alpha amino acid and peptide synthesis

fermentation

natural amino acids are synthesized this way

PI

the pH at which the net charge of a molecule is 0, the concentration of the dipolar ion is at it’s max and the concentrations of the cationic and anionic form are equal.

HVZ amino acid synthesis limitations

1. Huge NH3 excess outcompetes the formation of the bromo-acid

2. polyalkylation is not an issue - product is not more nucleophilic than ammonium (product is aa and N group is predominately +)

3. Low Yield because the Ca is too crowded for NH3 to attack easily

4. racemic because sp2 enol can attack from either face of the pi bond

5. PBr3 needed bc COOH does not readily enolize

hvz amino acid steps

1. activation: carboxylic OH attacks PBr3 forming acyl bromide R-CO-Br

2. Acyl Bromize tautomerizes to enol form

3. Enol attacks Br2 at Ca

4. Hydrolysis adds at carbonyl carbon and Br is displaced

5. NH3 does SN2 with Br on Ca and amino acid is formed.

amidomalonate amino acid synthesis limitations

1. achiral substrates create racemic products

2. SN2 alkylation fails with tertiary alkyl halides (halide attached to a carbon attached to three other carbons)

3. Fails with amino acids (val, thr, iso) that have side chains that branch immediately at the carbon attached to the a-carbon (ala, phe) (due to SN2 conditions)

amidomalonate amino acid synthesis steps

1. deprotonation of acidic H by strong base (NaOEt)

2. attack of R-halide group by carboanion

3. hydrolysis to get rid of Et groups

4. decarboxylation to remove additional carboxyl group

5. hydrolysis of the amine bond to create amino acid

gabriel amino acid synthesis limitations

1. achiral substrates create racemic products

2. needs a good SN2 electrophile, halide-CH2CO₂Et

3. can only occur with glycine

malonic ester gabriel variant limitations

1. achiral substrates create racemic products

2. SN2 alkylation fails with tertiary alkyl halides (halide attached to a carbon attached to three other carbons)

3. Fails with amino acids (val, thr, iso) that have side chains that branch immediately at the carbon attached to the a-carbon (ala, phe) (due to SN2 conditions)

gabriel amino acid synthesis steps

1. Deprotonation of N-H on phthalamide group by KOtBu

2. N attack on halide- Ch2

3. hydrolysis of the carbonyl group to break C-N bond

4. protonation of NHR group using the new OH creating COO-

5. removal of Et by hydrolysis

6. hydrolysis of second carbonyl group to break the C-N bond

7. Both COO- and NH2 will be protonated by HCl

gabriel malonic ester synthesis steps

1. deprotonation of N-H by strong base (KOtBu)

2. attack of Br-CoetCoet group by N-

3. deprotonation of a-C by NaOet

4. attack of Br-R by carboanion

5. removal of phthalimide group by hydrolysis

6. removal of Et groups by hydrolysis

7. decarboxylation to remove additional carboxyl group

8. hydrolysis of the amine bond to create amino acid

9. double check mechanism