamido trihydroxyazepanes.

Recently the authors¹⁸³ have reported the synthesis of trihydroxy azepanes as NagZ inhibitors to increase sensitivity of Pseudomonas aeruginosa to β-lactams. Their synthesis commenced from easily available azidolactol 677, which was transformed to azepane 672 over three steps. The free hydroxyl group of compound 672 was mesylated and then subjected to nucleophilic substitution with sodium azide to get compound 673. The azido group of 673 was reduced under Staudinger condition and then coupled with acid chlorides to get amides 678–682, which on catalytic hydrogenation afforded azepanes 626, 683, 625 and 684–685. The ring N-Cbz group of compound 678 was deprotected with Lindlar's catalyst and coupled with alkyl bromides to get compounds 686 and 687. They were finally deprotected under catalytic hydrogenation to get 688 and 689 respectively (Scheme 91).

Scheme 91 Bleriot synthesis of N-acetyl polyhydroxyaminoazepanes.

5. Amino modified fused bicyclic azasugars

5.1 Amino-modified indolizidine azasugars

Liu and co-workers,¹⁹⁴ in 1991, reported the synthesis of 6-acetamido-6-deoxycastanospermine 695 and studied its inhibition against β-N-acetylglucosaminidases. Treatment of readily available castanospermine derivative 690 (ref. 195) with benzylchloroformate proceeded chemoselectively to provide 6-carbobenzyloxy derivative 691. Benzoylation of the other hydroxyl group was carried out with 4-bromobenzoyl chloride to get 692. Subsequent cleavage of the isopropylidene group followed by diacetylation afforded compound 693. Palladium catalyzed hydrogenolysis of Cbz group, mesylation of the resulting alcohol and successive invertive displacement with sodium iodide and sodium azide provided compound 694 with retention of configuration at C-6 position. Deacetylation using sodium methoxide, palladium catalyzed hydrogenation of azide to amine and subsequent N-acetylation afforded compound 695 (Scheme 92).

Scheme 92 Liu's synthesis of 6-acetamido-6-deoxycastanospermine and australine.

In 1994, Tyler and co-workers¹⁹⁶ encountered an interesting observation during the conversion of mesylate 696 (prepared from castanospermine in a few steps) to the corresponding azide 698. When the mesylate 696 was treated with NaN₃, a mixture of azido castanospermine 698 and azido australine 699 was obtained in a ratio of 2 : 1. This was rationalized through the intramolecular displacement of the mesyl group of 696 by ring nitrogen affording an aziridinium ion intermediate 697 which was attacked by the azide to give both 698 and 699. Subsequent reduction of the azides 698 and 699 and their N-acetylation provided 701 and 703 respectively. On the other hand, deacetylation of 696 under Zemplen's condition followed by treatment of the mesylate with a variety of primary amines provided 6-amino derivatives of castanospermine 704 (Scheme 93).

Scheme 93 Tyler's synthesis of amino derivatives of castanospermine and australine.

Later, in 1995, same authors¹⁹⁷ have also reported the synthesis of C-8 amino-modified castanospermine analogues. Castanospermine 31 (Fig. 5), when treated with dibutyl tin oxide and benzoyl chloride at −10 °C, afforded a regioisomeric mixture of tri-benzoylated castanospermines 705 and 706 in a ratio of 4 : 1. The major isomer 705 was mesylated to get 707 which on treatment with sodium azide in presence of HMPA afforded azide 708 and the rearranged product 709 in a ratio of 1.3 : 1. The azides 708 and 709 were separately reduced through catalytic hydrogenation to get the corresponding amines 710 and 711. Debenzoylation of 710 under Zemplen's condition provided 8-acetamido-8-deoxycastanospermine 712, whereas amines 710 and 711 when treated with acetic anhydride and then with sodium methoxide in methanol gave the corresponding acetamides 713 and 714 (Scheme 94).

Scheme 94 Tyler's synthesis of C-8 amino-modified castanospermine analogues.

They also reported the synthesis of homoamino analogue of castanospermine from 31 through the dibenzylated derivative 715, after separation from the regioisomer 716, replacement of the free OH by a cyano group to 717 and 718, and final reduction to 719, as described in Scheme 95.

Scheme 95 Tyler's synthesis of homoamino analogues of castanospermine.

In a similar line of modification, authors have also reported the synthesis of C-7 amino modified castanospermine derivative.¹⁹⁸ They started their synthesis from known compounds 720 and 722.¹⁹⁶ In a first approach, alcohol 720 was oxidized under Swern condition and the resulting ketone was treated with methoxylamine hydrochloride to get a diastereomeric mixture of oxime. Reduction of oxime with LAH followed by acetylation of the resulting amine delivered the corresponding acetamide derivative, which on O-deacetylation delivered 7-acetamido-7-deoxycastanospermine 721. Since the yield of the overall process is low, an alternative and better strategy was followed. Thus, debenzoylation of compound 722 provided a 1 : 1 mixture of silyl ethers 723 and 724. The relative percentage of the desired isomer 723 could be increased by a base mediated migration of 724. The stereochemistry of the C-7 hydroxyl group was then inverted through an oxidation–reduction process to get 725. The free hydroxyl group was subsequently mesylated and substituted with an azide to obtain 726, which when hydrogenated resulted in the formation of amine 727. Final deprotection of TBS and acetal groups was carried out in a single step using TFA to get the target compound 728 (Scheme 96).

Scheme 96 Tyler's synthesis of C-7 amino modified castanospermine derivative.

Alcaide et al.¹⁹⁹ in 2003, developed a Diels–Alder cycloaddition reaction of 2-azetidinone tethered aryl imines 729 and Danishefsky's diene 730 to prepare cycloadducts 731 and 732. They subsequently transformed these cycloadducts to azetidinone piperidines 733 and 734 over a few steps. These were then treated with sodium methoxide seperately, which resulted in the formation of indolizidinones 735 and 737. Treatment of the lactams 735 and 737 independently, with LAH afforded 8-amino indolizidine derivatives 736 and 738 respectively (Scheme 97).

Scheme 97 Alcaide's Diels–Alder cycloaddition approach towards the synthesis of protected amino substituted indolizidine iminosugars.

Later in 2005, the same authors²⁰⁰ have observed an enhancement in diastereoselectivity when the 1,3-cycloaddition of imines of β-lactam acetaldehydes was carried out with vinyl esters. They synthesized enantiopure amino modified indolizidine derivative 742 through 1,3-cycloaddition of optically pure β-lactam derived imine 740, obtained from precursor 739, and methyl acrylate, which when treated with sodium methoxide delivered the indolizidine derivative 742 (Scheme 98).

Scheme 98 Alcaide's Diels–Alder cycloaddition approach towards the synthesis of optically pure protected indolizidine iminosugars.

Pandey et al.,²⁰¹ in 2007, reported the synthesis and evaluation of an 8-amino derivative of castanospermine 748. They started their synthesis from acetylene tethered amine 745 prepared by the reductive amination of aldehyde 743 (ref. 202) with amine 744.²⁰³ The photoinduced electron transfer (PET) cyclization of 745 produced bicyclic exomethylene compound 746 as a single diastereomer. OsO₄ catalyzed dihydroxylation of 746 afforded diol 747, which on oxidative cleavage using NaIO₄ followed by NaBH₄ mediated reduction delivered the corresponding alcohol. Mesylation of the hydroxyl group and its subsequent treatment with sodium azide followed by catalytic hydrogenation and cleavage of the acetal group with HCl afforded (6S, 7S, 8R, 8aR)-8-amino-octahydroindolizine-6,7-diol 748 (Scheme 99).

Scheme 99 Pandey's synthesis of 8-amino derivative of castanospermine.

In 2009, Stubb and co-workers²⁰⁴ followed Tyler's strategy to synthesize amino-castanospermine and amino-australine analogues 749 and 750, and studied in detail their inhibition against exo-β-D-glucosaminidase (Fig. 13). The studies revealed that the amino castanospermine 749 is a very strong inhibitor of CsxA, with a K_i value of 610 ± 12 nm.

Fig. 13 Structures of amino-castanospermine and amino-australine analogues reported by Stubb.

Chmielewski and co-workers,²⁰⁵ in 2009, reported the synthesis of 8-aminoindolizidine 756. The primary hydroxyl group of lactone 751 was protected as its TBDPS ether to get 752 and subsequently treated with ammonia in methanol. Acetylation of its secondary hydroxyl group followed by treatment with PhI(OAc)₂ in MeOH produced Hofmann rearrangement product 753. Desilylation and then deacetylation provided 754. Appel reaction²⁰⁶ followed by palladium catalyzed hydrogenolysis and acetylation delivered 755 in three steps. The tertiary butyl group of 755 was cleaved using TFA which was then converted to the target indolizidine 756 using standard procedures (Scheme 100).

Scheme 100 Chmielewski's synthesis of 8-aminoindolizidine derivative.

5.2 Amino-modified pyrrolizidine azasugars

Chmielewski²⁰⁵ also reported the synthesis of 7-aminopyrrolizidine derivative 763. They started their synthesis from cycloadduct 757, which could be easily prepared as per their previously reported procedure.²⁰⁷ Lactone 757 was treated with ammonia to get amide 758 which was followed by protection of the free hydroxyl group as its TBDPS ether to get 759. It was then treated with PhI(OAc)₂ in MeOH, to get the Hofmann rearrangement product 760 with retention of configuration at C-3. TBDPS group of 760 was cleaved using TBAF and subsequent mesylation provided compound 761. It was then subjected to palladium catalyzed hydrogenation followed by acetylation to afford acetate 762. Removal of tertiary butyl group using TFA, subsequent acetylation and final deacetylation using ammonia in methanol afforded amino-pyrrolizidine 763 (Scheme 101).

Scheme 101 Chmielewski's synthesis of 7-aminopyrrolizidine derivative.

For the synthesis of 7-aminopyrrolizidine iminosugars 769 from 753 (Scheme 100), they developed a new strategy. Desilylation of 753 with TBAF in THF provided primary alcohol 764, which immediately underwent a facile intramolecular acetyl migration to form compound 765. The crude alcohol 765 was mesylated and when it was subjected to palladium catalyzed hydrogenative cleavage of the N–O bond, intramolecular cyclization also occurred through the nitrogen atom to get 7-aminopyrrolizidine derivative. This crude 7-aminopyrrolizidine was acetylated and purified as its bis-acetate 767. It was then transformed to target compound 769 by employing the standard deprotection sequence as described before (Scheme 102).

Scheme 102 Chmielewski's synthesis of 7-aminopyrrolizidine derivative.

Cardona and co-workers,²⁰⁸ in 2014, reported the synthesis of 6-azido hyacinthacine A2 and utilized it for the construction of first multivalent pyrrolizidine derivatives. The key step in their strategy was the stereoselective installation of an azido moiety at C-6 of the pyrrolizidine skeleton and subsequent click reaction to form different monovalent and dendrimeric alkyne scaffolds. They studied the glycosidase inhibition of all new compounds as well. They started their synthesis from hydroxy pyrrolizidine 770, which could be easily prepared through reported literature procedure.²⁰⁹ Mitsunobu reaction of 770 with DPPA and DIAD provided azido derivative 771. It was then subjected to catalytic hydrogenation and purified by Dowex 50WX8-200 resin to get amino-pyrrolizidine compound 772. Towards the synthesis of azido-pyrrolizidine derivatives 776, the hydroxyl group of 770 was mesylated to get 773 and then subjected to catalytic hydrogenation to get the triol 775. Finally, mesylate 775 when treated with sodium azide delivered the pyrrolizidine 776. The azido derivative 771 was also utilized to synthesize triazole derivative 774 (Scheme 103).

Scheme 103 Cardona's synthesis of 6-amino and 6-azido hyacinthacine A2.

5.2.1 Pochonicine. (+)-Pochonicine is a polyhydroxylated pyrrolizidine alkaloid isolated from a fungal strain, Pochonia suchlasporia var. suchlasporia TAMA 87.⁴⁴ Its structure was initially proposed as 40 by Nitoda and co-workers.⁴⁴ (+)-Pochonicine has been found to inhibit β-N-acetylglucosaminidases GLcNAcases with a (K_i) value of 0.162 nM, which is comparable to nagstatin 777. Takahashi and co-workers were first to synthesize (−)-pochonicine [(−)-778, the enantiomer of naturally occurring (+)-pochonicine] and three of its stereoisomers. Based on their synthesis, they revised structure of (+)-pochonicine as (+)-778 and also established its absolute configuration. Yu and co-workers later synthesized both (+)- and (−)-pochonicine 40, and a few of their stereoisomers, from D- and L-ribose-derived cyclic nitrones, respectively and they unequivocally reconfirmed the revised structure of (+)-pochonicine (+778) and its absolute configuration (Fig. 14).

Fig. 14 Nagstatin and enantiomers of pochonicine.

Takahashi's²¹⁰ first synthesis of (−)-pochonicine started with compound 779,²¹¹ which was converted to the key aldehyde 780 in fourteen steps. Allylation of aldehyde 780 was carried out by treating it with allylMgCl and ZnCl₂ at −78 °C to get a 77 : 23 mixture of diastereomers 781 and 782. Homoallylic alcohol 782 was transformed to azide 783 over a sequence of synthetic manipulations including TBS deprotection, tosylation, azide substitution and TBS protection of secondary hydroxyl group. Osmium tetroxide catalyzed dihydroxylation of olefin 783 in presence of NMO, protection of the resulting primary hydroxyl group as its TBS ether followed by mesylation of secondary hydroxyl group provided a mixture of diastereomers 784 and 785 over three steps. N-Boc deprotection followed by TEA mediated cyclisation of 784 afforded a mixture of diastereomers 786 and 787. Both the diastereomers were separately reduced by palladium catalyzed hydrogenation which was followed by acetylation. HCl mediated cleavage of the TBS and isopropylidene groups provided compounds 788 and 789. Compound 781 was also transformed to (−)-pochonicine (−778) and its other diastereomer 790, through the same strategy (Scheme 104).

Scheme 104 Takahashi's synthesis of (−)-pochonicine and its stereoisomers.

Yu²¹² and co-workers, in 2013, reported the synthesis of eight stereoisomers of pochonicine and studied their glycosidase inhibition activities. They started their synthesis from sugar derived nitrone 791, which could be easily obtained from D-ribose 177.²¹³ Cyanation of nitrone was done using trimethylsilyl cyanide to get compound 792 as a single diastereomer. RANEY® Ni catalyzed hydrogenation and then Boc protection provided compound 793. Exocyclic NH of compound 793 was converted to the corresponding acetate using LDA and Ac₂O, which was followed by detritylation to get 794. Primary hydroxyl group of compound 794 was oxidized and subsequent allylation under Barbier condition afforded homoallylic alcohol 795 after acetylation. The authors adopted almost the same strategy as that of Takahashi for the construction of the bicyclic system 797 from 796. Final deprotection of acetonide group and TBS ether was carried out with 6 N HCl to get compound (−)-778. The other stereoisomers of L-pochonicine series (−)-788, 789 and 790 were also prepared following separation of diastereomers at allylation and dihydroxylation steps (Scheme 105).

Scheme 105 Yu's synthesis of (−)-pochonicine and its stereoisomers.

In a similar fashion, (+)-pochonicine series (+)-778, ent-788, ent-789 and ent-790 were also obtained from L-ribose derived nitrone ent-791 (Scheme 106).

Scheme 106 Yu's synthesis of four stereoisomers of (+)-pochonicine.

Very recently our group²¹⁴ reported a concise synthesis of four new stereoisomers of (−)-pochonicine 778 and carried out their glycosidase inhibition studies. Selective deprotection of the primary benzyloxy group of 192 (ref. 215) using ZnCl₂ in a 5 : 1 mixture of acetic anhydride and acetic acid provided acetolysis of the primary O-benzyl group accompanied by N-acetylation of the side chain nitrogen atom to give the diacetate 798. Deacetylation of 798 followed by oxidation of the hydroxyl group using acetic anhydride and DMSO provided aldehyde 799. It was then treated with allyl bromide in presence of indium which resulted in the formation of an inseparable diastereomeric mixture of homoallylic alcohols 800 and 801 in a 1 : 1 ratio. Oxone mediated epoxidation of the double bond of 800 and 801 afforded a separable mixture of epoxy alcohols 802 and 803. Epoxy alcohol 803 was subjected to a novel one pot N-detosylative epoxide ring opening using Na–Hg furnishing a separable mixture of pyrrolizidine azasugars 804 and 805. Compounds 804 and 805 were finally deprotected through Birch reduction and subsequent N-acetylation of the resulting amine produced two new stereoisomers of (−)-pochonicine 808 and 809. In a similar way, diastereomeric epoxy alcohol 802 was also taken forward to get two more new stereoisomers of (−)-pochonicine, namely 812 and 813, through intermediates 810 and 811, respectively (Scheme 107).

Scheme 107 Ramesh's synthesis of stereoisomers of (−)-pochonicine.

5.3 Miscellaneous examples of amino modified bicyclic azasugar

Murphy and co-workers,²¹⁶ in 2009, reported the synthesis of polyfunctional bicyclic iminocyclitol scaffold by employing stereoselective intramolecular Huisgen cycloaddition reaction as the key step. They started their synthesis from compound 814 which was easily prepared from L-sorbose.²¹⁷ Chemoselective isopropylidene ring opening using 60% acetic acid afforded diol 815 which was then treated with thionyl chloride and pyridine to get a cyclic sulfite intermediate. Treatment of this intermediate with an excess sodium azide at 110 °C yielded bicyclic product 816. Removal of isopropylidene group using methanolic HCl provided polyhydroxylated compound 817 (Scheme 108).

Scheme 108 Murphy's synthesis of polyfunctional bicyclic iminocyclitol scaffolds.

5.3.1 Enzyme inhibition studies.

Iminocyclitols	Enzyme	IC50 (μM)/Ki/% inhibition	Reference
	α-N-Acetylglucosaminidase		55
	From bovine kidney	Ki = 9.8 μM
	From jack beans	Ki = 1.9 μM
	α-Glucosidase		71
	From baker's yeast	IC50 = 280 μM
	β-Glucosidase
	From almonds	>500 μM
	N-Acetyl-β-hexosaminidase
		IC50 = 0.16 μM
	From jack beans	Ki = 22 nM
	β-Glucosidase		73
	From almonds	Ki = 2.2 μM
	β-Hexosaminidase		87
	From jack beans	IC50 = 0.1 μM
	From human	IC50 = 0.3 μM
	α-N-Acetylglucosaminidase		55
	From bovine kidney	Ki = 68.6 μM
	From jack beans	Ki = 3.6 μM
	α-Mannosidase		59
	From almond	IC50 = 4.5 μM
		Ki = 1 μM
	From jack beans	IC50 = 6.2 μM
		Ki = 1.2 μM
	α-N-Acetylgalactosaminidase
	From chicken liver	IC50 = 2.3 μM
		Ki = 24 μM
	α-Galactosidase		59
	From coffee beans	100% (1 mM)
	β-Glucosidase
	From almond	99% (1 mM)
	Caldocellum saccharolyticum	97% (1 mM)
	α-Mannosidase
	From jack beans	97% (1 mM)
	Almond	97% (1 mM)
	α-N-Acetylgalactosaminidase
	Chicken liver	99% (1 mM)
	β-Glucosidase	Ki = 10 μM	76
	α-Glucosidase	Ki = >10^−3 M	76
	β-Glucosidase
	α-Galactosidase
	α-Mannosidase
	α-L-Fucosidase
	α-Glucosidase		71
	From baker's yeast	IC50 = 0.15 μM
		Ki = 53 nM
	β-Glucosidase
	From almonds	IC50 = 92 μM
	N-Acetyl-β-hexosaminidase
	From jack beans	IC50 = 92 μM
	α-Glucosidase		71
	From baker's yeast	IC50 = 0.28 μM
		Ki = 77 nM
	β-Glucosidase
	From almonds	IC50 = 92 μM
	Antiviral activities for		71
	JEV
	108	IC50 = 11.3 μM
	109	IC50 = 9.6 μM
	110	IC50 = 7.6 μM
	DEN-2
	108	IC50 = 11.8 μM
	109	IC50 = 4.7 μM
	110	IC50 = 6.0 μM
	β-Hexosaminidase		71
	Human	Ki = 2.6 nM
	β-N-Acetylgalactosaminidase		73
	From bovine kidney
	132	Ki = 1.1 × 10^−1 μM
	133	Ki = 1.4 × 10^−1 μM
	β-N-Acetylgalactosaminidase
	From human placenta
	132	Ki = 1.3 μM
	133	Ki = 5.1 × 10^−1 μM
	N-Acetyl-β-hexosaminidase		75
	From human
	142	IC50 = 9.5 μM
	143	IC50 = 4.1 μM
	144	IC50 = 38 μM
	145	IC50 = 10 μM
	146	IC50 = 18 μM
	α-Mannosidase		78
	From jack beans	IC50 = 700 nM
		Ki = 135 nM
	From almond	IC50 = 46 μM
		Ki = 9.5 μM
	α-Mannosidase		78
	From jack beans	IC50 = 55 μM
		92% inhibition at 1 mM
	Glioblastoma cells	97% inhibition
	LN18	At 300 μM (72 h)
	LNZ308	96% inhibition
		At 300 μM (72 h)
	Human golgi α-mannosidase II (hGMII)	IC50 = 0.3 μM	88
		Ki = 24 nM
	Human golgi α-mannosidase II (hGMII)	IC50 = 0.5 μM	88
		Ki = 31 nM
	α-Glucosidase		93
	From baker's yeast	IC50 = 3.5 mM
	β-Glucosidase
	From almonds	IC50 = 6.3 mM
	β-Galactosidase
	From E. coli	IC50 = 5.4 mM
	α-Galactosidase		93
	From coffee bean
	198	IC50 = 6.9 mM
	199	IC50 = 8.1 mM
	N-Acetyl-β-D-hexosaminidase		99
	From Streptomyces plicatus	Ki = 0.5 mM
	β-D-Glucosidase
	From Agrobacterium sp.	Ki = 0.8 mM
	α-L-Fucosidase		99
	From Thermotoga maritime	Ki = 0.12 mM
	N-Acetyl-β-D-hexosaminidase
	From Streptomyces plicatus	Ki = 0.5 mM
	N-Acetyl-β-D-hexosaminidase		101
	From jack beans	IC50 = 1.2 μM
	N-Acetyl-β-D-hexosaminidase		101
	From jack beans	IC50 = 4.5 μM
	N-Acetyl-β-D-hexosaminidase		101
	From jack beans	IC50 = 33 nM
	N-Acetyl-β-D-glucosaminidase		103
	From jack beans	IC50 = 61 μM
	β-Glucuronidase
	From bovine liver	IC50 = 26 μM
	From E. coli	IC50 = 15 μM
	N-Acetyl-β-D-glucosaminidase		103
	From bovine kidney	IC50 = 31 μM
	From HL60	IC50 = 18 μM
	From human placenta	IC50 = 15 μM
	From jack bean	IC50 = 3.4 μM
	α-L-Fucosidase		99
	From Thermotoga maritima	Ki = 0.2 mM
	β-Galactosidase		69
	Bovine liver	IC50 = 460 μM
		Ki = 228 μM
	Aspergillus orizae	IC50 = 540 μM
		Ki = 705 μM
	β-Hexosaminidase		87
	From jack beans	IC50 = 0.2 μM
	From human	IC50 = 0.6 μM
	α-Fucosidase		106
	From bovine kidney	IC50 = 206 nM
	From bovine epididymis	IC50 = 160 nM
	From Arthrobacter oxidans F1	IC50 = 80 nM
	N-Acetyl-β-D-glucosaminidase		104
	From bovine kidney	Ki = 3.8 × 10^−7 M
	N-Acetyl-β-D-glucosaminidase		116
	From jack bean	IC50 = 3.4 × 10^−7 M
		Ki = 2.3 × 10^−7 M
	From human placenta	IC50 = 6.0 × 10^−6 M
		Ki = 9.0 × 10^−7 M
	From bovine kidney	IC50 = 7.5 × 10^−6 M
		Ki = 6.0 × 10^−7 M
	NagZ		128
	From Pseudomonas aeruginosa	Ki = 300 nM
	β-N-Acetylhexosaminidase		130
	From Streptomyces plicatus	Ki = 80 μM
	β-N-Acetyl-glucosaminidase		135
	From human placenta	IC50 = 7.0 μM
	From bovine kidney	IC50 = 7.4 μM
	From HL-60	IC50 = 9.8 μM
	From jack beans	IC50 = 2.9 μM
	β-N-Acetyl-galactosaminidase
	From HL-60	IC50 = 17 μM
	β-N-Acetylhexosaminidase		112
	From human placenta	Ki = 7 μM
	From bovine kidney	Ki = 7.4 μM
	From jack beans	Ki = 2.9 μM
	α-Fucosidase		106
	From bovine kidney
	245	IC50 = 50 nM
	246	IC50 = 40 nM
		Ki = 30 nM
	247	IC50 = 200 nM
	From bovine epididymis
	245	IC50 = 170 nM
	246	IC50 = 20 nM
		Ki = 19 nM
	247	IC50 = 40 nM
	From Arthrobacter oxidans F1
	245	IC50 = 116 nM
	246	IC50 = 56 nM
		Ki = 47 nM
	247	IC50 = 119 nM
	β-N-Acetylhexosaminidase		111
	From human placenta	Ki = 5.6 μM
	From bovine kidney	Ki = 2.6 μM
	From jack beans	Ki = 2.6 μM
	α-N-Acetylgalactosaminidase		133
	From chicken liver	Ki = 0.081 μM
	From Charonia lampas	Ki = 0.136 μM
	β-Hexosaminidase
	From jack bean	IC50 = 1.8 μM
	From bovine kidney	IC50 = 4.2 μM
	From human placenta	IC50 = 8.3 μM
	From HL-60	IC50 = 2.2 μM
	β-N-Acetyl-glucosaminidase		135
	From human placenta	IC50 = 8.3 μM
	From bovine kidney
	From HL-60	IC50 = 4.2 μM
	From jack beans	IC50 = 7.1 μM
		IC50 = 1.8 μM
	α-N-Acetyl-galactosaminidase
	From chicken liver	IC50 = 0.32 μM
	β-N-Acetyl-galactosaminidase
	From HL-60	IC50 = 23 μM
	β-N-Acetylhexosaminidase		111
	From human placenta	Ki = 8.3 μM
	From bovine kidney	Ki = 4.2 μM
	From jack beans	Ki = 1.8 μM
	β-N-Acetylhexosaminidase		112a
	From human placenta	Ki = 427 μM
	From bovine kidney	Ki = 524 μM
	From jack beans	Ki = 130 μM
	β-N-Acetylhexosaminidase		112a
	291a
	From human placenta	Ki = 56 μM
	From bovine kidney	Ki = 138 μM
	From jack beans	Ki = 26 μM
	291b
	From human placenta	Ki = 33 μM
	From bovine kidney	Ki = 82 μM
	From jack beans	Ki = 19 μM
	291c
	From human placenta	Ki = 2.1 μM
	From bovine kidney	Ki = 4.1 μM
	From jack beans	Ki = 1.1 μM
	291d
	From human placenta	Ki = 20 μM
	From bovine kidney	Ki = 24 μM
	From jack beans	Ki = 10 μM
	N-Acetyl-β-D-glucosaminidase		112b
	From human placenta
	295a	Ki = 118 μM
	295b	Ki = 909 μM
	295d	Ki = 8.6 μM
	From bovine kidney
	295a	Ki = 88 μM
	295d	Ki = 5.9 μM
	From jack bean
	295a	Ki = 75 μM
	295b	Ki = 363 μM
	295d	Ki = 13.4 μM
	N-Acetyl-β-D-glucosaminidase		112b
	From human placenta
	296a	Ki = 4.9 μM
	296b	Ki = 0.6 μM
	296c	Ki = 27 μM
	296d	Ki = 4.9 μM
	From bovine kidney
	296a	Ki = 2.9 μM
	296b	Ki = 0.65 μM
	296c	Ki = 38 μM
	296d	Ki = 11 μM
	From jack bean
	296a	Ki = 24 μM
	296b	Ki = 2.3 μM
	296c	Ki = 20 μM
	296d	Ki = 9.5 μM
	NagZ		128
	From Pseudomonas aeruginosa	Ki = 51 μM
	NagZ		128
	From Pseudomonas aeruginosa	Ki = 35 μM
	NagZ		128
	From Pseudomonas aeruginosa	Ki = 33 μM
	β-N-Acetylhexosaminidase		130
	From Streptomyces plicatus
	405	Ki = 5.0 μM
	406	Ki = 4.3 μM
	β-N-Acetylhexosaminidase		130
	From Streptomyces plicatus
	407	Ki = 6.3 μM
	408	Ki = 4.6 μM
	N-Acetylhexosaminidase A	IC50 = 6 μM	132
	N-Acetylhexosaminidase A	IC50 = 11 μM	132
	β-N-Acetyl-glucosaminidase		135
	From human placenta	IC50 = 5.7 μM
	From bovine kidney	IC50 = 2.1 μM
	From HL-60	IC50 = 5.4 μM
	From jack beans	IC50 = 1.5 μM
	β-N-Acetyl-galactosaminidase
	From HL-60	IC50 = 26 μM
	β-N-Acetyl-glucosaminidase		135
	From human placenta	IC50 = 7.3 μM
	From bovine kidney	IC50 = 3.1 μM
	From HL-60	IC50 = 7.9 μM
	From jack beans	IC50 = 3.4 μM
	α-N-Acetyl-galactosaminidase
	From chicken liver	IC50 = 5.6 μM
	β-N-Acetyl-galactosaminidase
	From HL-60	IC50 = 44 μM
	β-N-Acetyl-glucosaminidase		135
	From human placenta	IC50 = 2.7 μM
	From bovine kidney	IC50 = 1.2 μM
	From HL-60	IC50 = 1.7 μM
	From jack beans	IC50 = 2.7 μM
	β-N-Acetyl-galactosaminidase
	From HL-60	IC50 = 14 μM
	β-N-Acetyl-glucosaminidase		135
	From human placenta	IC50 = 45 μM
	From bovine kidney	IC50 = 40 μM
	From HL-60	IC50 = 52 μM
	From jack beans	IC50 = 22 μM
	α-N-Acetyl-galactosaminidase
	From chicken liver	IC50 = 11 μM
	β-N-Acetyl-glucosaminidase		135
	From human placenta	IC50 = 8.2 μM
	From bovine kidney	IC50 = 3.7 μM
	From HL-60	IC50 = 8.3 μM
	From jack beans	IC50 = 1.9 μM
	α-N-Acetyl-galactosaminidase
	From chicken liver	IC50 = 6.3 μM
	β-N-Acetyl-galactosaminidase
	From HL-60	IC50 = 35 μM
	β-N-Acetyl-glucosaminidase		135
	From human placenta	IC50 = 18 μM
	From bovine kidney	IC50 = 12 μM
	From HL-60	IC50 = 22 μM
	From jack beans	IC50 = 17 μM
	β-N-Acetyl-galactosaminidase
	From HL-60	IC50 = 74 μM
	β-N-Acetyl-glucosaminidase		135
	From human placenta	IC50 = 10 μM
	From bovine kidney	IC50 = 8.1 μM
	From HL-60	IC50 = 16 μM
	From jack beans	IC50 = 24 μM
	β-N-Acetyl-galactosaminidase
	From HL-60	IC50 = 62 μM
	NagZ		136
	From Vibrio cholera (Vc)	Ki = 9.4 μM
	From Salmonella typhimurium (St)	Ki = 23.2 μM
	O-GlcNAcase (OGA)	Selectivity ratio Ki OGA/Ki VcNagZ >53
		Selectivity ratio Ki OGA/Ki StNagZ >22
	α-L-Fucosidase		141
	From bovine epididymis	IC50 = 105 nM
	Lysosomal β-hexosaminidase		144
	From homogenate of human spleen	IC50 = 5 μM
		Ki = 2.4 μM
	Lysosomal β-hexosaminidase A
	From human spleen	IC50 = 4.5 μM
		Ki = 2.8 μM
	Lysosomal β-hexosaminidase B
	From human spleen	IC50 = 3 μM
		Ki = 1.55 μM
	β-N-Acetyl-galactosaminidase		156
	From jack beans	IC50 = 385 μM
	Lysosomal β-glucocerebrosidase	Ki = 34 μM	160
	β-Glucosidase
	From Agrobacterium sp.	Ki = 220 μM
	Lysosomal β-glucocerebrosidase	Ki = 0.0075 μM	160
	β-Glucosidase
	From Agrobacterium sp.	Ki = 36 μM
	α-Fucosidase		166
	From bovine kidney	Ki = 25 nM
	α-Fucosidase		166
	From bovine kidney	Ki = 0.60 nM
	α-Fucosidase		166
	From bovine kidney	Ki = 0.50 nM
	β-Glucosidase		158
	From almonds	IC50 = 65.3 μM
	β-N-Acetylhexosaminidase		180
	From human placenta	IC50 = 56 μM
	From bovine kidney	IC50 = 67 μM
	From HL-60	IC50 = 265 μM
	From jack beans	IC50 = 48 μM
	β-N-Acetylhexosaminidase		181
	From human placenta	IC50 = 72 μM
	From bovine kidney	IC50 = 65 μM
	From HL-60	IC50 = 88 μM
	From jack beans	IC50 = 41 μM
	β-N-Acetylhexosaminidase		181
	From human placenta	IC50 = 302 μM
	From bovine kidney	IC50 = 624 μM
	From HL-60	IC50 = 394 μM
	From jack beans	IC50 = 95 μM
	β-N-Acetylhexosaminidase		181
	From human placenta	IC50 = 46 μM
	From bovine kidney	IC50 = 36 μM
	From HL-60	IC50 = 52 μM
	From jack beans	IC50 = 22 μM
	α-N-Acetyl-galactosaminidase
	From chicken liver	IC50 = 1.1 μM
	HeLa cells		149
	From human cervical carcinoma
	822	IC50 = 61.6 μM
	823	IC50 = 43.2 μM
	HL-60 cells
	From leukaemia cell line
	822	IC50 = 10.7 μM
	823	IC50 = 38 μM
	Transglycolase		176
	From Clostridium difficile	Ki = 6.3 μM
	β-N-Acetylglucosaminidase		182a
	From jack bean	Ki = 0.4 μM
	From bovine liver	Ki = 0.7 μM
	Amyloglucosidase		186a
	From Aspergillus niger	IC50 = 152 μM
		85%(1 mM)
	From Rhizopus mould	IC50 = 245 μM
		85%(1 mM)
	Amyloglucosidase		186a
	From Aspergillus niger	IC50 = 105 μM
		95%(1 mM)
	From Rhizopus mould	IC50 = 143 μM
		92%(1 mM)
	α-L-Fucosidase		186a
	From bovine epididymis	IC50 = 100 μM
		82%(1 mM)
	α-Mannosidase		190
	From jack beans	Ki = 364 μM
	α-Fucosidase
	From bovine kidney	Ki = 10.6 μM
	Salmonella typhimurium		183
	OGA (O-GlcNAcase)
	626	Ki = 0.7 μM
	683	Ki = 2.2 μM
	625	Ki = 47 μM
	684	Ki = 190 μM
	NagZ
	626	Ki = 0.4 μM
	683	Ki = 0.4 μM
	625	Ki = 7.4 μM
	684	Ki = 27 μM
	HexA (β-hexosaminidase)
	626	Ki = 3.6 μM
	Salmonella typhimurium		183
	OGA (O-GlcNAcase)	Ki = 2 μM
	688	Ki = 22 μM
	689
	HexA (β-hexosaminidase)
	688	Ki = 14 μM
	689	Ki = 51 μM
	β-N-Acetylglucosaminidase		194
	From human placenta	IC50 = 0.5 μM
	From bovine kidney	IC50 = 1.5 μM
	From jack bean	IC50 = 1.6 μM
	From porcine placenta	IC50 = 0.4 μM
	From bovine epididymis	IC50 = 0.7 μM
	β-N-Acetylglucosaminidase		212
	From A. oryzae	IC50 = 11 μM
	From bovine kidney	IC50 = 0.49 μM
	From HL-60	IC50 = 0.46 μM
	From human placenta	IC50 = 0.30 μM
	From jack bean	IC50 = 0.046 μM
	β-N-Acetylgalactosaminidase
	From A. oryzae	IC50 = 12 μM
	From HL-60	IC50 = 1.9 μM
	β-N-Acetylglucosaminidase		212
	From bovine kidney	IC50 = 1.2 μM
	From HL-60	IC50 = 0.61 μM
	From human placenta	IC50 = 0.38 μM
	From jack bean	IC50 = 0.24 μM
	β-N-Acetylgalactosaminidase
	From HL-60	IC50 = 2.0 μM
	β-Glucosidase		201
	Lysosomal	IC50 = 1.4 mM
	Amyloglucosidase		208
	From Aspergillus niger	IC50 = 15.3 μM
		Ki = 18.2 μM
		98%(1 mM)
	N-Acetylglucosaminidase (crude)		210
	Spodoptera litura	IC50 = >14 200 nM
	From jack bean	IC50 = 3130 nM
	β-N-Acetylglucosaminidase		212
	From A. oryzae	IC50 = 0.33 μM
	From bovine kidney	IC50 = 0.021 μM
	From HL-60	IC50 = 0.018 μM
	From human placenta	IC50 = 0.012 μM
	From jack bean	IC50 = 0.0016 μM
	β-N-Acetylgalactosaminidase
	From A. oryzae	IC50 = 0.30 μM
	From HL-60	IC50 = 0.049 μM
	β-N-Acetylglucosaminidase		212
	From A. oryzae	IC50 = 11 μM
	From bovine kidney	IC50 = 0.51 μM
	From HL-60	IC50 = 0.38 μM
	From human placenta	IC50 = 0.22 μM
	From jack bean	IC50 = 0.042 μM
	β-N-Acetylgalactosaminidase
	From A. oryzae	IC50 = 9.1 μM
	From HL-60	IC50 = 1.4 μM
	β-Galactosidase		214
	From E. coli
	806	IC50 = 0.766 mM
	β-N-Acetylglucosaminidase
	From jack bean
	808	IC50 = 0.273 mM
	809	IC50 = 0.265 mM
	812	IC50 = 0.382 mM
	813	IC50 = 0.504 mM

6. Conclusions and future prospects

This review article has highlighted that chemistry and biology of amino-iminocyclitols have gained enormous interests since last two decades. It is quite evident that replacement of hydroxyl groups of natural iminosugars by amino substituents have led to novel molecules with enhanced and specific inhibition of various enzymes. Of particular interest are the acetamido derivatives of such unnatural iminocyclitols which are found to be selective or even specific inhibitors of N-acetylhexosaminidases with IC₅₀ values ranging from μM to nM. Such inhibitors play important roles as antivirals, drugs for osteoarthritis and also as potential chemical chaperones for storage disorders such as Tay-Sachs, Sandhoff diseases. Recent isolation of (+)-pochonicine as the first naturally occurring amino-modified iminocyclitol from a fungal source and its inhibition of β-N-acetylglucosaminidases in nM range from various sources indicate that this molecule could be a potential lead not only against human diseases but also as fungicides and insecticides. This finding has provided a new direction that looks beyond the domain of human diseases alone. Having a library of amino-iminocyclitols and their structure–activity relationship with various enzymes been carried out, it is now possible to identify promising molecules amongst them for further development as drug candidates, while a few others may require further fine-tuning of their structures to act against specific targets. It is hoped that this review article would prove to be handy for those engaged in such an endeavor and entice others towards this exciting inter-disciplinary research area.

References

1. (a) D. L. Zechel and S. G. Withers, Acc. Chem. Res., 2000, 33, 11–18; (b) C. S. Rye and S. G. Withers, Curr. Opin. Chem. Biol., 2000, 4, 573–580; (c) M. L. Sinnott, Chem. Rev., 1990, 90, 1171–1202; (d) P. Bojarova and V. Křen, Trends Biotechnol., 2009, 27, 199–209.
2. (a) Essentials of Glycobiology, ed. A. Varki, R. D. Cummings, J. D. Esko, H. H. Freeze, P. Stanley, C. R. Bertozzi, G. W. Hart and M. E. Etzler, Cold Spring Harbor, NY, 2nd edn, 2009; (b) Glycoscience, ed. B. O. Fraser-Reid, K. Tatsuta and J. Thiem, Springer, Berlin, 2001.
3. A. D. Elbein, Y. T. Pan, I. Pastuszak and D. Carroll, Glycobiology, 2003, 13, 17R–27R.
4. (a) A. J. Krentz and C. J. Bailey, Drugs, 2005, 65, 385–411; (b) P. H. Joubert, H. L. Venter and G. N. Foukaridis, Br. J. Clin. Pharmacol., 1990, 30, 391–396; (c) P. H. Joubert, G. N. Foukaridis and M. L. Bopape, Eur. J. Clin. Pharmacol., 1987, 31, 723–724.
5. (a) O. Ando, M. Kifune and M. Nakajima, Biosci., Biotechnol., Biochem., 1995, 59, 711–712; (b) N. Asano, M. Takeuchi, Y. Kameda, K. Matsui and Y. Kono, J. Antibiot., 1990, 43, 722–726.
6. (a) I. Bucior and M. M. Burger, Curr. Opin. Struct. Biol., 2004, 14, 631–637; (b) C. U. Kim, W. Lew, M. A. Williams, H. T. Liu, L. J. Zhang, S. Swaminathan, N. Bischofberger, M. S. Chen, D. B. Mendel, C. Y. Tai, W. G. Laver and R. C. Stevens, J. Am. Chem. Soc., 1997, 119, 681–690.
7. L. Somsak, V. Nagy, Z. Hadady, T. Docsa and P. Gergely, Curr. Pharm. Des., 2003, 9, 1177–1189.
8. (a) M. J. Humphries, K. Matsumoto, S. L. White and K. Olden, Cancer Res., 1986, 46, 5215–5222; (b) P. E. Goss, M. A. Baker, J. P. Carver and J. W. Dennis, Clin. Cancer Res., 1995, 1, 935–944; (c) Y. Nishimura, T. Satoh, T. Kudo, S. Kondo and T. Takeuchi, Bioorg. Med. Chem., 1996, 4, 91–96; (d) T. M. Wrodnigg, A. J. Steiner and B. J. Ueberbacher, Anti-Cancer Agents Med. Chem., 2008, 8, 77–85.
9. (a) E. Steinmann, T. Whitfield, S. Kallis, R. A. Dwek, N. Zitzmann, T. Pietschmann and R. Bartenschlager, Hepatology, 2007, 46, 330–338; (b) L. A. Augustin, J. Fantini and D. R. Mootoo, Bioorg. Med. Chem., 2006, 14, 1182–1188; (c) I. Robina, A. J. Moreno-Vargas, A. T. Carmona and P. Vogel, Curr. Drug Metab., 2004, 5, 329–361; (d) A. S. Metha, B. Gu, B. Conyers, S. Ouzounov, L. Wang, R. M. Moriarty, R. A. Dwek and T. M. Block, Antimicrob. Agents Chemother., 2004, 48, 2085–2090; (e) D. Pavlovic, D. C. A. Neville, O. Argaud, B. Blumberg, R. A. Dwek, W. B. Fischer and N. Zitzmann, Proc. Natl. Acad. Sci. U. S. A., 2003, 100, 6104–6108; (f) A. S. Mehta, B. Conyers, D. L. J. Tyrrell, K.-A. Walters, G. A. Tipples, R. A. Dwek and T. M. Block, Antimicrob. Agents Chemother., 2002, 46, 4004–4008; (g) M. Block and R. Jordan, Antiviral Chem. Chemother., 2001, 12, 317–325; (h) A. Mehta, N. Zitzmann, P. M. Rudd, T. M. Block and R. A. Dwek, FEBS Lett., 1998, 430, 17–22; (i) C. G. Brodges, S. P. Ahmed, M. S. Kang, R. J. Nash, E. J. Porter and A. S. Tymes, Glycobiology, 1995, 5, 249–253; (j) T. M. Block, X. Lu, F. M. Platt, G. R. Foster, W. H. Gerlich, B. S. Blumberg and R. A. Dwek, Proc. Natl. Acad. Sci. U. S. A., 1994, 91, 2235–2239.
10. (a) G.-N. Wang, G. Reinkensmeier, S.-W. Zhang, J. Zhou, L.-R. Zhang, L.-H. Zhang, T. D. Butters and X.-S. Ye, J. Med. Chem., 2009, 52, 3146–3149; (b) E. R. Benjamin, J. J. Flanagan, A. Schilling, H. H. Chang, L. Agarwal, E. Katz, X. Wu, C. Pine, B. Wustman, R. J. Desnick, D. J. Lockhart and K. J. Valenzano, J. Inherited Metab. Dis., 2009, 32, 424–440; (c) Z. Yu, A. R. Sawkar, L. J. Whalen, C.-H. Wong and J. W. Kelly, J. Med. Chem., 2007, 50, 94–100; (d) T. D. Butters, R. A. Dwek and F. M. Dwek, Glycobiology, 2005, 15, 43R–52R; (e) A. R. Sawker, W.-C. Cheng, E. Beutler, C.-H. Wong, W. E. Balch and J. W. Kelly, Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 15428–15433; (f) J.-Q. Fan, S. Ishii, N. Asano and Y. Suzuki, Nat. Med., 1999, 5, 112–115; (g) P. J. Meikle, J. J. Hopewood, A. E. Clague and W. F. Carey, JAMA, J. Am. Med. Assoc., 1999, 281, 249–254.
11. (a) C.-Y. Wu and C.-H. Wong, Chem. Commun., 2011, 47, 6201–6207; (b) P. H. Seeberger, Chem. Commun., 2003, 1115–1121; (c) C. R. Bertozzi and L. L. Kiessling, Science, 2001, 291, 2357–2364; (d) Z. Shriver, S. Raguram and R. Sasisekharan, Nat. Rev., 2004, 3, 863–873; (e) R. A. Dwek, Chem. Rev., 1996, 96, 683–720; (f) J. Hirabayashi and K.-I. Kasai, Trends Glycosci. Glycotechnol., 2000, 12, 1–5; (g) T. Feizi and B. Mulloy, Curr. Opin. Struct. Biol., 2003, 13, 602–604; (h) N. Asano, Glycobiology, 2003, 13, 93R–104R; (i) E. S. H. EI Ashry, N. Rashed and A. H. S. Shobier, Pharmazie, 2005, 55, 403–415; (j) H. Ghazarian, B. Idoni and S. B. Oppenheimer, Acta Histochem., 2011, 113, 236–247; (k) P. Sears and C.-H. Wong, Angew. Chem., Int. Ed., 1999, 38, 2300–2324.
12. L. K. Campbell, D. E. Baker and R. K. Campbell, Ann. Pharmacother., 2000, 34, 1291–1301.
13. (a) C. J. Heneghan, I. J. Onakpoya, M. Thompson, E. A. Spencer, M. Jones and T. Jefferson, BMJ, 2014, 348, g2547; (b) T. Jefferson, M. Jones, P. Doshi, C. B. Del Mar, R. Hama, M. Thompson, E. A. Spencer, I. J. Onakpoya, K. R. Mahtani, D. Nunan, J. Howick and C. J. Heneghan, Cochrane Database Syst. Rev., 2014, 4, 1–560.
14. (a) J. R. Smith, C. R. Rayner, B. Donner, M. Wollenhaupt, K. Klumpp and R. Dutkowski, Adv. Ther., 2011, 28, 927–959; (b) F. G. Hayden, R. L. Atmar and M. Schilling, N. Engl. J. Med., 1999, 341, 1336–1343; (c) K. McClellan and C. M. Perry, Drugs, 2001, 61, 263–283.
15. (a) C. Ficicioglu, Ther. Clin. Risk Manage., 2008, 4, 125–131; (b) D. Elstein, C. Hollak, J. M. F. G. Aerts, S. van Weely, M. Maas, T. M. Cox, R. H. Lachmann, M. Hrebicek, F. M. Platt, T. D. Butters, R. A. Dwek and A. Zimran, J. Inherited Metab. Dis., 2004, 27, 757–766.
16. B. E. Maryanoff, S. O. Nortey, J. F. Gardocki, R. P. Shank and S. P. Dodgson, J. Med. Chem., 1987, 30, 880–887.
17. B. Ernst and J. L. Magnani, Nat. Rev. Drug Discovery, 2009, 8, 661–677.
18. J. I. Weitz, N. Engl. J. Med., 1997, 337, 688–699.
19. (a) A. D. McNaught, Pure Appl. Chem., 1996, 68, 1919–2008; (b) A. E. Stütz, Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond, Wiley-VCH, Weinheim, 1999; (c) P. Compain and O. R. Martin, Iminosugars-From Synthesis to Therapeutic Applications, John Wiley & Sons Ltd, West Sussex, England, 2007; (d) A. E. Stütz and T. M. Wrodnigg, Adv. Carbohydr. Chem. Biochem., 2011, 66, 187–298.
20. (a) S. Inouye, T. Tsuruoka and T. Niida, J. Antibiot., Ser. A, 1966, 19, 288–292; (b) T. Tsuruoka, H. Fukuyasu, M. Ishii, T. Usui, S. Shibahara and S. Inouye, J. Antibiot., 1996, 49, 155–161.
21. M. Yagi, T. Kouno, Y. Aoyagi and H. Murai, Nippon Nogeik. Kaishi, 1976, 50, 571–572.
22. (a) P. Compain, O. R. Martin, C. Boucheron, G. Godin, L. Yu, K. Ikeda and N. Asano, ChemBioChem, 2006, 7, 1356–1359; (b) A. Metha, S. Ouzounov, R. Jordan, E. Simsek, X. Lu, R. M. Moriarty, G. Jacob, R. A. Dwek and T. M. Block, Antimicrob. Agents Chemother., 2002, 13, 299–304; (c) N. Asano, H. Kizu, K. Oseki, E. Tomioka, K. Matsui, M. Okamoto and M. Baba, J. Med. Chem., 1995, 38, 2349–2356; (d) S. V. Kyosseva, Z. N. Kyossev and A. D. Elbein, Arch. Biochem. Biophys., 1995, 316, 821–826; (e) N. Asano, K. Oseki, H. Kizu and K. Matsui, J. Med. Chem., 1994, 37, 3701–3706; (f) T. Kajimoto, K. K.-C. Liu, R. L. Pederson, Z. Zhong, Y. Ichikawa, J. A. Porco and C.-H. Wong, J. Am. Chem. Soc., 1991, 113, 6187–6196; (g) B. Lesur, J.-B. Ducep, M.-N. Lalloz, A. Ehrhard and C. Danzin, Bioorg. Med. Chem. Lett., 1997, 7, 355–360; (h) Y. Yoshikuni, Agric. Biol. Chem., 1988, 52, 121–128; (i) H. Hettkamp, G. Legler and E. Bause, Eur. J. Biochem., 1984, 142, 85–90.
23. N. Asano, K. Yasuda, H. Kizu, A. Kato, J.-Q. Fan, R. J. Nash, G. W. J. Fleet and R. J. Molyneux, Eur. J. Biochem., 2001, 268, 35–41.
24. (a) J. M. H. van Den Elsen, D. A. Kuntz and D. R. Rose, EMBO J., 2001, 20, 3008–3017; (b) D. A. Winkler and G. Holan, J. Med. Chem., 1989, 32, 2084–2089; (c) J. Bischoff and R. Kornfeld, Biochem. Biophys. Res. Commun., 1984, 25, 324–331; (d) D. R. P. Tulsiani, T. M. Harris and O. Touster, J. Biol. Chem., 1982, 257, 7936–7939; (e) N. Ishida, K. Kumagai, T. Miida, T. Tsuruoka and Y. Yumoto, J. Antibiot., Ser. A, 1967, 20, 66–71.
25. T. Niwa, T. Tsuruoka, H. Goi, Y. Kodama, J. Itoh, S. Inouye, Y. Yamada, T. Niida, M. Nobe and Y. Ogawa, Antibiotics, 1984, 37, 1579–1586.
26. (a) Y. Miyake and M. Ebata, Agric. Biol. Chem., 1988, 52, 661–666; (b) Y. Miyake and M. Ebata, Agric. Biol. Chem., 1988, 52, 153–158; (c) Y. Miyake and M. Ebata, Agric. Biol. Chem., 1988, 52, 1649–1654; (d) G. Legler and S. Pohl, Carbohydr. Res., 1986, 155, 119–129.
27. (a) A. Kato, N. Kato, E. Kano, I. Adachi, K. Ikeda, L. Yu, T. Okamoto, Y. Banba, H. Ouchi, H. Takahata and N. Asano, J. Med. Chem., 2005, 48, 2036–2044; (b) T. Tsuruoka, H. Fukuyasu, M. Ishii, T. Usui, S. Shibahara and S. Inouye, J. Antibiot., 1996, 49, 155–161; (c) G. Legler, Adv. Carbohydr. Chem. Biochem., 1990, 48, 319–384; (d) T. Niwa, S. Inouye, T. Tsuruoka, Y. Koaze and T. Niida, Agric. Biol. Chem., 1970, 34, 966–968; (e) S. Inouye, T. Tsuruoka, Y. Koaze and T. Niida, Tetrahedron, 1968, 24, 2125–2144; (f) S. Inouye, T. Tsuruoka and T. Niida, J. Antibiot., Ser. A, 1966, 19, 288–292.
28. K. Ikeda, M. Takahashi, M. Nishida, M. Miyauchi, H. Kizu, Y. Kameda, M. Arisawa, A. A. Watson, R. J. Nash, G. W. J. Fleet and N. Asano, Carbohydr. Res., 2000, 323, 73–80.
29. (a) N. Asano, M. Nishida, A. Kato, H. Kizu, K. Matsui, Y. Shimada, T. Itoh, M. Baba, A. A. Watson, R. J. Nash, P. M. de Q. Lilley, D. J. Watkin and G. W. J. Fleet, J. Med. Chem., 1998, 41, 2565–2571; (b) P. Jakobsen, J. M. Lundbeck, M. Kristiansen, J. Breinholt, H. Demuth, J. Pawlas, M. P. T. Candela, B. Andersen, N. Westergaard, K. Lundgren and N. Asano, Bioorg. Med. Chem., 2001, 9, 733–744; (c) N. Asano, M. Nishida, M. Miyauchi, K. Ikeda, M. Yamamoto, H. Kizu, Y. Kameda, A. A. Watson, R. J. Nash and G. W. J. Fleet, Phytochemistry, 2000, 53, 379–382.
30. (a) I. Dragutan, V. Dragutan and A. Demonceau, RSC Adv., 2012, 2, 719–736; (b) D. Bini, F. Cardona, M. Forcella, C. Parmeggiani, P. Parenti, F. Nicotra and L. Cipolla, Beilstein J. Org. Chem., 2012, 8, 514–521; (c) G. Horne, F. X. Wilson, J. Tinsley, D. H. Williams and R. Storer, Drug Discovery Today, 2011, 16, 107–118; (d) A. M. Scofield, L. E. Fellows, R. J. Nash and G. W. J. Fleet, Life Sci., 1986, 39, 645–650; (e) A. D. Elbein, M. Mitchell, B. A. Sanford, L. E. Fellows and S. V. Evans, J. Biol. Chem., 1984, 259, 12409–12413.
31. (a) R. J. Nash, E. A. Bell, G. W. J. Fleet, R. H. Jones and J. M. Williams, J. Chem. Soc., Chem. Commun., 1985, 738–740; (b) R. J. Nash, E. A. Bell, G. W. J. Fleet, R. H. Jones and J. M. Williams, J. Chem. Soc., Chem. Commun., 1985, 738–740.
32. (a) N. Asano, K. Ikeda, L. Yu, A. Kato, K. Takebayashi, I. Adachi, I. Kato, H. Ouchi, H. Takahata and G. W. J. Fleet, Tetrahedron: Asymmetry, 2005, 16, 223–229; (b) K. Yasuda, H. Kizu, T. Yamashita, Y. Kameda, A. Kato, R. J. Nash, G. W. J. Fleet, R. J. Molyneux and N. Asano, J. Nat. Prod., 2002, 65, 198–202; (c) O. Muraoka, S. Ying, K. Yoshikai, Y. Matsuura, E. Yamada, T. Minematsu, G. Tanabe, H. Matsuda and M. Yoshikawa, Chem. Pharm. Bull., 2001, 49, 1503–1505; (d) M. T. H. Axamatwaty, G. W. J. Fleet, K. A. Hannah, S. K. Namgoong and M. L. Sinnott, Biochem. J., 1990, 266, 245–249; (e) G. W. J. Fleet, S. J. Nicholas, P. W. Smith, S. V. Evans, L. E. Fellows and R. J. Nash, Tetrahedron Lett., 1985, 26, 3127–3130.
33. (a) R. J. Molyneux, Y. T. Pan, J. E. Tropea, A. D. Elbein, C. H. Lawyer, D. J. Hughes and G. W. J. Fleet, J. Nat. Prod., 1993, 56, 1356–1364; (b) R. J. Molyneux, M. Benson, R. Y. Wong, J. E. Tropea and A. D. Elbein, J. Nat. Prod., 1988, 51, 1198–1206.
34. N. Asano, T. Yamauchi, K. Kagamifuchi, N. Shimizu, S. Takahashi, H. Takatsuka, K. Ikeda, H. Kizu, W. Chuakul, A. Kettawan and T. Okamoto, J. Nat. Prod., 2005, 68, 1238–1242.
35. (a) H. Kayakiri, K. Nakamura, S. Takase, H. Setoi, I. Uchida, H. Terano, M. Hashimoto, T. Tada and S. Koda, Chem. Pharm. Bull., 1991, 39, 2807–2812; (b) T. Shibata, O. Nakayama, Y. Tsurumi, M. Okuhara, H. Terano and M. Kohsaka, J. Antibiot., 1988, 41, 296–301.
36. (a) A. A. Watson, R. J. Nash, M. R. Wormald, D. J. Harvey, S. Dealler, E. Lees, N. Asano, H. Kizu, A. Kato, R. C. Kato, A. J. Cairns and G. W. J. Fleet, Phytochemistry, 1997, 46, 255–259; (b) A. Kato, I. Adachi, M. Miyauchi, K. Ikeda, T. Komae, H. Kizu, Y. Kameda, A. A. Watson, R. J. Nash, M. R. Wormald, G. W. J. Fleet and N. Asano, Carbohydr. Res., 1999, 316, 95–103; (c) R. E. Lee, M. D. Smith, R. J. Nash, R. C. Griffiths, M. McNeil, R. K. Grewal, W. Yan, G. S. Besra, P. J. Brennan and G. W. J. Fleet, Tetrahedron Lett., 1997, 38, 6733–6736.
37. (a) B. G. Winchester, I. Cenci di Bello, A. C. Richardson, R. J. Nash, L. E. Fellows, N. G. Ramsden and G. Fleet, Biochem. J., 1990, 269, 227–231; (b) I. Cenci di Bello, G. Fleet, K. Namgoong, K.-I. Tadano and B. Winchester, Biochem. J., 1989, 259, 855–861; (c) G. Trugnan, M. Rousset and A. Zweibaum, FEBS Lett., 1986, 195, 28–32; (d) P. R. Dorling, C. R. Huxtable and S. M. Colegate, Biochem. J., 1980, 191, 649–651.
38. (a) R. Saul, J. J. Ghidoni, R. J. Molyneux and A. D. Elbein, Biochemistry, 1985, 82, 93–97; (b) R. Saul, J. P. Chambers, R. J. Molyneux and A. D. Elbein, Arch. Biochem. Biophys., 1983, 221, 593–597; (c) R. J. Molyneux, J. N. Roitman, G. Dunnheim, T. Szumilo and A. D. Elbein, Arch. Biochem. Biophys., 1986, 251, 450–457.
39. (a) T. Aoyagi, H. Suda, K. Uotani, F. Kojima, T. Aoyama, K. Horiguchi, M. Hamada and T. Takeuchi, J. Antibiot., 1992, 45, 1404–1408; (b) R. J. Molyneux, Y. T. Pan, J. E. Tropea, M. Benson, G. P. Kaushal and A. D. Elbein, Biochemistry, 1991, 30, 9981–9987.
40. I. Pastuszak, R. J. Molyneux, L. F. James and A. D. Elbein, Biochemistry, 1990, 29, 1886–1891.
41. A. Michalik, J. Hollinshead, L. Jones, G. W. J. Fleet, C.-Y. Yu, X. G. Hu, R. G. van Well, F. X. Wilson, A. Kato, S. F. Jenkinson and R. J. Nash, Phytochem. Lett., 2010, 3, 136–138.
42. (a) A. Kato, E. Kano, I. Adachi, R. J. Molyneux, A. A. Watson, R. J. Nash, G. W. J. Fleet, M. R. Wormald, H. Kizu, K. Ikeda and N. Asano, Tetrahedron: Asymmetry, 2003, 14, 325–331; (b) A. A. Bell, L. Pickering, A. A. Watson, R. J. Nash, Y. T. Pan, A. D. Elbein and G. W. J. Fleet, Tetrahedron Lett., 1997, 38, 5869–5872.
43. R. J. Nash, L. E. Fellows, J. V. Bring, G. W. J. Fleet, A. Girdhar, N. G. Ramsden, J. M. Peach, M. P. Hegarty and A. M. Scofield, Phytochemistry, 1990, 29, 111–114.
44. H. Usuki, M. Toyooka, H. Kanzaki, T. Okuda and T. Nitoda, Bioorg. Med. Chem., 2009, 17, 7248–7253.
45. N. Asano, H. Kuroi, K. Ikeda, H. Kizu, Y. Kameda, A. Kato, I. Adachi, A. A. Watson, R. J. Nash and G. W. J. Fleet, Tetrahedron: Asymmetry, 2000, 11, 1–8.
46. (a) S. H. Kang and D. H. Ryu, Tetrahedron Lett., 1997, 38, 607–610; (b) F. Popowycz, S. Gerber−Lemaire, C. Schütz and P. Vogel, Helv. Chim. Acta, 2004, 87, 800–810.
47. (a) C. Dulsat and N. Mealy, Drugs Future, 2009, 34, 147–149; (b) N. J. Weinreb, J. A. Barranger, J. Charrow, G. A. Grabowski, H. J. Mankin and P. Mistry, Am. J. Hematol., 2005, 80, 223–229; (c) L. A. Sorbera, J. Castanez and M. Bayes, Drugs Future, 2003, 28, 229–236.
48. L. K. Campbell, D. E. Baker and R. K. Campbell, Ann. Pharmacother., 2000, 34, 1291–1301.
49. (a) K. Afarinkia and A. Bahar, Tetrahedron: Asymmetry, 2005, 16, 1239–1287; (b) M. S. M. Pearson, M. Mathé-Allainmat, V. Fargeas and J. Lebreton, Eur. J. Org. Chem., 2005, 2159–2191; (c) N. Asano, K. Oseki, H. Kizu and K. Matsui, J. Med. Chem., 1994, 37, 3701–3706.
50. (a) P. Merino, I. Delso, E. Marca, T. Tejero and R. Matute, Curr. Chem. Biol., 2009, 3, 253–271; (b) N. Asano, Cell. Mol. Life Sci., 2009, 66, 1479–1492; (c) Y. Minami, C. Kuriyama, K. Ikeda, A. Kato, K. Takebayashi, I. Adachi, G. W. J. Fleet, A. Kettawan, T. Okamotoe and N. Asano, Bioorg. Med. Chem., 2008, 16, 2734–2740; (d) F. Cardona, A. Goti and A. Brandi, Eur. J. Org. Chem., 2007, 1551–1565.
51. M. E. C. Caines, S. M. Hancock, C. A. Tarling, T. M. Wrodnigg, R. V. Stick, A. E. Stütz, A. Vasella, S. G. Withers and N. C. J. Strynadka, Angew. Chem., Int. Ed., 2007, 46, 4474–4476.
52. P.-H. Liang, W.-C. Cheng, Y.-L. Lee, H.-P. Yu, Y.-T. Wu, Y.-L. Linand and C.-H. Wong, ChemBioChem, 2006, 7, 165–173.
53. (a) U. K. Pandit, H. S. Overkleeft, B. C. Borer and H. Bieräugel, Eur. J. Org. Chem., 1999, 959–968; (b) T. M. Wrodnigg, Monatshefte für Chemie, 2002, 133, 393–426; (c) B. G. Winchester, Tetrahedron: Asymmetry, 2009, 20, 645–651. and references cited therein; (d) B. L. Stocker, E. M. Dangerfield, A. L. Win-Mason, G. W. Haslett and M. S. M. Timmer, Eur. J. Org. Chem., 2010, 1615–1637; (e) D. J. Wardrop and S. L. Waidyarachchi, Nat. Prod. Rep., 2010, 27, 1431–1468; (f) G. Horne, F. X. Wilson, J. Tinsley, D. H. Williams and R. Storer, Drug Discovery Today, 2011, 16, 107–118; (g) I. Dragutan, V. Dragutan and A. Demonceau, RSC Adv., 2012, 2, 719–736; (h) R. Lahiri, A. A. Ansari and Y. D. Vankar, Chem. Soc. Rev., 2013, 42, 5102–5118.
54. (a) Y. Nishimura, J. Antibiot., 2009, 62, 407–423; (b) E. M. Sánchez-Fernández, R. Rísquez-Cuadro, M. Aguilar-Moncayo, M. I. García-Moreno, C. Ortiz Mellet and J. M. García Fernández, Org. Lett., 2009, 11, 3306–3309; (c) E. M. Sánchez-Fernández, R. Rísquez-Cuadro, M. Chasseraud, A. Ahidouch, C. Ortiz Mellet, H. Ouadid-Ahidouch and J. M. García Fernández, Chem. Commun., 2010, 46, 5328–5330; (d) E. M. Sánchez-Fernández, R. Rísquez-Cuadro, C. Ortiz Mellet, J. M. García Fernández, P. M. Nieto and J. Angulo, Chem.–Eur. J., 2012, 18, 8527–8539; (e) G. Allan, H. Ouadid-Ahidouch, E. M. Sánchez-Fernández, R. Rísquez-Cuadro, J. M. García Fernández, C. Ortiz Mellet and A. Ahidouch, PLoS One, 2013, 8, e76411; (f) R. Rísquez-Cuadro, J. M. García Fernández, J.-F. Nierengarten and C. Ortiz Mellet, Chem.–Eur. J., 2013, 19, 16791–16803; (g) E. M. Sánchez-Fernández, E. Álvarez, C. Ortiz Mellet and J. M. García Fernández, J. Org. Chem., 2014, 79, 11722–11728; (h) E. M. Sánchez-Fernández, V. Gomez-Perez, R. Garcia-Hernandez, J. M. García Fernández, G. B. Plata, J. M. Padron, C. Ortiz Mellet, S. Castanys and F. Gamarro, RSC Adv., 2015, 5, 21812–21822; (i) E. M. Sánchez-Fernández, R. Gonçalves-Pereira, R. Rísquez-Cuadro, G. B. Plata, J. M. Padrón, J. M. García Fernández and C. Ortiz Mellet, Carbohydr. Res., 2016, 429, 113–122; (j) M. Abellán Flos, M. I. García Moreno, C. Ortiz Mellet, J. M. García Fernández, J.-F. Nierengarten and S. P. Vincent, Chem.–Eur. J., 2016, 22, 11450–11460.
55. Y. Takaoka, T. Kajimoto and C.-H. Wong, J. Org. Chem., 1993, 58, 4809–4812.
56. J. Liu, A. R. Shikhman, M. K. Lotz and C.-H. Wong, Chem. Biol., 2001, 8, 701–711.
57. S. G. Davies, A. L. A. Figuccia, A. M. Fletcher, P. M. Roberts and J. E. Thomson, Tetrahedron, 2014, 70, 3601–3607.
58. E. Abraham, S. G. Davies, N. L. Millican, R. L. Nicholson, P. M. Roberts and A. D. Smith, Org. Biomol. Chem., 2008, 6, 1655–1664.
59. F. Popowycz, S. Gerber-Lemaire, C. Schütz and P. Vogel, Helv. Chim. Acta, 2004, 87, 800–810.
60. N. Ikota, H. Nakagawa, S. Ohno, K. Noguchi and K. Okuyama, Tetrahedron, 1998, 54, 8985–8998.
61. F.-M. Kieß, P. Poggendorf, S. Picasso and V. Jäger, Chem. Commun., 1998, 119–120.
62. A. J. Blake, E. C. Boyd, R. O. Gould and R. M. Paton, J. Chem. Soc., Perkin Trans. 1, 1994, 2841–2847.
63. D. Damour, M. Barreau, J.-C. Blanchard, M.-C. Burgevin, A. Doble, F. Herman, G. Pantel, E. James-Surcouf, M. Vuilhorgne and S. Mignani, Bioorg. Med. Chem. Lett., 1996, 6, 1667–1672.
64. D. Damour, J.-C. Depezay, Y. Le Merrer, S. Mignani, G. Pantel, L. Poiout and L. Gauzy, PCT Int. Appl., WO9635686 A1 19961114, 1996.
65. L. Poitout, Y. Le Merrer and J.-C. Depezay, Tetrahedron Lett., 1996, 37, 1609–1612.
66. S. H. Kang and D. H. Ryu, Tetrahedron Lett., 1997, 38, 607–610.
67. T. M. Wrodnigg, A. E. Stütz and S. G. Withers, Tetrahedron Lett., 1997, 38, 5463–5466.
68. K. Dax, B. Grigg, V. Gressberger, B. Kölblinger and A. E. Stütz, J. Carbohydr. Chem., 1990, 9, 479–499.
69. T. M. Wrodnigg, S. G. Withers and A. E. Stütz, Bioorg. Med. Chem. Lett., 2001, 11, 1063–1064.
70. A. Berger, A. de Raadt, A. Gradnig, G. Grasser, M. H. Low and A. E. Stütz, Tetrahedron Lett., 1992, 33, 7125–7128.
71. P.-H. Liang, W.-C. Cheng, Y.-L. Lee, H.-P. Yu, Y.-T. Wu, Y.-L. Linand and C.-H. Wong, ChemBioChem, 2006, 7, 165–173.
72. R. C. Reynolds, N. Bansal, J. Rose, J. Friedrich, W. J. Suling and J. A. Maddry, Carbohydr. Res., 1999, 317, 164–179.
73. M. Takebayashi, S. Hiranuma, Y. Kanie, T. Kajimoto, O. Kanie and C.-H. Wong, J. Org. Chem., 1999, 64, 5280–5291.
74. C. Saotome, C.-H. Wong and O. Kanie, Chem. Biol., 2001, 8, 1061–1070.
75. J. Liu, M. M. D. Numa, H. Liu, S.-J. Huang, P. Sears, A. R. Shikhman and C.-H. Wong, J. Org. Chem., 2004, 69, 6273–6283.
76. I. McCort, S. Fort, A. Duréault and J.-C. Depezay, Bioorg. Med. Chem., 2000, 8, 135–143.
77. I. McCort, A. Duréault and J.-C. Depezay, Tetrahedron Lett., 1996, 37, 7717–7720.
78. H. Fiaux, W. Popowycz, S. Favre, C. Schütz, P. Vogel, S. Gerber-Lemaire and L. Juillerat-Jeanneret, J. Med. Chem., 2005, 48, 4237–4246.
79. G. W. J. Fleet and J. C. Son, Tetrahedron, 1988, 44, 2637–2647.
80. S. Lemaire-Audoire, M. Savignac and J.-P. Genet, Tetrahedron Lett., 1995, 36, 1267–1270.
81. K. M. Bonger, T. Wennekes, S. V. P. de Lavoir, D. Esposito, R. J. B. H. N. van den Berg, R. E. J. N. Litjens, G. A. van der Marel and H. S. Overkleeft, QSAR Comb. Sci., 2006, 25, 491–503.
82. K. M. Bonger, T. Wennekes, D. V. Fillippov, G. Lodder, G. A. Marel and H. S. Overkleeft, Eur. J. Org. Chem., 2008, 3678–3688.
83. E. R. Van Rijssel, T. P. M. Goumans, G. Lodder, H. S. Overkleeft, G. A. van der Marel and J. D. C. Codée, Org. Lett., 2013, 15, 3026–3029.
84. P. Szcześniak, E. Maziarz, S. Stecko and B. Furman, J. Org. Chem., 2015, 80, 3621–3633.
85. P. Merino, I. Delso, T. Tejero, F. Cardona, M. Marradi, E. Faggi, C. Parmeggiani and A. Goti, Eur. J. Org. Chem., 2008, 2929–2947.
86. (a) M. Marradi, S. Cicchi, J. I. Delso, L. Rosi, T. Teiero, P. Merino and A. Goti, Tetrahedron Lett., 2005, 46, 1287–1290; (b) F. Cardona, E. Faggi, F. Liguori, M. Cacciarini and A. Goti, Tetrahedron Lett., 2003, 44, 2315–2318.
87. E.-L. Tsou, Y.-T. Yeh, P.-H. Liang and W.-C. Cheng, Tetrahedron, 2009, 65, 93–100.
88. (a) T.-J. R. Cheng, T.-H. Chan, E.-L. Tsou, S.-Y. Chang, W.-Y. Yun, P.-J. Yang, Y.-T. Wu and W.-C. Cheng, Chem.–Asian J., 2013, 8, 2600–2604; (b) W.-C. Cheng, J.-H. Wang, W.-Y. Yun, H.-Y. Li and J.-M. Hu, Eur. J. Med. Chem., 2017, 126, 1–6.
89. M. Moura, S. Delacroix, D. Postel and A. N. Van Nhien, Tetrahedron, 2009, 44, 2766–2772.
90. M. Ginisty, C. Gravier-Pelletier and Y. Le Merrer, Tetrahedron: Asymmetry, 2006, 17, 142–150.
91. D. Declerck, S. Josse, A. N. V. Nhien and D. Postel, Tetrahedron Lett., 2009, 50, 2171–2173.
92. D. Declerck, A. N. V. Nhien, S. Josse, J. Szymoniak, P. Bertus, C. Bello, P. Vogel and D. Postel, Tetrahedron Lett., 2012, 68, 1802–1809.
93. (a) M. Ganesan, R. V. Madhukarrao and N. G. Ramesh, Org. Biomol. Chem., 2010, 8, 1527–1530; (b) A. Shandilya, M. Ganesan, F. Parveen, N. G. Ramesh and B. Jayaram, Carbohydr. Res., 2016, 429, 87–97.
94. (a) V. Kumar and N. G. Ramesh, Org. Biomol. Chem., 2007, 5, 3847–3858; (b) V. Kumar and N. G. Ramesh, Chem. Commun., 2006, 4952–4954.
95. (a) A. L. Win-Mason, S. A. K. Jongkees, S. G. Withers, P. C. Tyler, M. S. M. Timmer and B. L. Stocker, J. Org. Chem., 2011, 76, 9611–9621; (b) A. L. Win-Mason, E. M. Dangerfield, P. C. Tyler, B. L. Stocker and M. S. M. Timmer, Eur. J. Org. Chem., 2011, 4008–4014.
96. (a) B. Bernet and A. Vasella, Helv. Chim. Acta, 1979, 62, 1990–2016; (b) B. Bernet and A. Vasella, Helv. Chim. Acta, 1979, 62, 2400–2410; (c) A. A. Strecker, Ann. Chem. Pharm., 1850, 75, 27–45.
97. E. M. Dangerfield, S. A. Gulab, C. H. Plunkett, M. S. M. Timmer and B. L. Stocker, Carbohydr. Res., 2010, 345, 1360–1365.
98. (a) M. K. Gurjar, R. Nagaprasad and C. V. Ramana, Tetrahedron Lett., 2002, 43, 7577–7579; (b) C. P. J. Glaudemans and H. G. Fletcher Jr, J. Am. Chem. Soc., 1965, 87, 4636–4641.
99. B. L. Stocker, S. A. K. Jongkees, A. L. Win-Mason, E. M. Dangerfield, S. G. Withers and M. S. M. Timmer, Carbohydr. Res., 2013, 367, 29–32.
100. (a) B. Davis, A. A. Bell, R. J. Nash, A. A. Watson, R. C. Griffiths, M. G. Jones, C. Smith and G. W. J. Fleet, Tetrahedron Lett., 1996, 37, 8565–8568; (b) J. P. Shilvock, J. R. Wheatley, B. Davis, R. J. Nash, R. C. Griffiths, M. G. Jones, M. Müller, S. Crook, D. J. Watkin, C. Smith, G. S. Besra, P. J. Brennan and G. W. J. Fleet, Tetrahedron Lett., 1996, 37, 8569–8572; (c) T. B. Mercer, S. F. Jenkinson, B. Bartholomew, R. J. Nash, S. Miyauchi, A. Kato and G. W. J. Fleet, Tetrahedron: Asymmetry, 2009, 20, 2368–2373.
101. B. J. Ayers, A. F. G. Glawar, R. F. Martίnez, N. Ngo, Z. Liu, G. W. J. Fleet, T. D. Butters, R. J. Nash, C.-Y. Yu, M. R. Wormald, S. Nakagawa, I. Adachi, A. Kato and S. F. Jenkinson, J. Org. Chem., 2014, 79, 3398–3409.
102. B. J. Ayers, N. Ngo, S. F. Jenkinson, R. F. Martinez, Y. Shimada, I. Adachi, A. C. Weymouth-Wilson, A. Kato and G. W. J. Fleet, J. Org. Chem., 2012, 77, 7777–7792.
103. A. Tran, B. Luo, Y. Jagadeesh, N. Auberger, J. Desire, S. Nakagawa, A. Kato, Y. Zhang, Y. Blériot and M. Sollogoub, Carbohydr. Res., 2015, 409, 56–62.
104. T. Kajimoto, K. K.-C. Liu, R. L. Pederson, Z. Zhong, Y. Ichikawa, J. A. Porco and C.-H. Wong, J. Am. Chem. Soc., 1991, 113, 6187–6196.
105. R. L. Pederson, K. K.-C. Liu, J. F. Rutan, L. Chen and C.-H. Wong, J. Org. Chem., 1990, 55, 4897–4901.
106. R. Wischnat, R. Martin, S. Takayama and C.-H. Wong, Bioorg. Med. Chem. Lett., 1998, 8, 3353–3358.
107. S. Takayama, R. Martin, J. Wu, K. Laslo, G. Siuzdak and C.-H. Wong, J. Am. Chem. Soc., 1997, 119, 8146–8151.
108. S. G. Davies, A. L. A. Figuccia, A. M. Fletcher, P. M. Roberts and J. E. Thomson, J. Org. Chem., 2016, 81, 6481–6495.
109. S. G. Davies, A. L. A. Figuccia, A. M. Fletcher, P. M. Roberts and J. E. Thomson, Org. Lett., 2013, 15, 2042–2045.
110. A.-R. Samy, S. Hinderlich, W. Reutter and A. Giannis, Angew. Chem., Int. Ed., 2004, 43, 4366–4370.
111. A. de la Fuente, R. Martin, T. Mena-Barragán, X. Verdaguer, J. M. Garcia Fernández, C. Ortiz Mellet and A. Riera, Org. Lett., 2013, 15, 3638–3641.
112. (a) A. de la Fuente, T. Mena-Barragán, R. A. Farrar-Tobar, X. Verdaguer, J. M. G. Fernández, C. O. Mellet and A. Riera, Org. Biomol. Chem., 2015, 13, 6500–6510; (b) A. de la Fuente, R. Rísquez-Cuadro, X. Verdaguer, J. M. G. Fernández, E. Nanba, K. Higaki, C. O. Mellet and A. Riera, Eur. J. Med. Chem., 2016, 121, 926–938.
113. A. Hasegawa, E. Tanahashi and M. Kiso, Carbohydr. Res., 1980, 81, 249–259.
114. A. Hasegawa, Y. Kawai and M. Kiso, Carbohydr. Res., 1978, 63, 131–137.
115. A. Hasegawa and H. G. Fletcher Jr, Carbohydr. Res., 1973, 29, 223–237.
116. G. W. J. Fleet, P. W. Smith, R. J. Nash, L. E. Fellows, R. B. Parekh and T. W. Rademacher, Chem. Lett., 1986, 1051–1054.
117. G. W. J. Fleet and P. W. Smith, Tetrahedron Lett., 1985, 26, 1469–1472.
118. H. Bӧshagen, F.-R. Heiker and A. M. Schüller, Carbohydr. Res., 1987, 164, 141–148.
119. E. Kappes and G. Legler, J. Carbohydr. Chem., 1989, 8, 371–388.
120. A. M. Schüller and F.-R. Heiker, Carbohydr. Res., 1990, 203, 308–313.
121. M. Kiso, M. Kitagawa, H. Ishida and A. Hasegawa, J. Carbohydr. Chem., 1991, 10, 24–45.
122. R. H. Furneaux, G. J. Gainsford, G. P. Lynch and S. C. Yorke, Tetrahedron, 1993, 49, 9605–9612.
123. I. K. Khanna, J. F. Koszyk, M. A. Stealey, R. M. Weier, J. Julien, R. A. Mueller, N. Rao and L. Swenton, J. Carbohydr. Chem., 1995, 14, 843–878.
124. J. I. Cho, S. Yoon, K. H. Chun and J. E. Nam Shin, Bull. Korean Chem. Soc., 1995, 16, 805–808.
125. G. Gradnig, G. Legler and A. E. Stütz, Carbohydr. Res., 1996, 287, 49–57.
126. T. Granier and A. Vasella, Helv. Chim. Acta, 1998, 81, 865–880.
127. C.-W. Ho, S. D. Popat, T.-W. Liu, K.-C. Tsai, M.-J. Ho, W.-H. Chen, A.-S. Yang and C.-H. Lin, ACS Chem. Biol., 2010, 5, 489–497.
128. T. Yamaguchi, B. Blázquez, D. Hesek, L. Mijoon, L. I. Llarrull, B. Boggess, A. G. Oliver, J. F. Fisher and S. Mobashery, ACS Med. Chem. Lett., 2012, 3, 238–242.
129. (a) M. Lee, W. Zhang, D. Hesek, B. C. Noll, B. Boggess and S. Mobashery, J. Am. Chem. Soc., 2009, 131, 8742–8743; (b) D. Hesek, M. Lee, W. Zhang, B. C. Noll and S. Mobashery, J. Am. Chem. Soc., 2009, 131, 5187–5193.
130. A. J. Steiner, G. Schitter, A. E. Stütz, T. M. Wrodnigg, C. A. Tarling, S. G. Withers, D. J. Mahuran and M. B. Tropak, Tetrahedron: Asymmetry, 2009, 20, 832–835.
131. B. L. Mark, D. J. Vocadlo, D. Zhao, S. Knapp, S. G. Withers and M. N. G. James, J. Biol. Chem., 2001, 276, 42131–42137.
132. G. Schitter, A. J. Steiner, G. Pototschnig, E. Scheucher, M. Thonhofer, C. A. Tarling, S. G. Withers, K. Fantur, E. Paschke, D. J. Mahuran, B. A. Rigat, M. B. Tropak, C. Illaszewicz, R. Saf, A. E. Stütz and T. M. Wrodnigg, ChemBioChem, 2010, 11, 2026–2033.
133. D. Best, P. Chairatana, A. F. G. Glawar, E. Crabtree, T. D. Butters, F. X. Wilson, C.-Y. Yu, W.-B. Wang, Y.-M. Jia, I. Adachi, A. Kato and G. W. J. Fleet, Tetrahedron Lett., 2010, 51, 2222–2224.
134. A. C. Weymouth-Wilson, R. A. Clarkson, D. Best, M.-S. Pino-Gonzalez, F. X. Wilson and G. W. J. Fleet, Tetrahedron Lett., 2009, 50, 6307–6310.
135. A. F. G. Glawar, D. Best, B. J. Ayers, S. Miyauchi, S. Nakagawa, M. Aguilar-Moncayo, J. M. G. Fernández, C. O. Mellet, E. V. Crabtree, T. D. Butters, F. X. Wilson, A. Kato and G. W. J. Fleet, Chem.–Eur. J., 2012, 18, 9341–9359.
136. K. A. Stubbs, J.-P. Bacik, G. E. Perley-Robertson, G. E. Whitworth, T. M. Gloster, D. J. Vocadlo and B. L. Mark, ChemBioChem, 2013, 14, 1973–1981.
137. G. Jacoby, Clin. Microbiol. Rev., 2009, 22, 161–182.
138. J. F. Billing and U. J. Nilsson, Tetrahedron, 2005, 61, 863–874.
139. E. D. Goddard-Borger and R. V. Stick, Org. Lett., 2007, 9, 3797–3800.
140. (a) A. Kilonda, F. Compernolle, S. Toppet and G. J. Hoornaert, J. Chem. Soc., Chem. Commun., 1994, 2147–2148; (b) A. Kilonda, F. Compernolle and G. J. Hoornaert, J. Org. Chem., 1995, 60, 5820–5824.
141. A. Vasella and A. Peer, Helv. Chim. Acta, 1999, 82, 1044–1065.
142. G. J. Joly, K. Peeters, H. Mao, T. Brossette, G. J. Hoornaert and F. Compernolle, Tetrahedron Lett., 2000, 41, 2223–2226.
143. A. Kilonda, F. Compernolle, K. Peetters, G. J. Joly, S. Toppet and G. J. Hoornaert, Tetrahedron, 2000, 56, 1005–1012.
144. R. J. B. H. N. Van den Berg, W. Donker-Koopman, J. H. Van Boom, H. M. F. G. Aerts and D. Noort, Bioorg. Med. Chem., 2004, 12, 891–902.
145. T. Trnka and M. Cerny, Collect. Czech. Chem. Commun., 1971, 36, 2216–2225.
146. R. Hoos, A. B. Naughton and A. Vasella, Helv. Chim. Acta, 1993, 76, 1802–1807.
147. H. S. Overkleeft, J. Van Wiltenburg and U. K. Pandit, Tetrahedron Lett., 1993, 34, 2527–2528.
148. R. J. B. H. N. Van den Berg, D. Noort, E. S. Milder-Enachace, G. A. Van der Marel, J. H. Van Boom and H. P. Benschop, Eur. J. Org. Chem., 1999, 2593–2600.
149. L. Zhang, F. Sun, Y. Li, X. Sun, X. Liu, Y. Huang, L.-H. Zhang, X.-S. Ye and J. Xiao, ChemMedChem, 2007, 2, 1594–1597.
150. X.-S. Ye, F. Sun, M. Liu, Q. Li, Y. H. Wang, G. S. Zhang, L.-H. Zhang and X.-L. Zhang, J. Med. Chem., 2005, 48, 3688–3691.
151. Y. Zhou and P. V. Murphy, Org. Lett., 2008, 10, 3777–3780.
152. D. D. Long, M. D. Smith, A. Martin, J. R. Wheatley, D. G. Watkin, M. Müller and G. W. J. Fleet, J. Chem. Soc., Perkin Trans. 1, 2002, 1982–1998.
153. M. B. Pampín, F. Fernández, J. C. Estévez and R. J. Estévez, Tetrahedron: Asymmetry, 2009, 20, 503–507.
154. (a) I. McCort, S. Fort, A. Duéault and J.-C. Depezay, Bioorg. Med. Chem., 2000, 8, 135–143; (b) T. D. Heightman and A. Vasella, Angew. Chem., Int. Ed., 1999, 38, 750–770.
155. J. A. Tamayo, F. Franco and D. L. Re, Synlett, 2010, 9, 1323–1326.
156. M. Ganesan, R. V. Salunke, N. Singh and N. G. Ramesh, Org. Biomol. Chem., 2013, 11, 599–611.
157. R. G. Soengas and A. M. S. Silva, Tetrahedron Lett., 2013, 54, 2156–2159.
158. C. Matassini, S. Mirabella, X. Ferhati, C. Faggi, I. Robina, A. Goti, E. Moreno-Clavijo, A. J. Moreno-Vargas and F. Cardona, Eur. J. Org. Chem., 2014, 5419–5432.
159. (a) D. Vonlanthen and C. J. Leumann, Synthesis, 2003, 1087–1090; (b) M. I. García-Moreno, P. Díaz-Pérez, C. Ortiz-Mellet and J. M. García Fernández, J. Org. Chem., 2003, 68, 8890–8901; (c) K. Bischofberger, A. Jordaan, M. Potgieter and P. L. Wessels, S. Afr. J. Chem., 1981, 34, 33–40.
160. M. Zoidl, B. Müller, A. Torvisco, C. Tysoe, M. Benazza, A. Siriwardena, S. G. Withers and T. M. Wrodnigg, Bioorg. Med. Chem. Lett., 2014, 24, 2777–2780.
161. A. Duréault, I. Tranchepain, C. Greck and J.-C. Depezay, Tetrahedron Lett., 1987, 28, 3341–3344.
162. A. Duréault, C. Greck and J.-C. Depezay, Tetrahedron Lett., 1986, 27, 4157–4160.
163. (a) A. Duréault, C. Greck and J.-C. Depezay, J. Org. Chem., 1989, 54, 5324–5330; (b) J. Fitremann, A. Duréault and J.-C. Depezay, Tetrahedron Lett., 1994, 35, 1201–1204.
164. T. K. Chakraborty and S. Jayaprakash, Tetrahedron Lett., 1997, 38, 8899–8902.
165. W. R. Kobertz, C. R. Bertozzi and M. D. Bednarski, J. Org. Chem., 1996, 61, 1894–1897.
166. C.-Y. Wu, C.-F. Chang, J. S.-Y. Chen, C.-H. Wong and C.-H. Lin, Angew. Chem., Int. Ed., 2003, 42, 4661–4664.
167. (a) G. W. J. Fleet, S. K. Namgoong, C. Barker, S. Baines, G. S. Jacob and B. Winchester, Tetrahedron Lett., 1989, 30, 4439–4442; (b) J. P. Shilvock and G. W. J. Fleet, Synlett, 1998, 554–556.
168. G. W. J. Fleet, N. G. Ramsden and D. R. Witty, Tetrahedron, 1989, 45, 319–326.
169. B. L. Ferla, P. Bugada, L. Cipolla, F. Peri and F. Nicotra, Eur. J. Org. Chem., 2004, 2451–2470.
170. H. Paulsen and W. von Deyn, Liebigs Ann. Chem., 1987, 125–131.
171. M. S. M. Timmer, M. D. P. Risseeuw, D. V. Filippov, J. R. Plaisier, G. A. Van der Marel, H. S. Overkleeft and J. H. Van Boom, Tetrahedron: Asymmetry, 2005, 16, 177–185.
172. O. Šimák, J. Stanêk and J. Moravcová, Carbohydr. Res., 2009, 344, 966–971.
173. (a) D. M. Hall and O. A. Stamm, Carbohydr. Res., 1970, 12, 421–428; (b) K. Čapek, J. Stanêk and J. Jarý, Collect. Czech. Chem. Commun., 1974, 39, 1462–1478.
174. M. Mondon, N. Fontelle, J. Désiré, F. Lecornué, J. Guillard, J. Marrot and Y. Blériot, Org. Lett., 2012, 14, 870–873.
175. J. J. Posakony and A. R. Ferré-D’Amaré, J. Org. Chem., 2013, 78, 4730–4743.
176. C.-H. Hsu, M. Schelwies, S. Enck, L.-Y. Huang, S.-H. Huang, Y.-F. Chang, T.-J. R. W.-C. Cheng and C.-H. Wong, J. Org. Chem., 2014, 79, 8629–8637.
177. M. Hoffmann, F. Burkhart, G. Hessler and H. Kessler, Helv. Chim. Acta, 1996, 79, 1519–1532.
178. F.-E. Chen, J.-F. Zhao, F.-J. Xiong, B. Xie and P. Zhang, Carbohydr. Res., 2007, 342, 2461–2464.
179. C. Matassini, S. Mirabella, A. Goti and F. Cardona, Eur. J. Org. Chem., 2012, 3920–3924.
180. Y. Blériot, N. Auberger, Y. Jagadeesh, C. Gauthier, G. Prencipe, A. T. Tran, J. Marrot, J. Désiré, A. Yamamoto, A. Kato and M. Sollogoub, Org. Lett., 2014, 16, 5512–5515.
181. Y. Blériot, A. T. Tran, G. Prencipe, Y. Jagadeesh, N. Auberger, S. Zhu, C. Gauthier, Y. Zhang, J. Désiré, I. Adachi, A. Kato and M. Sollogoub, Org. Lett., 2014, 16, 5516–5519.
182. (a) H. Li, F. Marcelo, C. Bello, P. Vogel, T. D. Butters, A. P. Rauter, Y. Zhang, M. Sollogoub and Y. Blériot, Bioorg. Med. Chem., 2009, 17, 5598–5604; (b) F. Moris-Varas, X.-H. Qian and C.-H. Wong, J. Am. Chem. Soc., 1996, 118, 7647–7652.
183. M. Mondon, S. Hur, G. Vadlamani, P. Rodrigues, P. Tsybina, A. Oliver, B. L. Mark, D. J. Vocadlo and Y. Blériot, Chem. Commun., 2013, 10983–10985.
184. F. Marcelo, Y. He, S. A. Yuzwa, L. Nieto, J. Jiménez-Barbero, M. Sollogoub, D. J. Vocadlo, G. D. Davies and Y. Blériot, J. Am. Chem. Soc., 2009, 131, 5390–5392.
185. (a) P. Kulainthaivel, Y. F. Hallock, C. Boros, S. M. Hamilton, W. P. Janzen, L. M. Ballas, C. R. Loomis and J. B. Jiang, J. Am. Chem. Soc., 1993, 115, 6452–6453; (b) T. Saha, R. Maitra and S. K. Chattopadhyay, Beilstein J. Org. Chem., 2015, 9, 2910–2915.
186. (a) H. Li, Y. Blériot, J.-M. Mallet, E. Rodrigues-Garcia, P. Vogel, Y. Zhang and P. Sinaӱ, Tetrahedron: Asymmetry, 2005, 16, 313–319; (b) P. R. Andreana, T. Sanders, A. Janczuk, J. I. Warrick and P. G. Wang, Tetrahedron Lett., 2002, 43, 6525–6528.
187. A. J. Janczuk, W. Zhang, P. R. Andreana, J. Warrick and P. G. Wang, Carbohydr. Res., 2002, 337, 1247–1259.
188. R. A. Farr, A. K. Holland, A. W. Huber, N. P. Peet and P. M. Weintraub, Tetrahedron, 1994, 50, 1033–1044.
189. B. P. Bashyal, G. W. J. Fleet, M. J. Gough and P. W. Smith, Tetrahedron, 1987, 43, 3083–3093.
190. F. Morís-Varas, X.-H. Qian and C.-H. Wong, J. Am. Chem. Soc., 1996, 118, 7647–7652.
191. M. S. Valle and R. M. Braga, Synlett, 2008, 18, 2874–2876.
192. J. Kuszmann and P. Sohár, Carbohydr. Res., 1979, 74, 187–197.
193. H. Li, Y. Zhang, P. Vogel, P. Sinaÿ and Y. Blériot, Chem. Commun., 2007, 183–185.
194. P. S. Liu, M. S. Kang and P. S. Sunkara, Tetrahedron Lett., 1991, 32, 719–720.
195. P. S. Liu, W. J. Hoekstra and C.-H. R. King, Tetrahedron Lett., 1990, 31, 2829–2832.
196. R. H. Furneaux, G. J. Gainsford, J. M. Mason and P. C. Tyler, Tetrahedron, 1994, 50, 2131–2160.
197. R. H. Furneaux, G. J. Gainsford, J. M. Mason and P. C. Tyler, Tetrahedron, 1995, 51, 12611–12630.
198. R. H. Furneaux, G. J. Gainsford, J. M. Mason and P. C. Tyler, Tetrahedron, 1997, 53, 245–268.
199. B. Alcaide, P. Almendros, J. M. Alonso and M. F. Aly, Chem.–Eur. J., 2003, 9, 3415–3426.
200. B. Alcaide, P. Almendros, M. C. Redondo and M. P. Ruiz, J. Org. Chem., 2005, 70, 8890–8894.
201. G. Pandey, S. G. Dumbre, S. Pal, M. I. Khan and M. Shabab, Tetrahedron, 2007, 63, 4756–4761.
202. G. Pandey, S. G. Dumbre, M. I. Khan and M. Shabab, J. Org. Chem., 2006, 71, 8481–8488.
203. G. Pandey, G. D. Reddy and D. Chakrabarti, J. Chem. Soc., Perkin Trans. 2, 1996, 219–224.
204. B. Pluvinage, M. G. Ghinet, R. Brzezinski, A. B. Boraston and K. A. Stubbs, Org. Biomol. Chem., 2009, 7, 4169–4172.
205. S. Stecko, M. Jurczak, O. Staszewska-Krajewska, J. Solecka and M. Chmielewski, Tetrahedron, 2009, 65, 7056–7063.
206. T. W. Baughman, J. C. Sworen and K. B. Wagener, Tetrahedron, 2004, 60, 10943–10948.
207. S. Stecko, K. Paśniczek, M. Jurczak, Z. Urbańczyk-Lipkowska and M. Chmielewski, Tetrahedron: Asymmetry, 2006, 17, 68–79.
208. G. D'Adamio, C. Parmeggiani, A. Goti, A. J. Moreno-Vargas, E. Moreno-Clavijo, I. Robina and F. Cardona, Org. Biomol. Chem., 2014, 12, 6250–6266.
209. C. Bonaccini, M. Chiocchioli, C. Parmeggiani, F. Cardona, D. Lo Re, G. Soldaini, P. Vogel, C. Bello, A. Goti and P. Gratteri, Eur. J. Org. Chem., 2010, 5574–5585.
210. Y. Kitamura, H. Koshino, T. Nakamura, T. Tsuchida, T. H. Nitoda, K. Matsuoka and S. Takahashi, Tetrahedron Lett., 2013, 54, 1456–1459.
211. L. Cai, W. Guan, M. Kitaoka, J. Shen, C. Xia, W. Chen and P. G. Wang, Chem. Commun., 2009, 2944–2946.
212. J. S. Zhu, S. Nakagawa, W. Chen, I. Adachi, Y. M. Jia, X. G. Hu, G. W. J. Fleet, F. X. Wilson, T. Nitoda, G. Horne, R. Well, A. Kato and C. Y. Yu, J. Org. Chem., 2013, 78, 10298–10309.
213. C. W. Holzapfel and R. Crous, Heterocycles, 1998, 48, 1337–1342.
214. R. V. Salunke and N. G. Ramesh, Eur. J. Org. Chem., 2016, 654–657.
215. J. Frigell, J. A. Pearcey, T. L. Lowary and I. Cumpstey, Eur. J. Org. Chem., 2011, 1367–1375.
216. C. O'Reilly, C. O'Brien and P. V. Murphy, Tetrahedron Lett., 2009, 50, 4427–4429.
217. I. Izquierdo Cubero, M. T. P. Lopez-Espinosa and N. Kari, Carbohydr. Res., 1994, 261, 231–242.

---