Recent Developments in Glycosyl Urea Synthesis ⇑ Matthew J

Carbohydrate Research 385 (2014) 18–44

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Carbohydrate Research

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Minireview Recent developments in glycosyl urea synthesis ⇑ Matthew J. McKay, Hien M. Nguyen

Department of Chemistry, University of Iowa, Iowa City, IA 52242, United States article info abstract

Article history: The area of sugar urea derivatives has received considerable attention in recent years because of the Received 9 July 2013 unique structural properties and activities that these compounds display. The urea-linkage at the Received in revised form 8 August 2013 anomeric center is a robust alternative to the naturally occurring O- and N-glycosidic linkages of Accepted 9 August 2013 oligosaccharides and glycoconjugates, and the natural products that have been identified to contain these Available online 19 August 2013 structures show remarkable biological activity. While methods for installing the b-urea-linkage at the anomeric center have been around for decades, the first synthesis of a-urea glycosides has been much Keywords: more recent. In either case, the selective synthesis of glycosyl ureas can be quite challenging, and a Carbohydrate mixture of - and b-isomers will often result. This paper will provide a comprehensive review of the Urea a Pseudooligosaccharide synthetic approaches to a- and b-urea glycosides and examine the structure and activity of the natural Neoglycoconjugate products and their analogues that have been identified to contain them. Stereoselectivity Ó 2013 Elsevier Ltd. All rights reserved. Rearrangement

1. Introduction variation at the terminal sugar residue is what differentiates the members of this family and accounts for the range in activities they Replacing the traditional C–O–C and C–N–C linkages of glyco- display. The c-component of cinodine (Fig. 1) is comprised of an conjugates and oligosaccharides with a more robust functionality inseparable mixture of c1 (2) and c2 (3) and is up to 20 more is appealing to the development of carbohydrate-based therapeu- active than b-cinodine (1) (in vitro & in vivo studies),14 which tics with enhanced bio-availability and remarkable stability may be explained by the chemically labile carbonyl functionality 1 against acid and enzymatic hydrolysis; having direct application of the strained oxazolidone (c1, 2) and imidazolidone (c2, 3) in the development of anti-diabetic agents2–5 and aminoglycoside trans-fused rings which are incorporated at the terminal sugar res- antibiotics.6,7 In particular, the urea linkage (Fig. 1) at the anomeric idue of c-cinodine.15 A considerable increase in activity and 12- center is an interesting candidate for replacing the native O- and fold improvement in the safety margin (LD50/ED50) is observed N-linked glycosidic bonds and has the potential to increase resis- after modifying the c-structures to the semi-synthetic derivatives, tance to chemical and enzymatic degradation8 while maintaining N-Isopropyl c-cinodines (4, 5, Fig. 1).16,17 the properties of the natural compounds. Urea-linked glycosides A second class of compounds with the a-glycosyl urea linkage also have the potential to serve as small-molecule H-bond donors (the coumamidines, 6, 7, Fig. 2) was identified and characterized in asymmetric catalysis9 and are currently employed in the forest by Abbott Laboratories in 1988.18,19 The coumamidines are similar product industry in adhesive mixtures to reduce the level of toxic in structure to c-cinodine and differ only by the propanimidine, phenol in furniture and building materials.10 rather than spermidine, tether they possess. The coumamidines Though quite rare in nature, the glycosyl urea linkage has been were found to be highly active, as well; distancing themselves from identified as a component of the glycocinnamoylspermidine (also cinodine and aminoglycoside antibiotics by having additional bac- known as cinodine) antibiotics (Fig. 1), which were isolated and tericidal activity against anaerobes.20 characterized from a soil sample by the Lederle Laboratories in Unlike aminoglycosides, the cinodine and coumamidine antibi- 1977.11–13 These compounds are of special interest due to their un- otics are not inhibitors of bacterial protein synthesis. Rather, these ique structural features and broad-spectrum activity they display polycationic structures bind directly to bacterial DNA and even more against Gram-negative cell lines and Gram-positive aerobes. There tightly to gyrase B (organizational enzyme required for bacterial are three members in the cinodine family that have been identified DNA replication); eliciting elongation and filamentation of cells 21 (b, c1, c2) and share a common a-urea linked xylosamine-quino- prior to death. This type of targeting is desirable in antimicrobial vose core with a cinnamoyl-spermidene tether. Structural therapeutics, as the enzyme is known to serve an essential role in cellular function and is presumed to be present in all bacteria.22 A third glycosyl urea-containing compound, glycocinnasperim- ⇑ Corresponding author. Tel.: +1 319 384 1887; fax: +1 319 335 1270. icin D (8, Fig. 3), was isolated and characterized by Umezawa at the E-mail address: [email protected] (H.M. Nguyen).

RO O Me HO O H H O HO HO N N HO O NH O NH H2N HN O O HN NH H2N Me O O H2N HN 8 NH2 H HO R'HN N NH HN NH O O NH2 H N NH Figure 3. Glycocinnamoylsperimicin D. O

24,25 HO O the strain of Nocardia it was isolated from Ref. To the best of cinodine β (1) R= R' = H H2N our knowledge, a synthesis of the remaining cinodine or coumami- O NH dine antibiotics has not been reported due to difﬁculties associated

H2N with the selective construction of the 1,2-cis-2-aminosugar urea. The task of synthesizing glycosyl urea is by no means trivial.26 HO O cinodine γ1 (2) R= HN R' = H Approaches are often complicated by numerous steps and there N is a propensity for many donor types to undergo anomerization; NH 2 effectively removing them from consideration in selective urea O O synthesis. To add to this, the reactivity observed in generating O O the glycosyl urea-linkage can be highly dependent on the N cinodine γ2 (3) R= R' = H electronic properties and substitution patterns of the coupling O H HN O partners. This review will be divided into two sections; covering H N 2 the handful of methods available for the synthesis of b-glycosyl urea; and the few which are able to attain the a-linked urea struc- HO O N-isopropyl-cinodine γ1 (4) R= HN R' = Isopropyl ture. Each section will be further partitioned on the basis of the N type of reactive carbohydrate species used in the formation of NH2 O O urea-glycosides.

O O 2. b-Linked urea glycosides N N-isopropyl-cinodine γ2 (5) R= R' = Isopropyl O H HN O This detailed overview of the synthetic approaches to urea H N 2 glycosides will begin by covering reactions available for the syn- Figure 1. Cinodine antibiotics and semi-synthetic derivatives. thesis of urea glycosides with the b-orientation at the anomeric center. This was chosen for several reasons: (1) these compounds are generally easier to attain than their a-linked counterparts; RO O (2) there are more synthetic strategies available for constructing HO the b-compounds; (3) the first reported synthesis of b-urea glyco- O NH sides predates that of the a- by over a century. For this reason, our HN O H2N Me review will commence with the oldest of the b-urea syntheses: the O HN acid catalyzed condensation of glucose and urea. This type of reac- HO H2NNH HN NH tion requires no protection or deprotection strategies to prepare its O coupling partners and, as an interesting side-note, is not only NH2 NH where the synthesis of glycosyl urea would get its start, but is also the focus in some of the most recent advances being made in the O field. HO O R= HN coumamidine γ1 (6) 2.1. Carbohydrate hemiacetals N NH2 O O It has been more than 100 years since Schoorl first described the crystalline product of the condensation of glucose 9 and urea 10 O O (Scheme 1).27,28 At that time, there was report of difficulty in R= N coumamidine γ2 (7) O H HN reproducibly detecting the levels of lactose in the urine. This O prompted Schoorl to investigate his hypothesis that the sugar H2N was able to evade detection in the urine by somehow existing in Figure 2. Coumamidine antibacterial agents. combinatorial form with it. The endeavor would lead to the first chemical synthesis of glucosyl ureide 11 (Scheme 1) in 1903,29 though Schoorl’s method would be later characterized as problem- 23 Institute of Microbial Chemistry of Japan in 1985. This compound atic and ill-suited for achieving appreciable quantities from the has the cinnamoyl-spermidine tether in common with cinodine, reaction.30 though it lacks the third sugar residue and has a urea-bridged Improvements to Schoorls’ method were reported by Hynd in pseudodisacharide component in the b-orientation, instead of the the 1920’s after completing his studies as to whether glucose 9 a-linkage found in the cinodines and coumamidines. A total syn- and urea 10 (Scheme 1) would be able to couple under physiolog- thesis of glycocinnasperimicin D (8) has been reported by Ichikawa ical conditions.31 While that investigation would prove fruitless, (see Section 2c) and is of added significance because the compound Hynd discovered that by heating glucose in an excess of urea to is no longer acquirable from natural sources due to a mutation in 50 °C in dilute sulfuric acid, as much as 60–70% of the desired 20 M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44

O 10 HO 8-9% (Schoorl, 1900) HO O H O H2N NH2 HO (Hynd, 1926) HO N NH2 66% HO HO OH HO 32% (Benn & Jones, 1960) HO acid catalyst O 53% (Sano, 1961) D-glucose (9) β-glucoseureide (11)

Scheme 1. Acid catalyzed condensation of urea and glucose.

O Me HO H2N N HO H 12 HO O H H O N N (Helferich & Kosche, 1926) HO HO Me HO OH 6M aq. HCl HO O 9 HO 50oC, 16 d 13 (32%)

Scheme 2. Acid catalyzed-condensation of 1-methyl urea and glucose.

O 10 HO HO H OH HO H2N NH2 O H O H H HO + HO O OH HO O HO N NH2 N N O 5% aq. H SO HO HO OH 2 4 HO HO OH HO 70oC, 18 h 11 O O 14 9 predominates w/ predominate sw/ < > −1.0 equiv. glucose − 2.0 equiv. glucose

Scheme 3. Synthesis of glycosyl ureide and di-glucose urea. ureide 11 (Scheme 1) could be isolated after multiple extractions.32 The same conditions were screened with mannose substrate 15

Hynd had also reported the use of other acids to work in his prep- (Table 2), and it was discovered that FeCl3 (entry 2) was most aptly aration, though he felt they offered no discernible advantage over using sulfuric acid. An example with 6 M HCl would be reported later that year when Helferich and Kosche successfully condensed Table 1 Acid catalyst screening for the condensation of urea 9 and glucose 10 1-methyl urea (12) and 9 in the first synthesis of a urea-linked gly- 33 O coside 13 (Scheme 2). 10 HO HO Hynds’ modification to Schoorls’ procedure was robust enough H N NH HO O 2 2 HO O H that it remained the preferred method for obtaining the ureide of (7.0 equiv.) HO N NH2 HO OH glucose for many years, as is illustrated by its appearance in the HO HO acid catalyst O 34 9 11 work of Benn and Jones as late as 1960. They discovered that (3.0 equiv.) NH4Cl (1.0 equiv.), 2 h by elevating the temperature (70 °C) and reducing the concentration of acid, the time requirement of Hynd’s method could be Entry Catalyst % Conversiona reduced by several days. They also discovered that by altering 1 Amberlyst 15 81 the ratio of glucose and urea in the reaction (Scheme 3), symmet- 2 FeCl3 27 rical urea-linked pseudodisaccharide 14 could be isolated as the 3 ZnCl2 14 major product instead of ureide 11. Additional modification to 4 p-TsOH 37 5 Montmorillonite 14 Hynd’s method came from Sano in 1961, when he reported that 6 Without catalyst 14 Amberlite IR-120 is also effective at catalyzing the condensation a of glucose 9 and urea 10; forming 11 in 53% yield after 4 d.35 It Determined by HPLC. would be four more decades before further modifications would be made to Hynd’s protocol. In 2011, König and coworkers highlighted some of the desired Table 2 features that a method for converting biomass into platform chem- Acid catalyst screening for the condensation of urea 10 and mannose 9A icals should possess: (1) be a highly concentrated system using O 10 high concentrations of substrate; (2) be high yielding; and (3) have 36 HO OH H2N NH2 HO OH the shortest reaction times possible. To address these tenets, the O O H 37–43 HO (7.0 equiv.) HO group has applied their carbohydrate melt technology to the HO N NH2 HO OH acid catalyst condensation of glucose and urea, eliminating the need for solvent 15 (3.0 equiv.) NH Cl (1.0 equiv.), 2 h 16 O in the reaction (Table 1). Using Lewis acid catalysts in concentra- 4 tions of aldose as high as 3 M, König and coworkers were able to Entry Catalyst % Conversiona achieve significantly shorter reaction times than the fastest of the previous solution-based approaches (<2 h vs 42 h). Yields from 1 Amberlyst 15 75% 2 FeCl 81% their experiments were calculated by HPLC and the melt procedure 3 3 ZnCl2 Less active was able to generate an impressive 81% of glucosyl ureide 11 (Ta- 4 p-TsOH 64% ble 1, entry 1) with Amberlyst 15 as the catalyst. It was found that 5 Montmorillonite Less active 6 Without catalyst No report the addition of ZnCl2 and montmorillonite (entries 3 and 5) in the reaction provided no additional catalytic activity. a Determined by HPLC. M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44 21

Table 3 Condensation of urea-derivatives with glucose HO a 17-19 HO O 1) Ure (7.0 equiv.) (1.0 equiv.) β-Linked Ureas HO OH NH4Cl HO 20 and 21 2) Ac O, NaOAc 9 (3.0 equiv.) 2

Entry Urea Reaction time (h) Temp (°C) Product Isolated yield O AcO O AcO N NH AcO 1 HN NH 675 27% AcO O 17 20 O AcO O H H AcO N N H N N 2 2 285AcO 60% H AcO 18 O 21 O

3 24 110 Complex mixture — H2N N 7 19 H

O Me H2N N 12 (10 equiv.), HO 1) H AcO O AcO O H H HO 6M aq. HCl, rt, 3 d N N HO OH AcO Me HO Workup A: neutralization; concentration AcO Workup B: addition of Et O; filtration O 9 2 22 2) Ac2O, Pyridine Workup A: 68% yield (1:16 α/β) Workup B: 71% yield (β only)

Scheme 4. Synthesis of protected methyl glucose urea. suited for the transformation (81% of 16), though the reactivity was to be highly b-selective and highly sensitive to the size of urea. For only slightly superior to that observed with Amberlyst 15 (entry 1, example, branching at the a-position of the amine moiety of urea 75% of 16). 26 (entry 4) was found to significantly reduce the yield of urea gly- The studies continued by evaluating the performance of urea- coside 32 (24%) in comparison to the reaction where the urea derivatives in the carbohydrate melt system (Table 3). Only the nucleophile 24 lacked such branching (56%, entry 2). In addition, cyclic N,N0-ethylene urea 17 (entry 1) showed enough melting the ureas 27 and 28 derived from secondary amines (entries 5 point depression to form a clear melt, while the other cyclic ureas and 6) were found to generally perform poorly in this system. were just suspended in excess melted sugar component. The result In an effort to increase the efficiency of these reactions, (both in achieved in entry 2 illustrates that this observation had far less ef- terms of output and required amounts of urea), considerable atten- fect on performance than sterics of the nucleophilic urea did. In the tion was given to optimizing solvent conditions.18 These efforts reaction with N-octyl urea 19 (entry 3), a number of catalysts were were successful in reducing the necessary equivalents of urea in screened, though the poor reactivity of the compound required the reaction (Table 5). Under the new conditions, similar perfor- that temperatures be elevated to 110 °C. By this point, a number mance was achieved with the N-butyl urea 25 and phenylethyl of products were forming in the reaction and caramelization of urea 24 with only 2 equiv present in the reaction. The reactions the carbohydrate melt had begun to occur. with the secondary amine derived ureas 27 and 28 (entries 5 and Ichikawa has given considerable attention to the synthesis of 6) were still found to perform better using the original 10 equiv; urea glycosides proceeding through glycosyl isocyanates (see Sec- providing the desired products 33 and 34 in 40% & 49%, respec- tions 2c & 3a for details), though he has expressed interest in the tively. Urea-tethered amino-acid glycoconjugate 36 (entry 7) was condensation reactions of sugar and ureas, as well, due to the abil- achieved in 52% yield under the optimized conditions. ity of this reaction type to circumvent the myriad of protection/ To determine if substrates other than glucose would be compat- 44 deprotection steps common to other approaches. Ichikawa ible in the reaction, Ichikawa screened N-acetyl-D-glucosamine 37 would begin his investigations with a close examination of the with cyclohexylurea 23 (Scheme 5).18 After acetylation, the prod- reaction parameters of Helferich and Kosche (Scheme 2); generat- uct 38 was isolated in 61% yield and its structure was confirmed ing 1-methyl-3-glucosyl urea 22 (Scheme 4). Accordingly, the con- by comparison to an authentic sample prepared in a 6-step densation of 1-methyl urea 12 and glucose 9 in the presence of 6 M synthesis. HCl provided 68% of 22 in 1:16 a/b-ratio after acetylation. Because Through application of new technologies and painstaking there was difficulty experienced in separating the mixture of ano- experimentation into the optimization of a reaction developed mers in the product, an alternate workup was developed (workup nearly a century ago, the acid-catalyzed condensation of ureas B) where the addition of diethyl ether after the reaction was suffi- and aldohexoses has burgeoned into a formidable option for the cient to recrystallize the b-1-methyl-3-glucosyl urea 22 (71%). synthesis of simple b-urea glycoside structures. The methods in A variety of urea-derivatives were screened under the opti- this reaction class are able to avoid the additional protection and mized conditions (Table 4).18 In each case, the reaction was found deprotection sequences that are needed to limit undesired 22 M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44

Table 4 Synthesis of urea glycosides with glucose and urea-derivatives HO 1) Urea 23-28 (10 equiv.) HO O 6M aq. HCl, rt, 3d β-Linked Ureas HO OH HO Workup A: neutralization; 29 - 34 9 concentration 2) Ac2O, pyridine

Entry Urea Product Isolated yield a:b

O AcO O H H AcO N N AcO 1 H2N N 67 1:13 AcO H O 23 29 O AcO O H H Ph AcO N N 2N N AcO Ph 2 H AcO 56 1:13 O 24 30 O AcO O H H AcO N N H N N AcO 3 2 3 26 1:13 H AcO 3 O 25 31 O Me AcO O H H AcO N N Ph H2N N Ph AcO 4 H AcO 24 b Only 26 O Me 32 O AcO O H AcO N N 5 H2N N AcO 10 1:30 AcO 27 33 O O AcO Me O H AcO N Me N Me 6 H2N N AcO 6 1:30 AcO Me O 28 34

Table 5 Optimized condition for synthesis of urea glycosides from glucose

HO 1) Urea 23-28, 35 O o HO 2.4M aq. HCl, 50 C, 24 h β-Linked Ureas HO OH 29 - 34, 36 HO 9 2) Ac2O, NaOAc

Entry Urea Urea equiv. 2.4 M HCl/solvent (ratio) Product Isolated yield (%) a:b 1 23 2.0 2.4 M HCl–MeCN (1:4) 29 68 1:12 2 24 2.0 2.4 M HCl–MeCN (1:6) 30 63 1:9 3 25 2.0 2.4 M HCl–MeCN (1:6) 31 68 b Only 4 26 2.0 2.4 M HCl–MeCN (1:6) 32 69 b Only 5 27 2.0 2.4 M HCl–EtOAc (1:6) 33 27 1:30 10.0 2.4 M HCl–EtOAc (1:1) 40 1:19 6 28 2.0 2.4 M HCl–EtOAc (1:2) 34 30 1:30 10.0 2.4 M HCl–EtOAc (1:1) 49 1:13

7 35 2.0 2.4 M HCl–EtOAc (1:6) 36 52 1:19

O AcO Cbz O AcO O H NMe2 AcO N O HN H2N N HN NMe H AcO 2 Cbz O HN 35 36

O 23 HO H N N AcO 1) 2 (10 equiv.) HO O H AcO O H H o N N HO OH 2.4 M HCl-EtOAc (1:1), 50 C, 24 h AcO AcHN AcHN O 37 2) Ac2O, Pyridine 38 (61%, β only)

Scheme 5. Synthesis of N-acetyl urea glycoside from GlucNAc. M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44 23

AcO AcO AcO O Pt/C, H Me-N=C=O AcO 2 O 41 AcO O H H NH3 N3 AcO 13 AcO NH2 N N EtOAc AcO AcO Me AcO AcO AcO MeOH 39 40 22 O

Scheme 6. 1-Methyl glucose urea synthesis from sugar hemiaminal and methyl isocyanate. reactivity in other synthetic approaches. These reactions also com- reduction of glycosyl azide 39 with hydrogen and platinum. After prise a highly atom-economical approach to urea glycoside synthe- removing the solvent, the hemiaminal product 40 was left sis. Many of the reactions are performed in H2O or in the absence of overnight in a solution of CHCl3 and 41 to generate 64% of solvent, altogether, in the case of the carbohydrate melts; features 1-methyl-3-glucosyl tetraacetate urea 22. Subsequent removal of that will become more prominent with the future push for greener the protecting groups with ammonia in methanol provided the free chemistry. urea glycoside 13 (83%). In 2000, Ichikawa reported a similar reduction of a-azide (42) 2.2. C1-Aminosugars and subsequent treatment with cyclohexyl isocyanate 43 produces an inseparable mixture of a- and b-ureas, 44 (Scheme 7).46 This re- While the free-sugar substrates in the last section were likely sult confirmed an earlier one from Ogawa that the a-azide reduc- serving an electrophilic role in generating the urea-linkage, the tion proceeds without retention of anomeric stereochemical C1-aminosugars in this section are performing the opposite; in integrity.47 the nucleophilic addition to isocyanate derivatives. There is limited The most recent account of the C1-aminosugar being used for report of using this reaction type in the synthesis of urea glyco- the synthesis of urea-derivatives (Table 6) was from Burger in sides; however, this reactivity has been established for decades. 2003.48 In his investigation, the isocyanate 45 was reacted with In the early 70’s, Bannister would report the first reaction of a the aminosugars 40, 46–48 to give to the corresponding car- protected glucose hemiaminal 40 with methyl isocyanate 41 boxyl-activated urea species 49-51 (Table 6). These compounds (Scheme 6).45 The synthesis of aminosugar 22 was initiated by display several interesting features: (1) they can be directly applied to the synthesis of dipeptides, as illustrated in Table 7; (2) heating compound 49 in pyridine causes intramolecular cycliza- AcO 1) Pd/C, H2,Et3N, AcO O O tion to the dihydropyrimidine urea glucoside 58 (42%, Scheme 8); AcO Et2O / hexane (2:1) AcO O AcO AcO and (3) after stirring 50 in the presence of TFA, slow equilibration 2) N C O N AcO N AcO H to the a-anomer takes place over a 36 h period (1:3?3:1 a/b, 3 44 HN 42 43 Scheme 9). Because of the difficulties surrounding the separation of the Scheme 7. Mixture of products from reduction of a-azide and reaction with individual anomers of urea glycosides, it is unlikely that the isocyanate.

Table 6 Synthesis of glycosyl urea Scaffold for dipeptide synthesis

F3C F3C O N=C=O O F3C CF 3 45 O O O H H (RO) O (RO) O n NH2 n N N o 40, 46-48 CH2Cl2,0 C 49-51 O O

Entry Hemiaminal Urea glycoside Yield (%) a:b AcO F C 3 CF AcO O 3 NH AcO O AcO 2 O H H 1 AcO AcO N N O 88 1:12 40 AcO AcO O 49 O BzO F C 3 CF BzO O 3 NH BzO O BzO 2 O H H 2 BzO BzO N N O 74 1:3 46 BzO BzO 50 O O

AcO OAc F3C O CF3 AcO AcO OAc O AcO NH2 O H H 3 AcO N N O 83 1:13 47 AcO 51 O O

BzO OBz F3C O CF3 BzO BzO OBz O BzO NH2 O H H 4 BzO N N O 73 1:10 48 BzO 52 O O 24 M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44

Table 7 Dipeptide synthesis from urea glycoside precursors

F3C Ph CF3 53 O O H H t (RO) N N O H2N CO2 -Bu β-dipeptide n 54 57 NEM, DMF - 49-52 O O

Entry Urea glycoside b-Dipeptide Yield (%)

RO OH O H H H RO N N N CO2t-Bu RO RO O O Ph 1 49 54:R=Ac 86 2 50 55:R=Bz 74 RO OR OH O H H H RO N N N CO t-Bu RO 2 O O Ph 3 51 56:R=Ac 83 4 52 57:R=Bz 73

OH F3C CF3 O AcO O pyridine (25 equiv) AcO O H H O AcO N N O AcO N NH AcO CHCl ,reflux AcO 3 AcO AcO O O O 49 58 (42%)

Scheme 8. Dihydropyrimidene synthesis from intramolecular cyclization.

F C BzO 3 CF F C 3 BzO O 3 CF BzO O TFA 3 O H H O BzO O BzO N N BzO H BzO O CH2Cl2,36h HN N BzO O O 50 59 O 1:3 (α/β) 3:1 (α/β) O

Scheme 9. Equilibration to a-urea glycoside in presence of TFA.

AcO AcO AcO O AgNCO aq. NH H AcO AcO O 3 AcO O N=C=O N NH2 AcO xylene AcO AcO AcO 60 Br AcO 61 62 AcO O

Scheme 10. Fisher’s synthesis of glycosyl ureide from glycosyl bromide. reaction of sugar hemiaminals with isocyanates will gain much 1) H ,Pd/C AcO 2 AcO attention. If the synthesis of a well-deﬁned urea target is desired, 2) AcOCHO AcO O AcO O approaches generating a single product during the urea-forming N3 NC AcO 3) Ph P, CBr AcO step would be a superior choice. AcO 3 4 AcO 39 76% (3 steps) 63

pyridine N-oxide, 2.3. Glycosyl isocyanates cat. I2,CH3CN

Similar to the reaction of glycosyl amines and alkyl isocyanates, NH2 AcO the reversal of coupling roles (glycosyl isocyanates with nucleo- O H H 64 AcO AcO O AcO N N AcO philic amine) has been established as an efficient route to generat- AcO N=C=O AcO 95% ing glycosyl urea, as well. Fischer would be the first to report on O AcO 61 29 (2 steps) this, in 1914, during his synthesis of substituted glycosyl ureide 49 62 (Scheme 10). The reaction of tetraacetyl glucosyl bromide Scheme 11. Stereospecific synthesis of b-urea glycoside proceeding through 60 with silver cyanate in xylene was able to generate the corre- isocyanate. sponding glycosyl isocyanate 61. This compound was reacted with aqueous ammonia to generate 62. Fishers’ method for generating (generates both a- and b-anomers), though the exact ratio of prod- isocyanate 61 was later identified as lacking stereospecificity, ucts was never determined.50 M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44 25

Table 8 Conversion of b-isocyanide into b-urea glycosides

AcO N AcO 1) pyridine -oxide, O H H AcO O AcO NC cat. I2,CH3CN N N AcO AcO R AcO AcO 2) RR'NH O 63 32,33,65-67

Me Me AcO NHCbz AcO O H H O H AcO N N OMe AcO AcO AcO N N Me AcO AcO O O O Me 65 (95%) 66 (91%) AcO AcO O H AcO N N AcO O Me 33 (95%) O O AcO O AcO O H H Me O H H AcO N N AcO N N AcO AcO AcO AcO O O O O Me Me 32 (87%) 67 (95%) Me

AcO AcO AcO AcO 61 H H Ac H O O AcO O O OAc AcO O 2 AcO N N O AcO N=C=O AcO NH2 AcO OAc AcO AcO AcO 61 40 O 68 (92%)

Scheme 12. Urea-linked pseudodisaccharide from the addition of H2O to glycosyl isocyanate.

Table 9 Conversion of b-isocyanide into unsymmetrical urea pseudodisaccharides 1) pyridine N-oxide, R' O cat. I2,CH3CN O H (RO)n NC (RO)n N N 2) RR'NH R 69 70-72 O

AcO AcO O H O H AcO OBn AcO N O AcO N O AcO OAc OAc HN O HN BnO O 70 BnO (94%) BnO OMe 71 (89%) BnO BnO OMe OBz BzO BzO O H BzO N O NH BnO 72 (78%) O BnO OAllyl BnO

By the turn of the 21st century, the stereospeciﬁc synthesis of for oxidation of 63 to the desired isocyanate 61 (Scheme 11). glycosyl isothiocyanates had been extensively documented.51–56 After considerable experimentation, pyridinium-N-oxide with However, similar reports for attaining the glycosyl isocyanate catalytic iodine and molecular sieves was identiﬁed to be with high levels of anomeric selectivity were lacking. Ichikawa optimal. To avoid the problems associated with isolating the reac- and coworkers have recognized this challenge and given consid- tive isocyanate 61, the compound was captured in situ with erable attention to the oxidation of glycosyl isocyanides for use cyclohexylamine (64) to generate the b-urea glycoside 29 in in pseudo-oligosaccharide and neo-glycoconjugate synthesis. Fol- one pot, with complete retention of the stereochemical integrity lowing Ogawa’s protocol (step 1, Scheme 11),47 the b-amine was at C1 (95%, b-only). achieved as the sole product from the reduction of b-azide. This The reaction sequence was then investigated in the coupling of compound was stable enough for immediate reaction with formic a variety of primary and secondary amine nucleophiles with b-iso- anhydride (step 2), and after dehydration of the resulting form- cyanide 63 (Table 8) to afford the desired b-urea products 32, 33, amide (step 3), the b-isocyanide 63 was achieved as a single ano- 65, and 66 in excellent yield (89–95%). This method is also amena- mer (76%, 3 steps). With the pure b-isocyanide in hand, Ichikawa ble to carbohydrate amines; providing urea-linked pseudodisac- and coworkers set out to determine the most suitable conditions charide 67 in 95% yield. 26 M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44

Improvement to the synthesis of isocyanide 63 was made by Pyridine AcO O N AcO O using triphosgene in lieu of triphenylphosphine during the form- NC -oxide N=C=O 57 AcO AcO amide dehydration (step 3, 76 ? 90%, Scheme 11). It was found TrocHN I2,CH3CN TrocHN that in the absence of molecular sieves, the oxidation step would 73 74 generate trace amounts of N,N-Di-D-glucopyranosyl urea 68 (Scheme 12), likely due to the hydrolysis of isocyanate 61 to amine 40, followed by the attack of amine 40 on another molecule of Me NHBoc O isocyanate 61. To capitalize on this reactivity, a new protocol H2N BzO was developed (Scheme 12) where the addition of H O after the 2 NH O O oxidation was sufficient for generating symmetrical urea-linked BocN pseudodisaccharide 68 in 92% yield. NHBoc HN NHBoc The Prosperi group has extended Ichikawa’s protocol to the syn- 75 thesis of several unsymmetrical urea-linked pseudodisaccharides O 58 O H NHBoc 70–72 (Table 9). Common building blocks were used to access AcO N Me AcO O the carbohydrate donor and acceptor pairs and the b-(1?6)-, HN TrocHN BzO -(1?4)-, and -(1?2)-urea glycosidic linkages were installed with NH O O retention of stereochemical configuration and in good to excellent 76 (85%) BocN yields (89%, 94%, 78%, respectively). NHBoc HN NBoc Recently, Ichikawa and coworkers have applied the isocyanate approach in the construction of a urea-linked pseudodisaccharide 6 steps in the first total synthesis of glycocinnasperimicin D (8, Scheme 13).23 As previously mentioned (see Section 1), this target is of special interest because it is no longer available from natural Glycocinnasperimicin D (8) sources. The urea-forming step in the synthesis of 8 is highlighted in Scheme 13. Starting from the N-Troc protected glucosamine Scheme 13. First total synthesis of glycocinnamoylsperimicin D. isocyanide 73, oxidation to the isocyanate 74 and subsequent trapping with the highly-functionalized aminosugar 75 afforded limited appearance of urea-forming reactions in their report, it is the desired b-linked pseudodisacharide 76 in 85% yield. The target interesting to note that the isocyanate intermediate can be trapped 8 was achieved in 6 additional steps from 76. by other nitrogen nucleophiles, including the galactosyl formamide From the total synthesis of glycocinnasperimicin D (8, 84 shown in Scheme 14. Scheme 13), it is evident that Ichikawa’s protocol is amenable to The isocyanate pathway to the construction of b-urea-linked the use of glucosamine-derived isocyanate donors. The extent of glycosides has been extensively studied. This stereodefined ap- this compatibility is explored in Table 10.59 Similar to the glucosyl proach to glycosyl urea benefits from high output (in both the derivatives, the glucosamine isocyanides perform extremely well reduction of b-azide and the oxidation/urea forming step) and dis- under the mild and neutral oxidative conditions. However, low plays broad functional group compatibility. If water is present after yields observed in the synthesis of urea-linked glycopeptide 83 generating the isocyanate, formation of the symmetrical urea- required that 20 mol% of dibutyltin dilaurate catalyst be added in linked pseudodisaccharide will ensue. the reaction to activate the isocyanide 77. This minor addition was effective in doubling the output of the reaction (85%) without 2.4. 1,2-Oxazolidinone glucose disrupting the acetyl or Fmoc functionality. The most recent application of the isocyanate approach to the The cyclic carbamate (or 1,2-oxazolidinone) carbohydrate plat- synthesis of urea glycosides was reported by the FelfÖldi group form had been accessible decades prior to the discovery that it in their development of urea and biuret-derivative inhibitors of could be applied in the synthesis glycosyl ureas. Steyermark was rabbit muscle glycogen phosphorylase (RMGP).60 While there is the first to report on this unusual structure when it was attained

Table 10 Synthesis of glucosamine ureide derivatives

AcO 1) pyridine N-oxide, AcO R O O H 38,78-83 AcO NC cat. I2,CH3CN AcO N N AcO AcO R' AcHN 2) RR'NH AcHN 77 O

AcO AcO AcO AcO O H H AcO O H H O H N N N N AcO N N AcO Ph AcO AcO AcHN AcHN AcHN O R O O 78: R=H,92% 38 (93%) 80 (91%) 79: R=Me,92% AcO O H Me Me AcO AcO AcO N O AcO NHFmoc AcO O H O H H N N Me AcHN AcO N N AcO NH AcO CO Allyl AcHN Me O AcHN 2 O Me O Me O 81 (91%) O 83 (85%) 82 (92%) O O Me Me M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44 27

AcO AcO O H N O H AcO 1) pyridine -oxide, AcO AcO N O AcO AcO N O O cat. I2,CH3CN OAc AcO OAc NH AcO NC NH 2) Benzene, Heat OAc OAc OAc O + O O 63 AcO OAc AcO AcO O 84 OAc O OAc AcO AcO AcO NH2 OAc 85 (<5%) 86 (89%)

Scheme 14. Synthesis of glucopyranosylcarbonyl urea-linked pseudodisaccharide.

HO HO O Phosgene HO O HO (Steyermark, 1962) HO NH2 HO NH (a) Na CO 87 HO 2 3 O 30% 88 O

HO HO O H H HgO N N 88 (Bannister, 1972) (b) HO Me HO 89 S HO O HO CO2 88 HO N PPh3 (Pinter, 1985) (c) HO DMF 90 81%

Scheme 15. Synthetic routes to 1,2-oxazolidinone glucose.

Me Ichikawa (Table 11) and a variety of urea glycosides have been HO HN N Me HO N O 91 HO O H achieved from opening the cyclic carbamate of 86 with nucleo- HO N N 63 HO NH HO philic amine in H2O. In entries 1–4, the amine nucleophiles were H O HO 88 O 2 O reactive enough to open the oxazolidinone at room temperature. O 92 (88%) This enhanced reactivity arises from a release in ring strain during Scheme 16. Nucleophilic opening of 1,2-oxazolidinone to generate urea glycoside. the opening the 1,2-trans-fused system. In addition, the rigid structure of 88 prevents the lone-pair of electrons on nitrogen from delocalizing into the adjacent carbonyl group. Hindered secondary as an unexpected product 88 (Scheme 15a) from the reaction amines were found to be less reactive (entries 5–7), and heating 61 of D-glucopyranosylamine 87 with phosgene. Bannister would was required for acceptable levels of urea formation; aside from achieve this compound unexpectedly, as well, when it appeared the reactions with di-sec-butyl amine 99 and di-isopropyl amine instead of urea after reacting thiourea 89 and aqueous mercuric 100 (entries 7 and 8), where acceptable yields would remain elu- oxide (Scheme 15b).45 Pinter, surprised as well, attained 88 from sive at elevated temperatures, as well. A number of interesting compounds have been synthesized using the reaction of phosphinimine 90 with CO2, instead of the carbodiimide (Scheme 15c).62 various glycosyl carbamate donors (Schemes 17–20); including the 63 In 1995, Pinter would be the ﬁrst to report the use of 1,2-oxazo- spermidine urea-linked pseudotrisaccharide 103 (Scheme 17), 64 lidinone glucose in the preparation of urea glycoside 92 (88%, amino acid glycoconjugate 105 (Scheme 18), urea-linked 64 Scheme 16) when he reacted 88 with N-methylpiperazine 89. Since pseudopentasacharide 111 (Scheme 19), and the unsymmetrical 65 this event, the reaction type has been extensively studied by (1–4)-urea-linked pseudodisacharides 114 and 115 (Scheme 20).

Table 11 Synthesis of glycosyl ureas from 1,2-oxazolidinone glucose

HO 1 1) amine (R-H), H2O R 88 HO O H N 2) reverse phase HO R2 oxazolidinone column HO 93-101 O

Entry Product Equiv. of 88 T(°C) Time (h) Yield (%) 1 93: R1 =H,R2 = butyl 1.2 25 1 95 2 94: R1 =H,R2 = benzyl 1.2 25 1 88 3 95: R1 =H,R2 =(S)-methylbenzyl 1.5 25 2 80 4 96: R1 =H,R2 = cyclohexyl 1.5 40 4 84 5 97: R1 =H,R2 = cyclopentyl 2.0 60 3 71 6 98: R1 =R2 = ethyl 2.0 50 6 80 7 99: R1 =R2 = sec-butyl 2.0 50 12 8 8 100: R1 =R2 = isopropyl 2.0 70 12 0 9 101: R1 =R2 = phenyl 1.5 70 12 75 28 M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44

O HO H 88 N 1) HO N NH HO O H o 103 H2O, 50 C,12 h HO NH HO 2 2) Ac2O, Pyridine H OH NH2 HO O H H H N N N N O OH 102 71% HO O OH HO O O

Scheme 17. Synthesis of spermidine tethered urea trisaccharide.

O O NHBoc 104 HO NHBoc 1) HO H2N HO O 88 H2O, Et3N, RT,1 h HO H H HO N N 2) 0.1M HCl HO oxazolidinone O 3) reverse phase column 105 (85%)

Scheme 18. Synthesis of urea glycopeptide in water.

OH HO OH O OH O HN HO O O O HO N O HO O H HN n-Bu O O HO NH HO HO O OH HO HO HO O CbzHN OH 107 OPh HO 106 RHN H O/MeOH (1:3), RT, 24 h 108;R=Cbz OPh 2 H ,Pd/C,H O 109;R=H 2 2 OH HO OH O OH OH O O HO N HO O O HO O H HN HO O HO NH OH HO O OH 110 O HO O HO 111 O NH H O, RT, 24 h OPh 2 OH OH 73% HO O HO NH HO O O OH OH

Scheme 19. Synthesis of urea-linked pseudopentasaccharide.

OH o H2O, 40 C HO OH O O H H H2N HO HO O HO HO N N HO O HO HO NH HO 112 OPMP HO O HO 88 O OPMP O 114 (78%) HO OH O HO OH HO NH OH O O H H 113 O N N O 115 (89%) HO HO OH o HO H2O, 40 C O OPMP

Scheme 20. Synthesis of unsymmetrical urea-linked pseudodisaccharides.

The 1,2-oxazolidinone of carbohydrates has been established as nucleophiles, it may be necessary to elevate the temperature in or- a suitable platform for the stereospecific synthesis of b-urea der to facilitate the opening of the carbamate ring. glycosides from opening of the trans-fused cyclic carbamate with an amine nucleophile. This type of approach benefits from being 2.5. Glycosyl carbodiimide conducted in H2O at room temperature, and that generating the urea-linkage does not proceed through an oxocarbenium interme- The phosphine imide reaction of Staudinger66 was first applied diate, so anomeric scrambling of the products is not observed. Min- to urea-linked carbohydrate synthesis by Pinter in 1964 imal protecting group requirements and a compatibility with a (Table 12).67 It was recognized that the treatment of glycosyl azide variety of amine nucleophiles are hallmarks of the transformation. 39 with triphenylphosphine provides the iminophosphorane

With reactions involving substituted or hindered amine which could readily undego aza-Wittig reaction with CO2 or carbon M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44 29

Table 12 Symmetrical urea disaccharide synthesis proceeding through carbodiimide O PPh O CS (AcO) N 3 (AcO) N 2 n 3 n PPh3 Et2O (or CO2) 39, 116-118 Phosphine Imine O H O O H H (AcO) N C N O (OAc) 2 (AcO) N N O (OAc) 68, 120-123 n n n n AcOH, C6H6 Carbodiimide Urea O

Entry b-azide Phosphine imine (yield) Carbodiimide (yield) Symmetrical urea (yield)

AcO AcO H H Ac AcO AcO O AcO O O OAc N N N O 1 AcO 3 85% 86% AcO OAc AcO AcO 39 O 68 (98%) AcO OAc AcO OAc OAc H H Ac AcO O O O 2 82% Not determined N N O AcO N3 AcO OAc AcO AcO 116 O 120 (67%)

AcO O H H Ac AcO N O O AcO 3 AcO N N O OAc 3 AcO 89% 47% AcO 117 AcO O 121 (97%) AcO AcO Ac AcO O O H H HN AcO AcO N N O OAc 4 AcO N3 Not determined 85% AcO OAc AcNH AcNH 118 O 122 (83%) AcO O Ac OAc AcO AcO O O N AcO Ac OAc Ac Ac O 3 AcO O O O O OAc AcO O OO N N O O O 5 AcO AcO 70% 12% AcO O H H Ac OAc 119 AcO AcO OAc 123 (50%)

AcO CH3-N=C=O AcO AcO PPh3 O 41 O H2O AcO O H H 39 AcO AcO N N AcO N PPh3 AcO N C N Me AcO Me AcO 124 AcO 125 22 AcO O

Scheme 21. 1-Methyl urea glucoside synthesis via carbodiimide intermediate. disulfide to generate the symmetrical carbodiimide. After treatment with aqueous acetic acid, this carbodiimide is subsequently transformed into urea-linked pseudodisaccharide 68 (98%, entry 1). This approach has been successfully applied to a number of Table 13 Urea glycosides from reaction of iminophosphorane with amine monosaccharide and disaccharide b-azides 116–119 (entries 68 2-5). A pseudotetrasaccharide 123 (entry 5) with a urea-bridge O PPh3 O (AcO) N (AcO) N PPh joining two cellobiose units was synthesized using this novel n 3 n 3 approach, though the yield of carbodiimide and subsequent urea Amine, CO was significantly reduced in comparison to the monosaccharide 2 coupling reactions. The glycosyl phosphinimine 124 (Scheme 21) was also reported O H R (AcO) N N by Bannister to react efficiently with methyl isocyanate 41 to gen- n R' erate carbodiimide 125.45 The resulting carbodiimide intermediate 33, 126-130 O

125 was readily convertible to urea 22 after the addition of H2O. AcO AcO Me In addition to combining with itself in CO2, or isocyanate in the N AcO O H AcO O H absence of CO2, Pinter also reported glycosyl iminophosphorane to AcO N N AcO N N behave as a masked isocyanate in the presence of an amine nucle- AcO AcO O O 69 33 (92%) 126 (85%) ophile and CO2. This reactivity has been documented with both protected glucosyl and galactosyl donors using an assortment of OAc AcO Me AcO secondary amines (Table 13). N O H O H AcO N N Alternative to the Staudinger’s glycosyl iminophosphorane N N AcO AcO AcO AcO O route, glycosyl carbodiimides and their corresponding urea prod- O ucts can be accessed from the reaction of glycosyl isothiocyanates 127 (74%) 128 (94%) 70,71 with alkyl phosphine imines (Tables 14 and 15). Glycosyl isoth- Me Me AcO AcO iocynates, such as 131, are readily available in multi-gram quantity O H O O H AcO AcO N N Me from the isothiocyanation of glycosyl halides or aminosugars.52,72 AcO N N AcO AcO AcO Me An aza-Wittig-type reaction using glycosyl isocyanate 131 and O O 129 130 protected azide 139 was employed in the synthesis of calystegine (86%) (85%) 30 M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44

73 Table 14 B2 analogue 142 (Scheme 22). After generating the carbodiimide Reaction of glycosyl isothiocyanates with alkyl phosphine imines 140 and converting it to urea 149, a series of steps, including a AcO 1) phosphine imines ring-expansion, provided the 6-oxa-nor-tropane urea glycoside O AcO toluene, rt, 1 h Urea (22, 136-138) 142. AcO N C S AcO 131 2) H2O 70-90% The effect that the reversal of roles would have in the coupling reaction was investigated, as well (Scheme 23). Using protected Entry Phosphine imine Urea glucosyl iminophosphorane 124 and methyl isothiocyanate 148, no reaction was observed after several days in toluene. Only by N PPh AcO Me 3 AcO O H H refluxing the reaction mixture was the carbodiimide 125 able to 1 132 AcO N N Me be obtained in 40% yield. It is hypothesized that the electron-with- AcO 22 O drawing properties of pyranose ring of 124 helps to stabilize the N PPh AcO negative charge on the anomeric phosphinimine nitrogen which 3 O H H O AcO N N significantly attenuates its nucleophilic character. By way of con- AcO AcO O 2 AcO AcO trast, the same electron-withdrawing effect should enhance the AcO O AcO 133 AcO OMe reactivity of the glycosyl isothiocyanate by increasing the electro- 136 AcO OMe philic character. N PPh3 AcO O H H A similar reaction to one of glycosyl isothiocyanates with alkyl O AcO N N Me O AcO iminophosphorane has been employed by Garcia Fernandez in the O Me AcO O O synthesis of urea-linked oligosaccharides.74 An example can be O O O 3 Me 137 Me seen in Scheme 24, in the iterative approach to b-(1?6)-linked 134 O O Me O O urea pseudotrisaccharide 155. In these reactions, nucleophilic Me Me O amine is reacted with glycosyl isothiocyanate to first generate Me the thiourea-linked pseudooligosaccharide (e.g., 153), prior to its Me O N PPh3 AcO O O H H O conversion to glycosyl carbodiimide 154, and then urea 155. AcO N N O Me Me O AcO Glycosyl isothiocyanates have been shown to react efficiently O 4 AcO O Me with alkyl iminophosphoranes to generate glycosyl carbodiimides. 135 O O O 138 O The carbodiimide intermediates are readily converted to glycosyl Me Me Me Me urea. The electron-withdrawing nature of the pyranose ring en- hances the electrophilic character of isothiocyanate, allowing reactions with alkyl phosphinimines to be carried out at room

Table 15 Reactions of oligosaccharide isothiocyanate and alkyl phosphine imine AcO 1) phosphine imine AcO O AcO Urea (144-147) O O AcO N C S 70-90% AcO AcO toluene, r.t., 1h 143 AcO 2) H2O

AcO AcO AcO O AcO AcO O AcO O H O O H H AcO O H AcO N N N AcO N AcO AcO O AcO AcO AcO AcO 145 O O 144 O AcO O AcO OMe Me O AcO O O AcO Me O AcO O Me O O H H O AcO O AcO N N O Me AcO AcO O AcO Me AcO O H H AcO O Me AcO O O AcO N N Me 146 O AcO Me AcO Me 147 O

AcO AcO AcO AcO OAc AcO O N3 H OAc O 131 N C N OAc 1% TFA in N C N O O O OAc OAc OAc aq. acetone O H OAc OAc O OAc Me PPh3 O Me 65% O O 90% Me O O 139Me 140 Me 141 Me

O HO OH HO N C N OH H O HO OH HO HO OH 142

Scheme 22. Synthesis of calystegine B2 analogue. M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44 31

Me-N=C=S (148) No Reaction a common glycal precursor 156 (see Section 3c for a-selective syn- AcO toluene, rt, >72 h thesis) and a- and b-anomeric selectivity in the transformation is AcO O N PPh controlled by the nature of the palladium-ligand catalyst system. AcO 3 AcO AcO 124 148 In the first step of the procedure for attaining the b-urea glyco- Me-N=C=S ( ) AcO O N C N Me toluene, reflux, AcO sides, a neutral Pd(II) catalyst is employed to facilitate a concerted 2h AcO 125 (40%) [3,3]-sigmatropic rearrangement of glycal trichloroacetimidate 156 to the corresponding glycal trichloroacetamide 157 Scheme 23. Limited reactivity of glycosyl phosphinimines and alkyl (Scheme 26). The optimal conditions for the b-selective rearrange- isothiocyanates. ment (Table 16) are 2.5 mol % Pd(PhCN)2Cl2, 2.5 mol % tris(trime- thoxyphenyl)phosphine ligand 161 (TTMPP), and 10% of the temperature. In the reverse reaction, the electron-withdrawing ef- additional sigma donor ligand (either salicylaldehyde L-1 or fect reduces the nucleophilic character of glycosyl iminophosphor- 4-chloro-2-trifluoroacetylphenol L-2) at room temperature. anes and this compound will not react as readily with alkyl These conditions were subsequently screened on a number of isothiocyanate. However, the glycosyl iminophosphorane can react different glycal substrates that were populated with a variety of with carbon dioxide and nucleophilic amine to generate the corre- protecting groups (Table 16). In general, the rearrangement was sponding glycosyl carbodiimide. The symmetrical carbodiimide much faster with r-donor ligand L-2 (4-chloro-2-trifluoroacetyl- can be achieved as well from the glycosyl iminophosphorane by phenol) than with salicylaldehyde L-1 (Table 16), and the desired reacting itself with carbon dioxide in the presence of H2O. Overall, glycal acetamides 164–167 were obtained with higher b-anomeric because none of these reaction types proceeds through an selectivity. It was determined that substrates possessing a cyclic oxocarbenium intermediate, all maintain stereochemical integrity 4,6-acetal protecting group would undergo sigmatropic rearrange- at the anomeric center. ment to produce high yields (74–95%) of glycal trichloroacetamides 162–166 and moderate to good levels of b-selectivity 2.6. Glycal trichloroacetamides (a:b = 1:5–1:10). It is hypothesized that a cyclic protecting group on these glycal trichloroacetimidates restricts them in the tg con- Nguyen has recently developed his own method for the conformations, thus facilitating a cyclization-induced rearrangement 75 struction of glycosyl urea employing the palladium-catalyzed gly- (Scheme 26). On the other hand, substrates containing acylic pro- cal trichloroacetimidate rearrangement in its key step tecting groups at C4 and C6 would rearrange in a less b-selective (Scheme 25).75 What is unique about this type of approach is that manner because there is a competition between the concerted 75 both anomers of the rearrangement product can be achieved from rearrangement and ionization-recombination pathways.

H2N O N HO 150 N3 3 HO O H H AcO O AcO N N N C S HO AcO 1) NaOMe, MeOH AcO OMe HO O AcO 149 AcO S 2) 1,3-propanedithiol, 98% 151 HO HO OMe Et3N, MeOH 99% AcO 131 AcO O H H H2N AcO O AcO N N O H H NCS HO N N AcO AcO O H H HO 1) Ac 2O, pyridine HO O AcO AcO S N N HO HO HO O 2) HgO, CH Cl /H O 152 S HO 153 OH HO 2 2 2 99% S HO OMe HO 40% HO OMe AcO AcO O O H H AcO N C N AcO N N AcO O AcO O H H AcO AcO N C TFA, H2O AcO AcO AcO N O N N O AcO O 154 OAc AcO 76% OH AcO AcO 155 O AcO AcO OMe HO OMe

Scheme 24. Iterative synthesis of urea-linked pseudotrisaccharide.

RO Neutral OH RO H O 1) OsO ,NMO RO RO O Pd(II) O 4 O H H RO N RO N N Cl3C O HO R' Ligand CCl3 2) Cs2CO3,R'-NH2 156 NH 157 H 158 O

Scheme 25. Glycal-based approach to urea glycosides.

H HN N CCl 3 RO H O Neutral Pd(II)/L O CCl3 O RO O N 156 O O RO RO CCl3 RO RO H PdLn PdLn H 159 160 157

Scheme 26. Overman-type 3,3-sigmatropic rearrangement of glycal trichloroacetimidate. 32 M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44

Table 16 Pd(II)-catalyzed rearrangement of glycal trichloroacetimidates to b-acetamides 2.5 mol % Pd(PhCN) Cl , O 2 2 H O (RO)n 2.5 mol % TTMPP 161 O O (RO)n N Cl3C 10 mol % L-1 and/or L-2, CCl3 H NH CH2Cl2,rt,3-6h 162-168

H O O O Ph O H O H O H O N O O N O O N O CCl CCl CCl3 3 3 H 162 H H 164 163 L-1 95% (1:10) L-1 99% (1:5) L-1 90% (1:8) L-2 92% (1:10) L-2 90% (1:5) L-2 82% (1:14) t-Bu Cyc Si O Si O H O t-Bu O H Cyc O O O N O N CCl3 CCl3 165 H 166 H L-1 83% (1:4) L-1 74% (1:5) L-2 92% (1:8) L-2 80% (1:6)

PivO H O TrO H O PivO O N PivO O N CCl3 CCl3 H H 167 168 L-1 96% (1:2) L-1 84% (1:1) L-2 92% (1:3)

OH O OMe OH O CF 3 MeO P H 3 OMe Cl TTMPP (161) Salicylaldehyde (L-1) 4-Chloro-2-Trifluoroacetylphenol (L-2)

Me morpholine generates a 1,2-cis diol 171 (i.e. mannose), (2) it is hypothesized that the N-mannosyl trichloroacetamide is then con- Me O O O 0.5 mol % TMSOTf verted to glycosyl isocyanate 172 in situ in the presence of cesium Cl C O Decomposition 3 o CH2Cl2,0 C carbonate, and (3) upon exposure of isocyanate 172 to amine NH 169 nucleophile, and following acetylation, provides the corresponding Me b-glycosyl ureas 175–177 (Table 17) in 50–66% yield over three O steps. Toluene-d8 Me O H O O N While the urea glycosides are isolated in good to moderate 120 oC, 6 h CCl 170 β 1 3 yield, this approach beneﬁts from having a high atom economy, ( only) H (three of the atoms in the original trichloroacetimidate group are

Scheme 27. Lewis acid activation and thermal rearrangement of glycal incorporated into the final urea target), and that the rearrangement trichloroacetimidate. of the glycal trichloroacetimidate is also stereoselective, (both b- and a-trichloroacetamide (see Section 3c) are attainable from a common glycal trichloroacetimidate precursor). The nature of the palladium–ligand catalyst, rather than substrate, in these reac- To determine if a Lewis acid catalyst would be able to facilitate tions determines anomeric selectivity in the acetamide product. the rearrangement, a control experiment was conducted using There are a few drawbacks to this approach, in that the use of toxic 0.5 mol % TMSOTf (Scheme 27). This condition would only lead to osmium tetroxide is employed to functionalize the glycal and that the decomposition of starting material; suggesting that a Lewis- the scope of the transformation is limited to substrates incorporat- acid catalyzed activation strategy is not conducive to the ing a 1,2-cis-diol functional group (i.e., mannose substrates) rearrangement because of the acid-labile nature of the glycal tri- because of the dihydroxylation step. chloroacetimidate. To further establish the concerted nature of the palladium-catalyzed reaction, thermal rearrangement of 169 2.7. Glycosyl carboxylic acids was carried out to produce nearly quantitative yield of 170. How- ever, this reaction would take 6 h to reach completion at 120 °C. The final donor type utilized in the synthesis of b-urea glyco- The second step involved in Nguyen’s urea glycoside synthesis sides is the glycosyl carboxylic acid. Ikegami and coworkers have is the functionalization of the N-glycal trichloroacetamide 165.A reported that glucuronic acid 177 (Scheme 28) is able to undergo one-pot, three-step procedure was investigated; (1) dihydroxyla- a Curtius rearrangement while refluxing in benzene in the pres- tion of acetamide 165 with osmium tetroxide and N-methyl ence of piperidine 179 as a nucleophilic amine, triethylamine, M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44 33

Table 17 Functionalization of glycal trichloroacetamide and conversion to glycosyl ureas t-Bu t-Bu OH Si O O Si O O t-Bu O H OsO t-Bu O H Cs CO O N 4 O N 2 3 CCl HO DMF 165 3 NMO 171 CCl3 H H t t-Bu -Bu Si OAc Si OH t O H H t-Bu O R'-NH2 -Bu O O O O N N N C=O AcO R' HO then Ac2O 172 O H 175-177 H

Entry Amine Urea Yield t-Bu Si OAc Benzylamine t-Bu O O H H 1 O N N 66% (3 steps) 173 AcO Bn 175 O t-Bu OAc Si O Pyrrolidine t-Bu O H 2 O N N 50% (3 steps) 174 AcO 176 O t-Bu Me Si OAc N Methylpiperazine -Bu O O H 3 O N N 56% (3 steps) 91 AcO 177 O

In spite of the limited report of this carboxylic acid reaction O OH type being used in the synthesis of b-linked urea glycosides, it rep- O N resents an innovative and markedly different approach from other BnO + DPPA (2 equiv.) O BnO trends in the field. A potential drawback, however, is the limited HN BnO N Et N(2equiv.) OMe H 3 O substrate scope. Because of the refluxing conditions required for benzene BnO 178 179 (1 equiv.) BnO the Curtius rearrangement, substrates may be restricted to using 70% BnO 180 OMe robust protecting groups to limit decomposition and other side products. Additionally, acid-labile protecting groups may not be Scheme 28. Curtius rearrangement and conversion to urea. applicable under these conditions. and diphenylphosphoryl azide (DPPA) to afford C6-urea 180 in 70% 3. a-Linked urea glycosides yield.76 To further extend this method for installing urea at the anomer- While the last section was dedicated to the thorough examina- ic center, carboxylic acid donor 183 (Scheme 29) was prepared tion of the number of methodologies available for installing from the conversion of the lactone 181 into primary alcohol b-linked urea at the anomeric center of carbohydrates, there are 182,77 followed by oxidation with TEMPO. far fewer options to highlight in this section for the synthesis of The carboxylic acid 183 underwent the Curtius rearrangement the a-linked urea glycosides. There are two primary reasons for in the presence of several amine nucleophiles 184–187 (Table 18) the challenges associated with the stereoselective construction of and provided good to excellent yields of the desired b-linked urea a-glycosyl urea: (1) while the electron deficient sp- and 2 glycosides 188–191. For instance, coupling of carboxylic acid 183 sp - hybridized nitrogen atoms are known to display a preference to glycine 184 (entry 1) and lysine 185 (entry 2) afforded neo-gly- for axial (a) orientation at C1 due to anomeric effect, others (–NH2 coconjugates 188 and 189 in 93% and 84%, respectively. This meth- and –NHAc) prefer to reside in sterically less-congested equatorial 48 od is also suitable with iminosugar nucleophile 187 (entry 4), and (b) position. The order of axial preferentiality is as follows: 78 b-urea linked pseudodisaccharide 191 was obtained in 87% yield. –NPPH3 > –OAc > –N3 > –NHCOCF3 > –NHCOAr > –NH2 = –NHAc); The reactions, in general, were found to reach completion within and (2) few reactions which generate glycosyl urea are likely to 1 h, though the poor nucleophilicity of thymine analog 186 (entry proceed through an oxocarbenium intermediate. Therefore, the 3) extended this requirement to 13 h. Nevertheless, the desired relative energy differences of the half-chair conformations of the urea 190 was still isolated in 82% yield. transition state will not contribute to the anomeric distribution

MPMO MPMO MPMO O O TEMPO OH BnO BnO BnO O BnO BnO NaClO, NaClO O OH 2 BnO O BnO BnO Phosphate buffer BnO 181 182 183 CH3CN

Scheme 29. Preparation of glucosyl carboxylic acid derivative from lactone. 34 M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44

Table 18 Urea glycoside synthesis via curtius rearrangement of glycosyl carboxylic acid

R-NH2 MPMO 183 BnO O H H DPPA (2 equiv.) BnO N N R Et3N(2equiv.) BnO benzene 188-191 O

Entry R-NH2 Product Reaction time (h) Yield (%) MPMO BnO O H H N N CO Et 1 H2N-Gly-OEt 184 BnO 2 0.5 93 BnO 188 O MPMO BnO O H H BnO N N 2 H2N-Z-Lys-OMe 185 BnO 1.0 84 O NHZ 189 CO2Me O Bz NBz MPMO O N O HN O BnO O H 3 BnO N N 13 82 BnO 186 Me 190 O H OBn N OBn BnO OBn OBn MPMO OBn 4 O H 0.5 87 BnO OBn BnO 187 BnO N N BnO 191 O

AcO AcO AcO H ,Pd/C,Et N O AcO O 2 3 AcO + AcO O AcO AcO NH2 AcO THF AcO AcO AcO N NH2 3 192 α 40 β 42 (α) ( ) ( )

N C O

AcO AcO AcO O AcO O H H N N AcO + AcO AcO H AcO HN N O 193 (α) 29 (β) O

Scheme 30. Multiple products from the reduction of a-glycosyl azide and reaction with alkyl isocyanate. of the product. Both of these factors limit preference for the a-urea with cyclohexyl isocyanate 43 to generate a mixture of glycosyl glycoside and increase the difficulties associated with achieving it urea products, b-29 and a-193. Furthermore, the individual over the b-isomer; hence, the fewer number of topics to discuss anomers were found to be extremely difficult to separate. here. Methodologies in this section are able to either circumvent Therefore, an alternative pathway had to be developed to attain a these limiting factors, or to exploit them, in constructing the pure a-urea product. a-glycosyl urea linkage. In following the same procedure used for generating b-isocyanide from the b-glycosyl azide (see Section 2c), reduction 3.1. Glycosyl isocyanates of a-azide 42 was carried out with hydrogen and Pd/C, followed by the N-formylation of the amine products, to provide forma- Ichikawa was the first to develop an effective preparation of mides a-194 and b-195 (Scheme 31) in nearly quantitative yield. a-urea glycosides.57 In the previous section (see Section 2c), we The compounds 194 and 195 were stable enough to purify, yet observed how reduction of the b-glycosyl azide generates comprised an inseparable mixture at this stage. Subsequent b-glycosyl amine as the sole product in the reaction. The same dehydration of the glycosyl formamides using triphosgene conditions, for instance, when applied to the reduction of provided 89% of isocyanides 196 and 63 as a 4:1 a/b-mixture of a-glycosyl azide 42 (Scheme 30), produce a mixture of b-amine anomers which was easily separated by column chromatography. 40 and a-amine 192. These amines subsequently react directly With pure a-isocyanide 196 (Scheme 31) in hand, mild oxidation M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44 35

AcO triphosgene, AcO O AcO AcO Et N, CH Cl AcO O 1) H2,Pd/C,Et3N AcO AcO O H 3 2 2 42 (α) N H AcO 63 AcO AcO AcO 2) AcOCHO HN H AcO 89% N C O 97% 194 (α) 195 (β) (4:1 α/β) 196 (α) O

NH2 AcO AcO AcO O O 64 pyridine N-oxide AcO AcO 196 (α) AcO AcO H cat. I2, AcO HN N 3Α mol sieve N 91% 197 (α) C 198 (α) O O

Scheme 31. Synthesis of a-isocyanide and conversion to a-urea glycoside.

Table 19 Conversion of a-isocyanide into a-urea glycosides AcO AcO pyridine N-oxide, O O AcO AcO cat. I ,3Α mol sieve AcO 1 AcO 2 AcO R AcO 1 2 then, R R NH HN N 2 N C 204-209 R 196 (64, 199-203) O

Entry Amine nucleophile Equiv. of nucleophile Product Yield (%) AcO H2N AcO O AcO 64 1 3.0 AcO H 91 HN N 204 O AcO HN AcO O AcO 2 199 3.0 AcO 89 HN N 205 O Me AcO AcO O H2N AcO 3 3.0 AcO H 91 200 HN N 206 O Me Me AcO O Me AcO AcO Me Me HN 4 3.0 AcO 91 201 Me HN N Me Me 207 O Me

Me O NH2 AcO O AcO O Me Me O AcO O O AcO H O Me 5 O O 1.4 HN N 84 202 Me Me 208 O O O Me Me O AcO AcO O H N OMe AcO 2 NHCbz 6 NHCbz 0.5 AcO H 86 HN N 203 OMe 209 O O

using pyridine N-oxide and catalytic I2 was carried out to gen- and showed no signs of epimerization at C1 during oxidation erate the a-isocyanate 197, which was trapped in situ using or the addition step. cyclohexylamine 64. The resulting a-glycosyl urea 193 was The condition was screened using a variety of amine nucleo- obtained in 95% yield (69% overall yield from the a-azide 42) philes 64 and 199-203 (Table 19), and in each case, was able to 36 M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44

AcO 3.2. Glycosyl carbodiimides AcO O AcO pyridine N-oxide, AcO AcO O 1) AcO In 2002, Györgydeák would report that the reaction of b-gluco- cat. I2,3Α mol sieve AcO AcO HN O OAc AcO syl azide 39 (Scheme 33a) with trimethylphosphine in CH2Cl2 2) H2O N C 210 (92%) HN would proceed at room temperature to provide the corresponding 196 O OAc glycosyl iminophosphorane.79 When this intermediate was reacted AcO with carbon disulfide (step 2, Scheme 33a), the symmetrical AcO carbodiimide product 212 was attained in 80% yield. There were pyridine N-oxide, 1) AcO O Α difficulties, however, involved in applying this procedure with cat. I2,3 mol sieve AcO 196 AcO Ac the a-glucosyl azide 42 (Scheme 33b), and led to a complex H O AcO 40 HN N OAc mixture of products. 2) O AcO O In 2006, Bernandi reported that the a-tetrabenzylated glucosyl AcO NH2 O OAc 211 (89%) azide 213 (Scheme 34) was successful in reacting with trimethyl AcO OAc phosphine to generate iminophosphorane 214. This compound Scheme 32. Synthesis of a-(1?1)-linked urea pseudodisaccharides. was then reacted with benzyl isocyanate 215 in situ to generate the a-linked carbodiimide 216.80 During purification of 216, how- generate the desired a-urea glycoside in excellent yield ever, a small amount of conversion to the corresponding a-glycosyl (84–91%). The reaction was subsequently applied to the synthesis urea 217 (Scheme 34) was observed. a-(1?1)-urea linked pseudodisaccharide 210 and 211 (Scheme 32). In order to improve the yield of a-glycosyl urea 217 It was found that with slight modification to the procedure, (addi- (Scheme 34), the procedure was modified by treatment of the tion of H2O to the a-isocyanate instead of amine), the symmetrical resulting carbodiimide intermediate with aqueous hydrogen per- N,N-di-a,a-D-glucopyranosyl urea 210 could be achieved in 92%. oxide. This slight modification was sufficient to fully convert the Alternatively, N,N-di-a,b-D-glucopyranosyl urea 207 was attained carbodiimide (e.g., 216) to the glycosyl urea 217 (Scheme 35)in if b-glycosyl amine 40 was added to the isocyanate instead of 71% yield, and exclusively as an a-isomer. The reaction was applied H2O. This tunable reactivity is reminiscent of that observed with to the fully benzylated a-galactosyl azide 218, as well, with a the b-glycosyl Iminophosphoranes in the presence of CO2 (see similar yield and anomeric selectivity (70% yield, a-only). Section 2e). To test the scope of the reaction, a variety of different electro- Ichikawa has done a remarkable job of investigating the reac- philic species were screened with with a-glucosyl azide 213 tivity and synthesis of the glycosyl isocyanides. These substrates under the optimized conditions (Table 20). In the reaction with are robust precursors for the synthesis of a-urea glycosides and isocyanates 220 and 224 (entries 1 and 2), the desired a-glucosyl produce very high yields after oxidation to the corresponding iso- ureas 225 and 228 were obtained in 74% and 67%, respectively, cyanate and reaction with nucleophilic amine. The only short- and only formation of the a-anomer was observed. However, this coming with this approach is that the reaction is stereospecific new protocol is not suitable in the reaction with propyl isocya- instead of selective, and that there is only moderate preference nate 223 (entry 4). During purification of the reaction mixture for generating the a-isocyanide in the reduction of the a-azide using silica gel chromatography, epimerization at C1 of the urea (4:1 a/b-ratio). The extra step requirements and loss of material product 227 (entry 4) would occur. Quite unusual, as well, is that from this approach comprise only a minor drawback to what is a slow equilibration to a 3:1 a/b-mixture of urea products would otherwise an exceptional method for synthesizing both a- and occur in CDCl3 over the course of four days at room temperature. b-glycosyl ureas. This result suggests that the simple a-alkyl urea derivates may

AcO 1) PMe3,CH2Cl2 AcO AcO O O AcO Ac N AcO (a) AcO 3 2) CS2 AcO N C N O OAc AcO O 39 (β) AcO OAc 212 (80%)

AcO O 1) PMe3,CH2Cl2 AcO Complex Mixture (b) AcO AcO 2) CS2 42 (α) N3

Scheme 33. Divergent reactivity of peracetylated a- and b-glucosyl azides.

BnO BnO O BnO BnO N C N 216 N C O (64%) BnO BnO 215 BnO O PMe3 BnO O BnO BnO BnO CH Cl ,rt. BnO BnO N 2 2 O 3 N PMe3 BnO 213 214 BnO BnO H HN N 217 (15%) O

Scheme 34. Generation of carbodiimide after reduction of armed a-glucosyl azide. M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44 37

BnO protecting groups one can populate their donor with so that it O 1) PMe3 BnO 217 71%, α only will retain its ‘fully-armed’ state, and therefore, its reactivity. This BnO 2) PhCH NCO BnO 2 may not appear problematic at first, as the ease of which the ben- N 213 3 3) HCO2H/ H2O zyl ethers can be removed is demonstrated,74 but it severely lim- its the utility of the transformation if it cannot be efficiently OBn BnO OBn BnO applied to differentially protected, and/or highly functionalized, 1) PMe O 3 O 70%, α only carbohydrate substrates. The reaction is also stereospecific, not BnO BnO 2) PhCH2NCO stereoselective, as the anomeric orientation of the azide starting BnO BnO H N3 3) HCO2H/ H2O HN N material is what is reflected in the urea product. 218 219 O 3.3. Glycal trichloroacetamides Scheme 35. One-Pot Conversion of benzylated a-glycosyl azides to a-urea glycosides. In 2008, Nguyen reported the first stereoselective synthesis of a- and b-glycosyl ureas from a common precursor, glycal trichloroacetimidate 156 (Scheme 36).75 As observed earlier (see Section 2f), not be configurationally stable in acid media. Isothiocyanate 222 a neutral Pd(II) catalyst and ligand system facilitates a concerted (entry 3) did not perform well in this system either, though the [3,3]-sigmatropic rearrangement of 156 into the corresponding poor compatibility of glycosyl phosphinimines and alkyl isothio- b-glycal trichloroacetamide 157 (Scheme 25). The same imidate cyanates has been established (Scheme 23, Section 2e). Finally, 156 undergoes a step-wise ionization–recombination pathway in the 1,4-diisocyanobutane 224 (entry 5) was reacted with the the presence of cationic Pd(II) catalyst to generate the a-trichloro- glycosyl phosphinimine generated from azide 210 to afford the acetamide 229 (Scheme 36) with excellent levels of anomeric a-urea linked pseudodisaccharide 228 in 60% yield and with selectivity. In conversion to the corresponding urea 232, glycal excellent levels of selectivity. acetamide 229 is functionalized with catalytic osmium(IV)tetrox- The methods in this section have demonstrated that the ide to generate the 1,2-cis diol-containing N-mannose trichloroac- benzylated a-glucosyl and a-galactosyl azides can be viable plat- etamide 230. This diol is then either acylated or directly converted forms for a-urea glycoside synthesis after a modified Staudinger to urea with nucleophilic amine in the presence of cesium phosphine imide reduction to the reactive glycosyl phosphini- carbonate. mine. This process benefits from being able to achieve the urea The a-selective rearrangement conditions have been applied to product in a single pot starting from the azide; bypassing the a number of glycal substrates (Table 21) using only 0.5 mol % additional steps and purifications that other methods require. loading of commercially available Pd(II) catalyst, Pd(CH3CN)4 There are, however, some limitations inherent to using this (BF4)2, with an additional 2 mol% sigma donor ligand L-1 or L-3. approach. The first is with the narrow range of available The desired a-glycal trichloroacetamides 233–240 were achieved

Table 20 Synthesis of a-linked urea glucosides from a-glucosyl azide BnO O 1) PMe3 BnO α-Linked Urea Products BnO 2) Electrophile (220-224) (225 - 228) BnO N 213 3 3) HCO2H/ H2O(2:1)

Entry Electrophile Equiv. electrophile Product Yield (%) a:b N C O BnO BnO O 220 BnO 1 1.2 BnO H 74 P97:3 HN N 225 O N C O BnO O Me BnO 221 BnO 2 1.2 BnO H 67 P97:3 HN N 226 Me O N C S 3 1.2 225 19 P97:3 222 Me BnO NCO BnO O 223 BnO 4 1.2 BnO H No report 3.2:1 HN N 227 Me O NCO BnO OBn O BnO BnO OBn N C O BnO O OBn 5 224 0.5 BnO 60 P97:3 HN NH HN NH 228 O O 38 M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44

RO OH RO Cationic RO RO O O RO O Pd(II) H OsO4,NMO RO Cl3C O O HO Ligand 156 229 HN 230 HN CCl3 NH CCl3 O RO OH RO OH O O Cs2CO3 RO R'-NH2 RO HO HO H 231 N 232 HN N C R' O O

Scheme 36. Stereoselective a-glycosyl urea synthesis from glycal trichloroacetimidate.

Table 21 a-Selective rearrangement of glycal trichloroacetimidate with cationic Pd(II)-catalyst O O (RO) 0.5 mol % Pd(CH CN) (BF ) H n O 3 4 4 2 (RO)n O Cl3C 2mol%L-1 and/or L-3, 233-240 HN NH CH2Cl2,rt,1h yield (α:β) CCl3

H t O -Bu O O Ph O O O H O O H O H Si O t-Bu O O O O O H HN HN HN O 233 CCl3 234 CCl3 235CCl3 236 HN L-1 75% (11:1) L-1 81% (8:1) L-1 89% (10:1) L-1 81% (11:1) CCl3 L-3 96% (12:1) L-3 93% (6:1) L-3 87% (14:1) L-3 90% (14:1)

t-Bu Si Cyc t-Bu O PivO TrO O Si O O Cyc O PivO H PivO H O O O H O O H O O HN HN HN 237 HN 238 239 240 CCl3 CCl3 CCl3 L-1 70% (9:1) CCl3 L-1 91% (8:1) L-1 96% (23:1) L-1 82% (α -only) L-3 88% (13:1) L-3 96% (7:1) L-3 92% (30:1)

OH O OH O

H CF 3

L-1 Salicylaldehyde L-3 2-Trifluoroacetylphenol

in good to excellent a-selectivity and high yield. It is interesting to group in a-glycosyl ureas 246–249, even after the acetylation step. note that during the investigation of the b-selective, concerted Overall, the desired glycosyl ureas 243–249 were isolated in rearrangement using neutral Pd(II)-catalyst (Table 16, Section 2f), moderate to good yield (50–70%) over the one-pot, three-step the substrates lacking the cyclic protecting groups did not perform procedure with complete retention of stereochemical configura- as well as those that had them. Quite the opposite was observed tion at the anomeric carbon (See Table 22). with the cationic Pd(II) catalyst and the acetamide 239 incorporat- A series of carbohydrate amine nucleophiles (mannose 250, glu- ing the acyclic protecting groups, where the a-selectivity obtained cose 150, and galactose 202) were screened, as well, to generate was significantly higher than with the other substrates. Also nota- the corresponding a-urea-linked pseudodisaccharides 252–254 ble is the rearrangement of galactal substrate, where 82% of the tri- (Table 23) in moderate to good yield (50–75%). The condition chloroacetamide 240 was achieved as the exclusive a-anomer. was also applied with glucosamine substrate 251, generating the The resulting trichloroacetamides 236 and 239 were functional- first a-(1?2)-linked urea pseudodisaccharide 255 in 68% yield ized and reacted with a series of amines to generate the a-glycosyl (57% yield overall starting from glycal trichloroacetimidate). It is ureas (Table 2). The outcome of the reactions using primary amines interesting to note that the silyl protecting group was hydrolyzed (entries 1–3) was similar to those obtained with the cyclic second- during the course of the reaction, resulting in the isolation of the ary amines (entries 4–7), though there was enhanced performance fully acetylated urea product 255. observed in the coupling with N-methylpiperazine 91 (entry 6). This reaction type represents the first stereoselective synthesis The pivaloyl group in glycal trichloacetamide 239 (entries-7) was of a-glycosyl urea and uses a cationic palladium(II)-catalyzed step- hydrolyzed during the reaction, resulting in the free C4 hydroxyl wise rearrangement (ionization–recombination pathway) of glycal M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44 39

Table 22 Functionalizing the a-glycal trichloroacetamide and conversion into a-urea glycosides RO OAc O 1) OsO4,NMO,acetone (RO) H RO O n 2) Cs CO ,DMF,RR'NH O 2 3 2 AcO R HN HN N 236, 239 3) Ac2O, DMAP, pyridine R' CCl 243-249 3 O

Entry a-Tricholroacetamide Amine Urea Yield (%) (3 steps) t-Bu t-Bu OAc Si O Si O t-Bu O t-Bu O O H O 1 173 Benzylamine AcO 50 236 O HN 243 HN NHBn CCl 3 O t-Bu Si OAc t-Bu O O O 2 236 241 n-Butylamine AcO 58 244 HN NHBu

O t-Bu Si n-Bu t-Bu O O O 3 236 64 Cyclohexylamine AcO 59 245 HN NHCyc

O TrO TrO OAc O PivO H HO O O AcO 4 174 Pyrrolidine 58 239 HN 246 AcN N CCl3 O TrO OAc HO O AcO 5 239 179 Piperidine 61 247 AcN N

O TrO OAc O HO Me AcO N 6 239 91 Methylpiperazine 70 248 AcN N

O TrO OAc HO O AcO N N 7 239 238 Pyridylpiperazine 51 AcN N 51% 249 O

trichloroacetimidate to the corresponding a-glycal trichloroaceta- 3.4. Glycosyl trichloroacetamides mide in its key step, in high yield and with excellent a-selectivity. The reaction benefits from extremely low catalyst loading In an effort to address the limitations of their glycal-based (0.5 mol %), high atom-economy, and complete retention of stereo- methodology, the Nguyen group has recently developed an chemical integrity at the anomeric center during the functionaliza- alternative route to the stereoselective synthesis a-glycosyl urea tion of the glycal and subsequent conversion to the desired starting from glycosyl trichloroacetimidate 256 (Scheme 37).81 It glycosyl urea. The reaction is tolerant of multiple functional groups was envisioned that a transition-metal catalyst would be able to and responded positively to every nucleophilic amine that was effectively promote the ionization and rearrangement of a screened in the reaction. The utility of this approach is somewhat trichloroacetimidate leaving group and facilitate selective access limited, however, in that it takes additional steps to functionalize to the a-glycosyl trichloroacetamide 257 (Scheme 37). This new the glycal (using toxic osmium tetroxide) and the reaction has a approach provides access to a variety of carbohydrate a-linked very limited scope in that it can only be applied to the synthesis urea glycosides. of a-urea mannoside substrates via dihydroxylation of the glycal In light of the previous success using cationic palladium(II) cata- intermediates. Nevertheless, this is the first procedure that is able lyst in the rearrangement of glycal trichloroacetimidates, the same, to selectively achieve a- and b-urea glycosides from a common commercially available catalyst, Pd(CH3CN)4(BF4)2, was screened precursor. first with glycosyl imidate 259,(Table 24). When this catalyst did 40 M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44

Table 23 Synthesis of unsymmetrical a-urea pseudodisa charides from a-glycal trichloroacetamide t t-Bu -Bu Si OH Si t t O -Bu O -Bu O O O O H 1) OsO4, NMO, acetone HO O H 2) Cs2CO3,DMF,R'-NH2 HN N 236 HN 252-255 R' CCl 3 O

Entry Amine Urea Yield NH t-Bu Me O 2 OH Si O Me O t-Bu O O O O Me HO O 202 O H O 1 O HN N 75% (2 steps) Me 252 Me Me O O O Me Me

NH2 t-Bu OH Si O BnO O t-Bu O BnO O HO O OMe 2 BnO OMe H OBn 50% (2 steps) 150 253 HN N

O OBn BnO OBn t-Bu H2N BnO O Si OH t-Bu O BnO O O OMe HO O OMe 3 230 H BnO 57% (2 steps) 254 HN N

O OBn BnO AcO AcO OAc O AcO OAc AcO O AcO AcO OAc H2N H 4 251 255 AcN N O 68% (3 steps) O AcO OAc AcO

O O O (RO)n (RO)n (RO)n LnM(II) Cs CO RO RO 2 3 RO H O CCl3 HN CCl3 R-NH HN N 256 2572 258 R' NH O O

Scheme 37. Synthesis of a-glycosyl urea from a-glycosyl trichloroacetimidate.

Table 24 a-Selective transition metal catalyzed rearrangement of glycosyl trichloroacetimidate BnO BnO O O BnO Catalyst, CH Cl BnO BnO 2 2 BnO BnO 25o C, 1-14 h BnO O CCl3 HN CCl 259 260 3 NH O

Entry Catalyst Catalyst loading (mol %) Time (h) Yield a:b

1 Pd(CH3CN)4(BF4)2 5 5 NR —

2 Pd(PHCN)2(OTf)2 5 1 86 10:1

3 Pd(PHCN)2(OTf)2 2 1 85 10:1

4 Ni(PHCN)2(OTf)2 2 0.25 84 11:1

5 Ni(p-F-PhCN)4(OTf)2 2 0.25 88 10:1

6 Ni(p-MeO-PhCN)4(OTf)2 2 0.25 90 10:1

7 Ni(dppe)(OTf)2 2 1 94 14:1 8 AgOTf 6 14 72 5:1 9 TMSOTf 4 2 72 8:1

10 BF3OEt2 4 6 65 4:1 M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44 41

Table 25 Cationic Ni(II)-catalyzed rearrangement of glycosyl trichloroacetimidates O O (RO)n 2mol% (RO)n Ni(dppe)(OTf)2 O CCl3 261-266 HN CCl3 CH Cl ,25oC, 1-3 h 2 2 Yield (α:β) NH O

BnO BnO O O AllylO BnO O BnO AllylO BnO BnO AllylO TIPSO BnO HN CCl HN CCl 3 HN CCl3 3 261 262 263 91% (10:1) O 90% (20:1) O 87% (15:1) O

PivO OH OBn Me O BnO O Ph O O O BnO BnO BnO BnO BnO HN CCl HN CCl 3 HN CCl3 264 3 265 266 O 74% (18:1) O 91% (α only) 72% (α only) O

Table 26 Conversion of a-glycosyl trichloroacetamides into a-glycosyl ureas. O O (RO)n (RO)n Cs2CO3,DMF,R-NH2

HN CCl3 o HN NHR 260, 263-265 25 C, 10 - 24 h 267-270 O O

Entry R-NH2 Trichloroacetamides Glycosyl ureas Yield (%) Me BnO O N H BnO 1 265 BnO 88 174 267 HN N

O BnO O BnO N BnO 2 H 263 268 HN N 94 179 O OBn HN N Me Ph O O O BnO Me 3 91 264 N 75 269 HN N

O BnO HN N BnO O N BnO N N 4 242 260 BnO 93 HN N 270 O

not facilitate a reaction, attentions were turned to the presumably control experiments were conducted using silver triﬂate alone (en- more reactive palladium(II)-species (entry 2) generated in situ from try 8) or Lewis acids which are commonly employed in the activation

Pd(PhCN)2Cl2 and AgOTf. To their excitement, treatment of 259 with of glycosyl trichloroacetimidate (entries 9 and 10). While each was this new catalyst, Pd(PhCN)2(OTf)2 yielded 86% of the desired able to facilitate some degree of reaction, the yield, selectivity, and acetamide 260 as a 10:1 a/b-mixture of anomers. Further the reaction time in these experiments was not on par with those ob- experimentation identiﬁed that Ni(dppe)(OTf)2 (2 mol %) was the tained using the nickel catalyst, Ni(dppe)(OTf)2. optimal catalyst for the rearrangement of 259 (entry 7), and glycosyl With optimized rearrangement conditions in hand, Nguyen set acetamide 260 was obtained in 94% yield with excellent a-selectiv- out to determine the scope of the reaction by applying it to a vari- ity (a:b = 14:1). To determine if Lewis Acid activity was responsible ety of substrate types with a range of protecting groups (Table 25). for the reactivity observed using the nickel catalyst, or to determine The reaction proceeded smoothly using glucose, xylose, and quino- if residual silver triﬂate was catalyzing the reaction, a number of vose donors to generate the glycosyl acetamides 261–266 in high 42 M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44

Table 27 Synthesis of a-linked urea glycopeptides from a-glycosyl trichloroacetamides O O (RO)n (RO)n Cs2CO3,DMF,R-NH2

HN CCl3 o HN NHR 260, 264 25 C, 10 - 24 h 275-278 O O

Entry R-NH2 Trichloroacetamides Glycosyl ureas Yield (%)

H2N CO2Me BnO BnO O 271 BnO 1 260 BnO H 85 HN NCO2Me 275 O

CO2Me OBn Ph O Ph O NH O 2 BnO 272 2 264 H 88 276 HN N Ph

O CO2Me Me BnO O CO Me BnO Me 2 BnO Me 3 NH 260 BnO H 80 2 HN N 273 277 Me O CO2Me BnO Ph BnO O N BnO H OH Ph BnO 4 274 260 HN N 90 278 O Ph Ph OH

BnO BnO O BnO BnO KSCN, (C4H9)4NBr BnO O O BnO BnO N C S BnO BnO BnO Cl BnO 279 280α N C S 281β BnO 85% 6:1 (α/β)

Scheme 38. Synthesis of a-glycosyl isothiocyanate from a-glycosyl halide.

yield (72–91%) and with good to excellent a-selectivity By applying the transition-metal catalyzed rearrangement of the (a:b = 10:1–>20:1). Even the installation of the bulky O-TIPS group glycosyl trichloroacetimidate substrates to the corresponding at C2 did not curb the selectivity of the transformation, providing glycosyl acetamide intermediate, Nguyen has reduced his synthesis the corresponding glycosyl trichloroacetamide 262 in 90% yield of a-urea glycosides to a two-step procedure in comparison to and 20:1 a/b-ratio. glycal trichloroacetimidates. This method can be applied to a wide Continuing on with the synthesis of a-glycosy ureas, a selection variety of carbohydrate substrates (not limited to mannose sub- of the acetamides 260 and 263–265 was reacted with secondary strates as in the case with glycal trichloroacetimidates). Further- amine nucleophiles in the presence of cesium carbonate (Table 26). more, this approach beneﬁts from a high atom economy, with The reactions proceeded with retention of the stereochemical three of the atoms in the original trichloroacetimidate leaving integrity at the anomeric center and afforded the desired glycosyl group ending up in the ﬁnal urea structure. The procedure is high ureas in good to excellent yield (75–93%); most notably in entry 4, yielding and compatible with a variety of protecting groups and where acetamide 260 was coupled to N-methylpiperadylpiper- amine nucleophiles and provides the a-glycosyl urea products with azine 242 to generate urea 270 in 93% yield (82% yield overall excellent levels of a-selectivity, which is controlled by the nature of starting from glycosyl trichloroacetimidate). the nickel catalyst rather than the nature of the substrates or the The reaction was further applied in the synthesis of a-urea- protecting groups on the substrates. The only drawback to this linked amino acid glycoconjugates, as well (Table 27). Glycine approach to a-urea glycosides is that because the rearrange- 271 (entry 1) and valine 273 (entry 3) were successfully coupled ment consists of the activation of a leaving group at C1, it will to glucosyl trichloroacetamide 260 to provide neo-glycopeptides likely proceed through an oxocarbenium intermediate. Therefore, 275 and 277 in 85% and 80%, respectively. The L-proline derivative a non-participating group must be installed at C2 to avoid it 274 (entry 4) performed well under the same condition; affording from potentially interfering with the a-selectivity of the the a-linked urea neo-glycopeptide 278 in excellent yield (90%). rearrangement. M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44 43

O HO O H2N BnO BnO O BnO O O 282 HO OBn BnO HO BnO BnO HgO BnO 280α H HN N O BnO H HN N 96% 283 98% 284 S R HO OBn O HO HO O HO HO HN N OH 34% OH overall yield O OH trehazolin (285) HO

Scheme 39. Synthesis of trehazolin.

3.5. Glycosyl isothiocyanate volved with many of the other routes available. This reaction is

highly atom-economical and is also able to be carried out in H2O, While there is limited report of the a-glycosyl isothiocyanate or solvent-free, using carbohydrate melt technology. Ichikawa being used in the synthesis of a-urea glycosides, it is appropriate and König have done a fantastic job at bringing this reaction into to mention the reaction type, here, as it retains a-configuration the 21st century, and due to the recent interest vested in develop- at the anomeric center during the urea-forming step. The a-isothi- ing reaction strategies with reduced impact on the environment; ocyanate 280a is obtained in 6:1 a/b-ratio from the reaction of this type of reaction is likely to become more common in processes glycosyl chloride 279 and potassium thiocyanate with tetrabutyl- involved in the conversion of feedstock into platform chemicals. ammonium bromide catalyst (Scheme 38).82 In the synthesis of Another approach to b-urea that benefits from being carried out trehazolin 285 (Scheme 39), Chiara and coworkers react isothiocy- in H2O is the nucleophilic opening of the trans-fused cyclic carba- anate 280 with nucleophilic amine 282 to generate a-thiourea 283 mate ring of 1,2-oxazolidinone sugars with nucleophilic amine. before converting it to urea 284 with mercuric oxide.83 In 3 steps This stereospecific approach to b-urea glycoside formation gener- from urea 284, trehazolin 285 was achieved in 34% yield, overall. ates urea at the anomeric carbon without proceeding through an The limited use of this approach for the synthesis of a-urea glyco- oxocarbenium intermediate and forms the b-urea glycoside, exclu- sides is likely to result from difficulties in preparing the a-isothio- sively. Limited use of protecting groups and compatibility with a cyanates, where selectivity can be highly dependent on the variety of amines are highlights of this approach. Curtius rear- substrate and choice of protecting groups. rangement of b-glycosyl acid derivates is another viable route to b-urea glycosides, though refluxing conditions may not be amena- 4. Conclusion and future outlook ble to late-stage synthesis. C1-hemiaminal coupling to electrophilic isocyanate species has been utilized to prepare b-glycosyl Replacing the C–O–C and C–N–C linkages of glycoconjugates urea scaffolds for the synthesis of b-dipeptide analogues, though and oligosaccharides with a more robust functionality is appealing the anomeric mixture of products can be extremely difficult to to the development of carbohydrate-based therapeutics and has separate at the urea-stage. The problem is addressed by coupling direct application in the development of anti-diabetic agents and glycosyl isocyanates with nucleophilic amine, as the orientation aminoglycoside antibiotics. The urea linkage at the anomeric cen- at the anomeric center is set prior to generating urea and allows ter is an interesting candidate for replacing native O- and N-glyco- for a single anomeric product to be formed. The method can be sidic bonds and has the potential to increase resistance against used to achieve both b-urea glycosides and a-urea glycosides from chemical and enzymatic degradation. These modified carbohydrate the b-glycosyl azide and the a-glycosyl azide, respectively. An structures have applications in asymmetric catalysis and are alternate route to urea from the glycosyl azide involves Staudinger widely used in the forest product industry. The glycosyl urea is a phosphine imide reduction to glycosyl phosphinimine. The phos- component of the glycocinnamoylspermidine and coumamidine phinimine can react with CO2 in the presence of water to generate antibiotics; compounds which exhibit broad-spectrum activity symmetrical carbodiimides, or with CO2 and amine under anhy- against Gram-negative cell lines and Gram-positive aerobes. These drous conditions to generate the unsymmetrical carbodiimide, natural products can only be isolated in micro-heterogenous both of which are readily converted to urea with aqueous acid or amount, or no longer at all in the case of glycocinnasperimicin D. hydrogen peroxide. The glycosyl carboodiimide is also accessible Thus, chemical synthesis will be necessary to facilitate further re- from the reaction of glycosyl isothiocyanates and alkyl phosphini- search of these compounds and their analogues. Synthesis of glyco- mines after conversion from the thiourea with silver oxide and syl urea, however, is by no means trivial. b-Urea products are H2O. An oxocarbenium intermediate is not generated in the reac- generally easier to attain than a-urea structures, and separation tions proceeding through carbodiimide intermediate, allowing of anomers can be problematic. This review has highlighted the the Staudinger phosphine imide reaction to be used to attain the strengths and shortcomings of the various methods available for a-glycosyl ureas from a-azides, as well. However, this reactivity the synthesis of urea-linked glycosides. is only observed when substrates are fully-armed with benzyl While there are very few reports for the construction of a-gly- ether protecting groups. Nguyen has reported the first stereoselec- cosyl urea, there are several more available for attaining the b-urea tive synthesis of both a- and b-urea glycosides from a common structure. The acid-catalyzed condensation of urea derivatives with glycal trichloroacetimidate precursor, where the nature of the aldohexose substrates is able to simplify the synthesis of b-urea palladium catalyst/ligand system controls selectivity in the key glycosides by avoiding the protection and deprotection steps in- rearrangement step. While the ability to generate both a- and 44 M. J. McKay, H. M. Nguyen / Carbohydrate Research 385 (2014) 18–44 b-urea glycosides from a common starting material is highly desir- 26. For a recent review: Spanu, P.; Ulgheri, F. Curr. Org. Chem. 2008, 12, 1071–1092. able, this method is limited to mannose substrates and requires the 27. Schoorl, M. N. Akad. Wetensch. Amsterdam 1900, 410. 28. Schoorl, M. N. Rec. Trav. Chim. 1900, 19, 398. use of toxic osmium tetroxide to functionalize the glycal. In Ngu- 29. Schoorl, M. N. Rec. Trav. Chim. 1903, 22, 31–37. yen’s second transition-metal catalyzed approach to a-urea glyco- 30. Hewitt, J. A. Biochem. 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