Baran Group Meeting Kyle W. Knouse Carbs 2/10/18 6 OH C-5 Contents: Not included in this group meeting: 6 OH 4 What are Carbohydrates?, Roles Biomass to feedstock, Enzymatic glycosylation, 4 β 5 O Reference 5 O HO O OH in biological systems/metabolism, Synthetic carbohydrate polymers, Carbohydrates HO 1 HO OH HO 2 Glycoconjugates, Synthetic as chirons (Martinez, 2014), Nucleoside Chemistry HO 2 3 OH α 3 OH 1 OH challenges/highlights, (O’Hara, 2012; Gianatassio, 2013) HO OH History: Pyranose α-Pyranose OH -10,000 BC: Primitive sugarcane processing in New Guinea β- OH 62% 37% D-Glucose -1500 BC: Cotton cloth from India speards to Persia and China OH HO O -1891: Fischer reports the structure of glucose, mannose, fructose, and arabinose HO -1929: Haworth proposes ring structures for pyranose/furanose OH CHO OHC H -1940’s: Polysaccharides produce protective immune respons H HO H HO HO OH -1956-1963: OH OH HO H H OH -Bacterial peptidoglycan backbone structure HO HO OH O O HO H -major natural polysaccharides (chitin, cellulose, peptidoglycan) are β(1→4) linked H OH H OH HO H -mechanism of peptidoglycan biosynthesis and penicillin action OH -1972: high field NMR for glycan structure analysis CH OH HOH2C α-Furanose OH β-Furanose OH 2 0.5% 0.5% D-Glucose L-Glucose What is a Carb? - Carbohydrates are defined as “hydrates of carbon” polyhydroxyaldehydes, polyhydroxyketones and their derivatives Alpha vs. Beta (Starch vs. Cellulose): HO OH HO O Drugs: -Heparin OH HO -erythropoietin O O O Branching HO α(1→6) OH O O OH HO Starch OH O Linear O α(1→4) HO OH O Class Monomers Subclass Examples Starch - most common carbohydrate in human diets 6 Major classes -Pentoses Sugars (1-2) Mono/Disaccharides, Polyols Glucose, Sucrose, Sorbitol (potatoes, wheat, maize (corn), rice, and cassava) -Hexoses Oligosaccharides (3-9) Malto-oligosaccharides Maltodextrins -water soluble polysaccharide Polysaccharides (>9) Starches Amylose, Pectins, Cellulose -Hexosamines -highly branched polymer of glucose -Deoxyhexoses -linear glucose with α(1→4) glycosidic bonds. -Uronic Acids Other definitions: -branching α(1→6) bonds occurring every 24 to 30 glucose units -Sialic Acids - Monosaccharides = carbs that cannot be hydrolyzed into a simpler form - Polysaccharide = repeating oligosaccharides Amylose Cellulose - Most abundant biomass on Earth. Main component of the primary cell wall of - Glycan = general term for any of these… (left-haded helix) green plants, algae and some bacteria (biofilms) - Often encountered conjugated, >50% of all proteins are glycosylated - Glycoconjugate = mono/oligosaccharide attatched to -Cotton, wood, hemp, etc. a non-carbohydrate moiety (aglycone) -linear glucose with β(1→4)-glycosidic bonds. -no coiling or branching OH “Reducing Linear Cellulose End” Capable of reducing OH β(1→4) OH O O HO OH H2O2, Ferricyanide, O O HO Cu2+, Ag+ O O OH HO HO OH OH Baran Group Meeting Kyle W. Knouse Carbs 2/10/18 Monomeric Building Blocks Oligomeric Biomolecules Central Dogma of Molecular Biology: Letters of the alphabet OR Written Novel O Transcription Translation B B HO O O B DNA RNA Proteins O HO 5’ O P X O O OH B Replication HO B O O RO P DNA DNA Duplication DNA Linear O 4 canonical -displace X nucleobases O “DNA Chemistry” -oxidation O 3’ Information Modification results in (Peters, 2017) similar stereochemical complexity O Simple PG strategy O RHN N NH O 3’→5’ or C→N H N OA* 2 OH R R R HN R O NH Peptides H N Achiral link O Transcription 2 O RNA Information 20 proteogenic AA’s -activate RNA Synthesis R R -displace OA* C mRNA Often Post-Translationaly Nuclear Envelope Modified ( complexity) OR HO O O Linear and HO OH X Branched HO α RO OH Ribosome O RO OR OH O Information HO OH OH 6 HO O Protein HO 4 O Translation OH O HO β O Protein Synthesis “Highlights in Peptide and Carbohydrates RO HO 2 OH 3 OH 1 reducing Protein Synthesis” RO OR O R Only 36 building end (Mallins, 2016) H 5 potential sites Chiral link N OH blocks are needed to for reaction N construct 75% of the >50% of all proteins are glycosylated H 3299 mammalian Diversity: Hexamer R O oligosaccharides. Nucleotide* = 46 = 4096 Mammalian glycan Cell Surface Peptide* = 206 = 64 million structures comprise 78% of all the Motility/membrane eukaryotic glycans Carbohydrate** = 192 billion Signaling movement (charge distribution) ACS Chem. Biol., 2007, 2, 685. Chem. Sci. 2011, 2, 337. Provide structure (peptidoglycan) and preservation (trehalose) *Assuming natural NH2 phosphodiester/ CO H amide linkages Glycans are abundantly expressed on the 2 **based on the “ten outer-surface of prokaryoate and common” mammal eukaryote cells, creating a landscape of monosaccharides recognition sites, barriers and transporters Baran Group Meeting Kyle W. Knouse Carbs 2/10/18 Glycosyl Donors: O O Donor (D) Acceptor (A) Disaccharide (D-A) RO O Y Y = potential leaving group O Z Z O O Promotor (P) O Y O Y O Promotor β-linkage RO X HO RO O + Solvent (Ingnored) Z HO Y Z Z Z RO X Solvent O or Z Z RO α -linkage Two ways to set up reaction: X = Leaving Group Glycosyl Acceptor: O Z 1) Normal Procedure (disarmed donors) 2) Inverse Procedure (armed donors) R = Protecting Group O Y *Bulky groups at C-6 diminish 1→4 Z = participating or Z P D non-participating group (TBDPS, TBDMS, Piv) D + A D-A D + P + A P + A D-A Glycosyl Donors: For armed donors . O NH D P will decompose O O R O O O O . X P R Decomp. D.P A P A + P X CCl3 3 P P Glycosyl halides Glycosyl phosphates Trichloroacetimidates Pentenyl glycosides A D (TMSOTf) OBn X = Cl, Br (AgOTf) (TMSOTf) (NIS/Et3SiOTf D-A or F (SnCl /AgClO ) or Br ) 2 4 R=Alkyl, O-Alkyl 2 AcO HO O X = O, S, lone pair AcO O OTBS O O O AcO N O O OAc 3 S(O)Ar S BnO XR SEt O Et2O, OBn + TMSOTf (0.01 eq.) OBn S BnO O OBn NP: 43% Me O OBn Glycosyl sulfide Glycosyl sulfoxides Glycals IP: 78% Xanthathes OBn AcO (NIS/TfOH (Tf2O) (TMSOTf) (ZnCl2) Me O O O AcO O or DMTST) O OTBS O CCl O O O O 3 AcO N O R OAc 3 O R NH N O Tetrahedron Lett. 1991, 32, 3353 N O O R = H, Me PG Strategies: R R = OR’, SR’, CN Selective 1° protection (Bulky, TBS, Trt, 0 °C, limiting reagents, etc.) 2° equitorial. > 2° axial. OH Armed/Disarmed logic: cis/trans vicinal diols (acetal formation) O Highly dependent Slow HO OH O O on stereochem HO Selective 2° protection, X OH hemiacetal Bu2SnO, R-X + OBz OBz Esters induce slight Two step monomer: (H , ROH) Armed: C-2 = Ether positive charge, oxonium Disarmed C-2 - Ester, Amide, etc. formation is slower OH OAc OAc O Ac O O BF OEt O O O 2 3 Fast HO OH AcO OAc AcO X X HO AcO - AcO OH Pyridine OAc X OAc OBn OBn 100 °C, 1 hr. Baran Group Meeting Kyle W. Knouse Carbs 2/10/18 Not always the case! Kiliani Fischer Synthesis: 1. Acetone, H SO 1. NaH, CS , MeI 2 4 2 CN CN CHO CHO 2. TsCl, pyridine 2. Bu3SnH, AIBN CHO OH OTBS + O OH 3. NaBH4, DMSO 3. H OBn HO OH O HO OH + OH NaCN Heat [H] O 4. H , DMSO O 4. Ac2O, pyridine O OH OH OH OH CH2OH CH OH CH OH OH CH OH CH OH HO 5. Bu SnO HO 5. PhSH, BF OEt H2O 2 2 H2O 2 2 OH 2 O 3 BnO HO 6. BnBr, NaH OH O 6. NaOMe Br D-glyceraldehyde D-threose D-erythrose 7. TBSCl, Pyridine 7. BnBr, NaH Cycle is repeated until desired chain length (requires separation of epimers) 8. H2, Pd/C Me Me 8. Br2 Wohl Degradation: PG Migration: OH OR CHO N CN O SPh OR OR OH NH2OH OH Ac2O OH NaOMe CHO O SPh BzO O SPh OH OH OH OH Tf2O TfO N H2O AcOH MeOH O 3 HO N CH2OH CH2OH CH2OH CH2OH 3 Pyr. HO N3 Chem. Ber., 1893, 730 BzO O N Ph Modern Approach: Total Synthesis of the L-Hexoses - K. B. Sharpless Access to all 8 hexoses, D and L Epimerizations: Eliminations: OH OH SPh RO RO TsO N CHO i. [O], [H] 3 O O O NaN O CHO OR * OR OR ii. Mitsonobu OR O 3 OR O OR R-M AE * Payne OR Pummerer; OR DMF O OR CH2OR OR OR OR OR HO OR HO OR TsO CH2OR CH2OR CH2OR CH2OR TBSO TBSO Interesting transformations: *(+) or (–) tartrate *DIBAL = Retention O O K CO /MeOH = Inversion O PhMgBr O 2 3 OBz OBz “Since the mirror image of every compound in Fig. 2 can be prepared by simple O OMe O F TBSO exchange of the chiral ligand in the AE reaction, the formal synthesis of the D- Me DAST Me hexoses has also been achieved” Science, 1983, 220, 949 N 76% N 3 OH 3 OMe Selective 1° protection Ph J. Carb. Chem., 1985, 627 (Bulky, TBS, Trt, 0 °C, limiting reagents, etc.) Works well for: Ph Mannose BzO Galactose H N O BzO TBSO OH Arabinose O 1. H5IO6 O O O O BzO OH O Highly dependent O Rhamnose H H O 2. TEA, MeOH OH HO hemiacetal OMe on stereochem OMe (H+, ROH) HO R HO H OH R O O O BzO OH BzO OH Me Ph NH H O H WO 2010/015637 A1 90:10:-, 77% Ph O -:100:-, 97% DMTrO Proposed glucose ii.