Amino Acids

By G.C. BARRETT

Introduction

The 1994 literature covering the amino acids, from the point of view of their chemistry and biochemistry, is dealt with in this Chapter. The approach adopted is identical to that used in all previous Volumes of this Specialist Periodical Report. The Chapter concentrates on the literature covering the natural occurrence, chemistry, and analysis methodology for amino acids. Routine literature covering the natural distribution of well-known amino acids is excluded. Patent literature deals with material that also finds its way into the conventional literature, and is therefore excluded from this Chapter. It is easily reached through the appropriate sections of Chemical Abstracts (Section 34 in particular). The flow of Journal papers and secondary literature continues to accelerate, as far as the amino acids are concerned, and papers have been collected for this Chapter from major Journals and from Chemical Abstracts [to Volume 122 (1995), issue 91. Where it is helpful to refer to earlier Volumes of this Specialist Periodical Report, the formula (see Vol. 23, p. 3) is used. Most of the papers cited are only briefly described, so that adequate commentary can be offered for particular papers presenting significant advances in synthetic and analytical methodology relating to the amino acids, with mechanistically-interesting chemistry being given prominence. The coverage adopts the usual meaning of the term amino acids, i.e. aminoalkanoic acids H3N+ (R1R2C),C02-. Many conceivable structural types (for example, benzene derivatives carrying amino and carboxy groups) are excluded. Representative citations are offered, of analogues in which the carboxy group is replaced by a phosphorus oxyacid equivalent, H3N+-(R1R2C),P(0)(OH)(O-),1-4 e.g. (1S,2S)-phosphothreonine$ have important research applications; even the boron analogue R3N(BHR1),,-C02R may hold some similar p r o m i ~ e . ~

Textbooks and Reviews

A substantial source of information on instrumental and analytical protocols6 includes material on the amino acids. A similarly thorough coverage of topics in the synthesis of amino acids has been published.
1

Amino Acids, Peptides and Proteins

Several reviews will be found in appropriate sections of this Chapter, though others of a more general nature are collected here; these cover a-aminoisobutyric acid,8 carboranylalanine in neutron capture therapy: cyclopropane-based amino acids,1 1-aminocyclopropanecarboxylic acid synthesis,' cyclobutane-based amino acids,I2 synthesis of heterocyclic amino acids,13 uses of amino acid esters as chiral auxiliaries in organic synthesis,14 uses of a-amino acids in aminosugar synthesis,15and stereochemical details of metabolic reactions of amino acids. l 6 3
Naturally Occurring Amino Acids

3.1 Isolation of Amino Acids from Natural Sources - All fermentative processes for the production of amino acids require routine isolation of the product, and, like the production of amino acids through protein hydrolysis, the separation of mixtures is a common concluding stage to the process. This section is intended to select some less routine aspects of the isolation of amino acids, particularly those unexpected outcomes of otherwise straightforward procedures. Protein hydrolysis is most commonly accomplished using hydrochloric or methanesulfonic acids, but several alternative protocols have been suggested; mercaptoethanesulfonic acid (160-180') has been found to be effective.l 7 Continuous concentration of amino acids using a liquid emulsion membrane with a cation extractant, di-2-ethylhexylphosphoricacid, has been described. l 8 Preparative chromatographic isolation (gel filtration and partition) of pyridinoline' and of hydroxylysyl- and lysyl-pyridinolines20from biological fluids, and preparative chromatography of benzyl esters of basic amino acids2' and Nbenzyloxycarbonyl amino acids (Z-amino acids)22illustrate standard methods.

3.2 Occurrence of Known Amino Acids - Where common amino acids are found in meteorites, and in ancient fossils, an obvious first question, but one only recently addressed in a rational scientific manner, is: is the amino acid indigenous or has it been introduced subsequently? Further studies (see Vo1.25, p.3) based on sensitive GC-MS isotope-analytical techniques confirm the indigeneity of amino acids through identical 613C and 615N values for D- and L-enantiomers of a particular amino acid in thoroughly-cleaned 7000-1 O5 y samples, and in Pleistocene fossils.23Quaternary land snails given more detailed confirm this diagnostic test as far as neutral amino acids are concerned, but differing 613C values for D- and L-enantiomers of aspartic and glutamic acids introduce an element of doubt; presumably these amino acids as constituents of shell protein are subject to more complex diagenesis. Contemporary natural sources that have been shown to contain unusually interesting, though known, amino acids include D-aspartic acid (supplied by intestinal bacteria) in appreciable quantities in Octopus v ~ l g a r i sthe~ , ~ antimicrobial and antioxidant N-(p-coumary1)pipecolic acid in rhizomes of Cirsium brevicaule.26 Both D- and L-tert-leucine appear, together with D-kynurenine, as constituents of discodermin E, from the marine sponge Discodermia k i i e n ~ i s . ~ ~ a-Methylcysteine appears in condensed form in the cryoprotective agent

1: Amino Acids

thiazohalostatin (1) from Actinomadura.28 Another peptide from Verticilliurn coccosporum has been discovered to contain 2-amino-8-oxo-9-hydroxydecanoic acid.29 The presence of p-alanine in Clitocybe acromelalga, as its L-glutamide derivative30 adds another natural location to those already established for this P-amino acid. y-Hydroxy-L-glutamic acid occurs in bulbs of Hemerocallis longituba in the form of the amide, longitubanine (2; R = OH).31 Synthetic cis-4-methylproline is physically different from the compound located over the years in various natural sources, calling for some reconsideration of the structural assignment^.^^ The assessment of crosslinks that develop in vivo in proteins of higher species, as a result of ageing or disease, has become an important diagnostic criterion, and pyridinium crosslink^^^ and dityrosine crosslinks have been identified in bovine thyroglobulin.34 3.3 New Naturally Occurring Amino Acids - Mycestericins from Mycelia sterilia are potent immunosuppressants that have been shown to be hydroxylated a-hydroxymethyl-a-aminoalkanoic acids (3-5) of extraordinary types.35 Another new acyclic aliphatic a-amino acid also owes its fascination to the functional group that it contains, the first natural azoxy-containing antifungal agent, Lazoxybacilin (6), from Bacillus cereus NR299 1.36 Sphingofungins (7) are a new family of antifungal metabolites from Aspergillus fumigatus ATCC 20857.37New opines (8)38 and piperidine 2,4,5-tricarboxylic acid (9), are further metabolites (see from Clitocybe a ~ r o m e l a l g a ~ ~also Ref.30). Five new compounds (e.g., 10 and stereoisomers) related to domoic acid have been isolated from mussels.40

3.4 New Amino Acids from Hydrolysates - y-Hydroxy-tert-leucine is a constituent of polytheonamides A-C from the marine sponge Theonella swinhoei? and Zwittermicin A from Bacillus cereus is (1 l).42 The other new amino acids are mostly lactams condensed into more complex structures; the 2,5dihydrofuryl-y-lactams, fulvanines D and E (12), (1 3) from Hemerocallis f ~ l v a , 4 ~ anchinopeptolides 5-D (14) from the sponge Anchinoe tenacior,44 the antibiotic magnesidin A (15) from Vibrio g ~ z o g e n e s ,and the novel siderophore ~~ vibrioferrin (16) that develops in Vibrio parahuemolyticus in response to limitation of Fe in the culture
4

Chemical Synthesis and Resolution of Amino Acids

4.1 General Methods for the Synthesis of a-Amino Acids - The term general methods has been attached to a group of reactions that have become familiar through use for many years; these are covered in this Section as far as the a-amino acids are concerned. Relatively few novel ideas have been introduced under this heading in recent years, and those that have, have been concerned with the burgeoning area of Asymmetric Synthesis. Although given a Section of their own in this Chapter

Amino Acids, Peptides and Proteins

(3) R = ( , , R)-CH=CH(CH2)&H =CHCH(OH)(CH2)5Me. R = OH (4) R = ()-CH =CH(CH,)6CH(OH)(CH2)5Me; R2 = OH (5) R = (CH2)8CO(CH2)5Me; = OH; or R = ()- CHZCH R2 or R = ()-CH =CH(CH2)6CO(CH2)5Me; R2 = H

+
N +

M e

ey

coe-

Three-dimensionalfeatures at chiral centres of structures depicted in this chapter follow the convention:(a) horizontally-rangedatoms, and their bonds, and atoms in rings, are understood to be in the plane of the paper;

(b) atoms and groups attached to these atoms in (a) are ABOVE the page if ranged
LEFTWARDS and BELOW the page if ranged RIGHTWARDS: means

Rx

1: Amino Acids

R4H3
c02OH OH
(7) R = (CH2),CH(OH)(CH2),Me and N -acetylated, for Sphingofungin D; N -non-acetylated, for Sphingofungin B; NH3' replaced by NHC(= NH)NH2for Sphingofungin A

(8) R' = Pr', Bu', or Bus

(9)

CONH20

OH OH

OH

HO

$9,,"
OMe

Amino Acids, Peptides and Proteins

(1 4) various R

L
(15)

OH I (16) R = ( C H Z ) ~ O C O C H ~ C C H ~ C O ~ H C02H

Ar Ph OH Ph PhCONHCHC02H

ii, Reagents: i, A r p b ( 0 A ~ ) ~ ; NaOH in EtOH-H20; iii, H30+

Scheme 1

1: Amino Aci&

(Section 4.2) asymmetric synthesis methods are nearly always general methods of synthesis too. Other general reactions by which one amino acid is used as starting material for the synthesis of another, are mostly covered in the later Section 6.3 (Specific Reactions of Amino Acids). Long-established methods continue to be revisited as reliable routes, and many of these are used in syntheses of labelled amino acids (see Section 4.15). The alkylation of diethyl phthalimidomalonate (see Refs. 166,256) and diethyl acetamidomalonate (see also Refs.254,258), e.g. for a synthesis of 2-amino-7,7acids,47and the alkylation dimethyloctanoic and 2-amino-8,8-dimethylnonanoic of oxazolones, e.g. in an aspartic acid synthesis (17 + 18),48in a synthesis of aamino-P-phosphonopropionic acid,49and in an arylglycine synthesis (Scheme 1)50 and corresponding vinylglycine synthesi~,~ typical long-established methods. are Rearranged dimers that are well-known (usually unwanted) side-products from oxazolone alkylation, can be hydrolysed to give a-alkyl-a-amino acids.s2Addition followed by routine work-up, gives of a thiol to 4-benzylidene-2-methyloxazolone, a threolerythro-mixture of N-acetyl S-(p-methylbenzy1)-P-phenylcysteinemethyl ester.s3 A novel variant of the oxazolone procedure is represented in the conversion of a 4,4-bis(isopropylthio)oxazolone into amides or peptides, and its chlorinolysis (SO$&) to give halogenoglycine derivatives that are easily converted into other amino acids through halogen s ub~ t i t ut i on. ~ ~ These two general methods are essentially glycine alkylation procedures; other routes in this category include alkylation of glycine Schiff bases (phase-transfer catalysed alkylation of PhCH = NCH2C02Me + phenylalanine, mediated by microwave energy),55and corresponding syntheses of leucine, serine and aspartic acid,56 Michael additions, of (R10)2P(0)CH= CH257and a two-step alkylation CH (by R1 = CRCH2Br then y-elimination of Br) to give a-cyclopropylglycines.58 Similar approaches employing N-phena~yl-N-benzylglycine~~ N-(a-chloroand alkyl)-N-Boc-glycine60 as starting materials lead to azetidinecarboxylic acids and higher homologues. The corresponding use of N-oxides of glycine Schiff bases to prepare m-(N-hydroxyamino) acids,61 and of a-amidinoalkanoates (Scheme 2)62have a good deal in common, mechanistically. The [3,3]-rearrangement of N-protected glycine ally1 esters (19 + 20)63 exemplifies an alternative glycine alkylation process that has been well studied from the 1960s. Alkylation of a-halogenoglycine synthons (Scheme 3) is significantly facilitated by ZnC12, indicating a radical mechanism where the catalyst is both a radical initiator and chelates the substrate.@ Copper(1)-catalysed C1-transfer radical cyclization of N-(alk-3-enyl)-a-chloroglycinesgives prolines via 2-aza-5-alken-lyl radicals.65A similar study of the generation of the glycine a-radical formed by stannanes from a-bromo-, -benzyloxycarbonyloxy-,and -methoxy-glycine derivatives, and its alkanesulfenylation with disulfides, has been described.66Xanthates MeO2CNHCH(S2C0Et)CO2Me similarly yield radicals that add to alkenes to offer a valuable new general amino acid ~ynthesis.~ N-Protected a-hydroxyglycine esters are readily substituted, illustrated this year in a preparation of (p-vinylphenyl)glycine.68a-Acetoxy analogues have been employed in syntheses of ~inylglycine~~ propargyl hor nol ~ gues . ~ ~ and

Amino Acids, Peptides and Proteins

ph/B\+JR , -/ 0 F

iii,iv

R2

H3N

+R I
R2

Me2N

Me2N

Me2N

(+ epimer at

B)

Reagents: i, K+ PhBF3-/Me3SiCI; ii, KOBU, R2hal; iii, refluxing MeOH; iv, ethylenediamine / MeOH
Scheme 2

Reagents: i, CH2CH= CHSnBu3, ZnCI2.0Et2

Scheme 3

I: Amino Acids

Isocyanoacetates CNCH2C02R (see also Ref.255) perform well in aldol additions that show high diastereoselectivity to provide P-hydroxy-a-amino acids.71a-Nitroacetates are readily alkylated, Michael addition of ally1 acrylate followed by reductive cyclization giving N-hydroxy-pyroglutamate derivative^.^^ Amination processes leading to amino acids constitute an established group of general methods that have been exemplified this year by some of the oldest variants: reductive amination of a-ketocarboxylic acids using NH3/Raney and of methyl (1S,2R,3R)-3-hydroxy-2-methoxycyclohexanecarboxylate;74 ammonolysis or methylaminolysis of t-butyl b r ~ m o a c e t a t e ,and the ~~ corresponding process with diethyl bis(2-methylthioethyl)malonate.76 Addition of ammonia, primary amines, or hydroxylamine to substituted fumaric acids leads to corresponding aspartic acid analogue^,^' and corresponding Michael addition of N-acylisoureas (formed from a carbodi-imide and a carboxylic acid) to methyl hydrogen maleate to give N-carbamylaspartic acids.78 Further examples (see Vol. 26) of the formation of cyclic hydrazino-acids through cycloaddition of dienes to azodicarboxylates, have been p~blished~ also (see Ref. 199). Condensation of a primary amine (TiC14)with a y-chloro-a-ketoester to give a y-chloro-a-iminoester is followed by cyclization to give a 1-amino-2,2dialkylcyclopropanecarboxylic acid.80 Several examples of azidation, of enolatessl and of a-methoxyacrylonitriles (giving a-azidonitrates),82have been described as stages in a-amino acid syntheses. Diazonium salts are electrophilic a-aminating agents towards esters in the form of their ketene silyl ketals, yielding a-azo- or -hydrazono-esters which on hydrogenation yield a-amino acid esters.83Use of an alkyl sulfenimine R2S = NH as aminating agent towards a latent nucleophilic carboxy group equivalent has been given a preliminary a s s e ~ s m e n t . ~ ~ Amination through Stevens rearrangement of transient ammonium ylides formed between amines and diazoketones or diazoesters gives a-aminoketones or a-amino esters, respectively, in one step.85 Amidocarbonylation - the introduction of both amino and carboxy groups in a one-pot process - has been illustrated in an N-acetylglycine synthesis (paraformaldehyde, CO, and H2, with a cobalt-phosphine catalyst),86and the distantlyrelated equivalent process from aldehydes and CHC13 continues to be studied.87 Introduction of the carboxy function into a protected amine, to lead to the corresponding a-amino acid, can be accomplished in certain cases, e.g. by the oxidation of a phenyl group (CsH5- -+-C02H) using R u O ~ . ~ ~ Modifications to an amino acid side-chain could be described as a general method of amino acid synthesis, although examples of this approach constitute a somewhat miscellaneous collection and are mostly located later in this Chapter (Section 6.3). However, an interesting set of procedures for the alkylation of the dehydro-alanine derivative methyl 2-acetamidoacrylate)tricarbonyliron(O), has been described,89leading to PbP-tri-alkyl amino acids through successive treatment with 2 eq MeLi and an alkyl halide (see also Vo1.25, p.9). Contraction of a p-amino acid backbone could also be described as a general synthesis method for a-amino acids, and further examples (see Vo1.24, p.8) of the conversion of a-keto-&lactams into a-amino acid N-carboxylic acid anhydrides

10

Amino Acids, Peptides and Proteins

Reagents: i, Et2AICN; ii, 6M HCI, reflux Scheme 4

Reagents: i, PhCH2NH2,K2C03,CH2C12,r.t. 40 h; ii, NaOMe/ MeOH Scheme 5

L-aa

L
NHOSiMe3

epimer

Reagents: i, established methods; ii, Me3SiNHOSiMe$CH2C12,22 "C, 18h

Scheme 6

I : Amino Acids

11

have been accomplished by Baeyer-Villiger oxidation,g0 a process that is applicable to homochiral substrates, leading to j3-alkylserine N-carboxylic anhydridesg1The method has been also been illustrated in a synthesis of (R)-a,pdi-amino-y-hydroxyacid N-carboxylic anhydrides from p - l a ~ t a m s . ~ ~ 4.2 Asymmetric Synthesis of a-Amino Acids - Activity in this area continues to increase, both in the provision of new methodology and in the development of established methods, including well-known standard general methods of synthesis, some of which are described in the preceding section, and revisited here in asymmetric versions. Two thorough reviews cover the overall topicg3vg4and another review deals with asymmetric synthesis of 2,3-methano-amino acids (i.e., 1-aminocyclopropanecarboxylic acids).95 Modifications of standard general methods of a-amino acid synthesis are represented in a Strecker procedure employing a chiral ketone as catalyst for the equilibration of aminonitriles R1R2C(CN)NHCHRCN,96 and in an equivalent process using homochiral sulfinimines (illustrated for the (Ss)-configuration in Scheme 4).97 Amination reactions incorporating kinetic resolution (Scheme 5),98 and related )* hydroxylamination (Scheme 6 , illustrate further standard methods. Several examples of the alkylation of glycine derivatives can be grouped together: Michael addition of MeCH(CN)C02Me to vinyl ketones or acrolein catalysed by a Rh(1)-chiral phosphine complex, giving (R)-RCOCH2CHZCHMe(CN)C02Me in 83-93% e.e. and thence to (R)-a-methyl-a-amino acids through routine elaboration; loo stereoselective alkylation of glycine Schiff bases Ph2C = NCH2C02Butusing active methylene compounds and a (-)-cinchonidinederived chiral catalyst;lol aldolization of glycine with PhCHO, catalysed by supramolecular bilayer assemblies containing L-alanine-lipid peptides with pyridoxal and Cu(I1) salts, to give (S)+-phenylserine in modest enantiomeric excess; lo2 alkylation of (-)-menthy1 N-acetyl a-bromoglycine by allyltrimethylsilane catalysed by ZnC12 to give (S)-( +)-norvaline after hydrogenation (see also Scheme 3);lo3 for a synthesis of (-)-menthy1 N-acetyl a-hydroxyglycine by this research group using (-)-menthy1 glyoxalate + MeCONH2, see Ref. 104. Addition of a glycine enolate to the carbonyl group of a-D-ribohexofuranos-3ulose gives the corresponding (S)-a-(glycos-2-yl)glycine. The asymmetric benlo5 zylation of the carbanion from (-)-menthy1 hippurate and similar glycine derivatives carrying chiral auxiliary groups, although thoroughly researched over many years, was recently found to be unsuccessful when only one equivalent of base is used.lo6 In a broad study, the diastereoselectivity of this process was shown to be dependent upon the amount of additives and the nature of the N-acyl group and of the chiral ester. Alkylation of homochiral glycinamides gives generally good diastereosele~tivity.~~~ N-Boc-2-(tert-Butyldiethylsilyloxy)pyrrole is a glycine equivalent that underges aldol addition to homochiral aldehydes (Scheme 7) to give a-(polyhydroxyalky1)-a-aminoacids.lo* Further conventional approaches are described for phase transfer-catalysed Gabriel synthesis employing (-)-bornyl a-bromoalkanoates (optical purities from

12

Amino AcidF, Peptides and Proteins

1.7-47%);lo9 rather worse results are obtained in this reaction with various heterogeneous phase-transfer catalysts.' lo The conversion of lithium (1 S,2R,4R)10-dicyclohexylsulfamylisobornyl-2-cyano-3,3-diphenyl propanoate into PP-diphenyl-a-methylalanine (2 1 4 22) involves a Curtius rearrangement. A related approach for a synthesis of (S)-3,4-dichlorophenylalanine'l2 is completed by a subtilisin resolution (see Section 4.17) in view of the disappointing optical purity of the product of the synthesis. Photochemical amination of chiral silyl enol esters (23 in Scheme 8) has been illustrated in a synthesis of erythro-P-methyl-L-phenylalanine. l3 The Schollkopf bis-lactim ether synthesis continues in use (see also Ref.260) for acids,' l4 3the asymmetric synthesis of 2-amino-3-methyl-4-phosphonobutanoic fluoro-4-nitro-L-phenylalanine,' bicyclic lactams,' l 6 and (2S,3R)-3-methylglutamic acid. Alkylation of L-valine-derived piperazine-2,5-diones (24)followed by hydrolysis leads predominantly to (S)-a-amino acids. l 8 The S-configuration is induced by the chiral grouping in the substrate, during the hydrogenation of N-formyl-(Z)-dehydro-PBP-trifluorobutyrine(-)-menthy1 ester (25 -,26).l19 The other main interest in the asymmetric hydrogenation of dehydro-amino acid derivatives over the years has concentrated on achiral substrates, and on the development of improved asymmetric hydrogenation catalysts. A clear enhancement of enantioselectivity (e.e.'s of L-amino acids up to 99%) accompanies the incorporation of electron-donating aromatic substituents in vic-diarylphosphonites derived from carbohydrates, as the chiral moiety in a Rh(1)-chiral phosphine catalyst. I2O The role of the protecting groups in cinnamates subjected to this procedure has been assessed.12' The main focus of development of synthetic methodology continues to be the use of heterocyclic chiral auxiliaries, most of which have been favoured for several years now. Predominantly (2R)-syn-P-substituted serines are formed (d.e. 84100%) when the Ni(I1) complex of the Schiff base of N-benzyl-L-proline 0benzoylanilide is aldolized by m-fluorobenzaldehyde or by a fluorine-substituted alkanal. 122 Alkylation of the Schiff base using alkyl halides123illustrates the approach employed by this research group for many years, though they have now established aldolization of the chiral Schiff base (27) by aldehydes to be an efficient (better than 90% e.e.) alternative route to substituted ~ e r i n e s . Use of '~~ this synthon in a synthesis of the photoactivatable 4'-( 1-azi-2,2,2-trifluoroethyl)L-phenylalanine has been described as extremely efficient.125 N-Acryloyl and -crotonoyl-camphorsultams can be used for the synthesis of stereodefined aziridine-2-carboxylic acids through bromination, dehydrobromination, and aminolysis stages.126Construction of a cyclopropane ring on the well-known aminoalkenyl synthon R*-CH = C(NHZ)C02Me [R*-CH is the (S)glyceraldehyde moiety] and subsequent processing gives (1S,2R)- 1-amino-2-vinylcyclopropanecarboxylic acid (alias y5-dehydro-allocaoronamicacid). 127 The use of chiral N-acyloxazolidinones in various contexts (see also Ref.64) continues to give excellent results, illustrated in the synthesis of (-)-pyrimidoblamic acid (Scheme 9) the early stages being based on [4 + 21-cycloaddition of 2,4,6-tris(ethoxycarbonyl)- 1,3,5-triazine to 1-(dibenzylamino)-1-propyne); 128 P-branched phenylalanine~;'~~y p t ~ p h a n s ; 'and c@-dimethyl-l,2,3,4-tetrahytr ~~

' ''

'

'

I: Amino Acids

13

iii,iv

BocNH

protected 4-epi -polyoxamic acid Reagents: i, 0,O4sopropylidene-(R)-2,3-dihydroxypropanal, SnCI,, Et20; ii, KMnO,, C , I; HC, iii, LiOH, THF, then NaIO,; iv, NaIO,, R u 0 2

Scheme 7

KOH/MeOH then

Curtius rearrangement

NC

Me

Me02CNHXCHPhl

TBDMSO

MeoYYPh
I

NHC02Et

Me

Me

Reagents: i, ethyl azidoformate, hv

Scheme 8

14
Me

Amino Acids, Peptides and Proteins

Qi:6.
\

OH

OKNBZ 0

NHBoc CO,Et

rNdCONH2

Me

Me

Reagents: i, C0,Et

iii, Bu3SnHthen HCLEtOAc

Me

Me

CHO + Boc-Asp derivative; ii, Evans Sn enolate;

Scheme 9

1: Amino A c i h

15

droisoquinoline-3-carboxylicacids;' homoserine analogues (using the alternative Karady/Seebach oxazolidinone a p p r ~ a c h ) ; ' and (2S,3S)-threoninol and ~~ related compounds using the (R)-glycidol-derived oxazolidinone (28). 133 Homologous chiral heterocycles used in similar ways include oxaziridines [reaction with copper(1) salts to give products of N-centred radicals leading to cis-5-benzyl-Dp r ~ l i n e ] .cis-4,5-Disubstituted oxazolidin-2-ones are epimerized at C-5 via a N/ '~~ C-5 di-anion. 135 Piperainones carrying a homochiral N -subst i t ~ent '~~ provide a new variant of the well-established imidazolidin-5-one.1 An alternative to the ' 3 oxazolidinones is the lactam (28; -CH2- in place of ring -0-), shown to be a useful chiral a~x i1 ia r y .l~ ~ N-Acylated 5-substituted 3,3-dimethyl-2-pyrrolidinones created in this study have been used in illustrative asymmetric synt he~es. '~~ Routes based on recently-developed variants include the synthesis of yhydroxy-a-amino acids, illustrated for ( + )-bulgecinine, based on aldolization of the Cr(0)-modified acyloxazolidinone (Scheme 10; see Vo1.26, p. 16)," a highlydiastereoselective aldol reaction of a Cr(0)-complexed benzaldehyde derivative starting a synthesis of (29), an analogue of the N-terminal amino acid of nikkomycin B,I4l synthesis of (2S, 1'Sy2'S)-2-(carboxycyclopropyl)glycine from the serine-derived oxazolidine (e.g. compound 107),142 a synthesis of (2s)-Nand benzoyl 2-t-butyl-4-methylene-oxazolidin-5-one (Vo1,26, p. 16) for use in asymmetric synthesis, by bromination (Br2/hv) of the L-alanine-derived heterocycle, then dehydrobromination (NaI)y143and synthesis of (2R73S)- and (2S73R)precursors (30 and epimer, respectively; Scheme 11) illustrated for syntheses of pmethyl analogues of protein amino acids (Phe, Tyr, and His analogues; see also Vo1.26, p. 13).144 Alkylation of new heterocyclic 'chiral glycine derivatives' prepared from glycinamide (Scheme 12) follows the oxazolidinone philosophy,145 and hydrogemorpholinones (see Vo1.26, nation of homochiral3-ethyl-5-phenyl-3,4-didehydro p. 16) has led to (R)- and (S)-2-aminobutanoic acids from 2-oxobutanoic acid.'46 Particular examples, illustrating new synthons that are capable of being used in asymmetric syntheses more generally, have been reported; thus, the furan-2-one synthon (31), obtained from D-glucosamine, has been used in a synthesis of 4-hydroxy-L-pipecolicacid, 147 and D-glucosamine has been used in a preparation of Boc-L-serinal through periodate cleavage.148 D-Mannosamine is a starting material for a synthesis of sphingofungin D (7; Scheme 13).149 Kinetic resolution induced by L-( + )-di-isopropyl tartrate accompanies ButOOH/Ti(OiPr)4 oxidation of a-furanylamines (32 + 33 + 34) and ozonolysis of the residual L-afuranylamine leads to the N-toluene-p-sulfonyl L-amino acid. Unconventional asymmetric synthesis of amino acids features a homochiral a-amino acid as chiral auxiliary to generate an enantiomer of y-hydroglutamic acid,lS1'ring-contraction' through refluxing with ketones of 5-isonitroso-2,2-dimethyl-l,3-dioxan-4,6-dione v a a nitrosoketene (Scheme 14), cycloaddition to alkenes and routine elaboration i yielding L-a-amino acids,' 52 while ring-expansion is involved in a Coxoproline synthesis from a homochiral azetidinonecarboxylic acid (Scheme 15). 53

'

4.3 Synthesis of Protein Amino Acids and Other Naturally Occurring a-Amino Acids - This section continues the coverage of a-amino acid synthesis, showing

16

Amino Acids, Peptides and Proteins

RPh

ON x&

nPh + i i
R Cr(co),

rTPh 'xNTR
0

+ diastereoisomer
Reagents: i, BuLi, RCHO; ii, hv, CO[-Cr(CO),] Scheme 10

p -MeO-C,H,

AcO(CH& Me Me

Toyo
NHAc

Ph

Ph

Reagents: i, MeMgBr-CuBr.SMe2; ii, NBS Scheme 11

Reagents: i, LDA/THF,-78 "C; ii, RX; iii, TFNCH2C12then 0.2M HCI Scheme 12

I : Amino A c i h

17

( R ) -1,2-epoxyoctane

Me(CH2)5

I
\
RO Me(CH,),

iijii

A (CH),+'
NHAc

sphingofungin D (7) Reagents: i, 1 -heptyne, BuLi, BF3.0Et2; ii, Li, BU'OK, H,N(CH,)3NH2; iii, Et02C-N = N-CO,Et, Ph3P, PhC0,H then TBSCI; iv, Bu3SnH, AIBN then I,; v, synthon from N -acetyl-D-mannosamine, CrCI2/NiCI2/DMSO; vi, routine steps

Scheme 13

18

Am ino Acids, Pep tides and Proteins

oo &
O X 0

11,111

.. ...

R3

-0'

Reagents: i, R'COR', reflux; ii, R3CH =CH2; iii, a-amino acid by aq. NaHC03, then H2h0/O Pd-C

Scheme 14

pLOc

COZBZI I

0-

0-

J ii

Reagents: i, Me2SOCH2,DMSO; ii, HX; iii, ML,(cat.)

Scheme 15

J iii

4
ZNH Reagents: i, TolSCH2N02,then MeSOZCI, ii, Bu'COOK; iii, NH3 then ZCI

COzMe

Scheme 16

I: Amino Acids

19

applications of current methodology for the synthesis of natural products. Choice of route is usually tailored to the particular synthesis target, though alternative approaches are occasionally compared. The usual crop from the primary literature dealing with aspects of fermentative production of the common amino acids [L-lysine using Corynebacterium glutam i ~ u m ; L-aspartic acid using intact coryneform Brevibacterium fIavum MJ'~~ 233;'55 L-threonine using Brevibacterium l~ctofermentum;'~~ L-phenylalanine methyl ester from methyl trans-cinnamate using phenylalanine ammonia lyase;' 57 L-DOPA using a cell suspension culture of Mucuna p r ~ r i e n s ; ' ~ * D-amino and acids from enzymic hydrolysis of hydantoins by whole cells of Agrobacterium r ~ d i o b a c t e r ' ~is ]supplemented by reviews [production of amino acids using ~ genetically-engineered Serratia marcescens;'60 using aminopeptidases and aminoamidases;16' using hydantoinases; 162 L-aspartic acid using immobilized microo r g a n i s m ~ ; and L-DOPA using tyrosine phenol l y a ~ e ' ~ Details of routine '~~ ~]. studies of the biosynthesis of amino acids in plants have not been collected in this Chapter over the years, though there has been the custom to mention unusual studies, e.g. the enzymic synthesis of P-substituted alanines in plants,'65 and of 5hydroxy-4-0x0-L-norvaline in Streptomyces akiyoshiensis.166 A new synthesis of D-alloisoleucine from (S)-2-rnethylb~tanol'~~ compares favourably with two standard procedures, viz. inversion at C-2 of L-isoleucine and racemization of N-acetyl-L-isoleucine and resolution with hog acylase. New syntheses of protected D-threonine and L-allo-threonine'6g employ a little-used general method of a-amino acid synthesis (Scheme 16). Extraordinary syntheses of L-glutamic acid and L-a-aminoadipic acid'69 use chiral equivalents of cyclopentadienone and cyclohexadienone respectively (Scheme 17). The laboratory synthesis of 'MeBmt', the threonine derivative present in cyclosporin, has been reviewed.'70 A new synthesis in four steps'71from (22,4R)4-methyloct-6-yn-2-en-1-01 (Sharpless epoxidation and ring-opening with MeNH2 are the essential steps), offers an improvement on the heroic multistage first synthesis of MeBmt (see Vol. 17, p.8). A synthesis of 2-amino-4-hydroxy-3,3dimethylbutyric acid (alias pantonine) from 3-chloro-2,2-dimethylpropanol, 172 P-hydroxyhomoserine (an intermediate in mugeneic acid syntheses) in 12 steps173 acid (a constituent from cis-2-butene- 1,4-diol, (2S,3R)-2-amino-4-hydroxyadipic of theonellamide F) by asymmetric reduction of the corresponding P-ketoester obtained from L-aspartic acid,'74 quisqualic acid from L-serine via the Garner aldehyde (107, R = H; -CHO -+ -CH=NOH -CH2N(OH)CONHC02Et, e t ~ ) , stizolobic acid through a biomimetic route starting with a catechol '~~ aldehyde, 176 and the alicyclic relatives anticapsin and bacilysin starting with a Diels-Alder adduct of dehydroalanine with O-TMS-cyclohexadienol,177In the last-mentioned study, independent confirmation is provided that the previously announced stereochemistry of anticapsin requires revision [it has the (S)-configuration at C-4; see Vo1.26, p.41. Construction of the side-chain of arogenic acid, (yS)-b-( 1-carboxy-4-hydroxy-2,5-cyclo hexadien- 1-yl)-L-alanine, is conveniently achieved through Michael addition of the anion of methyl 1,6dihydrobenzoate to methyl N-acetyldehydroalaninate. 178 Further exploration of routes to vancomycinic acid precursors (35)'79*'80 polyoxamic acid (36; a synthesis involving and
+

20

Amino Acids, Peptides and Proteins

i-iv

H02C

H2T

/CH2

'1

)"

/CH-NBzl H02C
Reagents: i, -CH=CH

-CH2-CH2-;

ii, BzlNH2; iii, NaBH,;

iv, NaIO,, RuCI,

Scheme 17

OMe

'2

+
-02c0 HN H 3* OH

I : Amino Acids

21

-C6H5 + -C02H)181 has been reported. The same method of generating a carboxy group appears in a synthesis from a-aryl-P-alanines, of 2'-deoxymugineic acid and nicotianamine.Is2 Complex synthetic targets are also represented in cilastatin (37), constructed from L-cysteine, 7-bromo-2-oxoheptanoic acid, and ( + )-(S)-2,2-dimethylcyclopropanecarboxylic acid.Is3 The synthesis of several other cyclopropanes [trans-a-2-(carboxymethyl)cyclopropyl]glycine from Blighia unijugata, synthesized by dibromocyclopropanation of (38) prepared from Dserine;IX4 four stereoisomers of carnosadine (39; a set of constrained arginines, all see Vo1.26, p. 19);'85 (1 R,2S)- and (1S,2S)-dehydrocoronamic acids from dimethyl 2-vinylcyclopropanedicarboxylic acid (selectively hydrolysed by successive treatment with two esterases with different regioselectivities)then routine introduction of the amino group through the Curtius rearrangement'86] have been described. Full details (see Vo1.25, p.21) of a synthesis of (2S,4R)- and (2S,4S)-diastereoisomers of hypoglycin A have been described, incorporating a Sharpless epoxidation stage in an asymmetric methylenecyclopropane synthesis.187 (2R,3S)-3-Hydroxylysine has been synthesized through Hayashi's chiral ferroceno-gold catalysed oxazoline formation from 4-phthalimidobutanal and methyl isocyanoacetate, and the (2S,3R)-enantiomer through a route incorporating a Sharpless cis-hydroxylation.188 Total synthesis of the azctidinecarboxylic acid derivative, mugineic acid (40, X = H; equally correctly described either as a P-hydroxyornithine derivative or an a-hydroxy-GABA derivative) (see Vo1.25, p.23)Is9 and its 3-epi-hydroxyderivative (40; X = OH)'90 involve a common intermediate (41). The latter report also describes the synthesis of distichonic acid A, and 2'-hydroxynicotinamine. Naturally-occurring proline derivatives of continuing interest, the kainoids and bulgecinine, have been synthesized by new routes. Condensation of glyoxal with the (R)-phenylglycinol derivative (42) proceeds via a cyclic iminium ion that undergoes tandem aza-Cope-Michael reactions en route to (-)-a-allokainic acid.I9l A six-step route to DL-kainic acid (43 in Scheme 18) uses a similar reaction sequence to set up the ring system with the correct relative stereochemi ~ t r y . Further details have been published193of a synthesis of (-)-a-kainic acid '~~ employing a ring construction step based on the Pauson-Khand reaction (see Vo1.26, p.24) and the same research group has reported an effective synthesis of a-allokainic acid (Scheme 19).194A short, efficient route to 4-arylkainoids starts Radical cyclization of a protected L-serinal with trans-4-hydro~y-L-proline.'~~ (44)is at the heart of an elegant synthesis of (+)-b~lgecinine,'~~ reached also through reduction of appropriately substituted 2-amino-4-oxoalkanoic acids (45; somewhat capricious stereoselectivity is involved in the reduction).'97 Clavalanine and erythro-4-hydroxyornithinewere also prepared from the same starting material in this study. A route to (S)-(-)-pipecolic acid (46 --+ 47) employing the chiral oxazolidine approach is also capable of extension to the synthesis of 2- and 6-alkyl analogues. lg8 'PCA', an unusual hydrazino acid that is a constituent of the Luzopeptins, has been synthesized by the condensation of di-t-butyl azodicarboxylate with the dianion of (Me0)2CHCH2CH(OH)CH2C02Et also Ref.79).'99 (see

22

Amino Acids, Peptides and Proteins

HO

APh
0
(41)

MeOC (CH2)20B~' (CH2 ) 20 ut B

R Lo
Ph

I: Amino Acids

23

OH

N Z

R CO2Et

Reagents; i, Et3N, MeCN, r.t., then SnBu,H/AIBN, ZCI; ii, MeLi, TiCI,; iii, BF3.Et20; iv, oxidative ring-opening (RuO,/NaIO,); v, CH2=pph3 or CH212/Zn; vi, separate diastereoisomers then OH-, ion exchange Scheme 18

CO2Et

Reagents: i, MeCOCH =CH,;

ii, CH2=PPh2 Scheme 19

(44)

(+)-bulgecinine

24

Am ino Acids, Pep t ides and Proteins

4.4 Synthesis of a-Alkyl Analogues of Protein Amino Acids - The synthesis of homochiral examples of known absolute configuration of this class of substituted a-amino acid has been considered to be a difficult enterprise, but the extraordinary fact that a configurationally-stable anion can be generated from N-Boc-N-methyl-L-phenylalanine using Li 2,2,6,6-tetramethylpiperidide opens the door to a-alkyl analogues.200 The conventional approach, a-methylation of a Schiff base of a protein amino acid, is illustrated in a synthesis of a-methylhomocysteine (Scheme 20).201 aAllylation of pipecolic acid and ensuing steps yield the a-(2-alkoxycarbonyl)ethyl analogue.202The hydantoin route is often inappropriate, because of the drastic conditions needed to release the amino acid, but 3-(toluene-p-sulfonyl)hydantoins carrying adenine and thymidine side-chains are easily hydrolysed to give the corresponding amino acids, in dilute alkali at slightly elevated temperatures.203 Grignard addition to fluoroacetonitrile followed by routine stages gives afluoromethylglutamic acid, whose cyclization leading to the glutamate racemase inhibitor, aziridinoglutamate, has been worked The need for resolution is avoided in the chiral oxazolidinone approach, used for a synthesis of (S)-2-methylpr0line,~~~ although the oxazolidinone hydrolysis step that completes the procedure can be simplified.206 (S)-a-2-Aminoethylmethionine has been obtained in 18% yield from the 5-(methylthioethyl)oxazolidinone, through enolate alkylation with BrCH2CN and routine e l a b ~ r a t i o n . ~ ~ Stereoselective alkylation of isobornyl 2-cyanopropanoate is exemplified with syntheses of a-methyl-L- and D-tryptophan208and a-methyl-D- and -L-phenylalanine.209 ap-Di-alkylaspartic acids are readily obtained via p-lactams prepared from Schiff bases ArN = CRC02Me and ketenes.*I0

4.5 Synthesis of a-Amino Acids Carrying Alkyl Side-Chains, and Cyclic Analogues - With the proviso that use of one a-amino acid for the synthesis of another is covered in the later Section 6.3 (Specific Reactions of Amino Acids) papers collected here deal with approaches to aliphatic synthetic targets from other starting points. (S)-2-Aminosuberic acid has been prepared from (E)-CH2 = CH(CH2)5CH = CHCH20H through asymmetric epoxidation, ring-opening with benzhydrylamine, and oxidative cleavage.21 Other amination processes include Curtius rearrangement (diphenyl phosphoroazidate) of selectively-hydrolysed 2,2-dialkylcyclopropane- 1,l-dicarboxylic acid esters,212 and ring-closure of 2,5-dibromoadipic acid (R)-pantolactone esters using benzylamine to give trans-pyrrolidine2,5-dicarboxylic acids.213 1,2-trans-Placing of NH2 and OH in a 172-trans relationship on cyclopentadiene (AcOOH then NH3/MeOH) and Candida antarctica resolution starts a route to (2$,3R)-3-hydro~yproline.~l~ unusual An synthesis of 3-phenyl-3-hydroxyprolinefrom an N-benzoylethyl-N-toluene-psulfonylglycinamide involves photochemical c y c l i z a t i ~ n . ~ ~ ~ Carboxylation of 4-(hydroxymethy1)pyridine through reaction of its 0-trimethylsilyl-N-oxide with Me3SiGN and saturation of the ring leads to the 4-substituted piperidine-2-carboxylic acid.216 Hydrogenation of dimethyl

1: Amino Acids

25

ii, iii

H0,SCH2CH2,

M ,e Br-

( MeS)2C=N

H3ilC'CO2H

Reagents: i, base, MeI; ii, aq. HCI; iii, Br2, H20

Scheme 20

CH,Br Me02CN= CC0,Et

CH2Br Me02CNHCC02Et

C02Et
! . -

OCH2CFCH Reagents: i, HOCH2C E C H , (PPh,),Pd/CuI;

NHC02Me

Scheme 21

26

Amino Acids, Peptides and Proteins

3,5-pyridinedicarboxylateprovides a 1:1 cis-trans mixture of piperidine dicarboxylic acids.217

Models for Prebiotic Synthesis of Amino Acids - Conventional studies under this heading continue much as they have done for many years, represented by C02/CO/N2/H20 mixtures subjected to electric discharge (giving 6 protein amino acids, glycine predominating, and 2 non-protein amino acids when CO is abundant),218and by 6oCo y-irradiated aqueous glycine (Asp, Ser, Thr, and Glu, and MeNH2 + EtNH2 formed from reaction of a glycine radical with glycine breakdown products).219 Current speculation, that deep oceans were the sites of the origin of life, is helped by confirmation (hydrothermal synthesis; Vol. 25, p.34) of the generation of amino acids from C2H2/H20/02/H2/(NH4)2C03 mixtures at 200-275".220

4.7

Synthesis of a-Alkoxy a-Amino Acids, and Analogous a-Heteroatomsubstituted a-Amino Acids - Asymmetric synthesis of (R)-a-sulfenylglycine has been achieved by the reaction of MeSSMe with 2-hydroxypinan-3-one Schiff bases.221 Fmoc-a-Methoxyglycine has been prepared by addition of Fmoc-carbamate to glyoxylic acid, then 0-methylation by MeOH/H .222 Anodic a-methoxylation of a-amino acids has become a routine step in many synthetic applications (notably, substitution by alkyl groups), and illustrated with asparagine and serine derivat i v e and p~ 0~ i n e . ~ ~ ~ ~ ~ r 1 Independent studies were aimed at the provision of anomeric tetrahydrofuranosyl amino acids and pyranosyl analogues (Scheme 2 1)225(Scheme 22)226 within the context of analogues of the herbicide ( +)-hydantocidin, whose short synthesis (see Vo1.26, p.24) from P-D-ribofuranosyl amide results from fortuitous a-bromo P-amide formation and treatment with silver ~ y a n a t e . ~ ~ ' Several examples of the uses in synthesis, of glycine derivatives conforming to the title of this section, are cited elsewhere in this Chapter.
4.8
+

Synthesis of a-(a-Halogeno-alkyl) a-Amino Acids - A review has appeared describing Ukrainian work on the synthesis of fluorine-containing amino acids.228 A well-established route to PP-difluoroalanine from ZNHCH(CHF2)CH = CH2 through oxidation to generate the carboxy group, has been rendered a practical proposition through an efficient synthesis229 of H2NCH(CHF2)SEt.HBr.a-(Fluoromethyl)-P-fluoroalanine, an important intracell pH indicator, can be prepared in 44% overall yield from 1,3-difluoropropan2-01, through application of standard methods [ 1,3-difluoroacetone -, (FCH2)C = NCHPhCHzOH 3 (FCH2)CH(CN)NH2 using TMSCN].230 aTrifluoromethyl-a-amino acids are readily obtainable from imidazolidin-2,5diones (48).231 P-Difluoromethyl-m-tyrosine has been prepared through an uneventful Evans oxazolidinone synthesis.232 (2S,4S)-5-Fluoroleucine has been synthesized from L-pyroglutamic acid through diastereoselective methylation, followed by less stereochemically-demanding steps.233

1: Amino Acids

27

Reagents: i, TfOMe, then NaBH, and HgCI2; ii, Ag20 then CH2N2; iii, H2-Pd/C

Scheme 22

0e0 x
F3C CF3 (49) (48) X = O o r S

Reagents: i, Sharpless dihydroxylation; ii, SOCI,; iv, NaN3 and reduction

iii, NaIO4/RuCi3;

Scheme 23

28

Am in0 Acids, Pep t ides and Proteins

trans-4-Fluoro-L-pipecolic acid and the 4,4-difluoro-analogue have been prepared from di(ethy1amino)sulfur tetrafluoride and the oxazolidinone (49) available from L-aspartic and (2R,5R)-5-chloropipecolicacid has been obtained by elaboration of the readily-available N-methoxycarbonyl (S)-5TBDMSoxy-2-0xo-piperidine.~~~ Examples of side-chain halogenation of amino acid derivatives are to be found in the later Section 6.3, though it could be noted here, that 4-alkyl-5-ethoxyoxazoles (easily prepared from N-acylamino acids) are useful substrates for perfluorination. 236
4.9

Synthesis of a-(a-Hydroxyalkyl) a-Amino Acids - Hydroxylation of alkenes leading to hydroxyalkyl side-chains is represented in a number of different strategies. Where the a-amino acid moiety is in place, as with L-vinylglycine [CH2= CHCH(NH2)C02H], then 1,2-dihydroxylation using Os04 yields hydroxythreonine stereo~pecifically.~~~ a similar approach, In 1aminocyclohexene- 1-carboxylic acids, formed from 4-arylideneoxazolin-5-ones by Diels-Alder addition to dienes, give iodohydrins that yield y-hydroxy-a-amino acids through reductive dehalogenation and hydrolysis.238Protected aspartic acid enolates provide (3R)- and (3S)-hydroxy-L-aspartates through treatment with electrophilic hydroxylating agents.239 Grafting the a-amino acid moiety on to a hydroxylated structure is illustrated in a new synthesis of C-or-D-glucosyl-a-amino acids starting with a protected 1allyl- 1-deoxyglucose, then Sharpless epoxidation, selective mesylation, tritylation, and azidolysis and routine elaboration.240A similar approach leading to (2S,3S)and (2R,3R)-3-hydroxyleucine (Scheme 23) also succeeds because of favourable regio~electivity.~~~ Mercury(I1) oxide oxidation of D-glucosamine gives D-glucosaminic acid, and straightforward replacement of the 3-hydroxy group by H, giving (2S,4S,SR)-4,5,6-trihydro~ynorleucine.~~~ Monosaccharide-derived azidolactones continue to serve (see Vol. 26, p.33) as starting materials for tetrahydroxy- 1-aminocyclopentane- and cyclohexanecarboxylic acids with unambiguous threo-3-Hydroxy-L-glutamic acid244and (2S,3R)control of s t e r e o ~ h e m i s t r y . ~ ~ ~ 3-hydro~yornithine~~~ been prepared through a highly stereoselective iodohave cyclocarbamation of the chiral alkene (50) obtained from 0-benzyl-L-serine.
-- The synthesis of isoxazolidin-5-ones, and their use in the synthesis of fl-amino- and p-(Nhydroxy1amino)-alanines, has been described.246 Substitution of aminating agent for hydroxylating agent in a process described in the preceding section239has been successful in leading to (3R)- and (3S)-amino-L-aspartates. -

4.10 Synthesis of a-(a-Amino-alkyl) a-Amino Acids

4.11 Synthesis of a-Amino Acids Carrying Unsaturated Aliphatic Sidechains

As usual, there is interest in each of the categories covered by the heading of this Section: the ap-unsaturated-a-amino acids, alias dehydro-amino acids, are constituents of natural peptides, while they and their homologues (vinyl- and allyl-glycine) are increasingly valuable in synthesis. Protected dehydroalanine is easily formed from serine derivatives, treatment of

I : Amino Acids
0

29

BzNH,2 Ct 0 , E

OR
(511

RO
(52)

30

Amino Acids, Peptides and Proteins

Z-Ser(0Ts)OEt with Bu4NI/NaOH being currently re~ommended.~~ The potassium salt of N-acetyl a-(diethylphosphony1)glycine condenses readily with aldehydes, exemplified in the synthesis of dehydro-amino acids carrying long side chains, (E)- or (Z)-Et02CC(NHAc)= CHCk2(CH2),C02Me.248 N-Acyl-2,3dehydro-2-amino acid esters result from perrhenate-catalysed decomposition of a-azido acid esters in solution in organic solvents containing an acyl chloride.249 A general synthesis of ap-dehydroamino acids from a glycine derivative is exemplified with the preparation and hydrolysis of 4-alkylaminomethylenethiazo1-5-0nes.~~~ reaction sequence from the aldehyde (51) formed from The D-arabinose and L-serine, to the highly functionalized dehydroamino acid (52) postulated to be a constituent of azinomycins, includes a Wittig condensation with a g l y c y l p h ~ s p h o n a t e . ~ ~ ~ An ap-dehydroamino acid with an extended side-chain, methyl (-)-(Z)-2-(Zamino)-4,5-cyclopropane-hex-2-enoate been prepared through manipulation has of functional groups on 5-(t-butyldimethylsilyloxy)furan-2(5H)-one.252A more routine approach to such systems is Michael addition to a protected dehydroalanine, which offers convenient access to (Z)-dehydrotryptophans through PdC12/ NaOAc-AcOH catalysed reaction with indoles (see also Refs. 177,l 78).253
4.12 Synthesis of a-Amino Acids with Aromatic or Heteroaromatic Groupings in Side Chains - Increasing interest in the therapeutic use of common amino acids capable of neutron capture when carrying appropriate substituents has encouraged studies in the synthesis of organic boron derivatives (see also Refs.9,868). Standard methods have been applied for the synthesis of 0-and mborono-L-phenylalanines. Grignard reaction of 0- and m-bromotoluene with B(OMe)3 and functionalization so that alkylation of diethyl acetamidomalonate can be carried out, was followed by a-chymotrypsin resolution.254p-Borono-DLphenylalanine and -DL-phenylserine were prepared by aldolization of methylisocyanoacetate using the aldehyde (53).255 A series of papers has appeared, describing the synthesis of phenylalanines substituted in the phenyl moiety by carboranyl groupings. One of these starts with methyl pbromobenzoate via p-(HC = C)-C6H4CO2Me+ decaborane + (54), and reaction of the derived benzyl bromide with diethyl phthalimidomalonate + (55).256 Other standard methods are represented, e.g.257 the elaboration of an ally1 chain carrying a carboranylphenyl grouping, into the acyl group of a chiral N-acyloxazolidinone (cf. Section 4.2). 5-Fluoro-D- and L-DOPAs and *F-analogues have been prepared starting from 5-nitrovanillin, through the acetamidomalonate route and Balz-Schiemann substitution of a diazonium group by fluorine, followed by chromatographic resolution.258 6-Fluoro-L-DOPA and its 3-0-methyl derivative have also been obtained by standard synthetic methods.259 Homochiral bis-amino acid diary1 ethers exist in natural products, and 0arylation of tyrosine derivatives employing fluoroarenes has been established using suitably mild reaction conditions.260 Simple heteroaromatic side-chains are represented in P-(2-pyridyl)-L-alanine, prepared from 3-(2-pyridyl)acrylic acid through catalysis by L-phenylalanine

1: Amino Acids

31

ammonialyase (present in Rhodotorula rubra mycelium);261 and in the pyrimidine isostere (56) of the potent NMDA antagonist, SDZ EAB 515,262synthesized by alkylation of Ph2C = NCH2C02Me.~-Isoxazol-4-yl-L-alanines potent NMDA are agonists, and further synthetic studies (see Vo1.25, p.38) have been described of homologues (57 and 58),263 AMPA and 4-methylhomoibotenic acid have been prepared through cycloaddition of suitably substituted bromonitrile oxides to alkynes.264Resolution using (-)-phenylethylamine and absolute configurational assignment by X-ray crystal analysis is included in one of these preparations.263 A related alanine derivative that carries a P-heterocyclic moiety is the neurallyactive quisqualic acid. Conformationally-constrained analogues have been synthesized, using standard methods.265 The homochiral a-amino acid (59) carrying a thiazoline side-chain was obtained by a novel manipulation of the penicillin nucleus.266 P-Substituted tryptophans (see also Refs.129-131, 144, in Section 4.2) have been obtained by Lewis-acid catalysed ring-opening by indoles, of the aziridine (60). Opposing regioselectivities are observed; the lactone (61, from 60, RR' = 0) leads to p-amino acids, and the acetsl (60, R = H, R' = OTBDMS) yields (62) from which P-substituted tryptophans were obtained.267erythro-P-Alkylated tryptophans can be obtained by conjugate addition to (63) formed from the tryptophan derivative (64) that Crich's research group has been establishing as a valuable synthon in recent years.2683,4-Bridged tryptophans (65) are, likewise, obtained starting from tryptophan itself, via 4-bromodehydrotryptophan and Other cyclization of the derived 4-brom0-a-propenyl-DL-tryptophan.~~~ 3,4cyclized tryptophan analogues formed with the a-amino group through an isoleucyl bridge270 are members of a family of conformationally constrained amino acids that includes potential protein kinase C modulators. These analogues support a wide range of pharmacological studies that reflect the importance of derivatives of the parent amino acid, and the fact that N-ethylL-tryptophan benzyl ester is a weak antagonist at the Substance P(NK1) receptor has stimulated the synthesis of indole-substituted analogues [N-acetyl-L-(3',5'-ditrifluoromethy1)tryptophan was found to be particularly effective] by standard methods.271 An efficient synthesis of 5 - a ~ i d o t r y p t o p h a n ~ ~ ~ employs a standard route, starting from 5-nitroindole.
4.13 Synthesis of a-Amino Acids Carrying Sulfur- or Selenium-containing Side Chains - This class of amino acid is gaining further importance, since certain

sulfur functional groups react with nitric oxide. L-Thiocitrulline (readily prepared from L-ornithine) and its S-methyl derivative, and Lhomothiocitrulline, are potent inhibitors of nitric oxide synthase, and presumably owe this property to their structural similarity with arginine analogues.273 Conventional synthetic strategies are involved in the synthesis of S-alkyl-L~ y s t e i n e s * ~ ~ also Ref. 53) and of the conformationally-constrained L-methio(see nine (66) obtained by elaboration of the Diels-Alder adduct of 5-norbornen-2-01 with a protected d e h y d r ~ a l a n i n e . ~ ~ ~ L-( + )-Selenomethionine has been prepared from L-homoserine lactone and MeSeLi.276

32

Amino Acids, Peptides and Proteins

oCH2C02H

HO2C#:Y PhtN

c02-

1: Amino Acids

33

4.14 Synthesis of a-Amino Acids Carrying Phosphorus Functional Groups in Side Chains - Main areas of interest in compounds of this class, as distant isosteres of some common amino acids, are being sustained by current research (see also Refs.99,114), e.g. into the synthesis of (R)-4-oxo-5-phosphononorvaline, H203PCH2COCH2CH(N+H3)COi- (a selective NMDA glutamate site antagonist) in four steps from D-aspartic Stereoselective synthesis of L-phosphinothricin [MeP(0)(OH)CH2CH2CH(NH2)C02H], present in the herbicide glufosinate-ammonium, has been reviewed.278 The (mdifluoroalky1)phosphonate analogue of phosphoserine has been synthesized starting from O-benzyl-N-B~c-L-serine.~~~ l-(Z-Amino)-5-(Boc-amino)pentylphosphinic acid, an isostere of lysine, has been synthesized from 3,4dihydr0-(2H)-pyran.~~O Phosphonate-bridged phenylalanine derivatives (67) that are capable of selective de-protection so that they can be incorporated into peptides have been synthesized from the corresponding p-iodo-L-phenylalanines (an improved synthesis of this amino acid has been worked out), through Pd-catalysed coupling.281 The phosphonotyrosine isostere N-Fmoc-4-phosphono(difluoromethyl)-L-phenylalanine, has been prepared from the organozinc reagent from P-iodoalanine together with the requisite iodoarene,282and independently from the methyl ester N-Boc-(4-dimethylphosphonomethyl)-L-phenylalaof its diethylphosph~nate.~~~ nine (68) has been obtained through a route that employs the iodarene-organozinc reagent C-C-bond-forming methodology.284
4.15 Synthesis of Isotopically Labelled Amino Acids - All the familiar isotopes featured under this heading over the years are represented in the current literature. 2H-Labelled protein amino acids, intended to assist biosynthetic studies, often call for the most ingenious synthetic strategies, as illustrated by (2S,4S)- and (2S,4R)-[5,5,5-2H3]1eucine. route starts from (R)-pulegone The , [2-2H]citronellal -+ [5,5,5-2H3]i~~valeric (through de-carbonylation using acid Wilkinsons catalyst followed by oxidation), then follows standard steps.285 Labelled aziridines (69; prepared from labelled malates, starting with fumaratesl fumarase or by enzymic amination) serve as starting materials for syntheses of stereospecifically-[2H]-labelled D-serine, D-cystine, and P-chloro-D-alanine, through nucleophilic ring-opening.286 Synthesis of labelled D-(prop-2yny1)glycine (70) follows an identical strategy using a carbanion as n ~ c l e o p h i l e . ~ ~ ~ Regiospecific labelling of the aromatic ring in phenylalanine is achieved by treating a protected tyrosine tetrazolyl ether or its 0-or m-isomer, with 2H20.288 The development of established methods (see Vol. 26, p.38) allowing the preparation of 2H-L-glutamic acid, and 2H-, I3C- and 15N-L-glutamicacids, on a gram scale from 2-oxoglutaric acid, includes several points of interest; e.g. the involvement of glutamate dehydrogenase with 2H20 as solvent, for C-3- and C-4labelling, and exchange at C-4 by equilibration in 20% 2HC1-2H20.289 related A approach to 13C- and 15N-L-alanineusing alanine dehydrogenase, and to other 15N-L-a-aminoacids, includes full experimental C-Labelled amino acids are accessible only through super-rapid methods of synthesis (and equipment ensuring the safety of operators), due to the short

34

Amino Acids, Peptides and Proteins

half-life of the isotope, but this requirement has not only been met satisfactorily over recent years, but with sufficient leeway to permit purification to be included in the cycle. Thus, a 45-minute process (including HPLC purification) serves for the preparation of [P-' 'C]-p-chloro-L-phenylalaninefrom 4-Cl-C&4-* 'CH2Br and the Li enolate of a chiral imidazolinone (see Scheme 5 , Section 4.2) followed by hydrolysis.291 The special reactivity of the L-tryptophan-derived bis(Nmethoxycarbonyl)hexahydropyrrolo[2,3-b]indole (64, cf. Ref. 1 37) allows rapid alkylation by 11CH31en route to [a-"CH3]-L-tryptophan and its N-carboxylic anhydride.292The use of the Anatech RB-86 robotic synthesizer permits rapid synthesis of [1-' 'C]-L-tyrosine from the analogous i ~ o c y a n i d e(see ~ ~ ~ Vol. 19, p.20) and of [CH3-l'C]-L-methionine through robot-controlled methylation of homocysteine l a ~ t o n e . ~ ~ ~ a-[14C]Methyl-L-tryptophan has been prepared by methylation of the Li enolate of a Schiff base of an L-tryptophan, followed by enzymic resolution.295 and by similar processing of the L-tryptophan-derived bis(N-methoxycarbony1)hexahydropyrrolo[2,3-b]indole(64).296The ~t-[~H]methyl-analogue also prewas pared in the latter study. The simplest amino acid syntheses leading to labelled glycines, amination of [13C]bromoaceticacid esters with B o c ~ ~ ~ N - carboxylation of BocNand K ~ ~ ~ ~ MeCH2SnBu3with 14C02after lithiation with MeLi,298are typical of numerous syntheses of labelled protein amino acids over the years, a further example being 15N-[2H3]acetyl-L-aspartic acid as a standard for isotope dilution GC-MS analysis of N-acetyl-L-aspartic acid in urine.299The glycine isotopomers were used for spectroscopic assignments.297 ['sF]-Labelled amino acids, e.g. P-[18F]fluoro-alanine300 provide useful substrates for in vivo drug delivery and similar diagnostic studies, a popular substrate being 6-['*F]fluoro-L-DOPA, whose 3-0-methyl derivative has been prepared by fluorodestannylation of the corresponding stannylated DOPA.301 Saccharomyes cerevisiae mediates the synthesis of L-[35S]cysteine and -methionine from Na235S04.302 Aromatic iodination of tyrosine, by either the Chloramine-T/12 or analogous Iodogen methods, is a standard preparation of 2,5-di-iodotyrosine7and has been applied for ['251]-labellingof ~ t - m e t h y l - l - t y r o s i n e . ~ ~ ~ 4.16 Synthesis of P-Amino Acids and Higher Homologous Amino Acids Extraordinary growth of interest in this topic is evident in the current literature. The driving force, apart from the usual mechanistic interest in novel bondforming processes, must be the importance of the isolated examples of natural amino acids, amides and peptides within this category; perhaps also the intuitive expectation that many more physiologically-active natural j3-amino acids are waiting to be discovered. A major proportion of these studies now concerns stereoselective synthesis, and recent work with p-amino acids has been reviewed from this point of view.304 Some general methods are extensions of those used for the stereoselective synthesis of a-amino acids, such as the C - 5 - a l d o l i ~ a t i o n ~ ~ ~ and C-5-alkylati0n~~~ of six-membered chiral perhydropyrimidino-4-ones (Scheme 24) and alkylation at

1: Amino Acids

35

BzlOpC BocNH

-0pc
2 H Pmc: W - O p C a \ pH NH3

;;xNbR H C02Me

Me)/NvNoz Ph

Reagents: i, NH20H, then ZCVNaOH; ii, (CH20), , TsOH; iii, remove Z, then LiHDMS; iv, Amberlyst H-75; v, LiAIH4, then H30+

Scheme 24

36

Amino Acids, Peptides and Proteins

C-6 of unsaturated analogues (71),307 addition of chiral imines [(S)PhCHMeN = CHR to (E)- or (2)-a-silyloxyketene acetals mediated by chiral boron reagents,308or -CH2C02Meto ( + )-(S)-p-tolylS(0)N = CHPh to give (R)3-amino-3-phenylpropanoic acid,309 addition of the highly syn-stereoselective nitrogen nucleophile (R)-PhCHMeNLiCH2Ph to alkyl cinnamates (72 + 73)3l o and anti-addition to cr~tonates;~' reasons for high stereoselectivity in the the latter approach have been discussed.312 adducts can be further alkylated with The excellent stereoselectivity, and an example of this is included in the novel establishment of an asymmetric Michael addition of a homochiral magnesium A further example of a synthetic target amide (R)-PhCHMeN(MgBr)CH2Ph.313 that has been achieved through asymmetric Michael reactions is (2S,3R)-2methyl-3-aminopentanoic acid [(R)-PhCHMeNLiCH2Ph + t-butyl (E)-2-methyll penten-2-0ateI.~4 Amination of ethyl 2-methyl-4,4,4-trifluoroacetoacetate using benzylamine and appropriate further steps (including penicillin acylase resolution - the (R)-enantiomer is most readily hydrolysed) forms the basis of a synthesis of all four The stereoisomers of a-methyl-~-trifluoromethyl-j3-alanine.315 [ 1,3]-proton shift at the heart of this process can be biased by (-)-cinchonidine to give enantiomerically-enriched (R)-j3-fluoroalkyl-fI-amino acid derivatives (up to 36% e.e.).316A similar approach is seen in the addition of benzylamine to ethyl (R)-trans-4,5-0isopropylidene-4,5-dihydroxy-2-pentenoate (Scheme 25),3l 7 and in the addition of phthalimide salts to imides of chiral imidaz~lidinones.~'An interesting -+ alkylation process N02CH2CH2C02But N02CH[CH(OH)CH2F]CH2C02But uses 2-fl~oroethanol/COCl2.~~~ a-(0-Hydroxypheny1)-p-alanines are available .~~~ through the addition of (Me3Si)2N-Li to c o ~ m a r i n s Homochiral N-diphenylamino-3-amino-1,2-diols formed by aminolysis of epoxyalkanols can be converted into j3-amino acids via ally la mine^.^^^ Reductive dimethylamination of ap-unsaturated acids has been described.321 P-Amination of 3-hydroxycyclobutanecarboxylate esters through treatment with carbonyldi-imidazole and sodium azide involves an acylnitrene insertion step.322 Nucleophilic addition to imines (PhCH = NS02R + BrZnCH2C02But -+ H2NCHPhCH2C02H)323 and the related process with N-acyl-a-methoxya r n i n e ~ ~ ~ ~ one general approach to p-amino acid synthesis, while illustrate 1,2-~yanohydroxylationof alkenes by nitrile-imines [EtO,CC =N +N-CH2Ph 3-carboxypyrazolines RCH(CH2CN)NHCH2Ph]325 provides an alternative amination pathway. Hydrogenation of homochiral aziridine-2-carboxylates over 3 days gives P-amino acid esters.326 Further syntheses of N-benzoyl-(2R,3S)-3-phenylisoserinemethyl ester, the derivatized side-chain moiety of taxol, have been described, employing conventional synthesis and resolution, while the other incorporates yeast-catalysed reduction to introduce a second chiral centre into (S)-phenylglycine-derived acyl cyanides PhCH(NH2)COCN.328Diastereoselective reduction of N-protected P-amino-a-ketoacids has been achieved, by H2/RuCl/(R)-BINAP for the preparation of L-i~oserine,'~~ employing microbial reduction for the preparation of and (2R,3S)-(-)-phenyli~oserine.~~~ Although oxazolones offer standard routes to aamino acids, exploitation of their reactivity at C-2 in a j3-amino acid synthesis has
+

1: Amino Acids

37

also been realized (Scheme 26).331 This amounts to one-carbon homologation of an aldehyde, also achieved using nitromethane; the ensuing conversion (-CH2N02 + -C02H) involves drastic conditions (12M HC1,10O0,46 h) but is nevertheless appropriate for an erythro-phenylnorstatine synthesis.332 Examples of the extension of standard practice in the a-amino acid field are: alkylation of p-alanine carrying two chiral auxiliary groups, viz. N-(hydroxypinany1idene)-P-alanine (-)-menthy1 ester;333hydrogenation (H2/Pd) of 3-aryl-2-aminomethacrylic esters BocNiPrCH2C(= CHAr)C02Me gives racemic p-amino acid esters.334An asymmetric Diels-Alder approach gives the fused-ring didemnin analogues (74).335 Ireland enolate-Claisen rearrangement of p-alanine ally1 esters, (E)- and (Z)-RCH = CHCH202CCH2CHzNR' R2, leads to a-alkyl-&amino acids (75 and 76).336Alkylation a- to the carboxy group of a @-aminoacid derivative through the aldol route allows versatile chain extension.337 Amidiniomycin (77) has been synthesized from norbornylene via meso cisdicarbomethoxycyclopentane; the route depends on enzymic discrimination between enantiotopic ester groups for its success.338A synthesis of (2S,3R)-3amino-2-hydroxyalkanoic acids by amination of (78) may require a broader study if, as claimed, it is to be accepted as a 'general' synthetic route.339 Syntheses starting with an a-amino acid include Wolff rearrangement of the diazomethylketone derived from an N-protected a-amino acid340 followed by diazo-transfer and oxidation (dimethyl dioxirane) to give N-protected p-amino aketo-esters without racemization. Homologation, through the Wolff procedure, of protected L-arginine gives dipeptides when irradiation is performed in the presence of an amino acid ester.341One-carbon homologation of a-amino acids, by their conversion into 2-(2-aminoalkyl)thiaoles followed by hydrolytic thiazole cleavage and further elaboration (cf Scheme 22, Ref. 226) has been demonstrated to give a-hydroxy-&amino aldehydes and Jheptene Schmidt rearrangement of cis- 1-carboxy-2-carbomethoxy-bicyclo[2.2.1 gives the corresponding p-amino acid ester.343 Unprecedented syntheses of mechanistic interest have been described, by which unique p-amino acid targets have been attained (e.g. 79), by ring-contraction of tetrahydroisoquinoline alkaloids after l i t h i a t i ~ n ,and (80) from the 2-(p~~ naphthy1)oxazoline (8 1) by direct amination and alkylation followed by hydrolysis.345 Ozonolysis of N-ethoxycarbonyl-2,3-dihydropyrroles methanol gives the in corresponding N-formyl-N-ethoxycarbonyl+amino acid methyl esters; the wellknown oxidative ring-opening of 1,2,3,4-tetrahydropyridinesto give 5-aminoalkanals is also explored further in this study.'& An extension of the amination approach leading to p-amino acids has been established. A tandem conjugate addition-hydroxylation using (S)PhCHMeNLiCHzPh and [( + )-camphorsulfonylJoxaziridine leads to homochiral 3-amino-2-hydroxyalkanoicacids (82; R = Ph, alias allophenylnorstatine, a component of the HIV-protease inhibitor k y n o ~ t a t i n ) and ~ (83; R = hexyl, ; ~ ~ to alias m i ~ r o g i n i n ) .Both (2R73R)- and (2S,3R)-diastereoisomers of the last~~~ mentioned example were prepared, establishing the latter to be the absolute configuration of the natural ACE inhibitor. (3S,4S)-Statine and its isomers are

38

Amino Acids, Peptides and Proteins

Reagents: i, BzlNH2; ii, H P , Pd/C, EtOH Scheme 25

.NHBz

(R = OAc for the

S,S-isomer)

Reagents: i, Boc-phenylglycinal; ii, Et3N; iii, 6M-HCI, 110 "C, 12 h; it.,. S0Cl2; v, BzCI; vi, Pseudornonas fhorescens, vinyl acetate Scheme 26

I : Amino Acids

39

NH

OMe

OKNH

(79)

/N

40

Amino Acids, Peptides and Proteins

Ph P h

ZN R d

4
p

Ph Z $ N .

7
d R

OAc

iii

Ph\

P ZN h

zp/-o..
F

d R
(+ epimer as minor product)

Reagents: i, DIBALH; ii, AqO; iii, CH, =C(OMe)OTBDMS, ZnBr,

I: Amino Acids

41

easily prepared by aldol reactions of a protected L-leucinal, and a highly diastereoselective route has been established employing diethylaluminium enolates derived from [q-C5H5]Fe(CO)(PPh3)(COMe),to give the intermediate (84).350 Simple alternative routes, addition of lithiated methoxyallene to an N-Boc-aminoalkanal followed by ozonolysis [BocN(CH2Ph)CHiPrCH0 -+ BocN(CH2Ph)CHiPrCH(OH)C(OMe) C = CH2 = (2S,3S)-nor~tatine],~~~ amination of aldols ~-Boc-aminoalkanal/PhCH2C02Hdianion] with Ph3P(0)N3 and ring-opening of the resulting diastereoisomeric 4,5-disubstituted oxazolidin2 - 0 n e s , ~ ~ ~ azide ring-opening of the appropriate homochiral 2,3-epoxyalkand anol, giving statine and its 3 - e ~ i m e r , ~ ~typical of routes established over are ~ recent years. A further statine synthesis involves the use of a homochiral oxazinone (Scheme 27) that is alkylated in an unusual way.354Similar alkylation of N-protected N-aamino acid carboxylic anhydrides (NCAs) uses Meldrums acid (Scheme 28); reduction of the resulting tetramic acids gives statine analogues.355 Synthesis of y- and higher homologous amino acids is studied for much the same reasons that motivate efforts in the a-and p-amino acid area: the provision of authentic samples of biologically-important amino acids and their analogues, and also the growing interest in dipeptide and oligopeptide isosteres that 6-amino acids and higher homologues represent. Conformationally-constrained y-aminobutyric acid (GABA) is one way of describing the spirobicyclic condensation product (85) of 2-(N-benzylimino)cyclopentanecarboxylic acid with dibrom ~ e t h a n e L-erythro-a P-dihydroxyGABA and y-erythronine have been pre.~~~ pared through oxidative degradation of 4-aminopent- 1-ene-2,3-diols formed from penta-1,4-dien-3-01 by Sharpless epoxidation followed by a m i n a t i ~ n . ~ ~ Since dolaisoleucine t-butyl ester formed from the aldol adduct from 2-N-methylL-isoleucinal and t-butyl glyoxylate is identical with the natural y-amino acid, the (3R,4S,SS)-stereochernistrycan be assigned.358Dolaproine, a y-amino acid from through (-)-dolastatin 10, has been assigned the (2S,2R,3R)-stereochemistry examination of the product from a corresponding route from the Boc-L-prolinal/ (S)-HOCPh2CHPh02CEt aldol adduct, verified by X-ray crystal analysis.359An alternative route to natural dolaproine relies on preferential anti-addition of (Z)crotylboron reagents (86) to homochiral N-Boc-aminoalkanals (Scheme 29).360A simplified route to E/Z-y-amino acid esters Me02CNHCHRCH= CHCO,Et, through a one-pot partial reduction (DIBALH) to the aldehyde and homologation with (EtO)2P(O)CHLiCO2Et, has been described.361 Both enantiomers of 4aminohex-5-enoic acid (vigabatrin) have been prepared in this way, starting with N-Z-L- or -D-methionine methyl ester and concluding with reduction of the double bond and introduction of the terminal alkene group through oxidative elimination of methanesulfinic Wittig reactions of MeC( = PPh3)C02Me (or the corresponding phosphonate) with a-Boc-alaninal gives a 2: 1 anti/synacid mixture of 2-methyl-4-aminopentanoic derivatives after catalytic hydrogenat i ~ n . ~ ~ ~ A variety of routes exist, to lactams of various ring sizes, although their cleavage to give a-amino acids can be problematical. A study of N-acylated lactams from this point of view has established the use of toluene-p-sulfonic acid
+

42

Amino Acids, Peptides and Proteins

Reagents: i, Meldrum's acid, NEt3; ii, A, AcOEt; iii, NaBH,;

iv, NaOH, aq. acetone

Scheme 28

,OH

Reagents: i, THF, r.t.

Scheme 29

N Ts
(87)

CO,Me
NHTs

I : Amino Acids

43

in methanol for the purpose.364 Oxidation of N-Troc-piperidines with RuC13/ NaI04 and hydrolysis under unspecified conditions gives 5-aminoalkanoic acids.365 Pyrrolidin-2-one ring opening is the final stage in a synthesis of 4-amino2,2-dimethylbutanoic Diastereoselective alkylation of S-lactams carrying a chiral N-substituent has been established.367 A route to &-amino acids has been established, exemplified by regioselective addition of alkylcopper reagents to each of the four stereoisomers of the Ntoluene-p-sulfonylaziridine (87).368Analogues [(2R,4S)-5-amino-4-hydroxypentanoic acids] of a particular natural example of this family of amino acid have been synthesized from L-glutamic acid via the silylated a-hydroxymethyl-lactone (88).369 a-N-Boc-Aminoaldehydes yield &-amino y-hydroxyacid derivatives through condensation with allylic bromides,370 as do corresponding methyl ketones through reaction with a - b r o m ~ a l k a n o a t e s .Mitsunobu amination of ~~~ an allylic alcohol with phthalimide is a step in a route to a 6-aminoalkenoic acid.372 methodology, especially in topic areas under the heading of chromatographic resolution, would be an accurate description of current research. Analytical aspects (determination of enantiomer ratios by chromatographic and related means) are mostly covered in Section 7, and configurational assignments achieved through synthesis strategies are covered in earlier Sections. Classical laboratory procedures for the resolution of amino acids are represented in diastereoisomeric salt formation with homochiral sulfonic The procedure is usefully complemented by salicylaldehyde-mediated racemization, illustrated by a preparation of D-p-hydr~xyphenylglycine.~~~ N-Salicylidene- and pyridoxylidene-DL-amino acids have been resolved analogously, through chromatography of derived diastereoisomeric copper ~ h e l a t e s .Marfeys reagent ~~~ can be used both to generate diastereoisomeric derivatives and to assign absolute configuration to individual enantiomers, for example to m i c r i ~ y s t i n sUse has .~~~ been made of the different rates of condensation of ( + )-2-hydroxypinan-3-one with Schiff bases of DL-amino acids, to enrich samples with a particular enantiomer, to the extent of complete resolution in certain cases.377Examples of the resolution of higher homologous amino acids in this way are relatively rare, but vigabatrin enantiomers (see preceding Section, Ref.362) have been secured through acylation of 5-vinylpyrrolidin-2-one with (R)-PhCHMeC02H and subsequent crystallization.378 Resolution of DL-amino acids through preferential crystallization of one enantiomer is underpinned by idiosyncratic physical solid state behaviour; thus, L-phenylalanine crystals added to a DL-glutamic acid sample favour the crystallization of the L-enantiomer, but all attempts failed to achieve the corresponding result using D - ~ h e n y l a l a n i n e . ~ ~ ~ 4-Hydroxyproline assisted the resolution of DLallothreonine in analogous fashion.380Spontaneous resolution under racemizing conditions in prebiotic times was probably not of major importance, either for the origin of enantiomeric imbalance or for the amplification of any microscopic imbalance.38
4.17 Resolution of DL-Amino Acids - Active development of existing

44

Amino Acids, Peptides and Proteins

A widening range of both enzymes and non-protein DL-amino acids is being represented in resolution studies. The possibilities have been explored for the use of pronase with non-protein amino acid methyl esters,382Aspergillus niger lipase for kinetic resolution of pipecolic acid methyl ester,383Candida cylindracea lipase lipases for a-vinylglycine after reduction,385thiol with aziridinecarbo~ylates,~~ proteases with Z-amino acid methyl esters,386subtilisin Carl~berg,~~. amino l 2 an acid amidase from Mycobacterium neoaurum with a,u-disubstituted a-amino acid a m i d e ~decanoyl-a-chymotrypsin with N-dodecanoylamino acid p-nitrophenyl ,~~~ esters388 immobilized Aspergillus oryzae aminoacylase with N-acetyl-p-chlorophen ~ l a l a n i n eand ~ continuous column resolution of N-acetyl-DL-methio~ ~ for nine,3w and an aminoacylase from Streptovercillium olivoreticuli or penicillin acylase from E.coli for preparative-scale resolution of 0-and p-fluorophenylglycines.391Novel procedures have been studied; one featuring a D-amino acid oxidase/aminotransferase/L-glutamic system that converts racemic mixtures acid of common and non-protein amino acids into the L-enanti~mers;~~ another using immobilized enzymes in a tea-bag method, with N-acetylamino acid methyl esters in reverse micellar media;393and another establishing the resolution of Nacylamino acids using alcalase in supercritical C02.394 Aldolase from Streptomyces amakusaensis catalyses the reverse aldol reaction with (2S,3R)-P-hydroxya-amino acids, and therefore provides enantiomers when applied to the racemates.395 Most of the current research studies of resolution are based on physical principles, particularly involving chromatographic separation over chiral stationary phases (CSPs). The technique continues to develop rapidly, and reviews have appeared of Pirkle C S P S ~ ~ ~ preparative-scale resolution by this and approach.397 Long-established examples of CSPS are represented in recent papers, including cellulose thin-layer chromatography with a cyclodextrin-containing mobile phase, showing additive contributions to discrimination leading to large separation factors for t r y p t ~ p h a n s .Bovine serum albumin (BSA) ~~~ achieves the resolution of N-alkanoyl DL-[3H]leucines(the D-enantiomer is more strongly retained and separation factors are strongly dependent upon the solutes in the stationary phase.399 For the free amino acids in solutions at pH 7.0, the L-enantiomer is more strongly bound to BSA when it is immobilized in the form of a membrane.400 Cyclodextrins can accomplish the resolution of DL-alanine p-naphthylamide.401 New examples include p-cyclodextrins to which D- or L-phenylalanine cyanomethyl esters are linked,402 6-(3-aminopropylamino)-6deoxycyclomaltaheptaose (which binds L-tryptophan more strongly than p-cyclod e ~ t r i n ) or chiral alcohols immobilized within a poly(ethy1ene) film (enantio,~~ selective transport of amino acids)404 and 4-vinylpyridine-1 -vinylimidazole copolymers imprinted with N-Z-L-aspartic acid (see Vo1.26, p.49).405 Crystals of imprinted D-phenylglycyl-D-phenylglycineformed from solutions containing N-acetyl-L- or D-leucine ethyl ester are capable of enantioselective binding of these solutes.406 Capillary GLC of N-trifluoroacetyl-DL-amino acid n-butyl esters over L-Phe-tetra-amide CSPs has proved effective in enantiomer ratio determination^.^^ Chromatographic resolution on the ligand-exchange principle is represented in the use of copper(II)-6-deoxy-6-(N-histamino)-~-cyclodextrin

I : Amino Acids

45

(binding of D-amino acids is favoured),M8the use of copper(I1)- or nickel(I1)-Nsubstituted-L-proline-modified silica gel,409 and a similar use of (R)-2-aminoalkanol for chiral modification of stationary phases.410 Results obtained in ligand-exchange resolutions using a range of metal salts have been compared,41 and the routine method employing a chiral mobile phase additive has been studied for the resolution of fluorine-substituted phenylalanines and phenylglycines.41 Permeable membranes have been mentioned in the preceding paragraph, in their role as enantioselective barriers that can form the basis of preparative resolution technology. Membranes to which L-phenylglycine is bonded are more permeable to the D-enantiomer of this amino acid,413and hollow-fibre membranes carrying N-( 1-naphthyl)-L-leucine have shown promising enantioselecti~ity.~~ Liquid membranes are particularly promising in this respect, 5cholesteryl-L-glutamate forming the basis of mixed micelles that preferentially bind the D-enantiomer from solutions of DL-phenylalanine in the presence of copper(I1) ions.415 1,2,4-Triazole-containingcholesteryl esters offering preferential transport to D-phenylalanine primary alkylammonium salts.416Chiral discrimination is also revealed for Langmuir-Blodgett monolayers containing Npalmitoyl-DL-valine and DL-alanine and N-stearoyl-DL-valine, compared with L - a n a l o g ~ e s , by~ ~ ~ (cholesteryloxycarbony1)benzo-18-crown-6 mono layer^,^^^ and by a variety of emulsion liquid membranes;419and several other papers in this Symposium Volume, Ref.419). A promising development is the demonstration of enantiomeric enrichment of derivatized and free amino acids by foamforming chiral collectors.420 A 44-mer RNA that binds L-citrulline and D- or L-arginine has been reported .42 Speculation surrounding the methods by which DL-amino acid mixtures, generated in prebiotic times, were supplanted by L-enantiomers has shifted towards the consequences of parity-violating phase transition phenomena (BoseEinstein condensation activation),422a theory advanced by Salam (see Vol. 24, p.40) that he has recently reviewed.423Many of the main protagonists in this field have presented their ideas in this publication; favouring either parity-violating energy differences between L- and D-enantiomers of an amino a ~ i d , ~ ~ ~ through chiral interactions at the ocean-air interface (see Vo1.25, or through spontaneous a m p l i f i c a t i ~ n .The ~ * ~ ~ ~ of L-amino acids, as a ~ ~ emergence consequence of parity-violating energy differences leading to electroweak neutral currents, has been reviewed more recently429by an advocate of an alternative theory (see Vo1.26, p.51). The origin of chirality in amino acids and carbohydrates is suggested to lie in sonically-induced phase transitions; a D- or L,-amino acid will eventually accumulate through sonication of a racemic amino acid.430A much earlier idea, encapsulated in the Vester-Ulbricht theory, asserts that enantioselective destruction of the D-amino acids occurs more rapidly, relative to their L-enantiomers, under the influence of inherently asymmetric radiation. This has been reinvestigated to show that DL-leucine bathed in radiation from a 22Na weak positron source suffers more rapid destruction of its D-enanti0mer.4~~9~~~ ESR

46

Amino Acids, Peptides and Proteins

study of D- and L - a l a ~ ~ i and~of D- and L - l e ~ c i n degraded with 90Sr-90Y ne ~~ e~~~ P-radiation shows that irradiation generates more radicals in the D-enantiomer, and the Vester-Ulbricht theory is therefore claimed to be given further support. Reviews of origins of chirality and life, giving explanations that make lesser demands on the reader, have a p ~ e a r e d . ~ ~ ~ ? ~ ~ ~
5

Physico-Chemical Studies of Amino Acids

5.1 X-Ray Crystal Structure Analysis of Amino Acids and Their Derivatives - A pattern that has emerged in recent years, the revision of earlier data and determination of structures of new compounds, continues to be represented in the current literature. The fact that X-ray crystallographic instrumentation has become more sophisticated, so that results are more reliable, but also less tedious to obtain, is mainly responsible for the increased activity in this area. Crystal structures for free amino acids have been reported for DL-ala~~ine:~~ DLarginine (as its dihydrate, formate, and formate d i h ~ d r a t e ) ,L-arginine ~~~ fluor~borate,"~~ L-arginine maleate dihydrate,M L-histidine monoaCetate,44' L-histidinium phosphite and a re-investigation of monoclinic L-histidine,a2 and N-methylglycine monohydrogen p h o ~ p h i t e . ~ ~ Crystal structures of amino acids have been surveyed with particular reference to their propensity towards polymorphism.444 Derivatives that have been subjected to study are benzyl 2(S)-Boc-amino-4ox0-6-pheny1-5(E)-hexenoate,~~ DL-valine N-carboxyanhydride,46 N-monochlora~etyl-D-a-rnethyl-leucine,~~ N-acetyl-L-proline methyl ester, -(4S)hydroxy-L-proline methyl ester, and -(4S)-fluoro-L-proline methyl ester,448 N-chlorosulfonyl-L-proline benzyl ester,49 Z-[(E)-5-(p-nitrobenzyloxycarbonylmethinyl)]-L-proline t-butyl N-[N-benzyloxycarbonyl-L-1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl]-L-phenylalanine methyl ester,451 and Boc-Ltryptophan (2-thymin-1-y1)ethyl ester.452While crystalline N-acetyl L-proline methyl ester is characterized by a cis-peptide bond, the ring-substituted analogues adopt the trans-configuration.448

5.2 Nuclear Magnetic Resonance Spectrometry - An NMR study qualifies for inclusion in this section only if the object of the study involves more than routine support of synthetic studies. Conformational studies are included within this policy, and a familiar example, interpretation of 'H-NMR (as well as IR data) of C2HC13 solutions of N-acetyl-L-proline N-methylamide, provides more reliable conformer ratios based on improved understanding of spectral parameters.453 Related studies involving chloro-substituted t r y p t o p h a n ~ and~ bacoflen ~~ analogues [3-(thien-2-y1)- and 3-(furan-2-yl)-y-aminobutyric adopt the common approach of calling for data from both 'H-and 13C-NMR measurements. Establishment of absolute configuration of a-amino acid enantiomers, and of other a-chiral amines, through interpretation of 'H-NMR data of amides formed with (S)-0-methylmandelic and enantiomeric purity determination of

1: Amino Acids

47

deuteriated esters of amino acids through 2H-NMR measurements using poly(ybenzyl-L-ghtamate) in CH& as a chiral lyotropic liquid crystal solvent,457are studies that illustrate familiar stereochemical applications of 'H- and 2H-NMR Another analytical application is represented in the estimation of carbamate formation in aqueous solutions of amino while the extraordinary sensitivity of current NMR instrumentation is further illustrated (see Vo1.23, p.46) in the detection of glutamic acid, glutamine, and N-acetylaspartic acid in brain tissue.459NMR parameters for glycine in frozen aqueous solutions have been collected;460values of 'H-NMR spin-lattice and spin-spin relaxation times increase for aqueous solutions of glycine and proline with increases in temperature and c ~ n c e n t r a t i o n . ~ ~ ~ A 'magic angle spinning' study by 'H-NMR of Lalanine has been directed at the assessment of molecular dynamics in the solid state .462 13C-NMR studies with similar objectives have been reported; one broad study relates chemical shifts for each carbon atom to torsion angles for N-formyl-Lalanine- and - ~a lin e - am i desand ~ ~ ~ L-threonine and L-tyrosine?@ while another study illustrates the usefulness of 13C-NMRmeasurements for assessing protonation equilibria for ornithine, lysine, and hydroxylysine in aqueous dimethyl ~ulfoxide.~~' Spectra of N-alkyl- or aryl-N-carbamyl and their N-nitroso derivatives, have been correlated with structure.466 For 170-NMR, the frontiers continue to be pushed back but gaining results with little general applicability to revealing subtle details of amino acid structures in solutions; for example, further cross-polarized dynamic angle spinning data on 70-labelled amino acids have been collected.467Specialized applications continue, however, for 'P-NMR, with accurate enantiomeric analysis using amides formed from amino acids and the chiral phosphorinane HP(O)(OCHMeCH2NEt2)2,"6877Se-NMR data can be used for absolute configurational assignments to amino acids converted into imidaz01-2-selenones.~~~ 5.3 Optical Rotatory Dispersion and Circular Dichroism - Reports over the years have described the use of these techniques to determine subtle structural details for amino acids, though empirical rules sometimes fail. Thus, the CD spectrum of Nu-acetyl-L-ornithine and homologues is found to be what the simple rules predict for the D - conf i g~ r at i on,and ~ ~ ~ anomalous optical rotation data have been found for NE-acetyl-L-lysineand Na-acetyl-L-lysine.471and Naa ~ e t y l- l- a r g in in e Reliable correlation, of CD with absolute configuration, has .~ ~ ~ been established (L-derivatives show positive CD near 310 nm and negative CD at 280-290 nm) for Eu(fod)3 complexes of amino and of amino acid esters.474 The CD features of trinuclear complexes between amino acids and [M30(02CCH3)6L3In+(L = water or pyridine, n = 0 or 1) are suitable for the assignment of absolute configuration through the application of a semi-empirical helicity CD in the Soret wavelength region for solutions of homochiral amino acid derivatives and achiral porphyrins has been ascribed to hydrogen bonding association.476 Raman optical activity of amino acids (usually measured as CD) has been

48

Amino Acids, Peptides and Proteins

reviewed.477This is a topic area that has developed slowly, and its fundamental basis is still being worked out, assisted by studies such as comparisons of measured and calculated Raman CD for L-alanine and its i s o t ~ p o m e r s . ~ ~ ~
5.4 Mass Spectrometry - Increased activity associated with the newer instrumental techniques would be an appropriate inference based on the current literature covering mass spectrometric studies of amino acids and derivatives, There is also an awareness that some long-known variants of MS techniques have been under-used, such as negative ion measurement, which gives cleaner spectra intense [M-11- peaks for N-phosphofor N-(2,4-dinitrophenyl)amino amino and can allow discrimination between the four yhydroxyornithine diastereoisomers after bis(N-benzyloxycarbonylation).481 Both positive- and negative-ion modes have been applied to generate spectra from free amino acids (glycine, methionine, histidine, and cysteine), the spectra showing prominent [M-11- and [M*-l]- peaks.482 New techniques providing spectra of amino acids themselves include time-offlight MS of phenylalanine bombarded with 2.5 MeV carbon ions,483and pulsed laser-initiated ionization4esorption of tryptophan embedded in rhodamine B and and of crosslinking amino acids pyridinoline and its deoxy- and glucosylgalactosyl-derivatives.48s Cluster ion formation from a mixture of two different amino acids in a Na+-containing matrix has been studied, leading to an Na+ ion affinity scale for amino acids (a Li+ affinity scale was constructed similarly).4861H-2H-Exchange involving amino acids and CH302H,487 and gasphase proton affinity studies for amino acids, have been the subject of study over several years, applied to glycine and its i ~ o t o p o m e r sCorresponding FT-ion .~~~ cyclotron resonance studies of phenylalanine and its N-methyl- and NNdimethyl-analogues have been described.489Theoretical aspects have been presented, of kinetics of protonation leading to cluster ions [(amino acid)2-H] + in the gas phase.490 Gas-phase basicities, a subtly-different parameter, have been determined for amino acids49with particular attention to lysine and histidine, by the kinetic method. 5.5 Other Spectroscopic Studies of Amino Acids - Several projects cited in preceding sections have relied on more than one spectroscopic technique, commonly including IR and other vibrational spectroscopic methods. A remarkably simple positive answer to the question: do diastereoisomeric interactions exist between enantiomers in the solid state? has emerged from IR spectra of L-proline, DL-proline, and of an equimolar mixture of the two, which is not simply the weighted average of the preceding two spectra.492The result does not, of course, clarify the nature of these interactions, but much more detail is available through IR studies of glycine in neon, argon, and krypton matrices (three different conformers are established for the first and a similar result for proline and *H-labelled p r ~ l i n eIR-Raman spectroscopy of solid L.~~~ aspartic acid and 2H4- and ~SN-isotopomers495 of solid L-glutamic acid and and 2H4- and SN-isotopomers496 yield fundamental vibration modes for these amino acids.

I : Amino A c i h

49

Another familiar interest is revealed in the establishment of intramolecular hydrogen-bonding patterns for derivatives of p- and y-amino acids through IR study of CH2C12solutions.497 The rotational spectrum of p-alanine determined in a free-expansion jet spectrometer provides evidence for the existence of the same types of intramolecular interactions within two conformers, as already found in gaseous glycine and alanine.498 Photoelectron spectra have been determined for phenylalanine and its Nmethyl- and NN-dimethyl-analog~es.~~~ 5.6 Physico-Chemical S u i s of Amino Acids - This section covers useful tde interpretations, in terms of the behaviour of amino acids, of some simple laboratory measurements. Thus, the solubility behaviour of fourteen amino acids in water as a function of pH and temperature has been considered on the basis of fundamental structural and thermodynamic parameter^;^^ solubilities of Lisoleucine, L-leucine, and L-valine in aqueous NaOH increase as the NaOH concentration is increased, then decrease sharply after the 1:1-ratio has been passed.500The solubility of the dipeptide derivative Z-L-Asp-L-Phe-OMe (i.e., Zaspartame) in water containing L-phenylalanine methyl ester shows complex dependence upon concentration, pH and on other parameters, showing that the solutes interact in more ways than simply through ionic attractions and repulsions.501Concentrated proline solutions show non-ideal behaviour (freezing point depression and isopiestic data), and this explains the protective effect of proline on enzyme activity (due to the fact that it exerts a role as inert spacefilling solute to help maintain a native polypeptide c o n f ~ r m a t i o n ) . ~ ~ ~ The various lipophilicity scales for amino acids have been reviewed,503and a new hydrophilicity scale has been proposed based on calculations of solvation parameter^.^^ A multi-channel sensor system has been trained to correlate the 'taste' characteristics of amino acids.505 Guest-host studies continue (see also Section 4.17), with water-soluble calix[nlarenes (89; n = 4, 6, 8) that strongly bind amino acid methyl esters into their cavity.506The related cyclic tetramer forms 1:1-complexes with aromatic amino acids, and the chiral porphyrin (9 1) shows enantiodiscrimination towards amino acid esters.508The C2-symmetricchiral porphyrin analogue [92; R = (R)CH2CHMeOH] is an effective transporter of lithium salts of amino acids through CH2C12 membranes,509 and a phenanthroline-copper(1) template supports a bis(2-aminoacylpyridine) receptor that binds Z-L-glutamic acid and other dicarboxylic acids.510 similar mechanism accounts for the binding of Z-aspartic A acid to an 2-acylaminopyridine-substitutedheterocyclic template, to which a broader range of Z-amino acids shows modest binding.51 Cyclo-oligomers of cylindrical shapes have been synthesized that present amide groups to guest molecules, and show high selectivity towards N-acetylamino acid N-methylar n i d e ~ . The crown ether (93) has been shown to use its carboxy-group as well ~'~ as the macrocycle atoms to complex with amino acids.513 The enantiomeric discrimination factors that are sought in such studies are being put on a firmer numerical basis, as illustrated for standard molar enthalpies

50

Amino Acids, Peptides and Proteins

of binding by cyclodextrins of L- or D-phenylalanine and L-phenylalaninamide. Values have been determined by microcalorimetry, and are independent of c ~ n f i g u r a t i o n .Microcalorimetric data also show that the chiral discrimination ~'~ of L-ascorbic acid-Fe3 towards enantiomeric a-helical peptides is not exerted towards cysteine enantio~ners.~ Heterogeneous liquid systems are of growing interest, from the point of view of amino acid transport; systems studied recently (see also Refs.413-419) are basic amino acids/water/CHC13 + sodium di(2-ethylhe~yl)sulfosuccinate~*~ organic solvent/water/arylboronic acids + crown ethers,517and organic solvent/water/ 18-crown-6 + picric acid.518 Reverse micellar extraction of amino acids from aqueous media by di-octyldimethylammonium chloride is sensitive to co-solutes and physical parameter^.^'^ In the glycine or L-lysine/octyl P-D-glucoside/water systems, from 3 to 7 amino acid molecules can be bound by each molecule of the glucose derivative, resulting in a lowering of its critical micellar c o n c e n t r a t i ~ n . ~ ~ ~ Equilibria involving transfer of arginine, from solutions containing HC1 and NaCl to a cation exchange membrane, have been evaluated.521Sorption of amino acids on to ion exchange membranes has been Dipole moment data have been collected for L-cysteine and L - c y ~ t i n e . ~ ~ ~ A review has appeared covering solute-solute and solute-solvent interactions that occur in solutions of amino The viscosity of a solution of an amino acid has been related to the effects of the solute on water and data have been collected for viscosities of aliphatic a-amino acids in 0.5 and 2M urea.s26 Apparent molar volumes of aliphatic a-amino acids in 0.5 and 2M urea,527 and of aqueous L-valine, L-isoleucine, and L - l e ~ c i n e ~ ~ * been have calculated from densities and volumetric heat capacity data. Thermodynamic parameters, enthalpies of dilution of L-threonine and La ~ p a r a g i n eenthalpies of interaction of amino acids and peptides with crown ,~~~ ethers in water,530 apparent molal heat capacities and volumes of aliphatic aamino acids at 288-328K,531 and similar thermal properties of aminopolycarboxylic acid solutions532 have been collected. Microcalorimetric studies provide enthalpy of dilution data for ternary aqueous solutions that contain glycine, an alkanol, and another a-amino Electrical measurements for the effects of weak static and alternating lowfrequency magnetic fields on current flow through aqueous amino and potentiometric titrations leading to protonation constants for glycine in aqueous NaC1535and the proton-binding isotherm for g l y ~ i n have been presented, as e~~~ have corresponding dissociation constants for L-proline, L-histidine and Ltryptophan.537The protonation rates for L-tryptophan in acidic media decrease with increasing pH.538

5.7 Molecular Orbital Calculations for Amino Acids - Development of familiar themes under this heading is continuing with calculations of solvation energies of zwittenonic forms of glycine, alanine and serine in different conformations in water,539hydration parameters and conformations of N-acetylamino acid methyl esters,540and 2-(N-acetylamino)isobutyric acid N - m e t h ~ l a m i d e ~ ~ l of twenty and common amino acids substituted in the same way.542

I: Amino Acids
S03Na

51

S03Na
(89)

Ar

52

Amino Acids, Peptides and Proteins

Quantum mechanical force fields generated by [glycine.nH20] supermolecules in basic glycine solutions,543 electrostatic properties of amino acids modelled using atomic multiple moments,544and molecular connectivity models leading to structure-property relationships for amino illustrate another area of computational interest (see also Ref.546). Spectroscopic data generated through molecular orbital calculations concern vibrational frequencies of three non-ionized conformations of cysteine and ~ e r i n e chemical shift changes related to dihedral angles for glycine and ,~~~ g l y ~ i n a m i d e ,and ~gas-phase proton transfer energy values for eight of the ~~ protein amino acids.549An erratum has been published550concerning Ref.461 in Chapter 1 of Vol.26 (p.55).

Chemical Studies of Amino Acids

6.1 Racemization - Preparative applications of racemization are covered elsewhere in this Chapter (Section 4; e.g., Ref.l67), and the content of papers eligible for discussion in this section is usually limited to a narrow topic, e.g. that the rate of racemization of L-aspartic acid in water at 100" is increased when dimethyl sulfoxide is added.551 It has become clear that the dating of fossils based on the presumed constancy of racemization rates of their indigenous amino acids is liable to considerable error because of unspecifiable catalysis, though the basis of a claim, that the kinetics of amino acid racemization are non-linear, is obscure.552Application of the method to amber-entombed insects using samples ranging in age from 100 y to 130 x lo6 y can only provide results matching those of other dating methods if it is assumed that the amber environment retards racemization rates by a factor of greater than 104.553 This, indeed, represents slow racemization and is about the same rate as DNA degradation by d e - p ~ r i n a t i o n The ~ . ~ ~ dating method applied to Homo tirolensis (i.e. the male corpse found in 1991 at a high altitude in the Austrian Tyrol) and also to a specimen of ginger from Egypt, both of the same age (5200 y), in fact gave considerably different age values, and not only that, but the racemization rate in the colder specimen was faster!555Since 0- and di-tyrosine were detected in Homo tirolensis, and these are markers for free radical attack on proteins, the authors suggest that the hydroxyl radical formed by sunlight at high altitudes may accelerate amino acid racemization.
6.2 General Reactions of Amino Acids - This Section covers reactions at the amino and carboxy groups (and reactions at both) as well as reactions at the acarbon atom of or-amino acids + H3NCHRC02-; the following Section covers reactions of amino acid side-chains R. Thermolysis of butyrine, 3-amino- and 4-aminobutanoic acids gives many reaction products,556while decarboxylation of L-threonine and L-hydroxyproline occurs at 170" in cyclohex-2-enone, giving optically-active P - a m i n o - a l k a n ~ l s . ~ ~ ~ Irradiation of DL-lysine with soft X-rays causes the change of zwitterion to free

I : Amino Acidr

53

base, and decarboxylation leading to 1,5-diamin0pentane.~~~ Radicals formed by y-irradiation of D L - t h r e ~ n i n e ~ ~ ~ pyrolysis of DL-serine, DL-threonine and by and DL-tyrosine at 200-600" for 2-180 min560 have been studied by ESR. y-Radiolysis of aqueous phenylalanine leads to t y r ~ s i n e . ~ ~ ' Studies of these types, that often provide essential warnings of sample breakdown to those preparing samples of amino acids for analysis, are few and far between. However, in-depth study of the N-halogenation of amino acids and decomposition of the reaction products, continues to expand (see Vo1.26, p.56), with decomposition kinetics being determined for N - ~ h l o r o - v a l i n eand ~ , ~ ~ compared with data for N-chloro-sarcosine, -N-methylalanine, -N-methylvaline, and - p r ~ l i n eN-Bromo-amino acids have been studied.564 .~~~ The Grob fragmentation pathway that is followed by these derivatives in aqueous solutions565can be promoted by metal a l k ~ x i d e sN-Nitrosation (N204/CH2C12) a-(acetylami.~~~ of no)acids gives more stable products than hitherto believed, but they fragment in alkaline media to give a - h y d r o ~ y a c i d s Reaction within a Co(II1) complex .~~~ [formed with K3(Co(C03)3}] at a pyridoxylidene-amino acid ligand generates an a-hydroxy-a-amino A kinetic study of the nitrosation of imino acids has revealed intramolecular migration of the nitroso group from an intermediate nitrosylcarboxylate formed at high pH.569 Conversion of a-amino acids into a-nitro acids employing the powerful oxygen transfer agent HOF.MeCN (formed in aqueous MeCN with F2) involves racemization.570 N-Acylation reactions include formylation of amino acid esters with tri-ethyl ~ r t h o f o r m a t e ~ ~ ' conversion of N-formyl-a-trifluoromethyl-a-amino and acids into i s ~ c y a n i d e sThe analogous isocyanates OCNCR(CF3)C02Me .~~~ and hydrazides are starting materials for the synthesis of a ~ a p e p t i d e sand N-acryloyl-L,~~~ prolinamides have been prepared for the first time, for use in copolymer preparations.574 N-Acylation of amino acids using vinyl esters has been advocated575(the method is well-known in the literature). N-(L-Maley1)ation of amino acids (with glycine and proline as exceptions) can be accomplished with the aid of aminopeptidase A.576Solid-state N-phthaloylation of amino and 3-carboxybenzoylation of DL-alanine using isophthalic acid578has been assessed using differential scanning calorimetry. An analogous product (94), previously undetected, emerges from Maillard reactions involving y-aminobutyric acid, 6-aminocaproic acid, Na-acetyl-L-lysine, and p e n t o ~ e s Amadori com.~~~ pounds formed at an early stage of the Maillard process, have been generated from D-glucose and a-amino acids, and subjected to FAB-MS and NMR

N-[2-(4-Nitrophenyl)sulfonylethoxy)carbonyl]ation of amino acids gives Nprotection that can be reversed by bases in aprotic solvents.581 Novel N-alkylation of amino acid esters by tricarbonyl(cyclohexadieny1)iron cations,582and through high-pressure reaction with ~ x i r a n e s together with ,~~~ more traditional reductive alkylation methods using aldehydes (preparation of N-ally1 and -propargyl- derivatives,584 of PhCHO/NaTeH for preparation of use N-benzylamino acids585) have been described. The preparation of pure Nmethylamino acids by conversion of Z-amino acids into oxazolidinones using

54

Amino Aciak, Peptides and Proteins

formaldehyde followed by Et,SiH/TFA reduction (NaBH4 is somewhat less effective)586or by the corresponding reaction of N-benzylamino acids with the reduction step accomplished by h y d r ~ g e n a t i o n ) ,follows established metho~~~ dology. Direct methylation of N-Boc-0-TBDMS-D-tyrosine with MeI/BuLi/-78" seems, however, to proceed uneventfully.588Coupling (R)- or (S)-homophenylalanine ethyl ester with lactates gives (R,S)- and (S,R)-N-[(1-ethoxycarbonyl-3phenyl)pr~pyl]alanine.~~~ Procedures have been described for the preparation of N-(9-phenylfluoren-9-yl)-L-alanine -L-aspartic acid dimethyl ester.590Bis-Nand alkylation through reductive aminocyclization of L-valine methyl ester with ketoaldehydes is accomplished with high diastereoselectivity (Scheme 30), but with little stereochemical bias for simpler ketones.591N-Alkylation of sodium salts of secondary amino acids uses 4-chloro-N-benzylpyridin-2( 1H)-one (DMSO, 160180).592 Following recent results (see Vo1.26, p.62) that have established the condensation of amino acids to form peptides in aqueous NaCl by copper salts,593another non-enzymic reaction with the same outcome under putative prebiotic conditions has been established. This is based on cyanamide driving the reaction: FeS + H2S -+ FeS2 (Pyrite) which then brings about the condensation of thioglycollic acid HSCH2C02H so as to activate the amino acid carboxy group for peptide bond formation.594 A quite different discovery, but connected in its prebiotic relevance, concerns the finding that mixtures of amino acids can exert the catalytic activities shown by P-galactosidase, carbonic anhydrase, and c a t a l a ~ e . ~ ~ ~ Carbamylation of L-aspartic acid596and N-(9-acridinylthiocarbamoyl)ationof amino acids597have been described, the first of these studies being aimed at establishing the finer details of the biogenesis of dihydro-orotic acid, and the second providing a derivatization protocol that is some 6-22 times faster than phenylthiocarbamoylation, and giving a fluorescent product. y-Irradiation of amino acid solutions in the presence of the spin-trap 2-methyl2-nitrosopropane7 gives isolatable t-butylaminoxyl acids ButN(0.)CHRC02H,598 The solid-state reaction of p-benzoquinone with amino acids that is accomplished by grinding the mixture, gives a purple solid (A,.,ax 562 nm) that contains free radicals different from those generated when the reactants meet in aqueous solution.599 Selective removal of the t-butoxycarbonyl group from N-Boc-amino acid tbutyl esters occurs on treatment with dry HC1 in EtOAc; t-butyl ethers also survive the process.600 Oxidation of amino acids by peroxomonosulfate in aqueous alkali starts with electrophilic attack at nitrogen to give an imino acid through involvement of the a-CH proton.601There are, as usual, numerous papers covering routine oxidation studies of amino acids in the current literature, representative examples dealing with kinetics of chromium(VI)/HC104 oxidation of alanine, valine, and phenyl(this alanine,602and electrolytic oxidation of methionine to its s ~ l f o x i d e ~ * ~ study employs carbon, platinum or gold electrodes modified with Langmuir-Blodgett films of stearic acid or N-stearoyl-L-valine, and in the latter case, faster oxidation of the D-enantiomer was observed). Enhanced colour for the ninhydrin reaction has been reported for 5-arylninhy-

I : Amino Acids

55

d r i n ~That~the enolate ion of Ruhemann's Purple within two five-membered .~ rings of partial anti-aromatic character (as seen in the cyclopentadienyl anion) is the chromophore responsible for the long-wavelength absorption feature is backed up by molecular orbital calculations.605 Esterification studies that carry special interest include benzyl ester formation accompanying N-benzyloxycarbonylation, resulting from reaction of excess 2-C1 with a-isopropyl- and a-vinyl-a-amino acids.m6Also, the formation of aryl esters from N-phenylacetylglycine in the standard fashion (a phenol + dicyclohexylcarbodi-imide + py/TsOH) involves low yields,607which can be overcome through through esterification folan indirect route via N-Boc-N-phenylacetylglycine, lowed by Boc removal. N-Boc-Amino acid chloromethyl esters have been prepared using chlorosulfonylmethyl chloride C1S020CH2C1.608 The BOP reagent, although little used now in peptide synthesis after its replacement with safer alternatives, is advocated for mild esterification of N- and side-chain protected amino acidsm9 Dicyclohexylcarbodi-imide esterification (catalysed by DMAP) to couple syn-phenylisoserine to baccatin 111 to form taxol can be effected starting with the derivatized anti-compound.610Lipase-catalysed regiospecific esterification of the primary hydroxy group of butyl a-D-glucopyranoside to 2,2,2-trichloroethyl N-Boc-4-aminobutyrate has been reported;61 lack of space precludes mention of further routine papers covering enzymic esterification of amino acids that are in the current literature. Ester cleavage from N-acylated amino acid benzyl esters can be achieved using N-bromosuccinimide,612 or lithium iodide in aprotic non-polar solvents.613 Lithium iodide also cleaves methyl and tert-butyl esters. Studies of enantioselective hydrolysis of N-protected DL-amino acid esters show no signs of slackening. Remarkably large rate enhancements for the hydrolysis of L-isomers are achieved with careful optimization of salt concentration {[KCl] = 0.03M for the Ndodecanoyl-DL-phenylalanine p-nitrophenyl ester/Z-L-Phe-L-His-L-Leu-OH/ditetradecyldimethylammonium bromide chiral micelle system}.614 Similar studies exploring other chiral species have involved (2S)-N-benzyl-N-(long-chain alky1)P-aminoalkanob/Cu(II), Zn(II), or Co(I1) salts615and N-dodecyl-NN-dimethyl 1-octadecylammonium bromide vesicles carrying chiral amine groupings and metal salts.616 A more conventional approach is represented in subtilisinmediated transesterification of Z-DL-Ala-ONP with 1- b ~ t a n o l . ~ l ~ Reduction of the carboxy group of an N-protected a-amino acid to the primary alcohol function (-C02H + -CH,OH) is occasionally accomplished in a roundabout way, e.g. Boc-L-Val-OMe + RMgBr followed by 1%HF in MeCN,618 but BH3.SMe2619*620 LiA1H4 or is straightforward. These last two papers describe the application of Swern oxidation to the alkanols, to give the corresponding aldehydes (see also Ref.624; for the use of py.S03, see Ref.619), while the conversion of the primary alkanol into iodomethyl (PPh3/12) permits cyclization and further functional group transformations to be performed leading to 3-carboxycyclopentylamines;625 homochiral a-aminoalkanals are the increasingly valuable in broad areas of organic synthesis, and may be secured in high yield by LiA1(OBuf)3H reduction of either Boc-L-amino acid phenyl esters626(or the methyl ester of a protected a r g i n i ~ ~ e )or * ~ , ~ Boc-L-amino acid

56

Amino Acids, Peptides and Proteins

mixed anhydrides.628 DIBALH Reduction of diethyl L-aspartic and glutamic acids to aldehydes is a-selective, and if conducted in the presence of a lithium trialkylphosphonoacetate, leads to N-protected y-amino-@-unsaturated dicarboxylic acid esters.629 Reduction of benzyl aspartates and elaboration of the alkanols to enantiomerically-pure 3-amino and 3,4-diaminoalkanols has been described;630conversion of a-(N,N-dibenzy1amino)aldehydesinto nitriles (-CHO -+ -CH2CN) and ensuing alkylation and reduction gives 1,3-di-amine~.~~' The reduction of the equivalent N-urethane-protected carboxyanhydrides by DIBALH or lithium tris[(3-ethyl-3-pentyl)oxy]aluminium hydride gives high yields without r a ~ e m i z a t i o n ~ ~ ~ borohydride reduction gives the pro(sodium tected P - a m i n ~ a l k a n o l s ~ ~ ~ ) . Reduction of the Weinreb amide with lithium aluminium hydride gives the aldehyde [-C02H -+ -CONMe(OMe) -+ -CHO], and ensuing reductive amination with an amino acid ester has been described (-, -CH2NHCH2C02Me),634 though others have found this last step problemati~al.~~~ Dissolving metal reduction (Na/refluxing propan-1-01) of @,a-disubstituted amino acid amides is a new method of obtaining P - a m i n ~ a l k a n o l s . ~ ~ ~ Conversion of the carboxy group into the acid fluoride is straightforward with NNbis(alkoxycarbony1)-L-a-amino acids, without racemization, using cyanuric fluoride; the same starting materials give Boc-N-carboxyanhydrides with the Vilsmeier reagent (SOC12/DMF)637.638 Fmoc-amino acid chlorides are reduced [ B u ~ S ~ H / P ~ ( P P corresponding aldehydes in rather low yields.63sConverto ~ ~ ) ~ ] sion of the carboxy group of L-tryptophan into ketones via the Weinreb amide [-+ -CONMe(OMe) -+ -COCH2P(0)(OMe)2 -+ -CH = CHAr e t ~ ]or the one, ~ ~ ~ step Weinreb-amide-to-vinyl-ketone route using ally1 magnesium bromide,640 conversion of a methyl ketone, formed from a protected phenylalanine in this way, into an isopropyl group,@' and clean decarbonylation of an a-alkylpipecolic acid using diphenylphosphoroazidate,@2 illustrate further functional group manipulations. Cyclization of P-aminoalkanols with Ph2POC1 gives N-diphenylphosphinoyl a ~ i r i d i n e sReduction and cyclization of vinylglycine to the oxazolidinone, then .~~ N-allylation, can be accomplished in a one-pot process.644 The generation of heterocyclization products from N-acylated amino acids continues to attract mechanistic and synthetic interest, focussing on 2-alkoxyoxazol-5(4H)-ones formed from N-alkoxycarbonyl-L-amino acid mixed anhydrides and isopropenyl c h l ~ r o f o r m a t e ~ ~ from analogous symmetrical anhydrides and on treatment with NN'-di-isopropylcarbodi-imide.646Ureas, e.g. Boc-L-Ala-LN(Boc)CHMeCON('Pr)CONH'Pr, are also formed in this process by rearrangement of the symmetric anhydride to the N(Boc)-dipeptide followed by addition to the carbodi-imide. The generation of a mixture of N-acylisourea, symmetrical anhydride and oxazolone through reaction of an N-protected amino acid with a carbodi-imide does not involve significant racernization, which becomes more pronounced when an amine is introduced (as in the normal course of peptide synthesis). As this process continues, it is aminolysis of the anhydride initially, and of the oxazolone at later stages, that introduces racemized products.647 N-Methylamino acid esters react via an oxazolone and/or symmetrical anhydride

I: Amino Acids

57

Reagents: i, NaBH3CN or NaBH(OAc),;

ii, BU'OK, and Curtius rearrangement

Scheme 30

PhCONR2CHR'C02H

-+ !

R'COCH(OH)CF3 + PhCONR2COCH(OH)CF3

Reagents: i, TFAA, Py, 100 "C

Scheme 31

Reagents: i, CH2=C(OMe)C =CH2, etc.

Scheme 32

58

Amino Acids, Peptides and Proteins

in giving acyloxyphosphonium salts with the currently popular phosphonium peptide-bond-forming reagents PyBrOP and PyClOP (PyBOP reacts sluggishly in this process).Hs N-Acyl-N-benzylamino acids yield 5-trifluoromethyloxazoles when treated with TFAA/py in benzene (Scheme 3 1),&19 while N-2-hydroxybenzyl analogues yield tricyclic b e n z o x a ~ o l i n e s . ~ ~ ~ Equilibrium mixtures of thiazolinones, phenylthiocarbamoylamino acids and N-phenylthiohydantoins (PTHs) formed in the Edman peptide sequencing process can be converted into thiazolinones that are amenable to ring-opening with a fluorescent amine.651Other interesting five-membered heterocycles include (99, formed from an amino acid and [Cp.IrC1(p-C1)2], and capable of highly diastereoselective ligand complexatiodS2 and (96) formed from amino acids and diphenylborinic acid (cf- Vo1.26, ~ . 6 2 ) . ~ ~ ~ 1,3-Dipolar cycloadditions of amino acid-derived imines illustrated in previous Volumes of this series (see e.g., Vo1.23, p.55) continue to provide highlysubstituted five-membered heterocycles. Thus, decarboxylation of imines formed from amino acids and alloxan or 1-phenyl-3-methylpyrazolin-4,5-dione gives azomethine ylides that add to m a l e i r n i d e ~ .Highly-substituted homochiral ~~~ pyrrolidines are formed between N-acryloyl-L-proline benzyl ester and Formation of 3-(3,6-dioxopiperazin-2-yl)propaRCH = N + (Li)R2C-C02Me.655 noic acid from y-methyl glutamate and glycine ethyl ester656 exemplifies a familiar six-membered heterocyclic amino acid condensation product, while a more unusual ring-enlargement process (see Vo1.25, p.69) accompanies photolysis of N-phthaloyl-L-DOPA methyl ester protected in its side-chain by 3,4-methylenation (corresponding treatment of N-phthaloylthreonine and serine methyl esters gives phthaloylglycine through P - f r a g m e n t a t i ~ n ) . ~ ~ ~ 6.3 Specific Reactions of Amino Acids - The conventional use of this section over the years continues in this Volume, covering papers that concentrate mainly on reactions at the side-chain of a-amino acids. By their nature, these processes often amount to the use of one amino acid to synthesize another, and some papers that could have been located here can be found in the earlier synthesis Sections 4.1-4.15. Side-chain halogenation of aliphatic L-amino acid esters (as their N-phthaloyl derivatives) is stereoselective (particularly so with t-butyl esters), giving (2S,3R)P-hydroxyphenylalanine after substitution of the bromo-substituent that was introduced using NBS,658 and 4-bromo-L-glutamates (stereoselectivity not investigated, but the diastereoisomer mixture was easily separated).659Fluorination of a-fluoromethyltyrosine with acetyl hypofluorite gives the P-fluoroanalogue.6m o-Iodoal kenylglycines CH2 = CICH,CH(NHAc)CO,Et undergo Michael-type chain extension with CH2= CHC02Et/Pd(OAc)2 to give Et02CCH = CHCH = CHCH2CH(NHAc)C02Et.661 The corresponding reaction occurs with electrophiles, e.g. (E)-ICH ==CHCO2Et with O~E~.~~~ CH2= C ( S ~ B U ~ ) C H ~ C H ( N H A C ) CThe organozinc synthon formed from L-glutamic acid (side-chain -C02H - -2nI) undergoes Pd-catalysed condensa, tion with an aryl iodide to give enantiomerically-pure h ~ m o p h e n y l a l a n i n e s , ~ ~ ~

1: Amino Acidr

59

and the equivalent serine-derived synth01-P~ reacts with acryloyl chloride, followed either by cyclization to give 4-oxopipecolic acid, or by addition of benzylamine to give 4-0xolysine.~~~ Photo-activatable moieties have been added to the isopropenyl and carboxy side-chains of (-)-kainic acid.666 Diels-Alder additions of buta- 1,3-diene667and of Danishefsky's diene [or (E)PhCH = C(CN)C02Me or 2-methoxybuta- 1,3-diene]668 the 2-phenyloxazolone to derived from ap-dehydrophenylalanine (Scheme 32) gives 1-aminocyclohexenecarboxylic acids which can be categorized as conformationally-constrained analogues of common or-amino acids. A heterocyclic version (97) arises by 1,3dipolar addition of 2,6-dichlorobenzonitrile oxide to 4-methyleneoxazolidin-5Methylenation of the D-glyceraldehyde-derived 2-oxazolone gives a mixture of five cyclopropanes, with the (1S,2R)-derivative as predominant Conventional modifications to the alicyclic moiety of alicyclic a-amino acids include ethylene biosynthesis from 1-aminocyclopropanecarboxylic acid671and hydrogenolytic ring-opening of aziridinecarboxylates (98).672Studies of saturated heterocyclic imino acids include stereoselective additions of alkylcopper reagents to cyclic acyliminium ions formed from pipecolic and a remarkable ringexpansion (Scheme 33) of 5- and 6-membered members of this class to 8- and 9membered homologues through the reaction with acetylenic dipolarophiles of azomethine ylides formed with formaldehyde.674 Oxidation of urethane-protected L-proline methyl ester to L-pyroglutamic acid with iodosylbenzene/trimethylsilylazide/CH2C12 causes 5-substitution (inseralso tion of N3, C1, or OH; other substituents and reaction conditions can alter the pattern of reactions).675 Electrochemical oxidation of L-proline followed by 3,4-Dehydro-Lmethylcopper addition to give trans-5-methyl-L-pr0line.~~~ proline (from hydroxy-L-proline) serves as starting material in a route to (2S,3R74S)-epoxyproline(m-chloroperbenzoic acid) accompanied by its diastere ~ i s o m e r The ~ . ~ ~ epoxides give an 8.3:1-mixture of 3-methyl-4-hydroxy- and 4-methyl-3-hydroxyprolines through LiCuMe2 r i n g - ~ p e n i n g . ~ ~ ~ Regio- and stereoselective hydroxylation of the enolate of 4-oxoproline is a stage in a route to swainsonine [(2R,3S,4R)-3,4-dihydroxy-2-hydroxymethylpyrr0lidine].~~~ Hydroxy-L-proline is also the starting point (conversion into its cis-isomer) in a synthesis of 'de(hydroxymethy1)desulfo-analogues' of the 0-sulfonated glycopeptides, bulgecins A, B, and C.680 Aromatic side-chain modifications that have been accomplished include the from the corresponding tyrosine preparation of Boc-L-(4-~arboxy)phenylalanine O-triflate,681preparation of 0-glycosylated Fmoc-L-tyrosine pentafluorophenyl esters,682 anodic oxidation of 3,5-dibromotyrosine methyl ester to generate caremicolin models (99),683 anodic oxidation or thallium(II1) nitrate oxidation and zinc reduction to give isodityrosine and dityrosine derivatives.684Electrooxidation685and cyclic voltammetric monitoring of the oxidation686of L-DOPA, elaboration of the phenolic side-chain and transesterification of tyrosine, giving L-DOPA esters by combined tyrosinase and cl-chymotrypsin treatment,687 are also reported. 5-S-CysteinylDOPA undergoes oxidation under physiological conditions to give pheomelanins via 1,4-benzothia~ines.~~~ anion radical hide

60

Amino Acids, Peptides and Proteins

Reagents: i, HCHO; ii, RCfCC02Me Scheme 33

Br

TFAN \

C02Me Br H

c i
H

(99)

I: Amino Acids

61

attack on tyrosine generates the oxygen-centred phenoxide radical, and the eventual reaction product is d i - m - t ~ r o s i n e . ~ ~ ~ 320 Generation of a fluorescent species (hexcit nm, hem 392nm) by treatment of tryptophan with nitrous acid has been reported, without speculation or evidence for its structure.690X-Ray analysis691supports the structure (100) assigned to an Nim-trifluoroacetylated reaction product from the reaction of N-methoxycarbonyl-L-tryptophan methyl ester with TFA and pyridine; the minor reaction product (6%)692 is the all-cis isomer (101; R = H) accompanying 84% of the isomer with inverted ring junction protons, which is the product expected on the basis of existing knowledge of tryptophan cyclic tautomers. Thus, the wellestablished Nim-toluene-p-sulfonyl analogue, which undergoes a highly diastereoselective aldol addition to benzaldehyde after deprotonation with LDA,693has appeared in several papers recently (see also Ref.268). The diastereoselectivity of Pictet-Spengler processing of tryptophan esters (RCHO + H2N- -+ imine -+ carbolines) depends on the ester alkyl (2-Hydroxyethylthio)-substitution at positions 2 and 7 of the indole moiety of tryptophan by treatment with H ~ ( O A Cfollowed by mercaptoethanol explains a side-reaction observed during )~ peptide synthesis.695 Histidine chemistry described in the current literature covers a 1: 1: 1-adduct involving the imidazole moiety of the Na-acetylamino acid, with malondialdehyde and an alkanal (but no reaction in the absence of the alkana1),696 formation of a Michael-type adduct N-Z- 1(3)-(1'-formylmethy1)hexyl-L-histidine as a model for attack on proteins by lipid breakdown products,697 and P-attack by hydroquinone on a protected histidine to give the p-(2,3-dihydroxyphenyl) h o m ~ l o g u e . ~ ~ * S-[2-Carboxy- 1-(1H-imidazol-4-yl)ethyl]-3-thiolactic is a new histidine metaacid bolite isolated from urine; it has been synthesized from the cysteine adduct through HN02 d e - a m i n a t i ~ n . ~ ~ ~ Arndt-Eistert homologation of (2S,3S)-3-methylaspartic acid giving (2S,3R)-3methylglutamic acid competes favourably with a bis(1actim ether) synthesis.' l7 Rapoport-type alkylation of aspartic acid-derived enolates gives syn- or anti-2,3pyrrolidinedicarboxylic acids,700also independently prepared in essentially the same way;7o1 the same conformationally-constrained aspartic acid analogues have been synthesized from the glutamic acid-derived synthon (102).702a-tertButyl-y-methyl N-Z-glutamate gives the y-anion with lithium hexamethyldisilazide, which is a convenient source of y-substituted glutamic acids through reaction with e l e c t r ~ p h i l e s .The~ protected N-hydroxyornithine analogue ~~ FmocNHCH(C02H)CH2CH2CHRNHOCH2CH2SiMe3 emerges from a synthesis starting with L-glutamic acid (side-chain -C02H -CH = NOTBDMS) and cyclized via the N-hydroxysuccinimide ester to give NaNs-protected Ns-hydroxycyclo-ornithine and its h o m ~ l o g u e .2-Indolylmethyl ketone formation ~~ through the side-chain carboxy group of aspartic acid provides the novel sweet compound monatin after stereospecific conversion of the side-chain carbonyl group into -C(OH)(C02H)-.705 Protected L-pyroglutamic acid continues to be one of the most frequently-used chiral synthons in general organic chemistry, and no less so as starting material for the preparation of other amino acids. 4,4-Di-substitution can be accomplished
+

62

Amino Acids, Peptides and Proteins

after LiHDMA d e - p r o t ~ n a t i o n4-Methylenation and -cyclopropanation have ,~~~ been described, either via the 4-(dimethylaminomethyl)pyroglutamate formed from the lithium enolate of a pyroglutamate and Eschenmoser's salt, or through an imidazolidinone synthesis (see Section 4.2; introduction of a Independently, the same route has been folBu02CC( = CH2)CHZlowed by other workers, but with some different minor details.708 Reduction of the lactam carbonyl group of pyroglutamates to -CH2-, leaving other reducible functions intact, proceeds via the hemiaminal (successively, LiEt3BH and SiEt,H/ BF3.Et20).709 The hemiaminal was reacted with stabilized phosphonates to give products of Wittig synthesis that were isolated as 5-substituted prolines (103 + 104; trans:& = 5:l) through cyclization of the intermediate alkene.710 LPyroglutaminol methoxymethyl ether has been used to synthesize ( + )-1,8-di-epiand (-)-1-episwainsonine through construction of a piperidine ring on NH and ether functions, and manipulation of the pyrrolidine functional Pyroglutamic acid-derived synthons used in large-scale synthetic enterprises include (105; manzamine A);712and (106 and its epoxide; natural polyhydroxylated p y r r o l i d i n e ~ ) The ~ . ~ ~ L-pyroglutamate-derived synthon (106) can be subjected to stereoselective epoxidation to give (2S,3S)-3-hydroxyproline from which (-CO;?H + -CH20H) castanodiol can be obtained,714and (2S,3S)-3-methylproline and (2S,3R)-3-phenylproline were prepared similarly.715 Pyroglutaminyl chloride (from oxalyl chloride and T M S - p y r ~ G l u and~its N-Fmoc derivative )~ ~ (from Fmoc-L-glutamic acid via the dichloride formed using SOC13 have been obtained.717 NP-Glycosylated asparagines may be prepared by reaction of Fmoc-L-aaspartic esters with a glycosyl azide under the influence of Et3P/CH2C12.718 NPAralkyl-protected asparagines and glutamines can be cleaved by boron tris(trifluoroacetate) in T F A / A c O H . ~A~route to aspartic acid P-semi-aldehyde, based ' on ozonolysis of a protected allylglycine, avoids less satisfactory steps in routes from aspartic acid itself.720Low yields when reducing the acid chloride (30%) were encountered, however, in a route (-C02H + -COC1 + -CHO) from amethyl Z-L-aspartate, but could be improved when the reduction was performed in the presence of palladium.721Development of the N-acryloyl compound into the conformationally-constrained a-amino acid, 6-oxodecahydroisoquinoline-3carboxylic acid, is described in this The aldehyde was isolated as the dimethyl acetal, a device also used in a related study using glutamic acid y~emialdehyde,~~, which also features in a synthesis of differentially protected meso-2,6-diaminopimelic Appropriate protection was involved in all these studies, and in the latter route, manipulation of the side chain carboxy group (Wittig homologation etc) of the oxazolidinone was used. Formation of methyl ethers from protected serines and t h r e o n i n e ~and ~ ~~ benzyl ethers,726including benzylation providing precursors to photoactivatable ~ i d e - c h a i n sfollow standard phase transfer alkylation procedures. Routes to 2,~~~ acetamido-2-deoxy-~-D-glycosides,728 corresponding 2-acetamido-galactog a l a c t o ~ i d e s and ~ l y c o t e t r a ~ s e shave been explored. A cumber,~~ g ~~~ some route from &-hydroxy-L-norleucinegives homochiral3-amino-7-substituted azepinone~.~~~ (2R,3S,4R)-3,4-dihydroxy-2-hydroxymethylpyrrolidine and

1: Amino Acids

63

H02C

64

Amino Acids, Peptides and Proteins

(2S,3R,4S,5S)-3,4-dihydroxy-2,5-dihydroxymethylpyrrolidine been prepared have from D-serine and D-ribonolactone, respectively.733 A number of synthetic opportunities follow from the juxtaposition of amino, carboxy and primary alcohol functions in seiine, e.g. a lengthy synthesis of Fmoc-yy-di-t-butyl-y-carboxy-L-glutamic acid from D - ~ e r i n e . Here, the ~~~ carboxy group of the starting material becomes the extended side-chain of the product via an aldehyde, and the -CH20H side-chain becomes the eventual carboxy group, accounting for the 'L-from-D' nature of the process. The synthetic uses of L-serinal derivatives are proliferating, and two papers report improved syntheses of a protected form, the Garner aldehyde (107; R = H), one route735 avoiding the need for methyl iodide and benzene and the other, also explored for the threonine homologue (107; R = Me) using an LiBH4 and COC12/DMS0 sequence for the initial stages.736 D-Threonine gives the corresponding synthon through standard steps.737 P-Branched a-amino acids have been obtained through the sequence -CHO -+ -CH(OH)C=CH - bromoal, l e n e ~ A ~ ~ ~electrophilic L-alaninol synthon (108), prepared from L-serine, . new undergoes nucleophilic substitution by Gilman cuprates or Grignard reagent/ CuX complexes.739The related N-acylated synthon derived from L-serine (109; R 1 = But, R2 = H) gives bicyclic Dieckmann products leading to useful homochiral tetramic acids.740N-Z-L-Serine p-lactone reacts with trimethylsilylamines Me3SiNR2 primarily by alkyl oxygen cleavage, to give optically-pure p-aminoalanines (certain reaction conditions cause acyl-oxygen cleavage leading to ~ e r i n a m i d e s )The chiral oxazolidinone (1 lo), formed from serine, threonine .~~~ or cysteine (S in place of ring 0) using bis(trichloroethy1) carbonate742gives N-ally1 derivatives that undergo intramolecular oxime-alkene cycloaddition, to give p ~ r r o l i d i n e s Other ring-closure reactions involving serine include samar.~~~ ium(I1) iodide-mediated cyclization of N - a l l ~ l - ~ ~ p r ~ p a r g y l - s e r i n a l sto~ ~ and ~ give 2,3,4-trisubstituted pyrrolidines (1 11). Access to homochiral Salkylpiperazine-2-carboxylic acids (1 12) is initiated by condensation of L-serine with an a-amino (o-Aminoalky1)-a-amino acids, notably lysine, are also represented in broader organic synthesis, and the side-chain function has been developed into diazoacetamides L-N2CHCONH(CH2)4CH(NH2)C02Etthat have been added to C6*fullerenes to give a [60]fullerene-fused cyclopropane carrying an amino acid structure.747 Simpler side-chain modifications are illustrated by the preparation of NE-(carboxymethy1)-L-lysine and NS-(carboxymethy1)-L-ornithine through N'-(carboxyethy1)-L-ornithine synthase-mediated reductive condensation with g l y ~ x y l a t eand~conventional preparations of N"-Fmoc-L-lysine and NS-Fmoc,~ ~ L-ornithine from copper(I1) complexes of the amino acids.749A more involved sequence (successively, sodium nitroprusside, CBr4/PPh3, p-bromoaniline) leads to NQ-Z-N"-(p-bromopheny1)-L-lysine [similarly, to N'-(p-bromopheny1)L-histidine from Z - h i ~ t i d i n e ) The ~ . ~ ~ &-amino group of N*-Z-L-lysine methyl ester has been converted (dimethyldioxirane in acetone) into the nitrone [-NH2 -, -N+ (0-)= CMe21 from which (H then Ac20) Na-Z-NE-acetoxy-L-lysine methyl ester was secured.75' There may be useful analytical applications associated with the finding that the ninhydrin-Fe(II1) system reacts specifically
+

I: Amino Acids
R2g>C0,Me
R' N

65

OACHRR

H2

OSiMe2Bu'

R'

NHAc

Oq~NYcH*)3cH Me

\
C02H

C02Me Me0 C02Me

66

Amino Acidr, Peptides and Proteins

with lysine at pH 1 (but not with ornithine, arginine, histidine, proline or gly~ine.~~~ Reactions of the side-chain amino group of lysine, some of them modelling in vivo protein behaviour, have been studied. A useful synthon (113) for the synthesis of substituted piperidines, has been prepared in five steps from L-lysine using conventional precedents.753With 4,5-epoxy-Z(E)-heptenal (a lipid peroxidation product), lysine gives the pyrroles [114; R' = CH(C02H)(CH2)4NH2 or (CH2)&H(NH2)C02H; R2 = H, CH(OH)Et)] together with the isomeric compounds formed through the a-amino With methylglyoxal, reversible glycosylation occurs through conversion of the initially-formed imine into unknown 01igomers.~~~ process is irreversible with arginine, giving 43The dihydroxy-5-methylimidazolines(1 1 5, the imidazolin-4(5)-ones derived from ) these showing fluorescence (hexcit320 nm, hem 398 nm). L-Lysine has been acid converted into a protected L-a-amino-6-mercaptohexanoic via a pyridinium methyl ester in analogue.756Anodic oxidation of di-N-methoxycarbonyl-L-lysine methanol gave the a-methoxyoxazolidinone (1 16) whose stereoselective azidolysis and reduction have provided the first example of an optically-pure a-aminoamine.7s7 Efficient access has been worked out, to NG-methyl-D- and -L-arginine from the ornithines and MeNHC(SMe) = NH2+ I-,758 and further study of preparations of side-chain protected arginine, either the long way round [synthesis of w,w'-bis(urethane)s by Ns-guanylation of ornithine with bis(urethane)protected 1-guanylpyrazole~],~~~ or directly by o - a r e n e s u l f ~ n y l a t i o nIn ~ ~ latter study, . ~ the no improvement on a currently-used protecting group of this family, the Mtrgroup, was achieved by the introduction of electron-donating alkyl groups into the aryl moiety. Electro-oxidation of arginine at Pt electrodes liberates nitrate ion through an electron transfer mechanism.761 This is an interesting result, because it shows that inorganic nitrogen oxides can be released from arginine without the presence of nitric oxide synthase; the bustling activity in the nitric oxide area is illustrated by a synthesis of the NO synthase inhibitor N"-hydroxy-N"-methyl-Larginine in 8 steps from NG-Z-L-arginine.762 Tetrahydropyrimidines have been formed from reaction of 2,4-diaminobutyric acid with other amino and related tetrahydropyrimidin-4( 1H)-ones have been identified as self-degradation products of bellenamine (R)H2N(CH2)3CH(NH2)CH2CONHCH2NH2,a P-lysinamide from Streptococcus nashvillensis that shows useful immuno-enhancing HIV protease inhibitory action. The formaldehyde needed to generate the reaction products is supplied by hydrolytic cleavage of the -NHCH2NH2 moiety of the natural Methyl 4,5-diaminopentanoate cyclizes to 5-aminomethylpyrrolidinone and 5-aminopiperidinone in dilute aqueous alkali.765 The thiol function of cysteine shows important oxidation reactions, illustrated with a kinetic study of photo-oxidation (H202) of N-a~etylcysteine~~~ sensitized by N-(9-methylpurin-6-yl)pyridiniumsalts,767and one-electron oxidation by the azide radical anion at pH 10.5 leading to intramolecular proton abstraction and subsequent processes.768 S-Arenesulfenylation of cysteine derivatives, with the objective of placing a photoactivatable group at sulfur, has been achieved using

I: Amino Acids

67

the appropriate pyrid-2-yl d i s ~ l f i d e . ~ ~ ~ Thiolysis of S-(SCM)cysteine hydroS-Trifluoromethylation of chIoride in water gives S-(alkanesulfenyl)~ysteines.~~~ N,C-protected cysteines has been accomplished,771 and other S-protection strategies are featured in the current literature: (novel) S-(allyloxycarbonylaminom e t h y l ) a t i ~ n , and~ (traditional) benzylation with improved methods for ~~ introduction through benzyl cations or ArCHO/Et$3H.773 Cyclic ketimine formation from (2-aminoethyl)-L-cysteine mediated by snake venom L-amino acid o x i d a ~ parallels the process observed with the cystathionine de-amination e~~~ product, S-(2-oxo-2-carboxyethyl)-L-homocysteine.775 ketimine readily unThe dergoes autoxidation to the s ~ l f o x i d eNitric oxide is released from S-nitroso.~~~ cysteine under physiological conditions, and there have been several recent studies of the consequences of this, one being the destruction of zinc-sulfur clusters in proteins.777 Studies of methionine and other S-alkyl cysteines reflect similar themes. Slow oxidation of S-(2-propenyl)cysteine and its sulfoxide by aqueous nitric one- and two-electron oxidation of methionine by peroxynitrite HOONO via the (leading first to the sulfoxide and ultimately to the liberation of radical HOONO. ethylene),779and 2,2'-bipyridinium chlorochromate oxidation of methionine, established by a kinetic study to involve a sulfurane transition state.780 NPhthaloyl-L-methionine ethyl ester undergoes the expected reaction with S02C12 to give a a-chlorosulfide mixture that yields the aldehyde-containing side-chain on hydrolysis (-CHClSMe + -CHO).781S-Phenyl-L-cysteine is best oxidized to the sulfone with magnesium monoperoxyphthalate, giving a versatile synthon for preparations of (S)- or (R)-cycloalkylglycines and prolines and analogues.782 Facile alkylation a to the sulfone function with stereocontrol is also the basis of the use of the same synthon for syntheses of (2S,3S)- and (2R,3R)-pyrrolidine2,3-dicarboxylic 6.4 Effects of Electromagnetic Radiation on Amino Acids - The topics covered in this section over the years continue to surface in the literature, which has provided acounts of y-radiolysis of aqueous t y r ~ s i n e and ~ 3,5-di~~ iod~tyrosine.~~~ Photo-oxidation of 5-S-cysteinylDOPA at wavelengths longer than 320 nm gives benzothiazines, whereas cleavage of the aliphatic moiety to yield DOPA is the consequence of irradiation at 280-320 nm.786Time-resolved fluorescence of the protein cross-linking amino acid, dityrosine, has been evaluated.787 As usual, most of the papers concern tryptophan and its analogues, with investigations of products of photolysis of tryptophan in aqueous solutions,788 and of quenching of singlet oxygen by aqueous tryptophan (comparisons with tyrosine, histidine, methionine and cysteine were also included in this Fluorescence decay studies focus on constrained tryptophan analogues, e.g. 3amino-l,2,3,4-tetrahydrocarbazole-3-carboxylic acid,790and on a new reference compound with an ultra-short fluorescence lifetime.791Supersonic gas expansion studies of tryptophan and substituted analogues permit the allocation of fluorescence lifetimes to individual conformers.792 Phosphorescence decay of tryptophan involves energy transfer between individual molecules in the triplet excited

68

Amino Acids, Peptides and Proteins

state.793 Low-temperature UV photolysis of tryptophan yields stable products via anion and cation radicals, the products surviving warming to room temperature; they show themselves to be efficient luminescence q ~ e n c h e r s . ~ ~ ~ 7 Analytical Methods

7.1 Introduction - Several useful reviews of methods of amino acid analysis have appeared, e.g. analysis of dansylamino acids.795

7.2 Gas-Liquid Chromatography - The importance of sample clean-up prior to derivatization and GLC analysis of amino acids has been stressed.796 Derivatization incorporating an extractive alkylation of amino acids with pentafluorobenzyl bromide followed by N-heptafluorobutyroylation illustrates the greater attention being paid to sample authenticity, prior to GLC analysis incorporating negative ion CI-MS.797Similar derivatization approaches employ N(S)-isopropoxycarbonyl methyl esters (sulfur-containing amino acids),798and N(0)-isobutoxycarbonyl t-butyldimethylsilyl esters.799Alkyl chloroformates can provide a one-step derivatization procedure for amino acids in aqueous solution, to give N-alkoxycarbonylamino acid alkyl esters (the alkyl ester group derives from the breakdown of the chloroformate, but an alcohol is usually added in the reagent cocktail, to ensure complete reaction).800Use of a different alcohol, of course, gives more flexibility but also more complications, since ethyl esters are reagent is used.s0' also formed when the EtOCOC1/CF3CH20H/pyridine The stable isotope dilution technique has been employed in the otherwise standard GC-MS analysis of cysteic and homocysteic acids, and cysteinesulfinic and homocysteinesulfinicacids.802 Enantiomer separation by GLC has been reviewed.*03 Chiral GLC analysis of N-trifluoroacetylamino acid methyl esters on a 2,6-di-O-butyl-3-O-trifluoroacetyl-y-cyclodextrin capillary column,804and of N-trifluoroacetylamino acid isopropyl esters with Chirasil-L-Val as stationary phaseso5 has been accomplished.

7.3 Thin-Layer Chromatography - Routine they may be, but several projects have been reported recently that are useful; comparisons of cellulose with silica gel for their performance in quantitative TLC,806a study of resolution of DLamino acids on borate-gelled guaran-impregnated silica gelso7and on copper(I1)L-proline-impregnated silica gelso8 from the point of view of the analytical resolution of DL-amino acids. Careful attention to detail is rewarded by reproducible quantitative TLC of lysine, threonine and homoserine.809 The preceding studies base their results on conventional ninhydrin colourformation, though other spray reagents (p-dichlorodicyanobenzoquinone, applicable down to 0.1 pg,slo and 4-dimethylaminobenzaldehyde(for quantitative TLC of tryptophan)811continue to be advocated. New solvent systems py-C6H6 = 2520, MeOH-CC4 = 1220, and acetoneCH2C12 = 0.3:8, have been suggested for the TLC of PTHs.812

1: Amino Acidr

69

7.4 High Performance Liquid Chromatography - Not all the papers cited here deal simply with analytical studies; the chemistry of stationary phases and of derivatization protocols is frequently involved in the reports. Reviews have appeared of amino acid deri~atization,~ fluorogenic labelling,814 derivatization for enantiomeric analysis.815 and Nearly all HPLC analysis protocols for amino acids call for pre-column derivatization, usually the formation of a N-substituted amino acid mixture from the sample, prior to chromatographic separation and quantitation of the individual components. One commonly-used derivatization protocol is N-phenylthiocarbamoylation (PTC; for a review, see Ref.816), for amino acids in genera1817 and arogenic acid (the biogenetic precursor in plants of phenylalanine and tyrosine) in particular,818for aspartic and glutamic acids and a ~ p a r a g i n eand~ ~ ,~ hydrolysates of proteinaceous material in pollen820and in old paintings.821Use of the analogous N-butylthiocarbamoylamino acids seems to have no extra justification, though they show excellent chemical stability.8224-(3-Pyridinylmethylaminocarboxypropyl)phenylthiohydantoins, the cyclization-rearrangement products of the correspondingly-substituted PTC-amino acids, have been studied by HPLC-electrospray MS.823Conditions for HPLC analysis of PTH mixtures, avoiding reagent-related background peaks, have been established.824 N-(Fluoren-9-ylmethoxycarbonyl)amino acids (Fmoc-amino acids) are gradually gaining acceptance for HPLC analysis,825 reactions following derivatization being avoided by the use of heptylamine to remove excess reagent.826 A specialized interest is represented in HPLC of Fmoc-(S)-alk(en)yl-L-cysteine sulfoxides in Analysis of imino acids as Fmoc derivatives after removal of primary amines from samples by conversion into isoindoles (OPA-amino acids) using o-phthaldialdehyde and mercaptoethanol has been represented in analysis of glyphosate (N-phosphonomethylglycine),828 and in mainstream studies of protein amino acids,829 including special reference to automated analysis.830 The OPA-amino acid pre-treatment procedure also allows the estimation of 4-hydroxyproline in biological fluids as its P T C - d e r i ~ a t i v e . ~ ~ ~ OPA-Derivatization and quantitation of the derivatives continues to be confidently used, and a total time of 17 minutes has been claimed for analysis of an amino acid mixture.832 It has been used for L-lysine in wheat gliadin proteins,833for primary amino acids in rat plasma,834and in a rare example of post-column OPA-derivatization of amino acids separated by ion-exchange c h r o m a t ~ g r a p h y As~has been mentioned frequently in the recent literature .~ ~ (see Vo1.25, p.75) there is some uncertainty about the reliability of OPAderivatization because of limited stability of the derivatives, and a study has shown that OPA-amino acid derivatives decompose to the extent of about 6% over 15 h (though their methyl esters reach this point of decay after 8 h).836The structurally-related, highly fluorescent, derivatives formed using naphthalene-2,3dialdehyde continue to be explored.837 Comparison of HPLC analyses of D- and L-threo-P-methylphenylalanineby the o-phthaldialdehyde-mercaptopropionic method, use of Marfeys reagent acid (1 -fluoro-2,4-dinitrophenyl-5-L-alaninamide), alkaline acetic anhydride proand cedures, as well as the use of GLC (N-trifluoroacetyl isobutyl ester) leads to no

70

Amino Acids, Peptides and Proteins

particular r e c ~ m m e n d a t i o nN-Acetylamino acids in urine have been estimated .~~~ by HPLC with MS detection,839whereas derivatization at the carboxy group with 9-anthryldiazomethane has been advocated for the determination of N-acetylamino acids released from proteins using pro tease^.^^^ Benzoyl chloride has also been revisited for derivatization, and converts amino acids into 2-phenyl-5benzoyloxyoxazoles, permitting analysis at the 1 pmol level with the assistance of electrospray MS monitoring.841Analysis of kainic acid as either N-(4-azidobenzoy1)- or N-(4-azidoPTC)-derivatives, has been described.842 D a n s y l a t i ~ n ~ ~ dabsylation844provide stable derivatives and good HPLC and ~ separation can be achieved. One of these was aimed at verifying the stability of common amino acids in 6M HCl. Analysis by electrospray MS of underivatized basic amino acids and N-hydroxylamino acids is moderately successful, but dansylation gives improved reliability.845Dansyl-L-phenylalanine can be detected down to approximately 5 x mol levels.846 4-Hydroxyproline assay through dabsylation followed by OPA-derivatization provides reproducible results for low levels of a n a l ~ t e . ~ ~ ' In a comparison with PTC-derivatization, 6-aminoquinolinyl-N-hydroxysuccinimide treatment of amino acids (giving AQCamino acids; Lax nm)848is 248 clearly superior unless there is a minimal time delay between derivatization and HPLC.849Highly fluorescent asymmetric ureas are formed between amino acids and the carbamate of the AQC reagent, and HPLC analysis with their help gives results that compare well with classical ion-exchange analysis.850 Use of a polymeric reagent carrying this carbamate has been explored.s5' Post-column derivatization with 1,2-naphthoquinone-4-sulfonate(ha, 305 nm) has been applied to samples separated by ion-pair liquid c h r o m a t ~ g r a p h y . ~ ~ ~ Particular structural characteristics that allow specific analytical targetting are shown by some common amino acids. This is illustrated for cysteine and homocysteine analysis, conversion into the N-acetyl S-pyridinium derivative,853 or into derivatives formed with r n o n ~ b r o m o b i n a n eand derivatization using 7,~~~ fluorobenzo-2-oxa-l,3-diazole-4-sulfonate.855 Non-derivatized samples (electrochemical detection of cysteine, using a glassy carbon electrode),ss6 and of Sadenosyl-L-homocysteine and S-adenosyl-L-methionine by UV detection,857have proved to be suitable for analysis. An interesting development for the HPLC ionexchange analysis of underivatized amino acids exploits the chemiluminescence formed between amino acids and in situ-generated Ru(bipy)3.8s8Protocols for HPLC of related amino acids (excitatory amino acids carrying sulfonic and sulfinic acid s i d e - c h a i n ~ )and ~ , ~ ~ selenium analogues of sulfur-containing amino acids,860 have been worked out. Tryptophan and its 5-hydroxy-derivative in cerebral fluid have been estimated by HPLC with electrochemical detection,861and through fluoresence detection (hexcit 302 nm, hern 340 nm).862 Increasing numbers of HPLC studies of crosslinking amino acids reflect the importance of some of them as markers for metabolic disorders. Pyridinoline and its deoxy-analogue have dominated these reports,863 which describe minor differences in protocol, one of which (use of acetylated pyridinoline as internal standard)8H needs care so as to minimize its d e c o m p o ~ i t i o n Estimation of .~~~

1: Amino Acids

71

aldosine as its oxidative decarboxylation product (Fe3 ), 6-(3-pyridyl)piperidine2-carboxylic acid,866and of desmosine and isodesmosine as dansyl derivatives.867 Analysis of p-boronophenylalanine in tissue is an essential adjunct to studies of the uses of this amino acid in neutron capture therapy.868 Estimation of enantiomer ratios for amino acids is most commonly achieved now by modifications of the derivatization methods outlined above. Thus, the use or N-isobutyroyl-L- or Dof a homochiral thiol ( N - a c e t y l - L - c y ~ t e i n e ~ ~ ~ ? ~ ~ ~ ~ y s t e i n e ~ ~ ' .the~OPA procedure permits the complete separation of 18 DLin ~ ~ ) amino acids. One of these papersp70describes a dating study concentrating on aspartic acid extracted from dentin, and applicable down to 1 pmol levels. (+ )-I(9-Fluoreny1)ethyl chloroformate similarly yields diastereoisomer mixtures allowing the estimation of D/L-ratios of amino acids in crustacean nerve A new fluorophore, N-[4-(6-methoxy-2-benzoxazolyl)benzoyl]-L-proline, has been introduced for the same purpose.873 Protected amino acids for use in peptide synthesis have been derivatized with Marfey's reagent for enantiomeric purity estimations.874 The other main approach to HPLC determinations of enantiomer ratios involves the incorporation of chiral species into a silica gel stationary phase (a crown ether, applied to tyrosine and DOPA and analogues),8753-aminopropylated silica gel acylated by 2,4-dinitrobenzoyl-(R)-( -naphthyl)glycine for the 1 analysis of tryptophan and aspartic tetra-esters of calix[4]arenes bonded to silica gel for the estimation of DL-amino acid esters877)and bovine serum albumin bonded to silica gel for the resolution of D L - t r y p t ~ p h a n .Pirkle~~~ type columns have been used for enantiomeric analysis of amino acids the derivatized with 4-fluoro-7-nitro- or 4-dansyl-7-fluoro-2,1,3-benzoxadiazole, former reagent giving superior results.879 'Chiralcel-OD' [cellulose tris(3,5dimethylphenyl carbamate)] gives good results for a series of 17 Fmoc-amino acids.880

7.5 Fluorimetric Analysis - This section collects miscellaneous exploratory studies that have not been covered elsewhere in this Chapter, such as separation of derivatized amino acids using the fast centrifugal analyserS8' and enhancement of the fluorescence of naphthalene- 1,2-dialdehyde-derivatizedamino acids by cyclodextrins as mobile phase constituents in HPLC.882

7.6 Other Analytical Methods - Clearly, the applications of capillary zone electrophoresis (CZE) and related methods are developing rapidly, as demonstrated by the dedication of a CRC volume to it.883There are several applications in the amino acids One of these concentrates on CZE of cysteine and cystine employing electrochemical detection, as does anothe?86 that also covers a broader range of analytes. Separation of a mixture of 24 dansylamino acids is sharpened by Tween micelles in the liquid phase,887 and separation of PTHs with good distinction of artefactual peaks has been accomplished.888 These studies use sample preparation protocols that are familiar from the HPLC field, and this is also seen in use of Fmoc-derivatization for estimation of hydroxyproline in serum after OPA-treatment,889 enantiomeric

72

Amino Acids, Peptides and Proteins

separations of PTHs using N-dodecanoyl-L-serine, -glutamic acid, or -valine micelles,ggOand of dansylamino acids891 using cyclodextrins as buffer additives,892also used for dansyl- and OPA-amino acids.893The power of modern methodology is revealed in the estimation, at 140 ppm levels, of the enantiomeric purity of phenylalanine derivatized by 4-fluoro-7-nitrobenz-2,1,3oxadiazole and separated by CZE with cyclodextrin-containing buffers and using laser-induced (488 nm) fluorescence detection.894 Chiral stationary phases are also compatible with CZE enantiomeric purity determination, and mechanistic aspects have been explored.895The practice of CZE resolution has been reviewed.896 Immunoassay techniques have not been surveyed thoroughly in this Chapter over the years, though attention is drawn to unusual relevant studies such as the estimation of desmosine in biological
7.7 Assays for Specific Amino Acids - Most of the papers under this heading revolve around enzymatic methods, both in the biosensor category and in flow injection analysis techniques. However, the latter approach can also accommodate standard chemical methods of analysis, such as Chloramine-T oxidation of hydroxyproline to generate a stable colour with Ehrlich's reagent.898 Photometric estimation of tryptophan depends on the formation of a coloured complex by Fe3-t- /AcOH/glycollic acid oxidation.899 Simultaneous estimation of L-lysine and L-tyrosine based on enzyme-supported flow injection analysis uses two enzyme reactors and a single oxygen electrode.g00A similar approach accommodates L-alanine and L-phenylalanine, with a flow injection fibre optic biosensor providing the means of q u a n t i t a t i ~ n , ~ ~ ' also for chemiluminescence generated specifically when L-lysine is present, associated with a lysine oxidase/microbial peroxidase membrane.902 Measurement of oxygen generated in the latter system defines the L-lysine content of a sample.g03 More conventional biosensor studies also appear in the current literature, often leapfrogging existing technology, but usually adding further illustration of established methods. A 'micro-enzyme sensor', based on immobilized L-amino acid oxidase, has been proposed for the quantitation of L-amino acids in urine,904 and a combined L- and D-amino acid oxidase version assays total D- and Lamino acids.g05The immobilization of a peroxidase with a D-amino acid oxidase on an electrode measures D-amino acid concentrations in proportion to H202 liberated.906A process for the electrodeposition of poly(tyramine) on to electrodes provides amino groups through which an L-amino acid oxidase can be immobilized to give satisfactory sensors.9o7An estimation of D-amino acids is based on the formation of D-norleucine by bacterial D-amino acid transaminase coupled with 2-oxohexanoic acid.g08 The majority of current amino acid-biosensor reports concern L-glutamic acid and its relatives, with immobilized glutamic acid oxidaseW9 linked through glutaraldehyde to an aminopropyl-platinized platinum wire, for amperometric r n e a s u r e m e n t ~ .A ~similar glutarate-immobilized glutamic acid oxidase + ~ ~ glutaminase sensor permits amperometry of glutamic acid and glutamine, which

1: Amino Acids

73

together with lactic acid can be estimated as a total entity using rhodinized carbon electrode^.^^' The list is completed by an L-glutamic acid + NADH sensor,9* a glutamic acid decarboxylase-coatedelectrode?' and an L-glutamine sensor comprising kidney slices and an ammonia-sensingelectrode.914

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707 708 709 710

I : Amino Acids
715 716
717 718 719

95

720 72 1 722 723 724 725 726 727 728 729 730 73 1 732 733 734 735 736 737 738 739 740 741 742 743
744 745 746 747 748 749 750 751 752 753 754

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96 755 756 757 758 759 760 76 1 762 763 764 765 766 767 768 769 770 77 1 772 773 774 775 776 777 778 779 780 78 1 782 783 784 785 786

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I : Amino Acids
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97

A.J. Kungl, M. Breitenbach, and H.F. Kauffmann, Biochim. Biophys. Acta, 1994,
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805 806 807 808 809 810 811 812 813 814 815 816 817

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98

Amino Acids, Peptides and Proteins

818 819 820 82 1 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 85 1

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I : Amino A c i h
852 8 53 854

99

855 856
857 858 859

860 861 862 863

864 865 866 867 868

869 870 87 1 872 873 874 875 876 877

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I: Amino Acids
909 910 91 1 912 913 914

101

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