Welcome to 3FF3! Bio-organic Chemistry

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Welcome to 3FF3!Bio-organic Chemistry

• Jan. 7, 2008

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• Instructor Adrienne Pedrech
• ABB 417
• Email adriennepedrech_at_hotmail.com
• -Course website http//www.chemistry.mcmaster.ca/
  courses/3f03/index.html
• Lectures MW 830 F 1030 (CNH/B107)
• Office Hours T 1000-1230 F 100-230 or by
  appointment
• Labs
• 230-530 M (ABB 302,306) Note course
  timetable says ABB217 230-530 F (ABB 306)
• Every week except reading week (Feb. 18-22)
  Good Friday (Mar. 21)
• Labs start Jan. 7, 2008 (TODAY!)

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• For Monday 7th Friday 11th
• Check-in, meet TA, safety and Lab 1 (Isolation of
  Caffeine from Tea)
• Lab manuals Buy today!
• BEFORE the lab, read lab manual intro, safety and
  exp. 1
• Also need
• Duplicate lab book (20B3 book is ok)
• Goggles (mandatory)
• Lab coats (recommended)
• No shorts or sandals
• Obey safety rules marks will be deducted for
  poor safety
• Work at own pacesome labs are 2 or 3 wk labs.
  In some cases more than 1 exp. can be worked in a
  lab periodyour TA will provide instruction

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• Evaluation
• Assignments 2 x 5 10
• Labs -write up 15
• - practical mark 5
• Midterm 20
• Final 50
• Midterm test
• Fri. Feb. 29, 2008 at 700 pm
• Make-up test TBD
• Assignments Feb.6 Feb.13
• Mar.7 Mar.14
• Note academic dishonesty statement on outline-NO
  copying on assignments or labs (exception when
  sharing results)

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• Texts
• Dobson Foundations of Chemical Biology,
  (Optional- bookstore)
• Background Refreshers
• An organic chemistry textbook (e.g. Solomons)
• A biochemistry textbook (e.g. Garrett)
• 2OA3/2OB3 old exam on web
• This course has selected examples from a variety
  of sources, including Dobson
• Buckberry Essentials of Biological Chemistry
• Dugas, H. "Bio-organic Chemistry"
• Waldman, H. Janning, P. Chemical Biology
• Also see my notes on the website

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• What is bio-organic chemistry? Biological chem?
  Chemical bio?
• Chemical Biology
• Development use of chemistry techniques for
  the study of biological phenomena (Stuart
  Schreiber)
• Biological Chemistry
• Understanding how biological processes are
  controlled by underlying chemical principles
  (Buckberry Teasdale)
• Bio-organic Chemistry
• Application of the tools of chemistry to the
  understanding of biochemical processes (Dugas)
• Whats the difference between these???
• Deal with interface of biology chemistry

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Simple organics eg HCN, H2CO (mono-functional) C
f 20A3/B3
BIOLOGY
CHEMISTRY
Life large macromolecules cellscontain 100,
000 different compounds interacting
Biologically relevant organics polyfunctional
1 Metabolism present in all cell (focus of
3FF3) 2 Metabolism specific species, eg.
Caffeine (focus of 4DD3)
How different are they?
CHEMISTRY Round-bottom flask
BIOLOGY cell
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• Exchange of ideas
• Biology Chemistry
• Chemistry explains events of biology mechanisms,
  rationalization
• Biology
• Provides challenges to chemistry synthesis,
  structure determination
• Inspires chemists biomimetics ? improved
  chemistry by understanding of biology (e.g.
  enzymes)

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Key Processes of 1 Metabolism

• Bases sugars ? nucleosides
  nucleic acids
• Sugars (monosaccharides)
  polysaccharides
• Amino acids
  proteins
• Polymerization reactions cell also needs the
  reverse process
• We will look at each of these 3 parts
• How do chemists synthesize these structures?
• How are they made in vivo?
• Improved chemistry through understanding the
  biology biomimetic synthesis

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Properties of Biological Molecules that Inspire
Chemists

• Large ? challenges for synthesis
• for structural prediction (e.g. protein
  folding)
• 2) Size ? multiple FGs (active site) ALIGNED to
  achieve a goal
• (e.g. enzyme active site, bases in NAs)
• 3) Multiple non-covalent weak interactions ? sum
  to strong, stable binding non-covalent complexes
• (e.g. substrate, inhibitor, DNA)
• 4) Specificity ? specific interactions between 2
  molecules in an ensemble within the cell

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• 5) Regulated ? switchable, allows control of cell
  ? activation/inhibiton
• 6) Catalysis ? groups work in concert
• 7) Replication ? turnover
• e.g. an enzyme has many turnovers, nucleic
  acids replicates

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Evolution of Life

• Life did not suddenly crop up in its element form
  of complex structures (DNA, proteins) in one
  sudden reaction from mono-functional simple
  molecules
• In this course, we will follow some of the ideas
  of how life may have evolved

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RNA World

• Catalysis by ribozymes occurred before protein
  catalysis
• Explains current central dogma
• Which came first nucleic acids or protein?
• RNA world hypothesis suggests RNA was first
  molecule to act as both template catalyst
• catalysis replication

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• How did these reactions occur in the pre-RNA
  world? In the RNA world? in modern organisms?
• CATALYSIS SPECIFICITY
• How are these achieved? (Role of NON-COVALENT
  forces BINDING)
• a) in chemical synthesis
• b) in vivo how is the cell CONTROLLED?
• c) in chemical models can we design better
  chemistry through understanding biochemical
  mechanisms?

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Relevance of Labs to the Course

• Labs illustrate
• Biologically relevant small molecules (e.g.
  caffeine Exp 1)
• Structural principles characterization (e.g.
  anomers of glucose, anomeric effect,
  diastereomers, NMR, Exp 2)
• Cofactor chemistry pyridinium ions (e.g. NADH,
  Exp 3 4)
• Biomimetic chemistry (e.g. simplified model of
  NADH, Exp 3)
• Chemical mechanisms relevant to catalysis (e.g.
  NADH, Exp 3)

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• Application of biology to stereoselective
  chemical synthesis (e.g. yeast, Exp 4)
• Synthesis of small molecules (e.g. drugs,
  dilantin, tylenol, Exp 5,7)
• Chemical catalysis (e.g. protection activation
  strategies relevant to peptide synthesis in vivo
  and in vitro, Exp 6)
• All of these demonstrate inter-disciplinary area
  between chemistry biology

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• Two Views of DNA
• Biochemists view shows overall shape,
  ignores atoms bonds
• chemists view atom-by-atom structure,
  functional groups illustrates concepts from
  2OA3/2OB3

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Biochemists View of the DNA Double Helix
Minor groove
Major groove
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Chemists View
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BASES

• Aromatic structures
• all sp2 hybridized atoms (6 p orbitals, 6 p e-)
• planar (like benzene)
• N has lone pair in both pyridine pyrrole ?
  basic (H acceptor or e- donor)

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6 p electrons, stable cation ? weaker acid,
higher pKa ( 5) strong conj. base
sp3 hybridized N, NOT aromatic ? strong acid, low
pKa ( -4) weak conj. base

• Pyrrole uses lone pair in aromatic sextet ?
  protonation means loss of aromaticity
  (BAD!)
• Pyridines N has free lone pair to accept H
• ? pyridine is often used as a base in organic
  chemistry, since it is soluble in many common
  organic solvents

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• The lone pair also makes pyridine a H-bond
  acceptor e.g. benzene is insoluble in H2O but
  pyridine is soluble
• This is a NON-specific interaction, i.e., any
  H-bond donor will suffice

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Contrast with Nucleic Acid Bases (A, T, C, G, U)
Specific!

• Evidence for specificity?
• Why are these interactions specific? e.g. G-C
  A-T

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• Evidence?
• If mix G C together ? exothermic reaction
  occurs change in 1H chemical shift in NMR other
  changes ? reaction occurring
• Also occurs with A T
• Other combinations ? no change!

e.g. Guanine-Cytosine

• Why?
• In G-C duplex, 3 complementary H-bonds can form
  donors acceptors molecular recognition

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• Can use NMR to do a titration curve
• Favorable reaction because ?H for complex
  formation -3 x H-bond energy
• ?S is unfavorable ? complex is organized ?
  3 H-bonds overcome the entropy of complex
  formation
• Note In synthetic DNAs other interactions can
  occur

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• Molecular recognition not limited to natural
  bases

Forms supramolecular structure 6 molecules in a
ring
? Create new architecture by thinking about
biology i.e., biologically inspired chemistry!
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Synthesis of Bases (Nucleic)

• Thousands of methods in heterocyclic chemistry
  well do 1 example
• May be the first step in the origin of life
• Interesting because H-CN/CN- is probably the
  simplest molecule that can be both a nucleophile
  electrophile, and also form C-C bonds

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Mechanism?
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Other Bases?
Try these mechanisms!
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Properties of Pyridine

• Weve seen it as an acid an H-bond acceptor
• Lone pair can act as a nucleophile

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• Balance between aromaticity charged vs
  non-aromatic neutral!
• ? can undergo REDOX reaction reversibly

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• Interestingly, nicotinamide may have been present
  in the pre-biotic world
• NAD or related structure may have controlled
  redox chemistry long before enzymes involved!

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Another example of N-Alkylation of Pyridines
This is an SN2 reaction with stereospecificity
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References

• Solomons
• Amines basicity ch.20
• Pyridine pyrrole pp 644-5
• NAD/NADH pp 645-6, 537-8, 544-6
• Bases in nucleic acids ch. 25
• Also see Dobson, ch.9
• Topics in Current Chemistry, v 259, p 29-68

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Sugar Chemistry Glycobiology

• In Solomons, ch.22 (pp 1073-1084, 1095-1100)
• Sugars are poly-hydroxy aldehydes or ketones
• Examples of simple sugars that may have existed
  in the pre-biotic world

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• Most sugars, i.e., glyceraldehyde are chiral sp3
  hybridized C with 4 different substituents
• The last structure is the Fischer projection
• CHO at the top
• Carbon chain runs downward
• Bonds that are vertical point down from chiral
  centre
• Bonds that are horizontal point up
• H is not shown line to LHS is not a methyl group

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• In (R) glyceraldehyde, H is to the left, OH to
  the right ? D configuration if OH is on the
  left, then it is L
• D/L does NOT correlate with R/S
• Most naturally occurring sugars are D, e.g.
  D-glucose
• (R)-glyceraldehyde is optically active rotates
  plane polarized light (def. of chirality)
• (R)-D-glyceraldehyde rotates clockwise, ? it is
  the () enantiomer, and also d-, dextro-rotatory
  (rotates to the right-dexter)
• ? (R)-D-()-d-glyceraldehyde
• its enantiomer is (S)-L-(-)-l-glyderald
  ehyde
• ()/d (-)/l do NOT correlate

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• Glyceraldehyde is an aldo-triose (3 carbons)
• Tetroses ? 4 Cs have 2 chiral centres
• 4 stereoisomers
• D/L erythrose pair of enantiomers
• D/L threose - pair of enantiomers
• Erythrose threose are diastereomers
  stereoisomers that are NOT enantiomers
• D-threose D-erythrose
• D refers to the chiral centre furthest down the
  chain (penultimate carbon)
• Both are (-) even though glyceraldehyde is () ?
  they differ in stereochemistry at top chiral
  centre
• Pentoses D-ribose in DNA
• Hexoses D-glucose (most common sugar)

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Reactions of Sugars

• The aldehyde group
• Aldehydes can be oxidized
• reducing sugars those that have a free
  aldehyde (most aldehydes) give a positive
  Tollens test (silver mirror)
• Aldehydes can be reduced

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• Reaction with a Nucleophile
• Combination of these ideas ? Killiani-Fischer
  synthesis used by Fischer to correate
  D/L-glyceraldehyde with threose/erythrose
  configurations

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Reactions (of aldehydes) with Internal
Nucleophiles

• Glucose forms 6-membered ring b/c all
  substituents are equatorial, thus avoiding
  1,3-diaxial interactions

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• Can also get furanoses, e.g., ribose

• Ribose prefers 5-membered ring (as opposed to
  6) otherwise there would be an axial OH in the
  6-membered ring

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• Why do we get cyclic acetals of sugars? (Glucose
  in open form is ltlt 1)
• Rearrangement reaction we exchange a CO bond
  for a stronger C-O s bond ? ?H is favored
• There is little ring strain in 5- or 6- membered
  rings
• ?S there is some loss of rotational entropy in
  making a ring, but less than in an intermolecular
  reaction1 in, 1 out.

significant ve ?S! ??G ?H -
T?S
Favored for hemiacetal
Not too bad for cyclic acetal
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Anomers

• Generate a new chiral centre during hemiacetal
  formation (see overhead)
• These are called ANOMERS
• ß-OH up
• a-OH down
• Stereoisomers at C1 ?diastereomers
• a- and ß- anomers of glucose can be crystallized
  in both pure forms
• In solution, MUTAROTATION occurs

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Mutatrotation
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In solution, with acid present (catalytic), get
MUTAROTATION not via the aldehyde, but oxonium
ion

• At equilibrium, 3862 aß despite a having an
  AXIAL OHWHY? ANOMERIC EFFECT

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Anomeric Effect
oxonium ion
O lone pair is antiperiplanar to C-O s bond ?
GOOD orbital overlap (not the case with the
ß-anomer)
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Projections
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More Reactions of Sugars

• Reactions of OH group(s)
• Esterification
• Ethers

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b) Ethers (cont)

1. Acetals

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c) Acetals (cont)
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• These reactions are used for selective protection
  of one alcohol activation of another
  (protecting group chemistry)

1 alcohol is most reactive ?protect first
AZT
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e.g, synthesis of sucrose (Lemieux, Alberta)

• Can only couple one wayif we dont 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)

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Selectivity of Anomer Formation in Glycosides

• Oxonium ion can often be attacked from both Re
  Si faces to give a mixture of anomers.
• How do we control this?

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This reaction provides a clue to how an enzyme
might stabilize an oxonium ion (see later)