27.4 Synthesis of Amino Acids. From -Halo Carboxylic Acids CH 3 CHCOH BrO 2NH32NH32NH32NH3 +...

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


CHCH22CC66HH55CHCH33CCNNHH

OO

(90%)(90%)

ExampleExample

OO OO



OO

HBr, HHBr, H22O, heatO, heat

OO OO

HOCCCOHHOCCCOH

CHCH22CC66HH55HH33NN++

ExampleExample

OO OO



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.


NNHH33++

++ CHCH33CCOCCO22HH

OO

Transamination Transamination viavia LL-Glutamic Acid-Glutamic Acid


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

––


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.



NN

––

HH



NN

HH

––



NN

HH

Hydrolysis of the imine function givesHydrolysis of the imine function gives-keto glutarate and -keto glutarate and LL-alanine.-alanine.

––



NN

HH


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++


CHCH22CHCOCHCO22

––

NNHH33++

CHCH22CHCOCHCO22

––

NNHH33++

OO

OO22, enzyme, enzyme


CHCH22CHCOCHCO22

––

NNHH33++

OO

enzymeenzyme

CHCH22CHCOCHCO22

––

NNHH33++

HHOO


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


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


Dopamine is formed Dopamine is formed by decarboxylation by decarboxylation of of LL-DOPA.-DOPA.

OOHH

HH

HHHH

HHHH22NN

HHOO

DopamineDopamine


OOHH

HH

HHHH

OHOHHH22NN

HHOO

NorepinephrineNorepinephrine


OOHH

HH

HHHH

OHOHCHCH33NNHH

HHOO

EpinephrineEpinephrine

27.4 Synthesis of Amino Acids. From -Halo Carboxylic Acids CH 3 CHCOH BrO 2NH32NH32NH32NH3 +...

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Transcript of 27.4 Synthesis of Amino Acids. From -Halo Carboxylic Acids CH 3 CHCOH BrO 2NH32NH32NH32NH3 +...