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If I could make things in a beaker then surely this I what I would do. Stuff we do in glassware that copies nature.

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Presentation on theme: "If I could make things in a beaker then surely this I what I would do. Stuff we do in glassware that copies nature."— Presentation transcript:

1 If I could make things in a beaker then surely this I what I would do. Stuff we do in glassware that copies nature

2 The Amidomalonate Synthesis Used for synthesizing  -amino acids: Amidomalonate synthesis of amino acids is an extension of the malonic ester synthesis 1.Conversion of diethyl acetamidomalonate into an enolate ion by treatment with a base 2.S N 2 alkylation with a primary alkyl halide 3.Hydrolysis of both the amide group and the esters occurs when the alkylated product is warmed with aqueous acid 4.Decarboxylation takes place to yield an  -amino acid Preparation of aspartic acid from ethyl bromoacetate, BrCH 2 CO 2 Et Reaction yields a racemate 19.3 Synthesis of Amino Acids

3 Reductive Amination of  -Keto Acids Another method of synthesizing  -amino acids Reduces an  -keto acid with ammonia and a reducing agent – Preparation of alanine by treatment of pyruvic acid with ammonia in the presence of NaBH 4 Reaction proceeds through formation of an intermediate imine that is then reduced Reaction yields a racemate Synthesis of Amino Acids

4 During the course of a peptide synthesis, many different amide bonds must be formed in a specific order The solution of the specificity problem is to protect some functional groups rendering them unreactive while leaving exposed only those functional groups wanted for reaction To synthesize Ala-Leu, by coupling alanine with leucine 1.Protect the –NH 2 group of alanine and the –CO 2 H group of leucine to render them unreactive 2.Form the desired amide bond 3.Remove the protecting groups 19.7 Peptide Synthesis

5 Amino- and carboxyl-protecting groups Carboxyl groups are often protected by converting them into methyl or benzyl esters – Both groups are easily introduced by standard methods of ester formation – Both groups are easily removed by mild hydrolysis with aqueous NaOH – Benzyl esters can also be cleaved by catalytic hydrogenolysis of the weak benzylic C-O bond (RCO 2 –CH 2 Ph + H 2 PhCH 3 ) Peptide Synthesis

6 Amino groups are often protected as their tert-butoxycarbonyl amide, or Boc, derivatives – Protecting group is introduced by reaction of the amino acid with di- tert-butyl dicarbonate in a nucleophile acyl substitution reaction – Protecting group is removed by brief treatment with a strong organic acid such as trifluoroacetic acid, CF 3 CO 2 H Peptide Synthesis

7 Five steps are needed to synthesize a dipeptide such as Ala-Leu using the Boc protecting group Peptide Synthesis

8 Merrifield solid-phase method simplifies the synthesis of a large peptide chain Peptide synthesis is carried out with the growing amino acid chain covalently bonded to small beads of polymer resin In the original Merrifield procedure, polystyrene resin was used – 1 of every 100 or so benzene rings contained a chloromethyl (-CH 2 Cl) group – A Boc-protected C-terminal amino acid was bonded to the resin through an ester bond formed by S N 2 reaction Peptide Synthesis

9 With the first amino acid bonded to resin, a repeating series of four steps is carried out to build a peptide Peptide Synthesis


11 The most commonly used resins at present are the Wang resin or the PAM (phenylacetamidomethyl) resin The most commonly used N-protecting group is the fluorenylmethyloxycarbonyl, or Fmoc group Peptide Synthesis

12 Robotic, computer-controlled peptide synthesis used to automatically repeat the coupling, washing, and deprotection steps with different amino acids Each step occurs in high yield The peptide intermediates are never removed from the insoluble polymer until the final step Using this procedure, up to 30 mg of a peptide with 20 amino acids can be routinely prepared Peptide Synthesis

13 Ester and Ether Formation Monosaccharides exhibit chemistry similar to simple alcohols – Usually soluble in water but insoluble in organic solvents – Do not easily form crystals upon removal of water – Can be converted into esters and ethers Ester and ether derivatives are soluble in organic solvents and are easily purified and crystallized 21.6 Reactions of Monosaccharides

14 Esterification is normally carried out by treating the carbohydrate with an acid chloride or acid anhydride in presence of base – All –OH groups react including the anomeric –OH group Reactions of Monosaccharides

15 Carbohydrates are converted into ethers by treatment with an alkyl halide in the presence of base – the Williamson ether synthesis Silver oxide (Ag 2 O) gives high yields of ethers without degrading the sensitive carbohydrate molecules Reactions of Monosaccharides

16 Glycoside Formation Hemiacetals yield acetals upon treatment with an alcohol and an acid catalyst Treatment of monosaccharide hemiacetals with an alcohol and acid catalyst yields an acetal, called a glycoside Reactions of Monosaccharides

17 Reduction of Monosaccharides Treatment of an aldose or ketose with NaBH 4 reduces it to a polyalcohol called an alditol – Reduction occurs by reaction of the open-chain form present in aldehyde/ketone hemiacetal equilibrium – D -Glucitol, also known as D -sorbitol, is present in many fruits and berries and is used as a sweetener and sugar substitute Reactions of Monosaccharides

18 Oxidation of Monosaccharides Aldoses are easily oxidized to yield corresponding carboxylic acids called aldonic acids – Oxidizing agents include: Tollen’s reagent (Ag + in aqueous NH 3 ) – Gives shiny metallic silver mirror on walls of reaction tube or flask Fehling’s reagent (Cu 2+ in aqueous sodium tartrate) – Gives reddish precipitate of Cu 2 O Benedict’s reagent (Cu 2+ in aqueous sodium citrate) – Gives reddish precipitate of Cu 2 O (All three reactions serve as simple chemical tests for reducing sugars) Reactions of Monosaccharides

19 Fructose is a ketose that is a reducing sugar – Undergoes two base-catalyzed keto-enol tautomerizations that result in conversion to a mixture of aldoses (glucose and mannose) Reactions of Monosaccharides

20 Br 2 is a mild oxidant that gives good yields of aldonic acid products – Preferred over Tollen’s reagent because alkaline conditions in Tollen’s oxidation cause decomposition of the carbohydrate Reactions of Monosaccharides

21 Aldoses are oxidized in warm, dilute HNO 3 to dicarboxylic acids called aldaric acids – Both the –CHO group at C1 and the terminal –CH 2 OH group are oxidized Reactions of Monosaccharides

22 Enzymatic oxidation at the –CH 2 OH end of aldoses yields monocarboxylic acids called uronic acids – No affect on the –CHO group Reactions of Monosaccharides

23 The conversion of linoleic acid into elaidic acid Waxes, Fats, and Oils

24 Soap has been known since at least 600 BC Phoenicians prepared a curdy material by boiling goat fat with extracts of wood ash – Wood ash was used as a source of alkali until the early 1800s when Na 2 CO 3 was made by heating sodium sulfate with limestone Cleansing properties of soap were not generally recognized until the 18 th century Soap is a mixture of sodium or potassium salts of long-chain fatty acids produced by hydrolysis (saponification) of animal fat with alkali 23.2 Soap

25 Synthesis of short DNA segments, called oligonucleotides or oligos A nucleotide has multiple reactive sites that must be selectively protected and deprotected at the proper times Coupling of the four nucleotides must be carried out in the proper sequence Automated DNA synthesizers allow the fast and reliable synthesis of DNA segments up to 200 nucleotides in length – A protected nucleotide is covalently bonded to a solid support – One nucleotide at a time is added to the growing chain by the use of a coupling reagent – After the final nucleotide has been added, all the protecting groups are removed and the synthetic DNA is cleaved from the solid support 24.7 DNA Synthesis

26 Step 1 Attachment of a protected deoxynucleoside to a silica (SiO 2 ) support Done through an ester linkage to the 3′ –OH group of the deoxynucleoside Both the 5′ –OH group on the sugar and free –NH 2 groups on the heterocyclic bases must be protected – The deoxyribose 5′ –OH is protected as its p-dimethoxytrityl (DMT) ether DNA Synthesis

27 – Adenine and cytosine bases are protected by benzoyl groups – Guanine is protected by an isobutryl group – Thymine requires no protection DNA Synthesis

28 Step 2 Removal of the DMT protecting group by treatment with dichloroacetic acid in CH 2 Cl 2 – Reaction occurs by an S N 1 mechanism – Reaction proceeds rapidly due to the stability of the tertiary, benzylic dimethoxytrityl cation DNA Synthesis

29 Step 3 Coupling of the polymer-bonded deoxynucleoside with a protected deoxynucleoside containing a phosphoramidite group, R 2 NP(OR) 2, at the 3′ position Takes place in the polar aprotic solvent acetonitrile Requires catalysis by the heterocyclic amine tetrazole Yields a phosphite, P(OR) 3 DNA Synthesis

30 Step 4 Oxidation Phosphite product is oxidized to a phosphate by treatment with iodine in aqueous tetrahydrofuran in the presence of 2,6-dimethylpyridine The cycle is repeated until oligonucleotide chain of the desired sequence is built 1.Deprotection 2.Coupling 3.Oxidation DNA Synthesis

31 Step 5 Final step Removal of all protecting groups Cleavage of the ester bond holding the DNA to the silica – All reactions are done at the same time by treatment with aqueous NH 3 Purification by electrophoresis yields the synthetic DNA DNA Synthesis

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