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An intriguing example of how chirally enriched amino acids in the prebiotic world can generate sugars with D-configurati PowerPoint Presentation
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Cordova et al. Chem. Commun ., 2005 , 2047-2049 An intriguing example of how chirally enriched amino acids in the prebiotic world can generate sugars with D-configuration & with enantioenrichment: The Model:

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slide1

Cordova et al. Chem. Commun., 2005, 2047-2049

  • An intriguing example of how chirally enriched amino acids in the prebiotic world can generate sugars with D-configuration & with enantioenrichment:

The Model:

L-proline: a 2° amine; popular as an organocatalyst because it forms enamines readily

slide2
Mechanism: enamine formation

CO2H participates as acid

enantioenrichment
Enantioenrichment

% ee of sugar vs % ee of AA

  • Initially used 80% ee proline to catalyze reaction → >99% ee of allose
  • Gradually decreased enatio-purity of proline
    • Found that optical purity of sugar did not decrease until about 30% ee of proline!
    • Non-linear relationship!
slide5
 chiral amplification
    • % ee out >> % ee in!
  • Suggests that initial chiral pool was composed of amino acids
  • Chirality was then transferred with amplification to sugars → “kinetic resolution”
  • Could this mechanism have led to different sugars diastereomers?
  • Sugars →→ RNA world →→ selects for L-amino acids?
  • Small peptides?
catalysis by small peptides
Catalysis by Small Peptides
  • Small peptides can also catalyze aldol reactions with enantioenrichment (See Cordova et al. Chem. Commun. 2005, 4946)
  • Found to catalyze formation of sugars
  • It is clear that amino acids & small peptides are capable of catalysis i.e., do not need a sophisticated protein!
from amino acids peptides
From Amino Acids  Peptides
  • Peptides are short oligomers of AAs (polypeptide ~ 20-50 AAs); proteins are longer (50-3000 AAs)
  • Reverse reaction is amide hydrolysis, catalyzed by proteases
slide8
At first sight, this is a simple carbonyl substitution reaction, however, both starting materials & products are stable:
    • RCO2- -ve charge is stabilized by resonance
    • Amides are also delocalized &  carbon & nitrogen are sp2 (unlike an sp3 N in an amine):
slide9
Primary structure: AA sequence with peptide bonds
  • Secondary structure: local folding (i.e. -sheet & -helix)

-sheet

 helix

amide bond formation degradation
Amide bond: Formation & Degradation
  • Thermodynamics

Overall rxn is ~ thermoneutral (Δ G ~ 0)

Removal of H2O can drive reaction to amide formation

In aqueous solution, reaction favors acid

  • Kinetics

Very slow reaction

Forward:

slide11
Reverse:

T.I = tetrahedral intermediate

Reaction Coordinate Diagram:

TS2

TS1

ΔG

Charge separation

No resonance

 HIGH ENERGY!

T.I

Large EA for forward reaction

EA

EA

Large EA for reverse reaction

slide12
How do we overcome the barrier?
  • Heat

First “biomimetic” synthesis

Disproved Vital force theory

But, cells operate at a fixed temperature!

  • Activate the acid:

Activated acid

acid

slide13
Activation of carboxylic acid

e.g.

(Inorganic compound raises energy of acid)

Activation of carboxylic acid (towards nucleophilic attack) is one of the most common methods to form an amide (peptide) bond---in nature & in chemical synthesis!

  • Why is the energy (of acid) raised?
slide14
Recall carboxylic acid derivative reactivity:
  • Depends on leaving group:
    • Inductive effects (EWG)
    • Resonance in derivative
    • Leaving group ability
  • Nature uses acyl phosphates, esters (ribosome) & thioesters (NRPS)—more on this later
slide15
Catalysis
    • Lowering of TS energy
    • Usually a Lewis acid

catalyst such as

B(OR)3

  • Another problem with AA’s
    • This doesn’t occur in nature
    • Easy to form 6 membered ring rather than peptide
    • Acid activation can give the same product
slide16
With 20 amino acids  chaos!
  • How do we control reaction to couple 2 AAs together selectively & in the right sequence? & at room temp (in vivo)?
  • Biological systems & synthetic techniques employ protection & activation strategies!
    • For peptide bond formation
    • Many different R groups on amino acids  potential for many side reactions

i.e.,

slide21
Control!
    • Only way to ensure specificity is to orient desired nucleophile (i.e., CO2-) adjacent to desire electrophile (i.e., P)

What about Nonribosomal Peptide Synthase (NRPS)?

    • Uses thioesters
slide22
Once again, we see selectivity in peptide bond formation
    • As in the ribosome, the NRPS can orient the reacting centres in close proximity to eachother, while physically blocking other sites
chemical synthesis of peptides
Chemical Synthesis of Peptides
  • Synthesis of peptides is of great importance to chemistry & biology
  • Why synthesize peptides?
    • Study biological functions (act as hormones, neurotransmitters, antibiotics, anticancer agents, etc)
      • Study potency, selectivity, stability, etc.
    • Structural prediction
      • Three-dimensional structure of peptides (use of NMR, etc.)
  • How?
    • Solution synthesis
    • Solid Phase synthesis
    • Both use same activation & protection strategy
e g isopenicillin n
e.g. isopenicillin N:
  • To study enzyme IPNS, we need to synthesize tripeptide (ACV)
  • Small molecule → use solution technique
  • Synthesis (in soln) can be long & low yielding
  • But, can still produce enough for study
slide26

Protection of Carboxylic acid:

Selective Protection of R group (thiol):

slide27
Both the amino group & carboxylate of cysteine need to couple to another AA
    • But, we can’t react all 3 peptides at once (must be stepwise)
    •  we protect the amino group temporarily, then deprotect later

Protection of the Amine:

(BOC)2O = an anhydride

slide28
Now that we have our protected AA’s, we need to activate the carboxylate towards coupling

Activation & Coupling (see exp 6):

DCC = dicyclohexylcarbodiimide = Coupling reagent that serves to activate carboxylate towards nucleophilic attack