Natural Product Reports Recent Advances in Synthesis of Bacterial Rare Sugar 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 sugars 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 oligosaccharides 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 carbohydrate 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-galactose (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 polysaccharides, 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 monosaccharide 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 amino sugar at the 4-position. Owing to their biological importance, several building blocks using carbohydrate precursors have been routes starting from a variety of carbohydrates 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-Mannose 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. 2 | J. Name., 2012, 00, 1‐3 This journal is © The Royal Society of Chemistry 2012 Page 3 of 11 Natural Product Reports Journal Name ARTICLE 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 fucose (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).