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

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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

Cordova et al. Chem. Commun., 2005, 2047-2049
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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Enantioenrichment
ee of sugar vs ee of AA

• Initially used 80 ee proline to catalyze
  reaction ? gt99 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 gtgt 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)

?-sheet
? helix
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Amide bond Formation Degradation

• Thermodynamics
• Overall rxn is thermoneutral (? G 0)
• Removal of H2O can drive reaction to amide
  formation
• In aqueous solution, reaction favors acid
• Kinetics
• Very slow reaction
• Forward

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• Reverse

T.I tetrahedral intermediate
Reaction Coordinate Diagram
TS2
TS1
?G
Charge separation No resonance ? HIGH ENERGY!
T.I
EA
EA
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
acid
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• 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?

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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
• B(OR)3
• Another problem with AAs
• This doesnt 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
• i.e.,

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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)
Adenylation
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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 cant 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 AAs, 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