Carbohydrates

• Alkyl chains are normally drawn in a staggered conformation (Natta projection). Use of the Fischer projection represents the eclipsed (high energy) formation of the chain.

  
• Absolute stereochemistry is assigned either D or L, where D points to the right and L points to the left. This is labelled from the stereogenic centre.
• Most naturally occurring carbohydrates are in D form, and most amino acids are in L form.
• Pyran is a 6 membered ring where oxygen replaces a carbon (similar to furan). The hemiacetal carbon is the stereogenic centre.
• Beta is the substituent at the anomeric centre cis to the group emanating from the highest numbered chiral carbon atom in the ring.

  
• Alpha is the substituent at the anomeric centre trans to group emanating from the highest numbered chiral carbon atom in the ring.

  
• The anomeric centre is a site on enhanced activity, and can become one of two diastereomers when it cyclises.

  
• The formation of hemiacetals can be acid or base catalysed. The alcohol will act as a nucleophile and attack the ring, forming either a 5 or 6 membered ring.

  
• For pyranose sugars:

  • Six membered rings are flat but not puckered
  • Conformation minimises angle and torsional strain
  • Mainly adopts chair conformation
• Mills representations show the sugar as wedged and dashed substituents, and Haworth represents with the backbone and an attempted perspective with substituents 'up' or 'down'.

  
• Monosaccharides behave chemically as a mixture of three forms (acyclic, pyranose and furanose). This gives access to several functional groups:

  • Aldehyde in open chain
  • Hemiacetal in ring (closed form)
  • Hydroxyl groups in ring
• C6 hydroxyl groups are most accessible, with C2 - C5 being less accessible.
• Reactions at the anomeric centre (C1) can be used to control reactions. This includes glycosylation (alcohol reaction to form an acetal).

  
• Oxonium ions are formed during glycosylation reactions - a carbocation stabilised by conjugation which allows for formation of two diastereomers (alpha and beta). Alpha is preferred due to the anomeric effect.

  
• Ether PGs can protect all free hydroxyls and the anomeric hemiacetal.

  • Protected by NaH excess and MeI/BnBr
  • Cleaved by H2O2 and Fe(II)
  • Excess of reagents required to protect all groups

  
• Benzyl ethers are cleaved using hydrogenolysis. Selective deprotonation of ethers at the anomeric position can be done using aqueous acid (stoichiometric).

  
• Silyl ether PGs are used to protect hydroxyl groups as TMS.

  • Protected with TMSiCl and NEt3
  • Cleaved with acid
• Small silyl ethers can be removed under acidic conditions, and bulky ethers must be removed using TBAF (tetra-butyl ammonium fluoride).

  
• Diols react with an aldehyde or ketone to give an acetal or ketal respectively, catalysed by Bronsted or Lewis acids (H+ or M+).

  
• Removal of esters is done under basic conditions (NaOMe in MeOH). This can be done selectively to reverse glycosylation.

  
• Reaction of pyranose with acetone gives a 5-membered ring ketal. This reaction is selective for cis 1,2 hydroxyls to minimise ring strain. 6-mebered ring ketals C4 and C6 are disfavoured due to 1,3 - diaxial steric interactions.

  
• Amylose:

  • 1,4 linked polymer of glucose by alpha glycosidic bonds
  • Major source of food energy

  
• Cellulose:

  • 1,4 linked polymer of glucose with beta glycosidic bonds
  • Indigestible for mammals so cannot use as a food source

  
• Anomeric bromides:

  • Synthesised from anomeric acetates
  • Similar mechanism to cleavage of anomeric esters with mild acid
  • Alpha-anomer produced selectively
  • Thermodynamic product due to anomeric effect
  • Require activation by Ag or Hg salts

  
• Reaction of anomeric bromides:

  • Loss of Br- is assisted by Ag or Hg salts by SN1
  • SN2 displacement of cyclic intermediate leads to 1,2 trans relationship (major product)

  
• Anomeric fluorides:

  • Made by SN2 displacement giving inversion of stereochemistry
  • If substituent at C2 is an ester than NGP is observed
  • Can be difficult to synthesise alpha and beta anomeric fluorides stereoselectively

  
• Anomeric trichloroacetimidates:

  • Readily available by nucleophilic attack of anomeric hydroxyl by trichloroacetonitrile
  • Reactions predominantly SN2
  • Requires activation by Lewis acids BF3 or TMSOTf

  
• Selective synthesis of trichloroacetimidates is done using a weak base such as K2CO3. The rate of mutarotation is faster than the rate of alkylation, with the hemiacetal hydroxyl being less hindered therefore more reactive. The equatorial anomer is the major product.

  
• Axial trichloroacetimidate synthesis requires a strong base (NaH).

  • Complete deprotonation of anomeric OH by NaH
  • Attack of alkoxide is reversible, reaction under thermodynamic control
  • Anomeric effect favours axial anomer
  • Reaction quenched by aqueous acid

  
• Glycosylation agents:

  • Suitably protected carbohydrates that act as a glycosyl donor by activation (additional reagent)
  • Stereochemistry of glycosidic bond is determined by the donor and the group present at C3

  
• Problems associated with synthesis of glycosidic bonds:

  • Regioselectivity (solved with PGs)
  • Reactivity (solved through use of reactive LGs or activating agent)
  • Stereoselectivity (solved through use of directing groups e.g., esters for specific anomer)
• Enzymatic synthesis of oligosaccharides is done with glycosyl transferases. A different enzyme is required for every combination of donor/acceptor or regio/steroechemical outcome.

  
• DNA/RNA:

  • Linked through the 5' position to the 3' position on each nucleotide
  • Known as a biopolymer
  • Nucleotide stable conformation is in enol form for pyrimidines allowing for hydrogen bonds to form
  • Furanose > pyranose for nucleic acids

  
• Nucleoside anomers are typically the beta-anomer (1 and 4 substituents are cis) with the exception of 2-deoxyguanosine where the alpha anomer is found.

  
• B DNA:

  • Helical turn of 34 A roughly 10 - 11 bps
  • 22 - 24 A width
  • Right handed
  • C2 - endo, 'south'

  
• A DNA:

  • Helical turn of 28 A of 11 bps
  • 26 A width
  • Right handed
  • C3 - endo, 'north'

  
• Z DNA:

  • Helical turn of 45 A of 12 bps
  • 18 A width
  • Left handed

  
• Nucleosides:

  • Can act as antiviral or anticancer agents
  • Synthesised by Vorbruggen or transglycosylation
  • Require many protecting groups

  
• Synthesis of nucleosides with BzCl in pyrimidine adds PGs to make a common intermediate.

  1. Reaction with AcOH in catalytic H2SO4 to give an acetate LG
  2. Reactions with HX in AcOH to give a halide LG

  
• Hoffers' alpha-chlorosugar is a ribose sugar with two p-toluene PGs and a chloride leaving group.

  • Protected with p-toluyl chloride in pyrimidine
  • LG added with AcCl, AcOH and aqueous w/u
  • Reaction of AcCl in water produces HCl in situ