Bài giảng Organic Chemistry - Chapter 26: Amino Acids

Chapter 26: Amino AcidsIn nature, the most common representatives are 2-amino acids (α-amino acids) with the general formula RCH(NH2)COOH.R = alkyl, acyl, amino, hydroxy, mercapto, sulfide, carboxy, guanidino, or imidazolyl groupsAmino acids give rise to polyamides: polypeptides (proteins, enzymes)Amide linkageFor proteins, n ≥ 8000 and MW > 1,000,000. Proteins are crucial for transport (O2, hemoglobin), energy storage, catalysis, control of reactions, template for RNA/DNA action, antibodies, etc. More than 500 natural amino acids known Among the 20 main amino acids, 8 cannot be synthesized by the body (essential amino acids)Names: We use common names. α-Stereocenter usually S (or, old nomenclature, L, from L-glyceraldehyde) Essential amino acidsUsed in reversible disulfide bridgingMonosodium glutamate (MSG)R !Amino acids are acidic and basic: Exist aszwitterionspKa = 9-10pKa = 2-3ZwitterionGlycine as a zwitterionH3NCH2COO–+Synthesis of Amino AcidsHell-Volhard-Zelinsky, then Amination(racemic)Yields not greatBetter: Gabriel Synthesis ( RX  RNH2)2. Gabriel SynthesisMade from malonic ester by radical bromination (hν)General:(in combination with malonic ester synthesis)3. Strecker SynthesisRecall: When HCN is used in the presence of ammonia,e.g., NH4CN or NH4Cl/NaCN, it adds to the corresponding imine to give an aminonitrile:Adolf Strecker (1822–1871)StreckerRemember reductive amination and Mannich reaction!PeptidesAmino acids form peptide bondsDimer = dipeptide, trimer = tripeptide, and so on. The chain is arranged in space by H bonding, electrostatic attractions, hydrophobic-hydrophilic interactions (with water), and rigidity of the amide bond. Rigidity and planarity of the peptide bondsp2Transto the leftto the rightMain chainR, R’, R”, etc. are called the side chains. All stereocenters are assumed to be S.Amino acid (linear) sequence = primary structure.Three dimensional arrangement: secondary, tertiary, and quaternary structure.Secondary Structure: H-bonding array Pleated Sheet StructureTwo frequent arrangements α–HelixRight-handed spiral held by intramolecular H bonds3.6 Amino acids per turn; repeat distance 5.4 ÅTertiary Structure: three-dimensional array (further folding, coiling, and aggregation. Denaturation is the breakdown of this structure.)Example: superhelixTypical of fibrous proteins, such as myosin (in muscle), fibrin (in blood clots), and α-keratin (in wool, nails, and hair).Tertiary structure gives rise to pockets: Active sites or binding sites that provide perfect fit for substrates, e.g., drugs.Example: digestive enzyme chymotrypsin,a three-polypeptide molecule interconnected via disulfide bonds; 245 amino acids.Quaternary Structure: aggregation of several unitsExample: hemoglobin, the iron-containing oxygen-transport protein in the red blood cells of vertebratesSynthesis of PolypeptidesProtecting groups: Why? We need selectivity in building up the peptide sequence. Consider the synthesis of glycylalanine by dehydration of the component amino acids:Hence, amino end of Gly and carboxy end of Ala have to be protected.a. Amino end protection with Phenylmethoxycarbonyl(carbobenzoxy, Cbz)Like the hydrogenolysis of benzylic ethersUnstableSee Hofmann rearrangementb. Amino end protection with Tert-butyloxycarbonyl(Boc)(via tert-Bu cation)c. Carboxy Protection: esterificationSimple methyl or ethyl esters. Alternatively, to avoid base (or acid) hydrolysis, benzyl esters.ProtectionDeprotectionTrpTrp-OBzFormation of the amide bond for peptides uses a mild coupling reagent: dicycloheylcarbodiimide (DCC) as a dehydrating speciesMechanism: example-synthesis of Ala-Gly1. Activation of carboxy group (recall activations to alkanoyl halides or anhydrides) of N-protected AlaLooks like an anhydride2. Coupling with amino end of carboxy end protected Gly to give dipeptidePeptide bondt-Boc-Ala-Gly-OCH3Ala-GlyDNA and RNA: Natural Polymers Containing the Blueprint of LifeLife (in this context) is the synthesis of proteins, which run our (any) body. The information for protein synthesis is stored in DNA: deoxyribose nucleic acidThe information is “read” (expressed) with the help of RNA: ribonucleic acidExample: DNA chain.Backbone is a polymer of the sugar linked by phosphate groups as a diester.Structure of Nucleic AcidsPhosphoricacidThe information lies in the sequence of the bases attached to the anomeric carbon: There are four bases.Bases: All are aromatic heterocyclesFor DNA:For RNA: C, A, G andInstead of thymineTo visualize the aromaticity in the cyclic amides, formulate the dipolar resonance form, e.g. cytosine:Can hydrolyze to uracilmutation; fixed by repair enzyme, hence no U in DNA, but TPrimary structureDNA forms extraordinarily long chains (up to several centimeters) with molecular weights of as high as 150 billion. Like proteins, they adoptsecondary and tertiary structures: double helix! Why?RNA has OH here. Causes selfdestruction by hydrolysis after useWatson-Crick: hydrogen bonding through complementary pairs. In DNA: A-T, G-C (1:1 ratio)ATCGGives rise to double helix.......5.8 kcal mol-14.3 kcal mol-1Francis Crick 1916–2004 James Watson b. 1928 NP 1962(medicine)Complementarity:Replication of DNA in ProcreationIn humans 3.2 billion base pairs; error rate 1 in 10 billion!Protein synthesis Base sequence contains the informationThree-base sequences (codons) translate into a specific amino acid. DNA  mRNA  polypeptideMessenger RNAmRNA copies (as a complementary sequence, “codons”) a piece of DNA to be used to construct a particular peptide; transfer RNA (tRNA) containing complementary (to mRNA) 3-base sequences (“anticodons”) delivers the amino acids, and a catalyst (ribosome) puts the peptide together.Three base code (codon): # of combinations 43 = 64  more than enough for 20 amino acidsThe Human Genome(2007)Deciphering the sequence of 3.2 billion base pairsGenetic engineering: gene modifications, gene removals, new organisms, crops, foods, enzymes, medicines...The Future ?May the Coulomb force be with you!FarewellMay 6, 1919