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:
Cordova et al. Chem. Commun., 2005, 2047-2049
L-proline: a 2° amine; popular as an organocatalyst because it forms enamines readily
Mechanism: enamine formation
CO2H participates as acid
% ee of sugar vs % ee of AA
Overall rxn is ~ thermoneutral (Δ G ~ 0)
Removal of H2O can drive reaction to amide formation
In aqueous solution, reaction favors acid
Very slow reaction
T.I = tetrahedral intermediate
Reaction Coordinate Diagram:
Large EA for forward reaction
Large EA for reverse reaction
How do we overcome the barrier?
First “biomimetic” synthesis
Disproved Vital force theory
But, cells operate at a fixed temperature!
(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!
catalyst such as
Nature uses an Ester to activate acid (protein synthesis):
Each AA is attached to its specific tRNA
What about Nonribosomal Peptide Synthase (NRPS)?
Protection of Carboxylic acid:
Selective Protection of R group (thiol):
Protection of the Amine:
(BOC)2O = an anhydride
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