Carey - Organic Chemistry - sgchapt27

Carey - Organic Chemistry - sgchapt27

(Parte 1 de 2)

CHAPTER 27

The order of decreasing sequence rule precedence is

When the molecule is oriented so that the lowest ranked substituent (H) is held away from us, the order of decreasing precedence traces a clockwise path.

The reason why L-cysteine has the R configuration while all the other L-amino acids have the S configuration lies in the fact that the —CH2SH substituent is the only side chain that outranks —CO2 according to the sequence rule. Remember, rank order is determined by

CH2SH

H3N CO2 Clockwise; therefore R

L-Cysteine

NH3

CO2 HSCH2

HSCH2 H C

BackForwardMain MenuTOCStudy Guide TOCStudent OLCMHHE Website atomic number at the first point of difference, and —C—S outranks —C—O. In all the other amino acids —CO2 outranks the substituent at the stereogenic center. The reversal in the Cahn–Ingold–Prelog descriptor comes not from any change in the spatial arrangement of substituents at the stereogenic center but rather from a reversal in the relative ranks of the carboxylate group and the side chain. (c)The order of decreasing sequence rule precedence in L-methionine is

Sulfur is one atom further removed from the stereogenic center, and so C—O outranks C—C—S.

The absolute configuration is S.

27.2The amino acids in Table 27.1 that have more than one stereogenic center are isoleucine and threonine. The stereogenic centers are marked with an asterisk in the structural formulas shown.

(c)As base is added to the zwitterion, a proton is removed from either of two positions, the ammonium group or the phenolic hydroxyl. The acidities of the two sites are so close that it is not possible to predict with certainty which one is deprotonated preferentially. Thus two structures are plausible for the monoanion:

In fact, the proton on nitrogen is slightly more acidic than the phenolic hydroxyl, as measured by the pKavalues of the following model compounds:

pKa 9.75

pKa 9.27

HO andCH2CHCO2 NH2 OC H2CHCO2 NH3

HO CH2CHCO2 NH3

Isoleucine

CH3CH2CH CH3

NH3 Threonine

CH3CHOH

NH3

CH2CH2SCH3

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27.4At pH 1 the carboxylate oxygen and both nitrogens of lysine are protonated.

As the pH is raised, the carboxyl proton is removed first.

The pKavalue for the first ionization of lysine is 2.18 (from Table 27.3), and so this process is virtually complete when the pH is greater than this value.

The second pKavalue for lysine is 8.95. This is a fairly typical value for the second pKaof amino acids and likely corresponds to proton removal from the nitrogen on the carbon. The species that results is the predominant one at pH 9.

The pKavalue for the third ionization of lysine is 10.53. This value is fairly high compared with those of most of the amino acids in Tables 27.1 to 27.3 and suggests that this proton is removed from the nitrogen of the side chain. The species that results is the major species present at pH values greater than 10.53.

27.5To convert 3-methylbutanoic acid to valine, a leaving group must be introduced at the carbon prior to displacement by ammonia. This is best accomplished by bromination under the conditions of the Hell–Volhard–Zelinsky reaction.

NH3

3-Methylbutanoicacid 2-Bromo-3-methylbutanoicacid

Valine

(Principal form at pH 13)

(Principal form at pH 9)

NH3 (Principal form at pH 1)

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Valine has been prepared by this method. The Hell–Volhard–Zelinsky reaction was carried out in 8% yield, but reaction of the -bromo acid with ammonia was not very efficient, valine being isolated in only 48% yield in this step.

27.6 In the Strecker synthesis an aldehyde is treated with ammonia and a source of cyanide ion. The resulting amino nitrile is hydrolyzed to an amino acid.

As actually carried out, the aldehyde was converted to the amino nitrile by treatment with an aqueous solution containing ammonium chloride and potassium cyanide. Hydrolysis was achieved in aqueous hydrochloric acid and gave valine as its hydrochloride salt in 65% overall yield.

27.7The alkyl halide with which the anion of diethyl acetamidomalonate is treated is 2-bromopropane.

This is the difficult step in the synthesis; it requires a nucleophilic substitution of the SN2 type involving a secondary alkyl halide. Competition of elimination with substitution results in only a 37% observed yield of alkylated diethyl acetamidomalonate.

Hydrolysis and decarboxylation of the alkylated derivative are straightforward and proceed in 85% yield to give valine.

An amino acid reacts with this triketone to form an imine. O

Triketo form of ninhydrin

NCHCO2

RO Imine -Amino acid

RCHCO2 NH3

Triketo form ofninhydrinHydrated form of ninhydrin

2-AminoisopropylmalonicacidDiethyl acetamidoisopropylmalonate

NaOCH2CH3

CH3CH2OH Diethyl acetamidomalonate

Diethyl acetamidoisopropylmalonate

2-Bromopropane (CH3)2CHBr

NH3 2-Methylpropanal Valine

2-Amino-3- methylbutanenitrile

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This imine then undergoes decarboxylation.

The anion that results from the decarboxylation step is then protonated. The product is shown as its diketo form but probably exists as an enol.

Hydrolysis of the imine function gives an aldehyde and a compound having a free amino group. This amine then reacts with a second molecule of the triketo form of ninhydrin to give an imine.

Proton abstraction from the neutral imine gives its conjugate base, which is a violet dye.

27.9The carbon that bears the amino group of 4-aminobutanoic acid corresponds to the carbon of an -amino acid.

arises by decarboxylation ofCH2CH2CH2CO2

NH3 4-Aminobutanoic acid

NH3 Glutamic acid

H2O O

Violet dye

H2O O

NH2

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The dipeptide is written in its anionic form because the carboxyl group of the side chain is ionized at pH 7. Alternatively, it could have been written as a neutral zwitterion with a

CH2CH2CO2H side chain. (e)The peptide bond in Lys-Gly is between the carboxyl group of lysine and the amino group of glycine.

The amino group of the lysine side chain is protonated at pH 7, and so the dipeptide is written here in its cationic form. It could have also been written as a neutral zwitterion with the side chain H2NCH2CH2CH2CH2. (f)Both amino acids are alanine in D-Ala-D-Ala. The fact that they have the Dconfiguration has no effect on the constitution of the dipeptide.

Alanine Alanine

Lysine

NHCH2CO2 Glycine

Glycine Glutamic acid

Phenylalanine

NHCHCO2

CH3 Alanine

AFH3NCHC CH3

Alanine

NHCHCO2

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27.1(b)When amino acid residues in a dipeptide are indicated without a prefix, it is assumed that the configuration at the carbon atom is L. For all amino acids except cysteine, the Lconfiguration corresponds to S. The stereochemistry of Ala-Phe may therefore be indicated for the zigzag conformation as shown.

The Lconfiguration corresponds to Sfor each of the stereogenic centers in Ala-Phe. (c)Similarly, Phe-Ala has its substituent at the N-terminal amino acid directed away from us, whereas the C-terminal side chain is pointing toward us, and the Lconfiguration corresponds to Sfor each stereogenic center.

(d)There is only one stereogenic center in Gly-Glu. It has the L(or S) configuration.

(e)In order for the N-terminal amino acid in Lys-Gly to have the L(or S) configuration, its side chain must be directed away from us in the conformation indicated.

(f)The configuration at both -carbon atoms in D-Ala-D-Ala is exactly the reverse of the configuration of the stereogenic centers in parts (a) through (e). Both stereogenic centers have the D (or R) configuration.

27.12Figure 27.7 in the text gives the structure of leucine enkephalin. Methionine enkephalin differs from it only with respect to the C-terminal amino acid. The amino acid sequences of the two pentapeptides are

The peptide sequence of a polypeptide can also be expressed using the one-letter abbreviations listed in text Table 27.1. Methionine enkephalin becomes YGGFM.

Tyr-Gly-Gly-Phe-LeuLeucine enkephalin

Tyr-Gly-Gly-Phe-Met Methionine enkephalin

H3N H

H CH3

H CO2

H3CO

CO2

CO2

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(G), phenylalanine (F), and valine (V). Remember that the order is important; AG is not the same peptide as GA. Using the one-letter abbreviations for each amino acid the possibilities are

27.14Chymotrypsin cleaves a peptide selectively at the carboxyl group of amino acids that have aromatic

beVF.

The possible sequences for the unknown tetrapeptide are VFAG and VFGA.

27.15The Edman degradation removes the N-terminal amino acid, which is identified as a phenylthiohydantoin derivative. The first Edman degradation of Val-Phe-Gly-Ala gives the phenylthiohydantoin derived from valine; the second gives the phenylthiohydantoin derived from phenylalanine.

27.16 Lysine has two amino groups. Both amino functions are converted to amides on reaction with benzyloxycarbonyl chloride.

27.17The peptide bond of Ala-Leu connects the carboxyl group of alanine and the amino group of leucine.

We therefore need to protect the amino group of alanine and the carboxyl group of leucine. Protect the amino group of alanine as its benzyloxycarbonyl derivative.

CH3 Alanine

Benzyloxycarbonyl chloride

Z-Protected alanine

Val-Phe-Gly-Ala Phe-Gly-AlafirstEdman degradation second Edman degradation

ON C6H5N

NHCHCO H3NCHC

(CH3)2CH Valinylphenylalanine (VF)

Rest of peptideRest of peptidechymotrypsin

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Protect the carboxyl group of leucine as its benzyl ester.

Coupling of the two amino acids is achieved by N,N′-dicyclohexylcarbodiimide (DCCI)-promoted amide bond formation between the free amino group of leucine benzyl ester and the free carboxyl group of Z-protected alanine.

Both the benzyloxycarbonyl protecting group and the benzyl ester protecting group may be removed by hydrogenolysis over palladium. This step completes the synthesis of Ala-Leu.

27.18As in the DCCI-promoted coupling of amino acids, the first step is the addition of the Z-protected amino acid to DCCI to give an O-acylisourea.

This O-acylisourea is attacked by p-nitrophenol to give the p-nitrophenyl ester of the Z-protected amino acid.

27.19To add a leucine residue to the N terminus of the ethyl ester of Z-Phe-Gly, the benzyloxycarbonyl protecting group must first be removed. This can be accomplished by hydrogenolysis.

Z-Protected ethyl ester of Phe-GlyPhe-Gly ethyl ester

Z-Protected amino acid

O-Acylisourea R

ZNHCHCOO C NC6H11

O H2, Pd

Z-Protected alanine

Leucine benzyl ester

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The reaction shown has been carried out in 100% yield. Alternatively, the benzyloxycarbonyl protecting group may be removed by treatment with hydrogen bromide in acetic acid. This latter route has also been reported in the chemical literature and gives the hydrobromide salt of Phe-Gly ethyl ester in 82% yield.

Once the protecting group has been removed, the ethyl ester of Phe-Gly is allowed to react with the p-nitrophenyl ester of Z-protected leucine to form the protected tripeptide. Hydrogenolysis of the Z-protected tripeptide gives Leu-Phe-Gly as its ethyl ester.

27.20Amino acid residues are added by beginning at the C terminus in the Merrifield solid-phase approach to peptide synthesis. Thus the synthesis of Phe-Gly requires glycine to be anchored to the solid support. Begin by protecting glycine as its tert-butoxycarbonyl (Boc) derivative.

The protected glycine is attached via its carboxylate anion to the solid support.

Boc-Protected glycine tert-Butoxycarbonylchloride Glycine Boc-Protected glycine

Z-protected Leu-Phe-Gly ethyl ester p-Nitrophenyl ester ofZ-protected leucine Phe-Gly ethyl ester

Leu-Phe-Gly ethyl ester

O H2, Pd

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The amino group of glycine is then exposed by removal of the protecting group. Typical conditions for this step involve treatment with hydrogen chloride in acetic acid.

To attach phenylalanine to resin-bound glycine, we must first protect the amino group of phenylalanine. A Boc protecting group is appropriate.

Peptide bond formation occurs when the resin-bound glycine and Boc-protected phenylalanine are combined in the presence of DCCI.

Remove the Boc group with HCl and then treat with HBr in trifluoroacetic acid to cleave Phe-Gly from the solid support.

27.21The numbering of the ring in uracil and its derivatives parallels that in pyrimidine.

Pyrimidine

Uracil

5-Fluorouracil

Boc-Protected, resin-bound Phe-Gly resin1. HCl, acetic acid 2. HBr, trifluoroacetic acidH3NCHCNHCH2CO2

H2NCH2COCH2 resinO resinDCCI

Resin-bound glycine tert-Butoxycarbonylchloride Phenylalanine Boc-Protected phenylalanine acetic acid

Boc-Protected, resin-bound glycineResin-bound glycine

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(c)Guanosine is present in RNAand so is a guanine nucleoside of D-ribose.

27.23Table 27.4 in the text lists the messenger RNAcodons for the various amino acids. The codons for valine and for glutamic acid are:

Valine: GUU GUA GUC GUG Glutamic acid: GAA GAG

As can be seen, the codons for glutamic acid (GAAand GAG) are very similar to two of the codons (GUAand GUG) for valine. Replacement of adenine in the glutamic acid codons by uracil causes valine to be incorporated into hemoglobin instead of glutamic acid and is responsible for the sickle cell trait.

27.24The protonated form of imidazole represented by structure Ais stabilized by delocalization of the lone pair of one of the nitrogens. The positive charge is shared by both nitrogens.

The positive charge in structure B is localized on a single nitrogen. Resonance stabilization of the type shown in structure Ais not possible.

Structure Ais the more stable protonated form. B

HN CH2CHC NH

HN CH2CHC NH

HN CH2CHC NH

HOCH2

N N NH2N

HOCH2

NH2

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27.25The following outlines a synthesis of -alanine in which conjugate addition to acrylonitrile plays a key role.

Addition of ammonia to acrylonitrile has been carried out in modest yield (31–3%). Hydrolysis of the nitrile group can be accomplished in the presence of either acids or bases. Hydrolysis in the pres- ence of Ba(OH)2has been reported in the literature to give -alanine in 85–90% yield.

In the second step of the synthesis, compound Ais subjected to ester saponification. Following acidification, the corresponding diacid (compound B) is isolated.

Compound B is readily brominated at its -carbon atom by way of the corresponding enol form.

WhencompoundCisheated,itundergoesdecarboxylationtogivean -bromocarboxylicacid.

(Parte 1 de 2)

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