, ,Atnino Acids
`and Peptides
`
`G. C. BARRETT
`
`AND
`
`D. T. ELMORE
`
`..
`UCAMBRIDGE
`V UNIVERSITY PRESS
`
`Bausch Health Ireland Exhibit 2042, Page 1 of 12
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`

`

`.....
`
`Chemtstry library
`University of Wisconsin - Madison
`2361 Chemistry Building
`1101 University Avenue
`Madison, WI 53706-1396
`
`PUBLISHED BY THE PRESS SYNDICATE OF THE UNIVERSITY OF CAMBRIDGE
`The Pitt Building, Trumpington Street, Cambridge CB2 I RP, United Kingdom
`
`CAMBRIDGE UNIVERSITY PRESS
`The Edinburgh Building, Cambridge CB2 2RU, United Kingdom
`40 West 20th Street, New York, NY 10011-4211, USA
`IO Stamford Road, Oakleigh, Melbourne 3166, Australia
`
`© Cambridge University Press 1998
`
`This book is in copyright. Subject to statutory exception
`and to the provisions of relevant collective licensing agreements,
`no reproduction of any part may take place without
`the written permission of Cambridge University Press.
`
`First published 1998
`
`Printed in the United Kingdom at the University Press, Cambridge
`
`Typeset in Times NR 10/13pt
`
`[SE]
`
`A catalogue record for this book is available from the British Library
`
`ISBN O 521462924 hardback
`ISBN O 521468272 paperback
`
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`6
`
`Synthesis of amino acids
`
`6.1 General
`
`There is an abundant supply of L-enantiomers of most of the coded amino acids.
`These are made available through large-scale fermentative production in most cases,
`and also through processing of pi:otein hydrolysates. The early sections of this
`chapter cover this aspect, However, laboratory synthesis methods are required for
`the provision of most of the other natural amino acids and for all other amino acids,
`so the main part of this chapter deals with established syntheses.
`
`6.2 Commercial and research uses for amino acids
`
`In addition to the provision of supplies of common amino acids, there are growing
`needs for routes to new amino acids, since pharmaceutically useful compounds of
`this class continue to be discovered, which must be free from toxic impurities and
`homochirally pure in this particular context. Important functions for close ana­
`logues of coded and other biologically significant amino acids include enzyme inhibi­
`tion and retarding the growth of undesirable organisms (fungistatic, antibiotic and
`other physiological properties, possessed either by the free amino acids or by pep­
`tides containing them). Free amino acids that perform in this way are a-amino iso­
`butyric acid (an example of an a-methylated analogue of a coded amino acid),
`which has been proposed for the control of domestic wood-rotting fungi), and a­
`methyl-Dopa (a-methyl-3' ,4' -dihydroxy-L-phenylalanine), a well-known treatment
`for Parkinson's disease. Similar success for new therapeutic amino acids, based on
`their enzyme-inhibition properties, is indicated for amino acid� with a minimal
`structural change such as the substitution of a side-chain hydrogen atom by a
`fuorine atom.
`
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`6.3 Biosynth\:sis
`
`6.3 Biosynthesis: isolation of amino acids from natural sources
`
`Many examples of the discovery and isolation of amino acids from natural sources
`date from the early 1900s, though some were characterised several years before that
`(Greenstein and Winitz, 1961). Further new examples continue to be discovered,
`either as constitu�nts of proteins, revealing new post-translational processes for
`higher organisms (Tobie 1.3 in Chapter 1 ), or in the free or bound form (from fungal
`or bacterial sources or from marine organisms).
`
`6.3.1 Isolation of amino acids from proteins
`
`Hydrolysis of proteins and separation of the resulting mixture is an obvious, and
`traditional way (Greenstein and Winitz, 1961) of obtaining moderate quantities of
`the coded and post-translationally modified L-a-amino acids. However, because of
`the availability of viable methods of industrial synthesis, hydrolysis of proteins no
`longer offers a sensible apj,roa,c;h owing to its tedious and expensive nature and the
`fact that some amino acids are destroyed in the process (see Chapter 3).
`
`6.3.2 Biotechnological and industrial synthesis of coded amino acids
`
`Knowledge gained of biosynthetic routes to L-a-amino acids and isolation of the
`enzymes mediating the steps in these routes has been exploited for the industrial­
`scale manufacture of most of the coded L-a-amino acids. In some cases, the enzy­
`matic production of near-analogues of the coded L-a-amino acids can also be
`achieved (Goldberg and Williams, 1991; Rozzell and Wagner, 1992).
`To illustrate the methods, a culture medium that contains indole, pyruvic acid,
`tyrosine phenollyase and an ammonium salt, as well as the usual buffers and salts,
`will accumulate L-tryptophan; or will produce an indole-substituted L-tryptophan
`if indole itself is replaced by a substituted indole. L-Dopa formed in a system
`employing tyrosinase from Aspergillus terreus provides a further example of this
`approach (Chattopadhyay and Das, 1990).
`The crucial enzymes need not be isolated, since 'bio-reactors' containing micro­
`organisms that are fed with the appropriate starting materials are often more con­
`venient. L-Threonine from Brevibacterium ftavum, L-lysine from Corynebacterium
`glutamicum (Eggeling, 1994) and use of plant-cell suspension cultures illustrated by
`L-Dopa from Mucuna pruriens (Wichers et al., 1985) are examples. However, bio­
`engineering of the whole organisms to be used in this way may need to be carefully
`optimised to achieve reasonable yields. The other main opportunity offered by bio­
`technological methods is the conversion of one amino acid into a less plentifully
`available amino acid, e.g. the conversion of L-tyrosine into L-Dopa using Mucuna
`pruriens (Wichers et al., 1985).
`For a limited range of amino acids, this approach is increasingly in competition
`
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`SYNTHESIS OF AMINO ACIDS
`
`CO2·
`+I
`H3N-C-CH2OH ➔
`
`H
`
`D- or L-Serine
`
`C0-0 RX
`+ I
`I
`H3N-C-CH2 ➔
`I
`H
`(in N-protected form)
`
`CO2·
`+I
`H3N-C-CH2R
`
`H
`
`Scheme 6.1.
`
`with chemical synthesis, which can accomplish the necessary modifications in some
`cases more easily (Section 6.4). Examples of 'non-biotechnological' synthesis are
`provided by the industrial production of glutamic acid and lysine, conducted on a
`large scale (several thousand tons per year). DL-Glutamic acid is obtained from
`acrylonitrile, electrochemical reductive dimerisation and functional group mod­
`ifications giving the DL compound. DL-Lysine is obtained from caprolactam,
`through its 3-amino-derivative, which is resolved (Scheme 6.6) with L-pyroglutamic
`acid before ring-opening to give L-lysine.
`
`6.4 Synthesis of amino acids starting from coded amino acids other than glycine
`With the easy availability of many of the natural amino acids, some general methods
`for the synthesis of more complex structures are based on the modification of simple
`natural amino acids. An important benefit from this approach is the fact that homo­
`chirality at the a-carbon atom can be preserved in reactions at side-chains that are
`in current use.
`Thus, o- or L-serine can be converted through the Mitsunobu reaction into the
`homochiral a-amino-!3-lactone, a chiral synthon amenable to ring-opening by
`organometallic reagents (Pansare and Vederas, 1989) to give 13-substituted alanines
`(Scheme 6.1). 13-Iodo-L-alanine (also obtained from L-serine) can be elaborated
`similarly
`into
`the general class of 13-substituted alanines
`(L-serine➔
`H3N+CH(CH2l)CO2➔H3N+CH(CH2R)CO2 (Jackson et al., 1989)). L-Aspartic
`acid and L-glutamic acid serve the same function, electrophiles being substituted at
`the carbon atom next to the side-chain carboxy group after its deprotonation with
`lithium di-isopropylamide (Baldwin et al., 1989). As shown in this composite
`example from a number of research papers, the side-chain carboxy group can be
`transformed into other functional groups, when one starts with suitably protected
`glutamates and aspartates (Scheme 6.2).
`There are numerous other isolated examples of the conversion of a coded amino
`acid into another amino acid. These usually amount to applications of straight-
`
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`6.6 Other general methods
`
`-
`co2
`+ I
`H3N-C-CH2CH2C02H
`C02 R2
`I
`H
`Curtius
`I
`,
`D- or L-
`R NH-C-CH2CHR'C02 R 3 ➔
`rearrangement
`Glutamic acid
`I
`etc
`H
`
`➔
`
`-
`co2
`+ I
`H3N-C-CH2CHR'NH2
`I
`H
`D- or L-2,4-diamino­
`butanoic acid
`homologue
`
`Scheme 6.2.
`
`forward functional group chemistry - e.g. aromatic substitution reactions of phenyl­
`alanine and tyrosine- that have as their only additional requirement that protection
`of amino and carboxy groups may need to be considered.
`
`6.5 General methods of synthesis of amino acids starting with a glycine derivative
`
`Simplest of all the laboratory methods, in concept, are those general methods based
`on the alkylation of glycine derivatives shown in Scheme 6.3, particularly 2-acyl­
`amidomalonate esters (1), Schiff bases (2), oxazol-5(4H)-ones (alias 'azlactones', 3)
`and piperazin-2,5-diones (4).
`
`6.6 Other general methods of amino-acid synthesis
`
`The ex-amino-acid grouping, -NH-CHR-CO-O-, can be built up from its
`components through the Strecker synthesis (Equation (6.1) in Scheme 6.4) or by the
`Bucherer-Bergs synthesis (alias hydantoin synthesis; Equation (6.2) in Scheme 6.4).
`Three general methods - the diethyl acetamidomalonate, Strecker and
`Bucherer-Bergs syntheses - remain the most-used general methods, together with
`the oxazolone route (the Erlenmeyer 'azlactone' synthesis shown in Scheme 6.3). An
`even simpler synthesis, the Miller-Urey experiment in which some of the presumed
`atmospheric components in pre-biotic eras were shown to combine (Equation (6.3)),
`is not of practical interest since it gives mixtures with low yields and it cannot be
`directed towards a predominant target amino acid.
`Further general syntheses are shown in Scheme 6.5 (amination ofhalogenoalka­
`noic acid derivatives (Equation 6.4), carboxylation or carbonylation of alkylamines
`(Equation 6.5) and the Ugi 'four-component condensation' (Equation 6.6)). These
`are useful methods capable of development in certain cases for large-scale syntheses
`of simple amino acids.
`
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`SYNTHESIS OF AMINO ACIDS
`
`~ ~
`I
`I
`(iO
`(I)
`C~-co-NH-C-H ➔ C~•CO-NH-C-R
`➔
`I
`I
`<:¥~
`<:¥~
`
`( 1)
`
`Dl~-amino add
`
`Re1Q49111S: © ~
`
`. ele<:tl opile (Such • an alkyl helde, RX); (II) 8M hydroct,IOric acid, retu
`
`(2)
`
`ffllior p,odud
`
`minor p,odud
`
`acid hydl'Olysis
`➔
`
`c~-
`+ I
`H,N-C-R (Cl-a-amino acid) +
`I (major p,odud)
`H
`
`CO;f
`+I
`H,N-C-R (Dl-elkyl
`I
`glycine)
`R (minor produd)
`
`RCHO
`➔
`
`(CH,CO),O
`
`N---fCHR ~
`Pto~,>.a:o
`➔
`(3)
`
`Glycine etli,I ester➔
`
`➔ DL•amlno acid
`by hydrdysil
`
`Scbeme6.3.
`
`Strecm Synthesis
`
`RCHO + NH4CN ➔ NHr:HR-CN ➔ CL-a-amino acid
`
`Buchenlr~ Synthesis
`
`RCHO + (NH4►.zC03 ➔ NH- CHR ➔ DL-a-amino acid
`I
`I
`O•C C-0
`\
`I
`NH
`
`( 6.1)
`
`(6.2)
`
`Scheme6.4.
`
`Ni+ CH4 + ¥
`
`--SW90UR»
`➔
`
`Mbdurufannacida(fflOlllym-Mllnoacida)
`
`(6.3)
`
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`6. 7 Resolution
`
`9flllllrrt I
`hpaZlne
`Plillllllmlde .. BrCHRC<>ji ➔ DL-a• PhlhNCHR~H ➔ 1111N ecicl
`
`(6.4)
`
`ni-e--.lilnillrrocMallllllda~ .,.mnos,uup,e.g. tadlond NIINs
`vMl• , a-NllagelN>«:ld.~byl'lduclol'lofthe~)
`
`CWIMtlWTIINtWlt
`' C~ Ph
`
`C~Ph
`\I
`C
`I\
`HO:zC H
`
`➔
`
`\I
`C
`I\
`HiN H
`
`➔
`
`c~ CO:zH
`c~ Ph
`\/
`\/
`(OJ
`C
`C ➔
`/\
`/\ H20
`PhCONH H
`HiN H
`
`R( • }-■lllnine
`
`(s-.Ulllllr,..,....... -.gtheSc:MMrwnng■nall,c■nbelad ■nllogoully,
`IDlnlnlduoethe ■mnbldlorl)
`
`WM■4 ■-A ..... D :PC IP a:lde:edrt
`
`tctoC D :'II Ill :1PP1Pn ?Cw, •met: IC#
`L°"
`BocNaNBoc BocN-NHBoc 1) TFA
`I
`RCHC¥' ➔ RCl-rCO:zR'
`➔
`➔ ~no-add
`RCH~R' 2)H;iN
`
`Attft: ,.,,,..,.,.. 2' Ml 11 t:fl O( I UIIIDI:
`catalylt
`R1CONHi+R2cHO+CO ➔ R1CONHCH~Oji
`
`Scheme6.5.
`
`(6.5)
`
`(6.6)
`
`6.7 Resolution of DL-amino adds
`
`The requirements for homochirally pure a-amino acids have not ruled out any of
`these general synthetic methods (which all give racemic products), since resolution
`of DL•a-amino acids and their derivatives is a simple, albeit time-consuming, solu(cid:173)
`tion to this need Classical methods for resolution include physical separation of the
`DL-amino acids themselves (by chromatography on a chiral phase; e.g. resolution of
`DL-tryptophan over cellulose, see Section 4.15), fractional crystallisation of certain
`racemates or supersaturated solutions (through seeding with crystals of one enan-
`
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`SYNTHESIS OF AMINO ACIDS
`
`_ _ _ _ _ 11 _ _ _ _ _
`
`(±)PhCSNHCHBulc02H +(-)alkaloid➔ (+ )PhCSNHCHButco2-1(-)alkaloidH+ salt
`+
`(-)PhCSNHCHBulco2-J(-)alkaloidH+ salt
`/ separate by fradional
`/
`crystallisation, monitor by
`\
`circular dichroism
`(+ )PhCSNHCHButco2-1(-)alkaloidH+ salt
`(-)PhCSNHCHBulco2-J(-)alkaloidH+ salt
`POSITIVE c.d. centred near 390 nm
`NEGATIVE c.d. centred near 390 nm
`:.D-amino acid derivative
`:.L-amino acid derivative
`Treat with dill aq NaOH, extrad thiobenzoylamino acid l into organic solvent
`D(+)PhCSNHCl:IBulc02H
`L(-)PhCSNHCHBulc02H
`Remove thiobenzoyl I group by succe�ve treatment with Mel l and H2S
`L-t-leucine
`D-t-leucine
`
`Scheme 6.6. Resolution ofDL-t-leucine (Barrett and Cousins, 1975.)
`
`tiomer) and, more commonly, separation by crystallisation of diastereoisomeric
`derivatives (alkaloid salts of N-acylated DL-amino acids; fractional crystallisation of
`DL-amino acids derivatised with homochiral N-acyl and/or O-alkyl ester groups).
`Scheme 6.6 displays a typical amino-acid-resolution procedure applicable both on
`the laboratory scale and industrially (e.g. L-lysine manufacture, Section 6.3.2).
`Enzymic resolution is also generally useful. At first sight it is of restricted
`applicability, since most of the classical methods are based on the selectivity of a
`proteinase for catalysing the hydrolysis of the L enantiomer of an N-acyl derivative
`of a DL-amino acid (Equation (6.7)) or of a DL-amino acid ester. The normal sub­
`strates for these enzymes are derivatives of particular coded amino acids.
`
`DL-R1 coNHCHR2co2H ➔ D-R1CONHCHR2co2H + L-NH2CHR2C02H
`
`trypsin
`
`(6.7)
`
`However, the range of types of amino acids that can be resolved in this way is
`much greater than just the natural substrates (i.e. peptides made, up of the twenty
`coded amino acids), because methods to relax the specificity of the enzymes have
`been found, in some cases by using organic solvents for the reactions. Penicillin
`acylase from Escherichia coli and an aminoacylase from Streptoverci/lium o/ivoreti-
`
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`6.8 Asymmetric synthesis
`
`culi have been used for the preparative-scale resolution of phenylalanines and
`phenylglycines carrying fluoro-substituents in the benzene ring (Kukhar and
`Soloshonok, 1995; Soloshonok et al., 1993).
`The use of enzymes with hydantoins (Equation (6.2) in Scheme 6.4) is particularly
`suitable and can �e quite simple since various bacteria possess o-hydantoinase
`activity and can be �sed conveniently in a 'whole-cells' procedure that avoids the
`need to extract and purify the actual enzymes concerned. As in the principle shown
`in the 'trypsin' equation just above, one hydantoin is converted through hydrolysis
`into the o-amino acid, whereas the other remains unaffected.
`
`6.8 Asymmetric synthesis of amino acids
`The correct usage of the term asymmetric synthesis implies the involvement of at
`least one stereoselective reaction for the preferential or exclusive generation of one
`particular configuration at the chiral centre in the amino acid that emerges at the
`end of the synthesis (Barrett� 1985; Williams, 1989). The general methods ofamino­
`acid synthesis discussed above can all, in principle, be carried out in the stereo­
`selective mode, but then depend for their enantioselectivity on the use of a chiral
`catalyst or on the presence of a chiral centre in the ester moiety of the glycine syn­
`thons. The use of a chiral catalyst (such as a Cinchona alkaloid) is illustrated in the
`phase-transfer alkylation of imines (2 in Scheme 6.3), giving better than 99% enan­
`tiomeric excess when the alkylating agent is 4-chlorobenzyl chloride in the synthesis
`of 4-chloro-L-phenylalanine (O'Donnell and Wu, 1989).
`The approach exploiting a chiral centre that is already in the synthon is effective
`in a number of cases. The chiral moiety in the synthon diverts a reaction at a nearby
`prochiral centre in favour of one enantiomer (asymmetric induction). An excellent
`example of the latter is the Schollkopf method ( 4 in Scheme 6.3, see also 5 in Scheme
`6.7); hydrogenation of 'azlactones' (3 in Scheme 6.3) using a homogeneous chiral
`catalyst is one route illustrating the former approach. Use of chiral five-membered
`heterocyclic compounds (e.g., 6 and 7) offers an alternative successful approach to
`asymmetric amino-acid synthesis.
`In many of these cases, the new chiral centre is generated in an achiral starting
`material (e.g., the oxazolone), whereas in others (e.g., the imidazolidinone) the start­
`ing compound is homochiral and cannot be recovered. However, the 'chiral auxil­
`iary' approach in which a homochiral reactant is recovered unchanged at the end of
`an asymmetric synthesis is illustrated in some of the examples in Scheme 6. 7 (the
`Belokon and oxazolidinone methods are good examples). Many recent synth�ses
`have used all these methods and close variants thereof.
`To some extent, it is a matter of perceived ease of working, or favourable econom­
`ics, when it comes to choice of method; the piperazinedione route can be operated
`on a scale of several hundreds of grams (Schollkopf et al., 1985). Nonetheless, a
`major consideration is the stereochemical efficiency that is involved (i.e. the
`
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`SYNTHESIS OF AMINO ACIDS
`
`L--.c>Et ➔ E+:1: ., • H BILVTl-F
`
`O:t • .;;.fRX
`
`H "'
`Mt
`
`(5)
`
`<~••at¥
`--♦
`wlrileell¥ ...
`
`-------·-- ... ·-----------___ .,. ------
`....
`
`------------· --------------- -------------------- ---------·-
`
`0
`
`➔
`
`Mel--'tt;OR + R'X
`
`X
`eut H
`HomocHr' kl I ♦•--- 115)
`
`R '
`o~ .. .H
`,._,/ NcOR
`X
`
`Bui H
`
`.....,,_RCHOglwaa~IClkll;s.bacll.Ca(t&ll7))
`
`+ PhCH'AcHaCo.H ➔
`
`(7)
`
`'~Ph~
`t◄ 'o
`y
`
`•
`
`Ip
`
`?YR
`
`Ph
`
`0
`
`R•H ➔ R•Br ➔
`R•N. ➔ .R•NH,
`
`(l)t-.
`➔
`(b) RX
`
`Belollon IC al. ( 1988)
`
`Scheme6.7.
`
`diastereoisomer excess involved when one starts with a homochiral auxiliacy), since
`a more difficult purification of the product to complete enantiomeric purity is
`involved when small enantiomer excesses are achieved.
`In the Schollkopfpiperazinedione method, namely alkylation of the 2,5-diethoxy
`compound prepared from L-alanine methyl ester, values greater than 90% are rou(cid:173)
`tinely achieved for the alkylation yield and for the diastereoisomeric excess of the
`product (Allen et al., 1992). Similar results have been reported for the Belokon
`method and for the Seebach imidazolidinone method (though there are rather low
`allcylation yields in some cases).
`
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`6.9 Referenq:s
`
`6.9 References
`
`General sources of information on general synthetic methods for amino acids (Barrett,
`1985) and on asymmetric synthesis (Williams, 1989) are listed in the Foreword.
`
`Allen, M. S., Hamaker, L. K., La Loggia, A. J. and Cook, M. J. (1992) Synth. Commun. ,
`22, 2077.
`Baldwin, J. E., Nortli, M., Flinn, A. and Moloney, M. G. (1989) Tetrahedron, 45, 1453.
`Barrett, G. C. and Cousins, P. R . (1975) J. Chem. Soc., Perkin Trans. I, 2313.
`Belokon, Y N., Sagyan, A. S., Djamgaryan, S. M., Bakhrnutov, V. I. and Belikov, V. M.
`(1988) Tetrahedron, 44, 5507.
`Chattopadhyay, S. and Das, A. (1990) FEMS Microbial. Lett., 72, 195.
`Eggeling, L. (1994) Amino Acids, 6, 261.
`Goldberg, I. and Williams, R . A. (1991) Biotechnology of Food Ingredients, Van Nostrand­
`Reinhold, New York.
`Greenstein, J. P. and Winitz, M. (1961) Chemistry of the Amino Acids, Wiley, New York.
`Kukhar, V. P. and Soloshonok, V. A. (Ed.) (1995) Fluorine-Containing Amino Acids:
`Synthesis and Properties, Wiley, Chichester.
`Jackson, R . F. W, James, K.;·wytp.es, M. J. and Wood, A. (1989) J. Chem. Soc. , Chem.
`Commun. , 644.
`O'Donnell, M. J. and Wu, S. (1989) J. Amer. Chem. Soc. , 111, 2353.
`Pansare, S. V. and Vederas, J. C. (1989) J. Org. Chem. , 54, 2311.
`Rozzell, J. D. and Wagner, F. (1992) Biocatalytic Production of Amino Acids and Their
`Derivatives, Wiley, New York.
`Schollkopf, U., Lonsky, R. and Lehr, P. (1985) Liebigs Ann. Chem. , 413.
`Seebach, D., Juaristi, E., Miller, D. D., Schickli, C. and Weber, T. (1987) Helv. Chim. Acta,
`70, 237.
`Soloshonok, V. A., Galaev, I. Y, Svedas, V. K., Kozlova, E. V., Kotif, N. V., Shishkina, I. P.,
`Galushko, S. V., Rozhenko, A. B. and Kukhar, V. P. (1993) Bioorg. Khim. , 19, 467.
`Wiebers, H. J., Malingre, T. M. and Huizing, H. J. (1985) Planta, 166, 421.
`
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`Bausch Health Ireland Exhibit 2042, Page 12 of 12
`Mylan v. Bausch Health Ireland - IPR2022-00722
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