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

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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:

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

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Mechanism: enamine formation

CO2H participates as acid

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% 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!

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  •  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?

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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!

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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

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  • 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):

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  • Primary structure: AA sequence with peptide bonds

  • Secondary structure: local folding (i.e. -sheet & -helix)


 helix

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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


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T.I = tetrahedral intermediate

Reaction Coordinate Diagram:




Charge separation

No resonance



Large EA for forward reaction



Large EA for reverse reaction

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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


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  • Activation of carboxylic acid


    (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?

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  • 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

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  • Catalysis

    • Lowering of TS energy

    • Usually a Lewis acid

      catalyst such as


  • 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

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  • 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


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  • Nature uses protection & activation as part of its strategy to make proteins on the ribosome:

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Nature uses an Ester to activate acid (protein synthesis):


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Each AA is attached to its specific tRNA

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  • A specific example: tyrosyl-tRNA synthase (from tyr)

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  • 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

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  • 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

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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

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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

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Plan for Synthesis:

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Protection of Carboxylic acid:

Selective Protection of R group (thiol):

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  • 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

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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

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