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Recent Advances in Synthesis of Bacterial Rare Building Blocks and Their Applications

Journal: Natural Product Reports

Manuscript ID: NP-HIG-01-2014-000003.R1

Article Type: Highlight

Date Submitted by the Author: 13-Feb-2014

Complete List of Authors: Emmadi, Madhu; IIT Bombay, Department of Chemistry; Kulkarni, Suvarn; IIT Bombay, Deapartment of Chemistry

Page 1 of 11 Natural Product Reports

NPR RSCPublishing

HIGHLIGHT

Recent Advances in Synthesis of Bacterial Rare Sugar Building Blocks and Their Applications Cite this: DOI: 10.1039/x0xx00000x

Madhu Emmadi and Suvarn S. Kulkarni*

Received 00th January 2012, Covering: 1964 to 2013 Accepted 00th January 2012

DOI: 10.1039/x0xx00000x Bacteria have unusual glycans on their surfaces which distinguish them from the host cells. These

www.rsc.org/ unique structures offer avenues for targeting bacteria with specific therapeutics and vaccines. However, the rare are not accessible in acceptable purity and amounts by isolation from natural sources. Thus, procurement of orthogonally protected rare sugar building blocks through efficient chemical synthesis is regarded as a crucial step towards the development of glycoconjugate vaccines. This Highlight focuses on recent advances in the synthesis of the bacterial deoxy amino hexopyranoside building blocks and their applications to construct various biologically important bacterial O‐glycans.

1. Introduction Bacterial glycoproteins and contain rare deoxy 1- amino sugars which are not present on the human cell surface. 6 6 X 4 These important structural differences help to differentiate 5 O between the pathogen and the host cell and can be exploited for HO 3 2 1 OH target specific drug discovery and based vaccine AcHN development.7 However, these rare sugars are not available from natural sources. Chemical synthesis of orthogonally X= NH2,NHAc,OH,O protected rare sugar building blocks has therefore received considerable attention. The bacterial atypical sugars include, 2-acetamido-4-amino- H2N AcHN HO 2 2,4,6-trideoxy-D- (AAT), 2,4-diacetamido-2,4,6- O O O 3 4 trideoxy-D-galactose (DATDG), bacillosamine (Bac), N- HO HO HO 5 acetyl fucosamine (FucNAc), and D-xylo-6-deoxy-4- AcHN OH AcHN OH AcHN OH ketohexosamine (DKH)6 (Fig 1). These sugars form key components of a variety of bacterial glycoconjugates AAT FucNAc (zwitterionic , glycoproteins and DATDG oligosaccharides). There is growing evidence that the ability of the pathogen to express these unusual sugars is linked with O pathogenesis. A detailed account of the bacterial source, the AcHN O O type of sugars present and their associated disease is HO HO categorically presented in a recent review article by Dube and AcHN OH AcHN OH coworkers.1a In this Highlight we discuss the methods developed for chemical synthesis of the rare sugars. DKH Application of the rare building blocks in the Bac synthesis of various bacterial O-glycans is also presented. The unusual deoxy amino sugars depicted in Fig. 1 share Fig. 1 Structures of various bacterial rare sugar building blocks. some common structural features such as, the presence of equatorially oriented C2-NHAc, C3-OH and C5-CH3 groups. carbohydrate precursors are reported in literature. The structural variation of the C4 functionality alone results in several different sugars. For example, AAT bears an axial C4- 2. Classical carbohydrate approaches NH2 group, while DATDG and Bac have axial and equatorial C4-NHAc groups, respectively. DKH has a keto functionality A number of reports for the synthesis of rare at the 4-position. Owing to their biological importance, several building blocks using carbohydrate precursors have been routes starting from a variety of and non-

This journal is © The Royal Society of Chemistry 2013 J. Name., 2013, 00, 1‐3 | 1 Natural Product Reports Page 2 of 11 ARTICLE Journal Name documented in literature. The key steps involved in these deoxygenation approaches are deoxygenation at C-6 position and incorporation 1 X= Br, I, OMs on rsi 2 R= Ts, Ms, Tf, H of amine or hydroxyl functionality at C-4 and/or at C-2. ve In X R1=OBn,OMe,SEt, SPh, OMP RO O R2=N3,NHAc,NPhth 2.1 AAT and DATDG PMP PO O R1 n R2 sio D D O er -Glucosamine ( -GlcNH2) is the most suitable precursor for D-Glucosamine Inv O O AAT and DATDG as the requisite equatorial C2 amino BnHN 1 1 OH 2 function is already in place. Not surprisingly, most synthetic A MsO O procedures, for AAT and DATDG start from readily available Stepwise B O inversion with azide E O 8-14 RHN D-GlcNH2 (Fig 2, path A). These methods typically involve 6-Deoxy-D-glucal D-Mannosan O Azidonitration a C-6 deoxygenation via conversion of C-6 hydroxyl to 2 HO OH corresponding mesylate, iodide or bromide and their subsequent AcHN CD displacement with hydride. Introduction of amine functionality HO O 1 N R= H, AAT deoxygenation at C-4 position with inversion is usually achieved by SN2 R O edu R= Ac, DATDG 2 ctio O on displacement of C-4 hydoxyl (Mitsunobu conditions), mesylate, n rsi 1 ve I SEt In HN tosylate or triflate with azide or phthalimide as nucleophiles. In TfO O O OTBDPS 1984, Lönngren and coworkers accomplished the first synthesis Azidonitration Cl3C 2 N3 of an orthogonally protected AAT building block by employing D- the corresponding 4,6-dimesylate to achieve these two steps.9 D-Glucosamine van Boom and co-workers explored two different routes for the Fig. 2 Synthetic strategies employed for AAT and DATDG derivatives. synthesis of AAT and DATDG building blocks starting from D- mannose by stepwise introduction of amine functionality at C-4 (Fig 2. path C). Recently, an intramolecular displacement strategy was employed to introduce amine functionality at C-4 followed by at C-2 positions. In their first approach, D- 17 mannosan was transformed into DATDG15 via a multistep position of hexopyranosides. van der Marel and co-workers sequence involving 2,3-O-p-methoxy benzylidene acetal used 3-O-trichloroacetimidate to displace the C-4 triflate on 6- formation, triflation of 4-OH and azide displacement of C4 O- deoxy D-glucosamine scaffold to get to the oxazoline 18 triflate, followed by regioselective oxidative ring opening of intermediate (Fig 2, path D) whereas Bundle and co-workers 2,3-O-p-methoxy benzylidene acetal at O2, and finally triflation used 3-O-benzyl carbamate to displace the C-4 mesylate of 6- of 2-OH and subsequent azide displacement of C2 O-triflate deoxy-D-glucal (Fig 2, path E) followed by azidonitration to (Fig. 2, path B). For the synthesis of AAT derivative,16 introduce the C2-azido functionality. stereoselective reduction of C4-oxime of mannoside, followed 2.2 D-Fucosamine by conversion to glycal derivative and subsequent The most suitable precursor for the synthesis of D-fucosamine azidonitration to install the C2-azide function was carried out is D-galactosamine, since it is the C-6 deoxy analogue of the

Madhu Emmadi received his B. Suvarn Kulkarni received his Sc. from Chaitanya Degree M.Sc. (1993) and Ph.D. (2001) College, Warangal in 2007. in Organic Chemistry from and M. Sc. from School of University of Pune in 2001. Chemistry, University of After his Ph. D., he pursued his Hyderabad in 2009. He then post‐doctoral research in the joined the group of Professor laboratory of Professor Shang‐ Suvarn S. Kulkarni at IIT Cheng Hung at Academia Bombay for Ph. D. studies. His Sinica, Taipei on chemical research is focused on synthesis of glycans via one‐pot development of novel routes for the synthesis of bacterial rare protection of sugars. In 2005, deoxy‐amino sugars and their applications in total synthesis of he moved to University of California Davis to work with various bacterial glycoconjugates. Professsor Jacquelyn Gervay‐Hague and was engaged in glycosyl iodide mediated one‐pot synthesis of glycolipids. He returned to India in late 2008 and held a faculty position at IACS Kolkata prior to joining the Indian Institute of Technology Bombay in 2009. He was promoted to Associate Professor in 2012. His current research interests include devising newer ways for efficient chemical synthesis of complex glycoconjugates implicated in various infectious diseases as well as cancer.

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same. C-6 Deoxygenation of D-galactosamine derivative was 19 carried out using Barton-McCombie procedure or via 2 ion 20-23 ers reduction of C-6 iodide with a hydride source (Fig 3, path Inv AcO D D O A). Since -galactosamine is quite expensive, -glucosamine is AcO more often employed instead for this purpose (Fig 3, path B). Azidonitration 1 1 D-Fucal This transformation involves the preparation of C-6 bromide or 1 deoxygenation 2 deoxygenation C le ub n ion o sio mesylate and their displacement with hydride and followed by rs D er 2 nve nv X C-4 inversion of mesylate or triflate with benzoate as a I RO I i B A O 24-26 27 28 O H N O RO nucleophile. Carreira and Shibaev groups reported 2 PO NapO OR1 HO R OH R 1 elegant procedures for the synthesis of D-fucosamine N3 NH2 2 D-Bacillosamine X= Br, I, OTs, OMs derivatives by aminohydroxylation or azidonitration of D-fucal, R= OTf, R1= TBDPS R= Ts, Ms, Tf D-Galactosamine respectively (Fig 3, path C). More recently, Adamo and co- R1=OBn,OMe D R =NHAcorNPhth 29 2 workers carried out a double inversion at C-2 position of D- 2 D-Glucosamine 1 deoxygenation (6-deoxy galactose) by oxidation-reduction, triflation n rsio nve and azide displacement of the 2-O-triflate to access the D- I TfO X fucosamine derivative (Fig 3, path D). O P= Bz, X= OBz for 1 D-Galactosamine PO OBn P= H, X= I for 2 NHAc

on Fig. 4 Synthetic strategies for D‐bacillosamine derivatives. rsi ve deoxygenation In R O 2 X 1 1 O 3. De novo approaches RO O R2O PO R1 B 35-46 NHR2 C D-Fucal Over the years, de novo approaches have been extensively D-Glucosamine HO employed for the synthesis of variety of carbohydrates. R1=R2=Ac X= Br, I, OTs, OMs O R R =Isopropylidene Although most of the rare sugars can be accessed via classical HO 1 2 R= Ts, Ms, Tf OH Azidonitration or NH carbohydrate approaches, this usually involves lengthy routes to R2= Ac, Cbz, Me 2 Aminohydroxylation deoxygenation obtain orthogonally protected building blocks, while shorter D-Fucosamine D versions provide amino sugars bearing the participating groups HO X O A at C-2 position which cannot be used for α-glycosylation. To O O PO O OR overcome these problems, de novo approaches have been R1 NHR2 Double inversion via OH explored for synthesis of various rare sugars. oxidation-reduction and D-Fucose In 1994, a de novo route was first explored by Polt and co- D-Galactosamine N displacement of OTf 47 3 workers to synthesize N-methyl- D-fucosamine (Fig 5). In this R= -(H2C)3NHCbz method, O'Donnell's Schiff base 1 underwent chelation- Fig. 3 Synthetic strategies for D‐fucosamine derivatives. controlled reduction-alkylation using Bu2AlH- iBu3Al/CH3CH=CHLi to afford a trans alkene (dr = 20:1, separable by column), which was subjected to Sharpless dihydroxylation followed by acetylation to obtain the triacetate 2.3 D-Bacillosamine (Bac) 2 in 70% yield over 2 steps. Reduction of the imine and its C-4 Inversion of D-fucosamine with amine source gives the subsequent methylation in the presence of formaldehyde access to Bac. Accordingly, transformation of D- afforded the N-methyl derivative, which upon desilylation gave 30,31 32 33 glucosamine, D-galactosamine and D-fucal to the D corresponding -fucosamine derivatives as described above, 1. Bu2AlH−iBu3Al and subsequent nucleophilic displacement of their C-4 chloride, O 2. CH3CH=CHLi OAc OAc 70%, dr 20:1 mesylate, tosylate or triflate derivatives with azide nucleophile TBDMSO OMe TBDMSO 3. K2OsO2(OH)4 afforded the D-bacillosamine derivatives (Fig 4, paths A, B and NCPh2 Ph2CN OAc K3CO 3,K3Fe(CN)6 4. Ac O, pyridine C). All the classical carbohydrate approaches described so far 1 2 2 involve C-6 deoxygenation first and followed by C-4 inversion. 70% dr 6:1 Very recently, Imperiali and co-workers34 employed a reverse 1. NaBH3CN, OAc OAc HO approach via first carrying out a C-4 inversion on a D- CH2O 1 1. Swern oxidation 2 4 4 5 O galactosamine derivative with azide followed by C-6 iodide HO 3 5 1 2. 4% aq. HF HO 2 OAc 2. cat. KCN, MeOH 3 OH Ph2HCN Ph HCN displacement with simultaneous reduction of the azido group CH3 30% yield 2 under hydrogenation conditions (Fig 4, path D). over 4 steps Me 3 4 Fig. 5 De novo synthesis of N‐methyl‐D‐fucosamine by Polt and co‐workers.

This journal is © The Royal Society of Chemistry 2012 J. Name., 2012, 00, 1‐3 | 3 Natural Product Reports Page 4 of 11 ARTICLE Journal Name the primary alcohol 3. Oxidation of 3 and tandem cyclization reduced with DIBAL in a 1,2-manner and the so-formed under deacetylation conditions provided the N- unstable intermediate was subjected to acidic work-up to obtain methylfucosamine derivative 4. the rearranged α,β-unsaturated ketone intermediate. Reduction 48,49 Quintela and co-workers synthesized a D-fucosamine of the keto group under Luche conditions afforded glycal 13. derivative by employing a syn Aldol type reaction between 1,3- The free C3-OH group of glycal 13 was acetylated to afford 14. dioxolane-4-carboxaldehyde 5 and lithiated Schöllkopf’s bis- The introduction of the equatorial azido group at C-2 was lactim ether 6 (Fig. 6). The so-formed alcohol intermediate 7 carried out under azidonitration and azidoselenation conditions. was methylated and a selective cleavage of the bis-lactim ether In both the cases, mixtures of inseparable diastereomers followed by Cbz protection of the formed amine afforded 8. involving the configuration at C2 were obtained. For 15a, the Subsequent acid of the isopropylidene group, in situ mixture was separated during conversion to both a glycosyl lactonization and partial DIBAL reduction of the lactone gave a trichloroacetimidate and a glycosyl N- mixture of the and forms of D-fucosamine, phenyltrifluoroacetimidate. which upon hydrogenolysis of the Cbz group gave D- Seeberger’s group developed yet another de novo route to 52 fucosamine derivative 9 as a mixture of pyranose . synthesize D-fucosamine, Bac and DKH starting from L- Garner aldehyde by using chelation-controlled organometallic EtO additions (Fig 8). L-Garner aldehyde 16 was treated with 1. THF O 2. aq. NH Cl, 69% propynyl magnesium bromide and the formed alkyne was EtO Li 4 O N O N O N selectively reduced with red Al to give the trans allylic alcohol N 69% over 2 steps O OEt OEt which was subsequently O-alkylated to afford E-olefin 17. The 5 6 OH 7 acetonide group in 17 was cleaved to free the primary hydroxyl, 1. NaH, MeI, 95% which was oxidized with DMP to generate aldehyde 18. The 2. 0.25 N HCl, HO O NHCbz 1. TFA, H O, 88% EtOH, 80% 2 5 key intermediate 18 was subjected to Sharpless dihydroxylation O 4 3 O 1 4 2 CO Et and the obtained product was cyclized to give the desired D- 5 2 2. DIBAL MeO 2 3. CbzCl, Na CO , 1 3 2 3 OMe 3. H ,Pd/C,HCl H2N OH 99% 2 fucosamine derivative 19 as the major product (dr = 5:1, 85% over 2 steps 8 9 separable by column). The free 4-hydroxyl of 19 was oxidized Fig. 6 De novo synthesis of D‐fucosamine by Quintela and co‐workers. with DMP to give the DKH derivative 20. Alternatively, triflation of 19 and inversion with azide afforded D- bacillosamine 21. Similar reaction sequence on the D-Garner 50,51 53 Recently, Seeberger and co-workers developed an aldehyde led to respective L-fucosamine derivative. elegant and convenient method for the synthesis of AAT building block starting from commercially available N-Cbz-L- 1. H3CCCMgBr, CuI, 1. p-TSA, MeOH, O Me2S, dr 20:1, 91% OR threonine 10 using Dieckmann cyclization as a key step (Fig 7). 2. DMP, CH Cl 2. Red Al, Et2O, 73% 2 2 H O O First, N-Cbz-L-threonine 10 was subjected to esterification and 68-78% 3. RBr, NaH BocN followed by O-acetylation to obtain acetate 11, which BocN underwent Dieckmann cyclization in the presence of LHMDS. 17a.R=Bn83% O 16 17b.R=Nap99% O The crude Dieckmann cyclization product was methylated BnO BocHN % 7 using K2CO3/Me2SO4 to give methoxy enone 12, which was 8 OAc , P 1. OsO4,NMO HO M 20 D OR 1 2. AcCl, Py 5 O 5 4 O 2 1. LHMDS, THF 4 CHO RO 1 OH O 1. AcCl, MeOH 3 3 2 2 2. NaHCO3, R= Bn 73% BocHN 1 O O NHBoc dr 2:1 OAc 1 2. Ac2O, NEt3,DMAP Me2SO4 2 . . T R= Nap 71% f OH 4 18 N 19 a 2 O 5 3 OMe dr 5:1 N , NHCbz 95% over 2 steps 73% over 2 steps P 4 3 , y N O NHCbz 7 D 3 10 % M NapO 11 F BocHN OAc 21 CbzHN CbzHN 1. Ac2O, Et3N, 5 1. DIBAL, THF; H DMAP, 90% Fig. 8 Seeberger’s de novo synthesis of orthogonally protected FucNAc, Bac and 4 O O 1 DKH. 2. NaBH ,CeCl HO MeO 4 3 3 2 O 77% over 2 steps 54 12 13 Very recently, Schmid and co-workers developed a convenient synthesis of a DATDG derivative starting from L- CbzHN CbzHN CAN, NaN3,CH3CN Garner aldehyde using the nitro Aldol reaction as a key step 67%, dr= 3.5:1 O O 15a.R=ONO (Fig 9). L-Threonine 22 upon sequential esterification, N- AcO 2 AcO or R 15b.R=SePh N3 bocylation, acetonide protection, reduction to primary alcohol PhI(OAc) ,TMSN , 2 3 AAT and its oxidation gave L-Garner aldehyde derivative 23, which 14 Ph2Se2, 68%, dr = 1:1 Fig. 7 De novo synthesis of orthogonally protected AAT building blocks by was subjected to the nitro Aldol reaction with 2- Seeberger and co‐workers. nitroacetaldehyde diethylacetal to give key intermediate 24 in a

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1. SOCl ,MeOH 2 1 Deoxygenation 2. Boc2O, NaHCO3 2-nitroacetaldehyde OH O 3. 2-Methoxy propene, O diethylacetal, LiOH, OH X CSA, 90% over 3 steps THF-H2O, 0 °C 6 OH 6 OH O H 4 5 5 O 4 O 4. LAH, THF, 95% NBoc 74% HO NH2 SPh SPh 5. IBX, EtOAc, 98% HO 2 RO 3 2 23 3 1 1 22 N 28 31 3 OH OEt Ac O, DMAP, 2 X=N , PhthN, OH, AcO OH OEt Raney nickel, 2 Acylation 3 H , MeOH, 98% pyridine, 92% 2 O OEt Rare sugars O OEt D-mannose R=AcorBz NBoc NH2 NBoc NO2 Regioselective inversions 24 25 reactions

OAc OEt AcHN 4 Inversion 2 5 1 H2O, 100 °C 4 4 2 O O 5 3 OEt 1 6 OH 6 OTf HO 3 2 OH 4 5 Triflation 4 5 NBoc NHAc 37% AcHN HO O TfO O RO SPh RO SPh 26 27 DATDG 3 2 1 3 2 1 30a R=Ac Fig. 9 De novo synthesis of DATDG by Schmid and co‐workers. 29a R = Ac 30b R= Bz 3 29b R= Bz Inversion 1 D- D-rhamnosyl bistriflate 5:1 diastereomeric ratio. Raney nickel reduction of nitro group Fig. 10 Our strategy for the synthesis of rare sugar building blocks. in 24 afforded amine 25 which was acetylated to give fully protected ketal 26. Global deprotection with water at high temperature without any additional catalysts, and concomitant Accordingly, tosylation of β-D-thiomannoside 28 and its O to N acetate migration under the prevailing conditions subsequent reduction with LAH afforded the D-rhamnosyl directly furnished the DATDG derivative 27 in 37% yield. thioglycoside 33, which upon regioselective 3-O acylation using dimethyltin dichloride as a catalyst furnished the requisite 4. Via a one‐pot double serial and double parallel D-rhamnosyl 2,4 diols 29a and 29b in good yields (Fig. 11). nucleophilic displacements of D‐rhamnosyl 2,4‐triflates OH OH Methods developed for the synthesis of appropriately protected HO TsCl, Py, RT TsO LiAlH4,THF HO O O SPh HO rare sugar building blocks through classical carbohydrate HO 84% HO SPh 72% approaches are lengthy. De novo approaches on the other hand 28 32 are novel and elegant but still involve separation of diastereomers. In the quest to develop a short and general OH OH RCl, Me SnCl ,DIPEA protocol to access all the rare sugars, we embarked upon a HO O 2 2 HO O HO SPh RO SPh systematic study to carry out nucleophilic displacements of O- triflates on the D-mannose scaffold. To begin with, we 33 29a. R= Ac 89% 29b. R=Bz92% established conditions to efficiently transform β-D- Fig. 11 Synthesis of D‐rhamnosyl 2,4‐diols. thiomannoside into orthogonally protected D-glucosamine and D-galactosamine building blocks via stepwise serial inversion at 55 C2 or C2 and C4, by azide and nitrite ions, respectively. We With the 2,4-diols 29a/29b in hand, we carried out sequential envisioned that the study can be extrapolarated to synthesize triflation and regioselective nucleophilic displacements of the rare sugars and that the methodology can be augmented to fit D-rhamnosyl 2,4-bis-triflates 30 with various nucleophiles to the one-pot paradigm. These efforts culminated into access the rare sugar building blocks. The optimized reaction development of a divergent protocol for the synthesis of all rare conditions and yields are depicted in Fig 12. The D-rhamnosyl sugar building blocks starting from a readily available β-D- 2,4 diols 29a and 29b were treated with Tf2O, pyridine and the thiomannoside 28 (Fig. 10). It was envisaged that through a so formed 2,4-bis triflates 30a and 30b were as such treated regioselective C6-deoxygenation and O3-acylation, D-mannosyl with excess sodium azide to give DATDG derivatives 34 and tetraol 28 can be converted to D-rhamnosyl 2,4 diol 29. 35 respectively in essentially one-pot manner (Fig. 12). A Triflation and concomitant nucleophilic displacements of the challenging task was to incorporate two different amine resulting 2,4-bis-triflates 30 with various nucleophiles (N3, functionalities at C-2 and C-4 positions to obtain AAT PhthN, OH, OAc) would then afford all the rare sugar building derivative 36. For this purpose, the D-rhamnosyl diol 29b was blocks in a one-pot manner, if the desired regioselectivity could converted into its bis triflate derivative 30b and the be attained by tuning reaction conditions. We anticipated that regioselective C-2 OTf displacement was carried out at -30 °C the C2-OTf in 30 being more accessible as compared to the C4- using 1.0 equiv of TBAN3. After the displacement of C2-OTf OTf would be more reactive due to stereoelectronic effects. was complete, C4-OTf was displaced with phthalimide salt to afford AAT derivative 36 in 57% yield over 3 steps.

This journal is © The Royal Society of Chemistry 2012 J. Name., 2012, 00, 1‐3 | 5 Natural Product Reports Page 6 of 11 ARTICLE Journal Name

N3 O AcO SPh N3 34 82% over two steps N3

N3 O O BzO SPh BzO SPh N3 N3 41 35 a , c, 49% over 5 steps e 85% over two steps ,

a a, b , b a, b

PhthN OH O a, c, d O N3 a, c, e, a, b HO O AcO SPh RO SPh BzO SPh N 3 N3 40 36 a , c f , e 57% over 3 steps 45% over 5 steps c, e c, a, a,

AcO HO O O HO SPh AcO SPh N3 N3 39 37 HO 62% over 3 steps 58% over 3 steps O BzO SPh N3 38 60% over 3 steps

a) Tf2O, Py, DCM, 2 h; b) NaN3,DMF,8h;c)TBAN3 (1.0 equiv), CH3CN, o o -30 C,20h;d)PhthNK,DMF,10h;e)TBANO2,1.5h;f)H2O, 65 C, 1.5 h

Fig. 12 Synthesis of various rare sugar building blocks.

To access the D-fucosamine derivatives 37 and 38, first C2- as key steps, readily accessible β-D-thiomannoside 28 could be 56,57 OTf of 30a and 30b was selectively displaced with TBAN3 and transformed into various rare sugar building blocks. The subsequently C4-OTf displacement with TBANO2 was carried strategy was also successfully extended to construct various out again in essentially one-pot manner. For the synthesis of 3- orthogonally protected D-galacto configured glycosamine hydoxy D-fucosamine derivative 39 we employed a different building blocks, which can be utilized for the synthesis of strategy, in which after the displacement of C2-OTf in 30a, bacterial glycans.58 water was added and the reaction mixture was heated. Under the conditions, the O-3 acetate displaced the C4-OTf in an 5. Applications to total synthesis of bacterial intra-molecular manner from the top face to give 3-hydroxy D- glycoconjugates fucosamine derivative 39 in 62% yield over 3 steps. To In 2007, van der Marel and co-workers17 synthesized a fully synthesize the bacillosamine derivatives 40 and 41, the 4- protected repeating unit of zwitterionic hydroxy fucosamine derivatives 37 and 38 were again treated A1 (ZPS A1) found in Bacteroides fragilis, in with Tf2O, pyridine and the 4-triflates were displaced with which the rare sugar AAT building block is attached to the D- azide. In this way, by employing highly regioselective and one- galactosamine unit through α (1→4) linkage. As shown in Fig pot, nucleophilic displacements of 2,4-bistriflates 30a and 30b 13, using iterative dehydrative glycosylation conditions

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Ph2SO Ph CbzHN 49,TMSOTf, CbzHN 1. DDQ, MeOH, 86% Tf2O 44 81%, α/β=5.5:1 2. 51,TMSOTf,90% O O TTBP 43 Tf2O TTBP O AcO AcO 3. a) TBAF, AcOH O N N3 O 3 b) F3CC(NPh)Cl, O CF3 42 O OBn Cs2CO3,82% 1h 16 h 1h 16 h BzO O 50 4. EtSH, TMSOTf, 96% O 48 NH O -60 °C -40 °C RT -60 °C ° N3 OBz -40 C RT NapO OTBS BzO O OiPr O N3 CbzHN OBz O CbzHN BzO O O TCAHN MeO2C O 53,DMTST, AcO O AcO N ZPS A1 TTBP, 58% 3 repeating AcO 45 (62%) N3 OBn N O unit of 3 O OBn B. f ragilis O OBn O O 1. Et3SiH, Zwitterionic BzO O O O TfOH, 92% polysaccharide A1 BzO O N3 OBz BzO O O N SEt repeating unit of 3 O OiPr 2. 46,Ph SO, O N3 OBz BzO 2 B. f ragilis BzO O Tf2O, 17% BzO O OiPr OBz O O OBz BzO MeO C O OBz O BzO 2 BzO O 47 52 MeO2C 54

Ph BzO OBn NPh OBz O OH MeO C HO O 2 O TCAHN BzO HO OiPr O O O O CF O O O 3 BzO NapO OTBS O O AcO BzO O OiPr N3 O OBz HO HO N3 OH MeO2C BzO OH OBz OBz N3 49 44 46 BzO 42 53 43 51 Fig. 13 Synthesis of ZPS A1 of B. fragilis by van der Marel and co‐workers. Fig. 14 Synthesis of ZPS A1 of B. fragilis by Seeberger and co‐workers.

(hemiacetal, Ph2SO and Tf2O), 45 was assembled, Schmidt and co-workers14 accomplished the total synthesis in which the hemiacetal 42 was pre-activated and coupled with of the complex (lipoteichoic acid) of acceptor 43 to give the corresponding donor which Streptococcus pneumoniae. This complex lipoteichoic acid was sequentially activated by freshly added Tf2O and coupled contains AAT building block which is attached to D- with acceptor 44 to give the desired trisaccharide 45 (62%) in a galactosamine through α (1→4) linkage similar to ZPS A1. one-pot manner. Regioselective reductive benzylidene ring The synthesis of key disaccharide 57 was achieved by the opening of 45 with Et3SiH and TfOH gave its corresponding 4- activation of imidate donor 55 with TMSOTf and its coupling hydroxy derivative and its coupling with pre-activated AAT with acceptor 56 in good yields (Fig. 15). The key disaccharide donor 46 gave the tetrasaccharide repeating unit of B. fragilis in with the proper protecting groups was successfully utilized for a low yield of 17%. In this synthesis, since the AAT donor is the total synthesis of lipoteichoic acid 58 of S. pneumoniae. more difficult to prepare, the corresponding glycosylation was carried out at the late stage. The low yield in the glycosylation PhthN PhthN was attributed to the steric bias in the trisaccharide acceptor and TMSOTf, CH Cl , O 2 2 BzO O 76% the apparent low reactivity of AAT donor 46. Very recently, N BzO NH 3 the AAT building block 46 was also utilized for synthesis of all N OTBDPS 3 HO OTBDPS O possible trisaccharide repeating units of the type 1 capsular CCl3 O O 59 55 polysaccharide of Streptococcus pneumonia, Sp1. BnO BnO N3 N3 57 SPh SPh Seeberger and co-workers51 employed a convenient 56 O O strategy to accomplish the total synthesis of ZPS A1 (Fig. 14). Me N P 3 OH O O Through a systematic study, they found out that the coupling of OH O O O Lipoteichoic Acid of AAT with D-galactosamine acceptor has to be performed at the Me N P HO NHAc 3 HO S. pneumoniae initial stage and not at the late stage, to get better coupling O O O O O O NHAc yields. Accordingly, AAT imidate donor 48 was activated with H N O C H 3 NHAc P 11 23 TMSOTf and coupled with the D-galactosamine derived HO O O C H O O 13 27 acceptor 49 to afford the desired key disaccharide 50 in good OH OH O O HO H3N O O O yields with a α/β ratio of 5.5:1. Cleavage of naphthyl group, HO HO O O HO O HO O incorporation of galactofuranside 51 at O-3 and anomeric OH O HO HO AcHN functional group transformation afforded the trisaccharide 52. Activation of thioglycoside 52 and its coupling with the 58 acceptor 53 gave the required tetrasaccharide 54 repeating unit Fig. 15 Synthesis of lipoteichoic acid by Schmidt and co‐workers. of B. fragilis.

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Recently, Adamo and co-workers29 developed a novel The major challenge involved in the synthesis of disaccharide strategy for synthesis of rare D-and L-FucNAc building blocks fragment of ZPS A1 is stereoselective α-coupling of AAT and further employed these building blocks for the synthesis of donor to the D-galactosamine acceptor. To achieve exclusive repeating unit of capsular polysaccharide isolated from α-selectivity, first the thioglycoside AAT derivative 36 was Staphylococcus aureus (Fig. 16). The crucial step in this converted to its corresponding glycosyl bromide, activated with synthesis was the α-fucosylation, which was achieved by AgOTf and coupled with the D-galactosamine acceptor 68 to coupling of donor 60 with acceptor 59 to obtain trisaccharide give the disaccharide moiety 6956, 58 of ZPS A1 in 81% yield as 61 in moderate selectivity (α/β 2.8:1). The undesired β-isomer a single α-isomer (Fig 18). A unique feature of this synthesis is was separated and the desired α-linked trisaccharide was that both the coupling partners 36 and 68 were derived from D- subjected to global deprotection to afford the repeating unit of mannose as described earlier. S. aureus 62. PhthN PhthN BnO 1. Br2,CH2Cl2 O O O BzO OR BzO SPh 2. 68,AgOTf, BnO O O N3 OTBDPS TMSOTf, CH2Cl2 N3 o O BnO N O N3 3ÅMS,-30 C O 65% 3 N3 O OR BnO O OAc 36 2h,81% HO O AcO SPh N 60 BnO 3 α/β= 2.8:1 59 61 HO OTBDPS N3 R= -CH2(CH2)2NHCbz 1. Pd-C, MeOH/H2O, AcOH O 69 2. Ac O, MeOH, H O AcO SPh O 2 2 O CCl3 40% Over 2 steps BnO N3 O N3 N3 BnO O OAc NH HO BnO O 68 60 O ZPS A1 repeating unit OR O of B. f ragilis O O NHAc HO NHAc NHAc Fig. 18 Synthesis of key disaccharide of ZPS A1 of B. fragilis. O OH HO O HO 3 62,R=-CH2(CH2)2NHAc In 1995, Stimson et al. isolated a glycoprotein from N. Fig. 16 Synthesis of the repeating unit of S. aureus by Adamo and co‐workers. meningitidis and they proposed the structure of glycoprotein where a unusual trisaccharide Gal-(β 1-4)-Gal-(α 1-3)-2,4- In 2007, Ito and co-workers60,61 synthesized the diacetimido-2,4,6-trideoxyhexose [Gal(β 1-4)-Gal(α 1-3)- heptasaccharide 67 isolated from C. jejuni, which is composed DATDH] is attached to the pili through L-serine. Since the of D-bacillosamine and repeating D-galactosamine building configuration at C-4 position of the rare sugar (DATDH) was blocks with branched D- (Fig 17). The key disaccharide not defined, it was pertinent to synthesize both the variants of 65 for this purpose was obtained by the coupling of glycosyl the trisaccharide. Having access to both the rare sugar building fluoride donor 63 with bacillosamine acceptor 64 and it was blocks (DATDG 34 and Bac 40) through our protocol, we 56,57 62 elaborated into heptasaccharide unit 67 of C. jejuni via step- synthesized the L-serine linked 73 and 75 as wise glycosylations. shown in Fig 19. The major difficulties encountered in this synthesis are incorporation of successive α-glycosidic bonds. PF PO OBn DATDG thioglycoside 34 was converted to its corresponding PF PO OBn CpHfCl2-AgClO4 O imidate, which was activated with TMSOTf and coupled with O BnO BnO L-serine derivative 70 using THF as the participating solvent to F 92% N3 N3 furnish α-isomer 71, exclusively (Fig. 19 A). However, N3 O 63 O OR N3 O coupling of bacillosamine derivative 40, under the same OR 65 N3 PFR= pentafluoro HO conditions, afforded a mixture of α/β isomers (1.8:1). After propionyl N3 NaOMe/MeOH 64,R=TBDPS quantitative trying several conditions, α-selectivity was finally achieved via an in situ anomerization protocol. Thus, thioglycoside 40 was HO OBn converted to corresponding α-glycosyl bromide and reacted AcHN O O with acceptor 70 in the presence TBAI to afford α-product 74, OSitBu(c−Hex)2 BnO R1O exclusively (Fig. 19 B). 3-O-Acetate in 71 and 74 was cleaved AcHN N3 and the so formed 3-OH acceptors were individually coupled 67,R =(GalNAc-α1-4) -GalNAc(Glc-β1-3)- N3 O 1 2 OR α1-4-GalNAc-α1-4-GalNAc-α1-3- O with β (1→4) digalactosyl chloride 72 using AgOTf as the N3 66 promoter to give the trisaccharides 73 and 75, respectively, in Fig. 17 Synthesis of heptasaccharide of C. jejuni by Ito and co‐workers. exclusive α-fashion. Global deprotection of the trisaccharides 73 and 75 afforded the final target molecules in good yields. Having access to various rare sugar building blocks through our protocol, we accomplished the synthesis of key disaccharide 69 of ZPS A1 and the first total synthesis of the α- L-serine-linked trisaccharides 73 and 75 of N. meningitidis.

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Notes and references A) N 1. NBS, THF, H2O a 3 N Department of Chemistry, Indian Institute of Technology Bombay, 2. CCl3CN, DBU 3 1. Et3N, MeOH O 70% O 80% Mumbai 400076, India AcO SPh 70 AcO N3 3. ,TMSOTf, o N3 2. 72,AgOTf, 34 -78 C, THF, 92% O -30 °C, 80% 1. a) D. H. Dube, K. Champasa and B. Wang, Chem. Commun., 2011, 47, 87-101. b) S. A. Longwell and D. H. Dube Current OAc Opinion in Chemical Biology, 2013, 17, 41-48. c) A. AcO CbzHN CO2Me O OBz 71 Adibekian, P. Stallforth, M.-L. Hecht, D. B. Werz, P. Gagneux AcO O O and P. H. Seeberger, Chem. Sci., 2011, 2, 337–344. d) S. G. AcO L-serine linked N BnO 3 trisaccharide of Wilkinson, Prog. Lipid Res., 1996, 35, 283-343. BnO O N. meningitidis 2. L. Kenne, B. Lindberg, K. Petersson, E. Katzenellenbogen and O E. Romanowska, Carbohydr. Res., 1980, 78, 119-126. b). B. N3 73 O Lindberg, B. Lindqvist, J. Lönngren and D. A. Powell, Carbohydr. Res., 1980, 78, 111-117. c). H. Baumann, A. O. CbzHN CO2Me Tzianabos, J.-R. Brisson, D. L. Kasper and H. J. Jennings, B) Biochemistry, 1992, 31, 4081- 4089. d). N. Bergström, P.-E. N O Jansson, M. Kilian and U. B. S. Sørensen, Eur. J. Biochem., O 3 1. Et3N, MeOH N3 1. Br2,CH2Cl2 AcO AcO SPh 80% 2000, 267, 7147-7157. e). C. Karlsson, P.-E. Jansson and U. B. N3 N3 2. 72,AgOTf, 2. 70,TBAI,CH2Cl2 O S. Sørensen, Eur. J. Biochem., 1999, 265, 1091-1097. 40 52% over 2 steps -30 °C, 80% 3. E. Stimson, M. Virji, K. Makepeace, A. Dell, H. R. Morris, G. OAc AcO CbzHN CO2Me Payne, J. R. Saunders, M. P. Jennings, S. Barker, M. Panico, I. O OBz 74 Blench and E. R. Moxon, Mol. Microbiol., 1995, 17, 1201- AcO O AcO O L-serine linked 1214. BnO trisaccharide of 4. N. M. Young, J.-R. Brisson, J. Kelly, D. C. Watson, L. Tessier, BnO N. meningitidis N3 O P. H. Lanthier, H. C. Jarrell, N. Cadotte, F. St. Michael, E. O 75 Aberg and C. M. Szymanski, J. Biol. Chem., 2002, 277, N3 O 42530-42539. 5. P. Castric, F. J. Cassels and R. W. Carlson, J. Biol. Chem., CbzHN CO Me 2 2001, 276, 26479-26485. OAc 6. a). R. A. C. Siemieniuk, D. B. Gregson and M. J. Gill, BMC HO AcO O OBz Infect. Dis., 2011, 11, 314-321. b) E. Pinta, K. A. Duda, A. AcO O O Hanuszkiewicz, Z. Kaczynski, B, Lindner, W. L. Miller, H. CbzHN CO2Me AcO BnO Hyytiäinen, C. Vogel, S. Borowski, K. Kasperkiewicz, J. S. BnO 70 Cl Lam, J. Radziejewska-Lebrecht, M. Skurnik and O. Holst, 72 Chem. Eur. J. 2009, 15, 9747-9754. Fig. 19 Synthesis of L‐serine linked trisaccharides of N. meningitides. 7. L. Morelli, L. Poletti and L. Lay, Eur. J. Org. Chem., 2011, 5723-5777. 6. Outlook of the field 8. A. Liav, I. Jacobsen, M. Sheinblatt and N. Sharon, Carbohydr. Although first synthesis of a rare sugar dates back to 1964, Res., 1978, 66, 95-101. synthesis of bacterial glycans has received much attention in 9. H. Lönn and J. Lönngren, Carbohydr. Res., 1984, 132, 39-44. past few years. The recent protocols have opened up new 10. A. Medgyes, E. Farkas, A. Lipták and V. Pozsgay, doorways to access the orthogonally protected rare sugar Tetrahedron, 1997, 53, 4159-4178. building blocks in high yields. With ready availability of such 11. H. Liang and T. B. Grindley, J. Carbohydr. Chem., 2004, 23, monosaccharide blocks, the assembly of antigenic bacterial 71-82. glycans can be carried out in an expedient manner. These advances together with the recent breakthroughs in immuno- 12. Y. Cai, C.-C. Ling and D. R. Bundle, J. Org. Chem., 2009, 74, glycobiology are expected to speed up the development of 580-589. glycoconjugate vaccines and specific drugs for various 13. C. M. Pedersen, I. Figueroa-Perez, J. Boruwa, B. Lindner, A. J. infectious diseases. Ulmer, U. Zähringer and R. R. Schmidt, Chem. Eur. J., 2010, 16, 12627-12641. 7. Acknowledgements 14. C. M. Pedersen, I. Figueroa-Perez, B. Lindner, A. J. Ulmer, U. Zähringer and R. R. Schmidt, Angew. Chem. Int. Ed., 2010, 49, This work was supported by the Department of Science and 2585-2590. Technology (Grant No. SR/S1/OC-40/2009 and Council of 15. J. P. G. Hermans, C. J. J. Elie, G. A. van der Marel and J. H. Scientific and Industrial Research (Grant van Boom, J. Carbohydr. Chem., 1987, 6, 451-462. No.01(2376)/10/EMR-II). M.E. thanks CSIR-New Delhi for a fellowship.

This journal is © The Royal Society of Chemistry 2012 J. Name., 2012, 00, 1‐3 | 9 Natural Product Reports Page 10 of 11 ARTICLE Journal Name

16. P. Smid, W. P. A. Jörning, A. M. G. van Duuren, G. J. P. H. 42. R. Lorpitthaya, S. B. Suryawanshi, S. Wang, K. K. Pasunooti, Boons, G. A. van der Marel and J. H. van Boom, J. Carbohydr. S. Cai, J. Ma, X.-W. Liu, Angew. Chem. Int. Ed., 2011, 50, Chem., 1992, 11, 849-865. 12054-12057. 17. a). L. J. van den Bos, T. J. Boltje, T. Provoost, J. Mazurek, H. 43. A. B. Northrup and D. W. C MacMillan, Science, 2004, 305, S. Overkleeft and G. A. van der Marel, Tetrahedron Lett., 1752-1755. 2007, 48, 2697-2700. b). A. E. Christina, V. M. Blas Ferrand, 44. D. Enders and C.Grondal, Angew. Chem. Int. Ed., 2005, 44, F. de Bordes, W. A. Spruit, H. S. Overkleeft, J. D. C. Codée 1210-1212. and G. A. van der Marel, Carbohydr. Res., 2012, 356, 282-287. 45. a). R. S. Babu, M. Zhou and G. A. O’Doherty, J. Am. Chem. 18. I. Iynkkaran and D. R. Bundle, Carbohydr. Res., 2010, 345, Soc., 2004, 126, 3428-3429. b). H. Guo and G. A. O’Doherty, 2323-2327. Angew. Chem. Int. Ed., 2007, 46, 5206-5208. c). R. S. Babu 19. P. Busca and O. R. Martin, Tetrahedron Lett., 2004, 45, 4433- and G. A. O’Doherty, J. Am. Chem. Soc., 2003, 125, 12406- 4436. 12407. d). H. Guo and G. A. O’Doherty, J. Org. Chem., 2008, 20. U. Zehavi, and N. Sharon, J. Org. Chem., 1964, 29, 3654- 73, 5211-5220. e). Md. M. Ahmed, B. P. Berry, T. J. Hunter, 3658. D. J. Tomcik and G. A. O’Doherty, Org. Lett., 2005. 7, 745- 21. M. Perry and V. Oust, Can. J. Chem. 1974, 52, 3251-3255. 748. e). E. U. Sharif, H.-Y. L. Wang, N. G. Akhmedov and G. 22. D. Horton, G. Rodemeyer and H. Saeki, Carbohydr. Res., A. O’Doherty, Org. Lett., dx.doi.org/10.1021/ol403369h. 1977, 59, 607-611 46. A). O. Calin, R. Pragani and P. H. Seeberger, J. Org. Chem., 23. G. B. Jones, Y. Lin, Z. Xiao, L. Kappen and I. H. Goldberg, 2012, 7, 870-877. b). A. Adibekian, P. Bindschädler, M. S. M. Bioorg. Med. Chem., 2007, 15, 784-790. Timmer, C. Noti, N. Schützenmeister, and P. H. Seeberger, 24. P. J. Burger, M. A. Nashed and L. Anderson, Carbohydr. Res., Chem. Eur. J., 2007, 13, 4510-4522. c). M. S. M. Timmer, A. 1983, 119, 221-230. Adibekian and P. H. Seeberger, Angew. Chem. Int. Ed., 2005, 25. P. Szabó and D. Charon, Carbohydr. Res. 1994, 257, 145-153 44, 7605-7607. d). A. Adibekian, M. S. M. Timmer, P. 26. D. Horton and H. Saeki, Carbohydr. Res., 1978, 63, 270-276. Stallforth, J. van Rijn, D. B. Werz and P. H. Seeberger, Chem. 27. E. M. Carreira, J. Hong, J. Du Bois and C. S. Tomooka, Pure Commun., 2008, 3549-3551. Appl. Chem., 1998, 70, 1097-1103. 47. D. Sames and R. Polt, J. Org. Chem., 1994, 59, 4596-4601. 28. P. A. Illarionov, V. I. Torgov, I. I. Hancock and V. N. Shibaev, 48. V. Ojea, M. Ruiz and J. M. Quintela, Synlett, 1997, 83-84. Russ. Chem. Bull. Int. Ed., 2001, 50, 1303-1308. 49. M. Ruiz, V. Ojea and J. M. Quintela, Tetrahedron: 29. E. Danieli, D. Proietti, G. Brogioni, M. R. Romano, E. Asymmetry, 2002, 13, 1535-1549. Cappelletti, M. Tontini, F. Berti, L. Lay, P. Costantino and R. 50. R. Pragani, P. Stallforth and P. H. Seeberger, Org. Lett., 2010, Adamo, Bioorg. Med. Chem., 2012, 20, 6403-6415. 12, 1624-1627. 30. A. Liav, J. Hildesheim, U. Zehavi and N. Sharon, Carbohydr. 51. R. Pragani and P. H. Seeberger, J. Am. Chem. Soc. 2011, 133, Res., 1974, 33, 217-227. 102-107. 31. D. Bundle and S. Josephson, Can. J. Chem., 1980, 58, 2679- 52. D. Leonori, and P. H. Seeberger, Org. Lett., 2012, 14, 4954- 2685. 4957. 32. M. N. Amin, A. Ishiwata and Y. Ito, Carbohydr. Res., 2006, 53. D. Leonori1 and P. H. Seeberger, Beilstein J. Org. Chem., 341, 1922-1929. 2013, 9, 332-341. 33. E. Bedini, D. Esposito and M. Parrilli, Synlett, 2006, 6, 825- 54. C. Schmölzer, C. Nowikow, H. Kählig and W. Schmid, 830. Carbohydr. Res., 2013, 367, 1-4. 34. E. Weerapana, K. J. Glover, M. M. Chen and B. Imperiali, J. 55. M. Emmadi and S. S. Kulkarni, J. Org. Chem., 2011, 76, 4703- Am. Chem. Soc., 2005, 127, 13766-13767. 4709. 35. a). S. Y. Ko, A. W. M. Lee, S. Masamune, L. A. Reed III, K. 56. M. Emmadi and S. S. Kulkarni, Nat. Protoc., 2013, 8, 1870- B. Sharpless and F. J. Walker, Science, 1983, 220, 245-264. 1889. b). S. Y. Ko, A. W. M. Lee, S. Masamune, L. A. Reed III, K. 57. M. Emmadi and S. S. Kulkarni, Org. Biomol. Chem., 2013, 11, B. Sharpless and F. J. Walker, Tetrahedron, 1990, 46, 949- 3098-3102. 951. 58. M. Emmadi and S. S. Kulkarni, Org. Biomol. Chem., 2013, 11, 36. R. R. Schmidt, Pure Appl. Chem., 1987, 59, 415-424. 4825-4830. 37. A. Kirschning, M. Jesberger and K.-U. Schöning, Synthesis, 59. A. E. Christina, L. J. van den Bos, H. S. Overkleeft, G. A. van 2001, 507-540. der Marel and J. D. C. Codée, J. Org. Chem., 2011, 76, 1692- 38. I. Hemeon and A. J. Bennet, Synthesis, 2007, 1899-1926. 1706. 39. P. Vogel, In The Organic Chemistry of Sugars; D. E. Levy, P. 60. A. Ishiwata, S. Ohtaa and Y. Ito, Carbohydr. Res., 2006, 341, Fugedi, Eds.; Taylor and Francis Group/CRC Press: Boca 1557-1573. Raton, FL, 2006; pp 629. 61. M. N. Amin, A. Ishiwata and Y. Ito, Tetrahedron, 2007, 63, 40. B. Voigt, U. Scheffler and R. Mahrwald, Chem. Commun., 8181-8198. 2012, 48, 5304-5306. 62. M. Emmadi and S. S. Kulkarni, 2014, manuscript under 41. D. Crich and C. Navuluri, Org. Lett., 2011, 13, 6288-6291. review.

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TOC abstract

The Highlight describes recent advances in the synthesis of the bacterial deoxy amino hexopyranoside building blocks and their applications to construct various biologically important bacterial O-glycans.

TOC Graphic

Sugars

Carbohydrate approaches X O Prokaryotic HO OH AcHN Amino acid derivatives X= NH2,NHAc, OH,O De novo Rare sugars approaches

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