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					                                      Projections
    H            O                                  OH
        1
                                           H    1
                                                                O
        2
                 OH
                                                2
                                                         OH
HO      3
                                          HO    3                                 HO
        4        OH                                                                          O    OH
                                                4        OH
        5        OH
                                                5
            CH2OH
        6                                           CH2OH                               OH       OH
                                                6

                                          convential Fischer                       Haworth of ribose
                     turn on
                       side


HO                                         HO
            6
                              H                                     OH   
             5
                     OH                                     O
4
            OH                    O                 OH
                          1
OH           3
                      2                    OH
                     OH                                     OH

                                                    Haworth                   

                                                                         OH
                     More Reactions of Sugars
1)     Reactions of OH group(s):
     a)    Esterification:

                                O        O
          OH                                               OAc

                 O                  O                             O
HO                     OH                          AcO                   O
  HO                                                 AcO
           HO                                               AcO
                                                                              O
                           acetic anhydride:
                        reactive acid derivative           penta-O-acetyl--D-glucopyranose


     b)    Ethers:


                                                    SN2
                R-OH        +       Ph       Br                   R-Ph
                                                              Benzyl ethers
b) Ethers (con’t)
   HO                               Ph3CBr                  TrO
               O     OH                                                 O       OH
                                     SN1
                                    via stable
          OH       OH               carbocation                   OH        OH
                                 (cf malachite
                                 green)


   **SELECTIVE: steric hinderance          only 1o reacts          Tr = trityl =




c) Acetals
                                                 O
         TrO                                                      TrO
                        O     OH                                                 O       OH


                                                 H+
                   OH       OH                                              O        O
                                           (eg. TsOH)


               Acetonide: best for 5 - membered rings
                          requires cis OH groups
c) Acetals (con’t)

   HO
                                     O                    O
                 O                                 H
                                Ph       H                            O
        OH                                        Ph            OH
  OH                  OMe         TsOH
                                                           O               OMe
                 OH
                                                                      OH


       Benzaldehyde: prefers 6-membered ring
                     the 2 OH's can be cis or trans (provide they are diequatorial)


        WHY?


                                         Me2CO: requires R2 (Me) to be axial in 6-
            R1
                                                membered ring
       R2     O             O
             O                           PhCHO: can have R2 = H & Ph can be
                                                 equatorial
                                                * new stereocentre
These reactions are used for selective protection of one
  alcohol & activation of another (protecting group chemistry)
HO                                                        TrO
            O        T                                                O       T
                                     TrCl


       OH                                                        OH
                     1° alcohol is most
                     reactive protect                                     activate 2o
                                                            CH3SO2Cl
                     first                                                 alcohol

 TrO                                                       TrO
             O           T                                             O          T
                                     H2O
       OH

                                inverts stereochemistry           O
                                at C3                                     O
                                                                      S
                                                                  O
 MeSO2Cl        reactivate
                                                                                                  AZT
TrO                                       TrO                                  HO
            O        T          +                    O      T                                 O   T
                             N N N                                HCl
       OMs
                              SN2
                                                N3               remove Tr               N3
e.g, synthesis of sucrose (Lemieux, Alberta)

            OPG                              OPG
                                        OH               OPG
                   O
                                                   OPG
    PGO                   OH
      PGO                                      O
            PGO                   PGO



              Activate anomeric
              centre as oxonium
              ion


• Can only couple one way—if we don’t protect, get all
  different coupling patterns
• Yet nature does this all of the time: enzymes hold
  molecules together in the correct orientation, BUT the
  mechanism still goes through an oxonium ion (more on
  this later)
Selectivity of Anomer Formation in Glycosides
 • Oxonium ion can often be attacked from both Re & Si
   faces to give a mixture of anomers.
                                     +        Si face
                                   O


                       Re face

 • How do we control this?
         HO                                      AcO
                                  Ac2O
                   O                                          O
       HO              OH                      AcO                    OAc
        HO                                      AcO
              HO                 (Cf Exp 2)           AcO

                                                            HBr/AcOH

                                                  AcO
                                                                  O
                       -anomer is favored      AcO
                                                 AcO
                       due to strongly e-               AcO
                                                                      Br
                       withdrawing Br
                                                            -bromide
 AcO                            AcO
                      MeOH                                  AcO
                                          +
             O                        O
AcO                                                                    O
                               AcO                      AcO
 AcO                            AcO
       AcO            Ag2CO3                  O          AcO
                 Br                   O                               O
                                                                        O
                                                                      +

                                                  cis-fused dioxolenium ion---
                                                  must be axial!


                                                                      MeOH


                                                      AcO
                                                                  O
                                                    AcO                OMe
                                                     AcO
                                                           AcO

                                                    -glycoside activity



This reaction provides a clue to how an enzyme might
stabilize an oxonium ion (see later)
Examples of Naturally Occurring di- & oligo-
              Saccharides
Maltose:
       2 units of glucose
       a β sugar
       α glycoside
       1,4-linkage


Lactose (milk):
                              OH OH         OH
       galactose + glucose        O          O
                                       O          OH
       a β sugar             HO        HO
       β glycoside                OH         OH
       1,4-linkage
                                    HO
                                         O
Sucrose (sugar):                   HO
                                    HO
                                         OH OH
      glucose + fructofuranose                          CH2OH
                                           O
      a β sugar
                                                      OH
      α glycoside
                                                  O
      1,2-glycosidic bond                    CH2OH




                                             α-1,6-glycosidic bond
Amylopectin (blood cells):
      an oligosaccharide


           α-1,4-glycosidic bond
       Structure Determination of Sugars
• The following is an example to review & expand your
  knowledge of NMR
   – Consider the question of glycoside formation:

       HO                                     HO
                              H3O+                      O
                 O                                          OMe
     HO              OH                    HO
      HO                      MeOH          HO
            HO                                     HO

                                              or  anomer?



See NMR spectra of both anomers:
  They are different-diastereomers have different spectra,
  but which is which?
-methyl glucopyranose    HO
                                    O
                         HO                 OMe
                          HO
                               HO
                                        H
-methyl glucopyranose




                          HO
                                    O
                         HO              H
                          HO
                               HO
                                        OMe
These spectra are rich in independent information:
1) Chemical shift, :
   •   Reveals functional groups (see chart)
   •   Depends on inductive effects, # of EWGs &  bonds
   Inductive effects
       e.g.          Si CH3              CH3       Cl CH3
                      +   -         0    0        -   +

        Chemical
        shift (ppm)                       


   # of EWGs
        e.g. glucose– anomeric H is most downfield since 2 O atoms
        attached to C have more of an effect that 1 atom.  we can
        assign the anomeric proton in the both spectra of α and β
        methyl glucoside


    bonds –alkenes, aromatics, C=O, etc
2)       Integrals
     •      NMR is quantitative e.g. glycosides—area under anomeric
            signal = 1; area under the signal at  3.3 = 3x bigger,  3
            protons, must be a CH3 group


3)       Multiplicity
     •      Protons communicate their spins over 1, 2 or 3 bonds—
            reveals # of neighbors
            e.g. CH3-O group: a singlet, one line, no neighbors—nearst
            neighbor is 4 bonds away

            e.g. anomeric proton: a doublet, 2 peaks, one neighbor that is
            3 bonds away (recall n neighbors, n +1 peaks)


4)       Coupling Constant
     •      Distance between peaks in a multiplet is J, coupling
            constant—depends on geometry
4)       (con’t)
     •      e.g. α glycoside: 2 peaks are 4.650-4.632 = 0.018 ppm apart
            spectrometer frequency = 200 MHz
            J = 0.018 ppm x 200 MHz = 3.6 Hz
            For the β-glycoside, J = 8.0 Hz
     •      Different J values reflect different geometries:
                 H1 – C1 – C2 – H2 = 60° in α, = 180° in β
           J depends on geometry according to Karplus curve:

                                                At 60°, J is small
                                                 180°, J is large

                                           J reveals the geometry, i.e., the
                                          stereochemistry of the glycoside




                                 dihedral H-X-X-H
• But, looking at the spectra, note that the CHOH protons
  at C-2, C-3, C-4, C-5 & C-6 are all overlapping.
•  hard to measure each J value—How to use NMR to
  get a complete structure?
• What about a very complex case, i.e., sucralose, the
  sweetener in splenda:
   HO
             O
  HO
   HO                                  HO
        HO                                       O       Cl             Cl
                 O              Cl2                            O
                                      Cl
                      O    OH          HO            O
                                            HO
                      HO
         HO
                                                              OH   OH
                     OH
                                             SUCRALOSE
         SUCROSE




• Where are the chlorines? Which anomer is formed?
  Pyranose &/or furanose ring?
  A challenging structure—need advanced NMR methods
 Quick review of NMR theory & Pulse
                NMR:
Not an important part of exams, but may
  help on questions for assignments
Modern NMR spectrometers use pulse NMR, rather than
   CW; advantages are:
1) Can acquire full spectrum in 2-3 seconds, rather than
   2-3 min
2) Can add together data from many pulses—improves
   signal/noise
3) Can combine 2 or more pulses—allows magnetic
   billiards—
   e.g. make different CH, CH2, CH3 groups have
   different phase
   e.g. 2D NMR –COSY- to determine which H’s are
   coupled to one another
   e.g. 3D NMR –to determine protein structures &
   conformation in solution
How does it work? We’ll do a simple treatment
                                     apply magnetic field




       random fields associated
       with spinning nucleus                                       nuclei align with or against
       e.g. 1H (I = 1/2)                                           field:quantised spin + or - 1/2
           13C     "


Energy gap between states:
                                                            -1/2
                    E


                                                             E


                                                            +1/2




                             no                                        Bo
                             field                 Applied field


More spin states in low energy (Boltzmann) = net absorption
= resonance (signal!)
Mechanism of Absorption:

        pulse - excites all magnetic nuclei simultaneously


     on      off
                                                             emits electromagnetic radiation at
                                                             different frequencies
                  relaxation - nuclei return
                               to original
                               spin state
at equilibrium:                                                 FID = free induction decay
most alinged
with field




                                                                                             2-3 sec
Points about FID
a) A sin wave with frequency -o (the difference in the
    frequency of RF signal & frequency emitted from
    nucleus)  chemical shift
b) Decays with time as relaxation occurs (i.e., nuclei lose
    excitation)



Watch the FID on the 200 MHz when you get your
   spectrum!

Transform FID to
Frequency
domain
                            -o (i.e. )
  • In a real spectrum, the FID is a complex mixture of
    different sine waves with
        – Different frequencies -o, ie., different 
        – Different intensities, i.e. integral
        – Different relaxation rates, ie, different widths
  • FT resolves it all—based on a mathematical formula by
    Fourier (French mathematician 18th C)
  • FIDs can be added together to improve S/N: this is
    essential for e.g. 13C NMR
FID 1
                                                             Add together: S/N
                                                             improves by 2
FID 2



In general, S/N improves by 2 for each 22 = 4 times the number of
scans
• Going back to the spectrum of xxx: we have a
  problem—which CH is which & what pairs are coupled
  together?
• Use COSY, a 2D technique that plots  vs  on x X y
  axes               A      B


Cross-peaks                         Diagonal peaks
show coupled       B
pairs


               A




• Very useful—can work way around rings & assign
  protons
            COSY: How does it Work?
• Collect a series of spectra with different delay times:
                         FID 1




                                 FID 2


                                 Different magnetization vector than FID 1




• Series of FIDs & spectra are collected and a 2D contour
  map is generated (contour plot)
Contour plot:
• H vs H
• like a map
• if two 1H aren’t coupled = no
        crosspeak


                       A      B


Cross-peaks                       Diagonal peaks
show coupled       B
pairs
                                      H1           H2
               A
• COSY tell us which protons are coupled together!

Back to Sucralose
• Assign anomeric H in the pyranose
• Look for cross-peak → H-2
• Look for cross-peak from H-2 → H-3 etc

• Extremely useful in determining chemical shift
  assignment
   – Once each H in sucralose is assigned, you can measure the
     coupling constants, J
    e.g. H-1, d, J = 4 Hz  =5.37
     1 or both of the H1 & H2 are equatorial
         H-2 3.83 (by COSY), dd, 4 & 10 Hz J2,3 = 10 Hz
•  H2 & H3 are both axial
•  H1 is equatorial:
                              H
                               O
                                    H
                   HO
                             OH
                         H     O


• Try 6-membered ring
• Note the 2 diastereotopic protons at H6—see the
  coupling in the COSY spectrum
   – The chemical shifts are very close since they exhibit strong
     coupling
   – This is common with diastereotopic protons
   – Also see example in the benzoin lab (exp 7)
                  Other 2D Experiments
• TOCSY
  – Correlates all the spins in a coupled spectrum, e.g. sucralose
  – 2 spin sets: the pyranose & the furanose rings
• NOESY
  – Nuclear overhauser effect
  – Correlates protons that are close in space

                                        A relaxes &
                                        transfers magnetization
                                        to B


         A   B                  A   B                     A   B
                    irradiate

 Bo                     A
                                                          slight increase
                                                          or decrease in
                                                          signal to B
• NOESY is a 2D version—useful for protein
  conformations

13C   NMR:

• Usually acquired with protons decoupled
      – Simplifies spectra: each C  1 signal
      – Increased sensitivity: big nOe 1H  13C & singlet for each C (no
        coupling)
• But lose info  use DEPT
      – Singlet, but with attached proton info


• Even better: Combine 1H & 13C (HSQC/HMBC)
      – Cross-peaks show which H is attached to which C (HSQC) or
        adjacent H’s (HMBC)
      – Very useful in structure determination

				
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