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27.427.4Synthesis of Amino AcidsSynthesis of Amino Acids
From From -Halo Carboxylic Acids-Halo Carboxylic Acids
CHCH33CHCOHCHCOH
BrBr
OO
22NNHH33++HH22OO
CHCH33CHCOCHCO
NNHH33
OO
++
––
(65-70%)(65-70%)
++ NNHH44BrBr
Strecker SynthesisStrecker Synthesis
NNHH44ClCl
NaCNNaCN
CHCH33CHCOCHCO
NNHH33
OO
++
–– (52-60%)(52-60%)
CHCH33CHCH
OO
1. H1. H22O, HCl, heatO, HCl, heat
2. HO2. HO––
CHCH33CHCCHC
NNHH22
NN
Using Diethyl AcetamidomalonateUsing Diethyl Acetamidomalonate
CCCC
CCOCHOCH22CHCH33
HH
OO OO
CHCH33CHCH22OO
CHCH33CCNNHH
OO
Can be used in the same manner as diethyl Can be used in the same manner as diethyl malonate (Section 21.7).malonate (Section 21.7).
ExampleExample
1. NaOCH1. NaOCH22CHCH33
2. 2. CC66HH55CHCH22ClCl
OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
HHCHCH33CCNNHH
OO
OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
CHCH22CC66HH55CHCH33CCNNHH
OO
(90%)(90%)
ExampleExample
OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
CHCH22CC66HH55CHCH33CCNNHH
OO
HBr, HHBr, H22O, heatO, heat
OO OO
HOCCCOHHOCCCOH
CHCH22CC66HH55HH33NN++
ExampleExample
OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
CHCH22CC66HH55CHCH33CCNNHH
OO
HBr, HHBr, H22O, heatO, heat
OO
HCCOHHCCOH
CHCH22CC66HH55HH33NN++
(65%)(65%)
27.527.5Reactions of Amino AcidsReactions of Amino Acids
Acylation of Amino GroupAcylation of Amino Group
The amino nitrogen of an amino acid can be The amino nitrogen of an amino acid can be converted to an amide with the customary converted to an amide with the customary acylating agents.acylating agents.
OO
HH33NNCHCH22COCO––++++ CHCH33COCCHCOCCH33
OO OO
CHCH33CCNNHCHHCH22COHCOH
OO OO
(89-92%)(89-92%)
Esterification of Carboxyl GroupEsterification of Carboxyl Group
The carboxyl group of an amino acid can be The carboxyl group of an amino acid can be converted to an ester. The following illustrates converted to an ester. The following illustrates Fischer esterification of alanine. Fischer esterification of alanine.
++ CHCH33CHCH22OHOH
(90-95%)(90-95%)
HClHCl
OO
HH33NNCHCOCHCO––++
CHCH33
OO
HH33NNCHCOCHCHCOCH22CHCH33
++
CHCH33
––ClCl
Ninhydrin TestNinhydrin Test
Amino acids are detected by the formation of a purple Amino acids are detected by the formation of a purple color on treatment with color on treatment with ninhydrinninhydrin..
OHOH
OO
OO
OHOH++
OO
HH33NNCHCOCHCO––++
RR
OO OO
OO
NN
OO
––
OO
RCHRCH ++ COCO22 ++ HH22OO ++
27.627.6Some Biochemical ReactionsSome Biochemical Reactions
of Amino Acidsof Amino Acids
Biosynthesis of Biosynthesis of LL-Glutamic Acid-Glutamic Acid
This reaction is the biochemical analog of reductive This reaction is the biochemical analog of reductive amination (Section 22.11).amination (Section 22.11).
HOHO22CCHCCH22CHCH22CCOCCO22HH
OO
NNHH33++
enzymes andenzymes andreducing coenzymesreducing coenzymes
HOHO22CCHCCH22CHCH22CHCOCHCO22––
NNHH33++
Transamination Transamination viavia LL-Glutamic Acid-Glutamic Acid
LL-Glutamic acid acts as a source of the amine -Glutamic acid acts as a source of the amine group in the biochemical conversion of group in the biochemical conversion of -keto-ketoacids to other amino acids. In the exampleacids to other amino acids. In the exampleshown, pyruvic acid is converted to shown, pyruvic acid is converted to LL-alanine.-alanine.
HOHO22CCHCCH22CHCH22CHCOCHCO22––
NNHH33++
++ CHCH33CCOCCO22HH
OO
Transamination Transamination viavia LL-Glutamic Acid-Glutamic Acid
HOHO22CCHCCH22CHCH22CHCOCHCO22––
NNHH33++
++ CHCH33CCOCCO22HH
OO
enzymesenzymes
HOHO22CCHCCH22CHCH22CCOCCO22HH
OO
++ CHCH33CHCOCHCO22
––
NNHH33++
MechanismMechanism
HOHO22CCHCCH22CHCH22CCHHCOCO22––
NNHH33++
++ CHCH33CCOCCO22HH
OO
The first step is imine formation between theThe first step is imine formation between theamino group of amino group of LL-glutamic acid and pyruvic-glutamic acid and pyruvicacid.acid.
MechanismMechanism
HOHO22CCHCCH22CHCH22CCHHCOCO22––
NNHH33++
++ CHCH33CCOCCO22HH
OO
CHCH33CCOCCO22––
HOHO22CCHCCH22CHCH22CCHHCOCO22
NN
––
CHCH33CCOCCO22––
HOHO22CCHCCH22CHCH22CCOCCO22
NN
––
HH
Formation of the imine is followed by Formation of the imine is followed by protonproton removal at one carbon and removal at one carbon and protonationprotonation of another of another carbon.carbon.
CHCH33CCOCCO22––
HOHO22CCHCCH22CHCH22CCOCCO22
NN
––
HH
CHCH33CCOCCO22––
HOHO22CCHCCH22CHCH22CCOCCO22
NN
HH
––
CHCH33CCOCCO22––
HOHO22CCHCCH22CHCH22CCOCCO22
NN
HH
Hydrolysis of the imine function givesHydrolysis of the imine function gives-keto glutarate and -keto glutarate and LL-alanine.-alanine.
––
CHCH33CCOCCO22––
HOHO22CCHCCH22CHCH22CCOCCO22
NN
HH
HOHO22CCHCCH22CHCH22CCOCCO22
OO
––CHCH33CCOCCO22
––
NNHH33
HH
++
++
HH22OO
LL--Tyrosine is biosynthesized from Tyrosine is biosynthesized from LL--phenylalanine.phenylalanine.A key step is epoxidation of the aromatic ring to A key step is epoxidation of the aromatic ring to give an give an arene oxidearene oxide intermediate. intermediate.
Biosynthesis of Biosynthesis of LL-Tyrosine-Tyrosine
CHCH22CHCOCHCO22
––
NNHH33++
Biosynthesis of Biosynthesis of LL-Tyrosine-Tyrosine
CHCH22CHCOCHCO22
––
NNHH33++
CHCH22CHCOCHCO22
––
NNHH33++
OO
OO22, enzyme, enzyme
Biosynthesis of Biosynthesis of LL-Tyrosine-Tyrosine
CHCH22CHCOCHCO22
––
NNHH33++
OO
enzymeenzyme
CHCH22CHCOCHCO22
––
NNHH33++
HHOO
Biosynthesis of Biosynthesis of LL-Tyrosine-Tyrosine
Conversion to Conversion to LL-tyrosine is one of the major -tyrosine is one of the major metabolic pathways of metabolic pathways of LL-phenylalanine.-phenylalanine.
Individuals who lack the enzymes necessary to Individuals who lack the enzymes necessary to convert convert LL-phenylalanine to -phenylalanine to LL-tyrosine can suffer -tyrosine can suffer from PKU disease. In PKU disease, from PKU disease. In PKU disease, LL--phenylalanine is diverted to a pathway leading phenylalanine is diverted to a pathway leading to phenylpyruvic acid, which is toxic.to phenylpyruvic acid, which is toxic.
Newborns are routinely tested for PKU disease. Newborns are routinely tested for PKU disease. Treatment consists of reducing their dietary Treatment consists of reducing their dietary intake of phenylalanine-rich proteins.intake of phenylalanine-rich proteins.
DecarboxylationDecarboxylation
Decarboxylation is a common reaction of Decarboxylation is a common reaction of --amino acids. An example is the conversion of amino acids. An example is the conversion of LL-histidine to histamine. Antihistamines act by -histidine to histamine. Antihistamines act by blocking the action of histamine.blocking the action of histamine.
CHCH22CHCOCHCO22
––
NNHH33++NNHH
NN
DecarboxylationDecarboxylation
CHCH22CHCOCHCO22
––
NNHH33++NNHH
NN
––COCO22, enzymes, enzymes
CHCH22CHCH2 2 NNHH22
NNHH
NN
NeurotransmittersNeurotransmitters
The chemistry of the The chemistry of the brain and central brain and central nervous system is nervous system is affected by affected by neurotransmitters.neurotransmitters.
Several important Several important neurotransmitters neurotransmitters are biosynthesized are biosynthesized from from LL-tyrosine.-tyrosine.
OOHH
COCO22––
HHHH
HHHH33NN
++
LL-Tyrosine-Tyrosine
NeurotransmittersNeurotransmitters
The common name The common name of this compound is of this compound is LL-DOPA. It occurs -DOPA. It occurs naturally in the naturally in the brain. It is widely brain. It is widely prescribed to reduce prescribed to reduce the symptoms of the symptoms of Parkinsonism.Parkinsonism.
OOHH
COCO22––
HHHH
HHHH33NN
++
LL-3,4-Dihydroxyphenylalanine-3,4-Dihydroxyphenylalanine
HHOO
NeurotransmittersNeurotransmitters
Dopamine is formed Dopamine is formed by decarboxylation by decarboxylation of of LL-DOPA.-DOPA.
OOHH
HH
HHHH
HHHH22NN
HHOO
DopamineDopamine
NeurotransmittersNeurotransmitters
OOHH
HH
HHHH
OHOHHH22NN
HHOO
NorepinephrineNorepinephrine
NeurotransmittersNeurotransmitters
OOHH
HH
HHHH
OHOHCHCH33NNHH
HHOO
EpinephrineEpinephrine