-
Amino Acids, Peptides and Proteins
in Organic Chemistry
Edited by
Andrew B. Hughes
-
Further Reading
Fessner, W.-D., Anthonsen, T.
Modern BiocatalysisStereoselective and Environmentally
Friendly Reactions
2009
ISBN: 978-3-527-32071-4
Sewald, N., Jakubke, H.-D.
Peptides: Chemistry andBiology2009
ISBN: 978-3-527-31867-4
Lutz, S., Bornscheuer, U. T. (eds.)
Protein EngineeringHandbook2 Volume Set
2009
ISBN: 978-3-527-31850-6
Aehle, W. (ed.)
Enzymes in IndustryProduction and Applications
2007
ISBN: 978-3-527-31689-2
Wiley-VCH (ed.)
Ullmanns Biotechnology andBiochemical Engineering2 Volume Set
2007
ISBN: 978-3-527-31603-8
Budisa, N.
Engineering the Genetic CodeExpanding the Amino Acid Repertoire
for the Design of Novel Proteins
2006
ISBN: 978-3-527-31243-6
Demchenko, A. V. (ed.)
Handbook of ChemicalGlycosylationAdvances in Stereoselectivity and
Therapeutic Relevance
2008
ISBN: 978-3-527-31780-6
Lindhorst, T. K.
Essentials of CarbohydrateChemistry and Biochemistry2007
ISBN: 978-3-527-31528-4
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Amino Acids, Peptides and Proteinsin Organic Chemistry
Volume 1 - Origins and Synthesis of Amino Acids
Edited byAndrew B. Hughes
-
The Editor
Dr. Andrew B. HughesLa Trobe UniversityDepartment of ChemistryVictoria 3086Australia
All books published by Wiley-VCH are carefullyproduced. Nevertheless, authors, editors, andpublisher do not warrant the information containedin these books, including this book, to be free oferrors. Readers are advised to keep in mind thatstatements, data, illustrations, procedural details orother items may inadvertently be inaccurate.
Library of Congress Card No.: applied for
British Library Cataloguing-in-Publication DataA catalogue record for this book is available from theBritish Library.
Bibliographic information published bythe Deutsche NationalbibliothekThe Deutsche Nationalbibliothek lists thispublication in the Deutsche Nationalbibliograe;detailed bibliographic data are available in theInternet at http://dnb.d-nb.de.
# 2009 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim
All rights reserved (including those of translation intoother languages). No part of this book may bereproduced in any form by photoprinting,microlm, or any other means nor transmitted ortranslated into a machine language without writtenpermission from the publishers. Registered names,trademarks, etc. used in this book, even when notspecically marked as such, are not to be consideredunprotected by law.
Composition Thomson Digital, Noida, IndiaPrinting Strauss GmbH, MrlenbachBookbinding Litges & Dopf GmbH, HeppenheimCover Design Schulz Grak Design, Fugnheim
Printed in the Federal Republic of GermanyPrinted on acid-free paper
ISBN: 978-3-527-32096-7
-
Contents
List of Contributors XVII
Part One Origins of Amino Acids 1
1 Extraterrestrial Amino Acids 3Z. Martins and M.A. Sephton
1.1 Introduction 31.2 ISM 61.2.1 Formation of Amino Acids in the ISM via Solid-Phase Reactions 61.2.2 Formation of Amino Acids in the ISM via Gas-Phase Reactions 81.3 Comets 91.4 Meteorites 111.4.1 Sources of Meteoritic Amino Acids (Extraterrestrial versus
Terrestrial Contamination) 171.4.1.1 Detection of Amino Acids that are Unusual in the Terrestrial
Environment 171.4.1.2 Determination of the Amino Acid Content of the Meteorite Fall
Environment 171.4.1.3 Determination of Enantiomeric Ratios 181.4.1.4 Determination of Compound-Specic Stable Isotope Ratios
of Hydrogen, Carbon, and Nitrogen 181.4.2 Synthesis of Meteoritic Amino Acids 191.5 Micrometeorites and IDPs 231.6 Mars 231.7 Delivery of Extraterrestrial Amino Acid to the Earth and its
Importance to the Origin of Life 241.8 Conclusions 26
References 27
2 Terrestrial Amino Acids and their Evolution 43Stephen Freeland
2.1 Introduction 43
Amino Acids, Peptides and Proteins in Organic Chemistry. Vol.1 Origins and Synthesis of Amino Acids.Edited by Andrew B. HughesCopyright 2009 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 978-3-527-32096-7
V
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2.2 What are the 20 Terrestrial Amino Acids? 442.2.1 The 21st and 22nd Genetically Encoded Amino Acids 452.2.2 Do other Genetically Encoded Amino Acids Await Discovery? 462.2.3 Genetic Engineering can Enlarge the Amino Acid Alphabet 472.2.4 Signicance of Understanding the Origins of the
Standard Alphabet 482.3 What do We Know about the Evolution of the Standard Amino
Acid Alphabet? 492.3.1 Nonbiological, Natural Synthesis of Amino Acids 502.3.2 Biosynthetic Theories for the Evolutionary Expansion of the
Standard Amino Acid Alphabet 532.3.3 Evidence for a Smaller Initial Amino Acid Alphabet 552.3.4 Proteins as Emergent Products of an RNAWorld 562.3.5 Stereochemical Rationale for Amino Acid Selection 572.4 Amino Acids that Life Passed Over: A Role for
Natural Selection? 582.4.1 Were the Standard Amino Acids Chosen for High
Biochemical Diversity? 602.4.2 Were the Standard Amino Acids Chosen for Cheap
Biosynthesis? 622.4.3 Were the Standard Amino Acids Chosen to Speed Up Evolution? 622.5 Why Does Life Genetically Encode L-Amino Acids? 642.6 Summary, Synthesis, and Conclusions 64
References 66
Part Two Production/Synthesis of Amino Acids 77
3 Use of Enzymes in the Synthesis of Amino Acids 79Theo Sonke, Bernard Kaptein, and Hans E. Schoemaker
3.1 Introduction 793.2 Chemo-Enzymatic Processes to Enantiomerically Pure
Amino Acids 803.3 Acylase Process 813.4 Amidase Process 833.4.1 Amidase Process for a,a-Disubstituted a-Amino Acids 863.5 Hydantoinase Process 883.6 Ammonia Lyase Processes 903.6.1 Aspartase-Catalyzed Production of L-Aspartic Acid 913.6.2 Production of L-Alanine from Fumaric Acid by
an AspartaseDecarboxylase Cascade 923.6.3 Phenylalanine Ammonia Lyase-Catalyzed Production of
L-Phenylalanine and Derivatives 933.7 Aminotransferase Process 943.7.1 Aminotransferase-Catalyzed Production of D-a-H-a-Amino Acids 97
VI Contents
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3.8 AADH Process 993.9 Conclusions 102
References 103
4 b-Amino Acid Biosynthesis 119Peter Spiteller
4.1 Introduction 1194.1.1 Importance of b-Amino Acids and their Biosynthesis 1194.1.2 Scope of this Chapter 1194.2 Biosynthesis of b-Amino Acids 1204.2.1 Biosynthesis of b-Alanine and b-Aminoisobutyric Acid 1204.2.1.1 b-Alanine 1204.2.1.2 b-Aminoisobutyric Acid 1224.2.2 Biosynthesis of b-Amino Acids by 2,3-Aminomutases from
a-Amino Acids 1224.2.2.1 b-Lysine, b-Arginine, and Related b-Amino Acids 1244.2.2.2 b-Phenylalanine, b-Tyrosine, and Related b-Amino Acids 1274.2.2.3 b-Glutamate and b-Glutamine 1324.2.2.4 b-Leucine 1324.2.2.5 b-Alanine 1324.2.3 Biosynthesis of a,b-Diamino Acids from a-Amino Acids 1324.2.3.1 General Biosynthesis of a,b-Diamino Acids 1324.2.3.2 Structures and Occurrence of a,b-Diamino Acids in Nature 1324.2.3.3 Biosynthesis of Selected a,b-Diamino Acids 1354.2.3.3.1 Biosynthesis of b-ODAP 1354.2.3.3.2 Biosynthesis of the a,b-Diaminopropanoic Acid Moiety in the
Bleomycins 1364.2.3.3.3 Biosynthesis of the Penicillins 1374.2.3.3.4 Biosynthesis of the Capreomycidine Moiety in Viomycine 1374.2.3.3.5 Biosynthesis of the Streptolidine Moiety in Streptothricin F 1374.2.4 Biosynthesis of a-Keto-b-Amino Acids from a-Amino Acids 1394.2.5 De Novo Biosynthesis of b-Amino Acids by PKSs 1394.2.5.1 Introduction 1394.2.5.2 General Biosynthesis of Polyketide-Type b-Amino Acids 1414.2.5.3 Structures and Occurrence of Polyketide-Type b-Amino Acids
in Nature 1424.2.5.4 Biosynthesis of Selected Polyketide-Type b-Amino Acids 1494.2.5.4.1 Long-Chain b-Amino Acids Occurring as Constituents of
the Iturins 1494.2.5.4.2 Biosynthesis of the Ahda Moiety in Microginin 1514.2.5.4.3 Biosynthesis of the Ahpa Residue in Bestatin 1514.2.5.4.4 Biosynthesis of the Adda Residue in the Microcystins 1524.2.6 b-Amino Acids Whose Biosynthesis is Still Unknown 1524.3 Conclusions and Future Prospects 154
References 155
Contents VII
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5 Methods for the Chemical Synthesis of Noncoded a-AminoAcids found in Natural Product Peptides 163Stephen A. Habay, Steve S. Park, Steven M. Kennedy,and A. Richard Chamberlin
5.1 Introduction 1635.2 Noncoded CAAs 1645.3 Noncoded Amino Acids by Chemical Modication of Coded
Amino Acids 1855.4 Noncoded Amino Acids with Elaborate Side-Chains 2055.5 Conclusions 226
References 226
6 Synthesis of N-Alkyl Amino Acids 245Luigi Aurelio and Andrew B. Hughes
6.1 Introduction 2456.2 N-Methylation via Alkylation 2466.2.1 SN2 Substitution of a-Bromo Acids 2466.2.2 N-Methylation of Sulfonamides, Carbamates, and Amides 2496.2.2.1 Base-Mediated Alkylation of N-Tosyl Sulfonamides 2496.2.2.2 Base Mediated Alkylation of N-Nitrobenzenesulfonamides 2506.2.2.3 N-Methylation via Silver Oxide/Methyl Iodide 2526.2.2.4 N-Methylation via Sodium Hydride/Methyl Iodide 2536.2.2.5 N-Methylation of Triuoroacetamides 2576.2.2.6 N-Methylation via the Mitsunobu Reaction 2576.3 N-Methylation via Schiff s Base Reduction 2596.3.1 Reduction of Schiff s Bases via Transition
Metal-Mediated Reactions 2596.3.2 Reduction of Schiff s Bases via Formic Acid: The Leuckart
Reaction 2606.3.3 Quaternization of Imino Species 2616.3.4 Reduction of Schiff s Bases via Borohydrides 2636.3.5 Borane Reduction of Amides 2646.4 N-Methylation by Novel Methods 2656.4.1 1,3-Oxazolidin-5-ones 2656.4.2 Asymmetric Syntheses 2726.4.3 Racemic Syntheses 2776.5 N-Alkylation of Amino Acids 2806.5.1 Borohydride Reduction of Schiff s Bases 2806.5.1.1 Sodium Borohydride Reductions 2816.5.1.2 Sodium Cyanoborohydride Reductions 2816.5.1.3 Sodium Triacetoxyborohydride Reductions 2826.5.2 N-Alkylation of Sulfonamides 2826.5.2.1 Base-Mediated Alkylation of Benzene Sulfonamides 2826.5.3 Reduction of N-Acyl Amino Acids 2836.5.3.1 Reduction of Acetamides 284
VIII Contents
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6.5.4 Novel Methods for N-Alkylating a-Amino Acids 2846.5.4.1 Asymmetric Synthesis of N-Alkyl a-Amino Acids 2846.5.4.2 N-Alkylation of 1,3-Oxazolidin-5-ones 284
References 286
7 Recent Developments in the Synthesis of b-Amino Acids 291Yamir Bandala and Eusebio Juaristi
7.1 Introduction 2917.2 Synthesis of b-Amino Acids by Homologation of a-Amino Acids 2917.3 Chiral Pool: Enantioselective Synthesis of b-Amino Acids from
Aspartic Acid, Asparagine, and Derivatives 2987.4 Synthesis of b-Amino Acids by Conjugate Addition of Nitrogen
Nucleophiles to Enones 3007.4.1 Achiral b-Amino Acids 3007.4.2 Enantioselective Approaches 3047.4.2.1 Addition of Chiral Ammonia Equivalents to Conjugated
Prochiral Acceptors 3047.4.2.2 Addition of a Nitrogen Nucleophile to a Chiral Acceptor 3067.4.2.3 Asymmetric Catalysis 3087.5 Synthesis of b-Amino Acids via 1,3-Dipolar Cycloaddition 3127.6 Synthesis of b-Amino Acids by Nucleophilic Additions 3167.6.1 Aldol- and Mannich-Type Reactions 3167.6.2 MoritaBaylisHillman-Type Reactions 3217.6.3 Mannich-Type Reactions 3247.7 Synthesis of b-Amino Acids by Diverse Addition or
Substitution Reactions 3287.8 Synthesis of b-Amino Acids by Stereoselective Hydrogenation
of Prochiral 3-Aminoacrylates and Derivatives 3307.8.1 Reductions Involving Phosphorus-Metal Complexes 3317.8.2 Reductions Involving Catalytic Hydrogenations 3337.9 Synthesis of b-Amino Acids by use of Chiral Auxiliaries:
Stereoselective Alkylation 3347.10 Synthesis of b-Amino Acids via Radical Reactions 3387.11 Miscellaneous Methods for the Synthesis of b-Amino Acids 3407.12 Conclusions 3477.13 Experimental Procedures 3487.13.1 Representative Experimental Procedure: Synthesis of (S)-
3-(tert-Butyloxycarbonylamino)-4-phenylbutanoic Acid 3487.13.2 Representative Experimental Procedure: Synthesis of
(S)-2-(Aminomethyl)-4-phenylbutanoic Acid, (S)-19 3507.13.3 Representative Experimental Procedure: Synthesis of b3-Amino Acids
by Conjugate Addition of Homochiral Lithium N-Benzyl-N-(a-methylbenzyl)amide 352
7.13.4 Representative Experimental Procedure: Synthesis of Cyclic andAcyclic b-Amino Acid Derivatives by 1,3-Dipolar Cycloaddition 353
Contents IX
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7.13.5 Representative Experimental Procedure: Synthesis of (R)-3-tert-Butoxycarbonylamino-3-phenylpropionic Acid Isopropyl Ester usinga Mannich-Type Reaction 354
7.13.6 Representative Experimental Procedure: General Procedure for theHydrogenation of (Z)- and (E)-b-(Acylamino) acrylates by ChiralMonodentate Phosphoramidite Ligands 354
7.13.7 Representative Experimental Procedure: Synthesis of Chirala-Substituted b-Alanine 355
7.13.8 Representative Experimental Procedure: Synthesis of Chiral b-AminoAcids by Diastereoselective Radical Addition to Oxime Esters 357References 358
8 Synthesis of Carbocyclic b-Amino Acids 367Lornd Kiss, Enik}o Forr, and Ferenc Flp
8.1 Introduction 3678.2 Synthesis of Carbocyclic b-Amino Acids 3688.2.1 Synthesis of Carbocyclic b-Amino Acids via Lithium Amide-Promoted
Conjugate Addition 3698.2.2 Synthesis of Carbocyclic b-Amino Acids by Ring-Closing
Metathesis 3718.2.3 Syntheses from Cyclic b-Keto Esters 3728.2.4 Cycloaddition Reactions: Application in the Synthesis of Carbocyclic
b-Amino Acids 3758.2.5 Synthesis of Carbocyclic b-Amino Acids from Chiral Monoterpene
b-Lactams 3778.2.6 Synthesis of Carbocyclic b-Amino Acids by Enantioselective
Desymmetrization of meso Anhydrides 3788.2.7 Miscellaneous 3798.2.8 Synthesis of Small-Ring Carbocyclic b-Amino Acid
Derivatives 3838.3 Synthesis of Functionalized Carbocyclic b-Amino Acid
Derivatives 3858.4 Enzymatic Routes to Carbocyclic b-Amino Acids 3938.4.1 Enantioselective N-Acylations of b-Amino Esters 3948.4.2 Enantioselective O-Acylations of N-Hydroxymethylated b-Lactams 3948.4.3 Enantioselective Ring Cleavage of b-Lactams 3958.4.4 Biotransformation of Carbocyclic Nitriles 3968.4.5 Enantioselective Hydrolysis of b-Amino Esters 3968.4.6 Analytical Methods for the Enantiomeric Separation of Carbocyclic
b-Amino Acids 3978.5 Conclusions and Outlook 3988.6 Experimental Procedures 3998.6.1 Synthesis of Hydroxy Amino Ester Ethyl (1R,2S,4S)-
2-(Benzyloxycarbonylamino)-4-hydroxycyclohexanecarboxylate (205a)by Oxirane Ring Opening of with Sodium Borohydride 399
X Contents
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8.6.2 Synthesis of Bicyclic b-Lactam (1R,5S)-6-azabicyclo[3.2.0]hept-3-en-7-one (223) by the Addition of Chlorosulfonyl Isocyanateto Cyclopentadiene 399
8.6.3 Synthesis of b-Amino Ester Ethyl cis-2-aminocyclopent-3-enecarboxylate Hydrochloride (223a) by Lactam Ring-OpeningReaction of Azetidinone 223 400
8.6.4 Synthesis of Epoxy Amino Ester Ethyl (1R,2R,3R,5S)-2-(tert-butoxycarbonylamino)-6-oxabicyclo[3.1.0]hexane-3-carboxylate(225) by Epoxidation of Amino Ester 224 400
8.6.5 Synthesis of Azido Ester Ethyl (1R,2R,3R,4R)-4-Azido-2-(tert-butoxycarbonylamino)-3-hydroxycyclopentanecarboxylate (229)by Oxirane Ring Opening of with Sodium Azide 401
8.6.6 Isomerization of Azido Amino Ester to Ethyl (1S,2R,3R,4R)-4-Azido-2-(tert-butoxycarbonylamino)-3-hydroxycyclopentanecarboxylate(230) 401
8.6.7 Lipase-Catalyzed Enantioselective Ring Cleavage of 4,5-Benzo-7-azabicyclo[4.2.0]octan-8-one (271), Synthesis of (1R,2R)- and(1S,2S)-1-Amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic AcidHydrochlorides (307 and 308) 402
8.6.8 Lipase-Catalyzed Enantioselective Hydrolysis of Ethyl trans-2-aminocyclohexane-1-carboxylate (298), Synthesis of (1R,2R)- and(1S,2S)-2-Aminocyclohexane-1-carboxylic Acid Hydrochlorides(309 and 310) 404References 405
9 Synthetic Approaches to a,b-Diamino Acids 411Alma Viso and Roberto Fernndez de la Pradilla
9.1 Introduction 4119.2 Construction of the Carbon Backbone 4119.2.1 Methods for the Formation of the CbCc Bond 4119.2.1.1 Reaction of Glycinates and Related Nucleophiles with Electrophiles 4119.2.1.2 Dimerization of Glycinates 4169.2.1.3 Through Cyclic Intermediates 4179.2.2 Methods in Which the CaCb Bond is Formed 4209.2.2.1 Nucleophilic Synthetic Equivalents of CO2R 4209.2.2.2 Electrophilic Synthetic Equivalents of CO2R andOther Approaches 4239.2.3 Methods in Which the CbCb0 or CcCc0 Bonds are Formed 4249.3 Introduction of the Nitrogen Atoms in the Carbon Backbone 4259.3.1 From Readily Available a-Amino Acids 4259.3.2 From Allylic Alcohols and Amines 4279.3.3 From Halo Alkanoates 4289.3.4 From Alkenoates 4299.3.5 Electrophilic Amination of Enolates and Related Processes 4319.3.6 From b-Keto Esters and Related Compounds 4339.4 Conclusions 433
Contents XI
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9.5 Experimental Procedures 4349.5.1 (SS,2R,3S)-()-Ethyl-2-N-(diphenylmethyleneamino)-3-N-(p-toluenesul-
nyl)-amino-3-phenylpropanoate (14b) 4349.5.2 Synthesis of Ethyl (2R,3R)-3-amino-2-(4-methoxyphenyl)
aminopentanoate 32a via Asymmetric aza-Henry Reaction 434References 435
10 Synthesis of Halogenated a-Amino Acids 441Madeleine Strickland and Christine L. Willis
10.1 Introduction 44110.2 Halogenated Amino Acids with a Hydrocarbon Side-Chain 44210.2.1 Halogenated Alanines and Prolines 44210.2.2 Halogenated a-Amino Acids with Branched Hydrocarbon
Side-Chains 44510.2.2.1 Halogenated Valines and Isoleucines 44510.2.2.2 Halogenated Leucines 45110.3 Halogenated Amino Acids with an Aromatic Side-Chain 45710.3.1 Halogenated Phenylalanines and Tyrosines 45710.3.2 Halogenated Histidines 46010.3.3 Halogenated Tryptophans 46210.4 Halogenated Amino Acids with Heteroatoms in the Aliphatic
Side-Chain 46310.4.1 Halogenated Aspartic and Glutamic Acids 46310.4.2 Halogenated Threonine and Lysine 465
References 466
11 Synthesis of Isotopically Labeled a-Amino Acids 473Caroline M. Reid and Andrew Sutherland
11.1 Introduction 47311.2 Enzyme-Catalyzed Methods 47311.3 Chiral Pool Approach 47711.4 Chemical Asymmetric Methods 48311.5 Conclusions 48811.6 Experimental Procedures 48911.6.1 Biocatalysis: Synthesis of [15N]L-amino Acids from a-Keto Esters
using a One-Pot Lipase-Catalyzed Hydrolysis and Amino AcidDehydrogenase-Catalyzed Reductive Amination 489
11.6.2 Chiral Pool: Preparation of Aspartic Acid Semi-Aldehydes as KeySynthetic Intermediates; Synthesis of Methyl (2S)-N,N-di-tert-butoxycarbonyl-2-amino-4-oxobutanoate from L-aspartic Acid 489
11.6.3 Asymmetric Methods: Asymmetric Alkylation Using the WilliamsOxazine and Subsequent Hydrogenation to Give thea-Amino Acid 490References 491
XII Contents
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12 Synthesis of Unnatural/Nonproteinogenic a-Amino Acids 495David J. Ager
12.1 Introduction 49512.2 Chemical Methods 49712.2.1 Resolution Approaches 49712.2.2 Side-Chain Methods 49712.2.2.1 Introduction of the Side-Chain 49712.2.2.2 Modications of the Side-Chain 50012.2.3 Introduction of Functionality 50212.2.3.1 Nitrogen Introduction 50212.2.3.2 Carboxylic Acid Introduction 50312.2.3.2.1 Strecker Reaction 50312.2.4 Hydrogenation 50412.2.5 Other Chemical Methods 50812.3 Enzymatic Methods 50812.3.1 Acylases 50912.3.2 Hydantoinases 51012.3.3 Ammonia Lyases 51012.3.4 Transaminases 51112.3.5 Dehydrogenases 51312.3.6 Amino Acid Oxidases 51412.3.7 Decarboxylases 51512.4 Conclusions 51612.5 Experimental Procedures 51612.5.1 Side-Chain Introduction with a Phase-Transfer Catalyst 51612.5.2 Introduction of Nitrogen Through an Oxazolidinone Enolate
with a Nitrogen Electrophile 51712.5.3 Asymmetric Hydrogenation with Knowles Catalyst 51812.5.4 Asymmetric Hydrogenation with Rh(DuPhos) Followed by Enzyme-
Catalyzed Inversion of the a-Center 519References 520
13 Synthesis of g- and d-Amino Acids 527Andrea Trabocchi, Gloria Menchi, and Antonio Guarna
13.1 Introduction 52713.2 g-Amino Acids 52813.2.1 GABA Analogs 52813.2.2 a- and b-Hydroxy-g-Amino Acids 53413.2.3 Alkene-Derived g-Amino Acids 53913.2.4 SAAs 54113.2.5 Miscellaneous Approaches 54213.3 d-Amino Acids 54713.3.1 SAAs 54713.3.1.1 Furanoid d-SAA 547
Contents XIII
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13.3.1.2 Pyranoid d-SAA 55213.3.2 d-Amino Acids as Reverse Turn Mimetics 55413.3.3 d-Amino Acids for PNA Design 56213.3.4 Miscellaneous Examples 56413.4 Conclusions 566
References 567
14 Synthesis of g-Aminobutyric Acid Analogs 573Jane R. Hanrahan and Graham A.R. Johnston
14.1 Introduction 57314.2 a-Substituted g-Amino Acids 57514.3 b-Substituted g-Amino Acids 57914.3.1 Pregabalin 58114.3.2 Gabapentin 58414.3.3 Baclofen and Analogs 58414.4 g-Substituted g-Amino Acids 59214.4.1 Vigabatrin 59714.5 Halogenated g-Amino Acids 59914.6 Disubstituted g-Amino Acids 60014.6.1 a,b-Disubstituted g-Amino Acids 60014.6.2 a,g-Disubstituted g-Amino Acids 60114.6.3 b,b-Disubstituted g-Amino Acids 60414.6.4 b,g-Disubstituted g-Amino Acids 60414.7 Trisubstituted g-Amino Acids 60414.8 Hydroxy-g-Amino Acids 60514.8.1 a-Hydroxy-g-Amino Acids 60514.8.2 b-Hydroxy-g-Amino Acids 60614.8.3 a-Hydroxy-g-Substituted g-Amino Acids 61914.8.4 b-Hydroxy-g-Substituted g-Amino Acids 61914.8.5 b-Hydroxy-Disubstituted g-Amino Acids 63814.9 Unsaturated g-Amino Acids 64014.9.1 Unsaturated Substituted g-Amino Acids 64114.10 Cyclic g-Amino Acids 64414.10.1 Cyclopropyl g-Amino Acids 64414.10.2 Cyclobutyl g-Amino Acids 64814.10.3 Cyclopentyl g-Amino Acids 65314.10.4 Cyclohexyl g-Amino Acids 66314.11 Conclusions 66614.12 Experimental Procedures 66614.12.1 (R)-2-Ethyl-4-nitrobutan-1-ol (36c) 66614.12.2 N-tert-Butyl-N-(p-chlorophenylethyl) a-Diazoacetamide 66914.12.3 (R )-5-[(1-Oxo-2-(tert-butoxycarbonylamino)-3-phenyl)-propyl]-2,2-
dimethyl-1,3-dioxane-4,6-dione 67014.12.4 (R )- and (S)-[2-(Benzyloxy) ethyl]oxirane 671
XIV Contents
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14.12.5 Dimethyl (S,S)-()-3-N,N-bis(a-Methylbenzyl)-amino-2-oxopropylphosphonate 672
14.12.6 Boc-L-leucinal 67314.12.7 Cross-Coupling of N-tert-Butylsulnyl Imine and tert-Butyl
3-oxopropanoate 67414.12.8 (10S,4S)-4-Bromomethyl-1-(1-phenyleth-1-yl)-pyrrolidin-2-one 67514.12.9 ()-(R,S)-4-Amino-2-cyclopentene-1-carboxylic Acid 676
References 677
Index 691
Contents XV
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List of Contributors
XVII
Amino Acids, Peptides and Proteins in Organic Chemistry. Vol.1 Origins and Synthesis of Amino Acids.Edited by Andrew B. HughesCopyright 2009 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 978-3-527-32096-7
David J. AgerDSM Pharma ChemicalsPMB 1509650 Strickland Road, Suite 103Raleigh, NC 27615USA
Luigi AurelioMonash UniversityDepartment of Medicinal ChemistryVictorian College of Pharmacy381 Royal ParadeParkville, Victoria 3052Australia
Yamir BandalaCentro de Investigacin y de EstudiosAvanzados del Instituto PolitcnicoNacionalDepartamento de QumicaApartado Postal 14-74007000 Mxico DFMxico
A. Richard ChamberlinUniversity of California, IrvineDepartments of ChemistryPharmaceutical Sciences, andPharmacologyIrvine, CA 92697USA
Roberto Fernndez de la PradillaCSICInstituto de Qumica OrgnicaJuan de la Cierva 328006 MadridSpain
Enik}o ForrUniversity of SzegedInstitute of Pharmaceutical ChemistryEtvs u. 66720 SzegedHungary
Stephen FreelandUniversity of MarylandBaltimore CountyDepartment of Biological Sciences1000 Hilltop Circle,Baltimore, MD 21250USA
Ferenc FlpUniversity of SzegedInstitute of Pharmaceutical ChemistryEtvs u. 66720 SzegedHungary
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Antonio GuarnaUniversit degli Studi di FirenzePolo Scientico e TecnologicoDipartimento di Chimica OrganicaUgo Schiff Via della Lastruccia 1350019 Sesto FiorentinoFirenzeItaly
Stephen A. HabayUniversity of California, IrvineDepartment of ChemistryIrvine, CA 92697USA
Jane R. HanrahanUniversity of SydneyFaculty of PharmacySydney, NSW 2006Australia
Graham A.R. JohnstonUniversity of SydneyAdrien Albert Laboratory of MedicinalChemistryDepartment of PharmacologyFaculty of MedicineSydney, NSW 2006Australia
Andrew B. HughesLa Trobe UniversityDepartment of ChemistryVictoria 3086Australia
Eusebio JuaristiCentro de Investigacin y de EstudiosAvanzados del Instituto PolitcnicoNacionalDepartamento de QumicaApartado Postal 14-74007000 Mxico DFMxico
Bernard KapteinDSM Pharmaceutical ProductsInnovative Synthesis & CatalysisPO Box 186160 MD GeleenThe Netherlands
Steven M. KennedyUniversity of California, IrvineDepartment of ChemistryIrvine, CA 92697USA
Lornd KissUniversity of SzegedInstitute of Pharmaceutical ChemistryEtvs u. 66720 SzegedHungary
Z. MartinsImperial College LondonDepartment of Earth Science andEngineeringExhibition RoadLondon SW7 2AZUK
XVIII List of Contributors
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Gloria MenchiUniversit degli Studi di FirenzePolo Scientico e TecnologicoDipartimento di Chimica OrganicaUgo Schiff Via della Lastruccia 1350019 Sesto FiorentinoFirenzeItaly
Steve S. ParkUniversity of California, IrvineDepartment of ChemistryIrvine, CA 92697USA
Caroline M. ReidUniversity of Glasgow, WestChemDepartment of ChemistryThe Joseph Black BuildingUniversity AvenueGlasgow G12 8QQUK
M.A. SephtonImperial College LondonDepartment of Earth Science andEngineeringExhibition RoadLondon SW7 2AZUK
Hans E. SchoemakerDSM Pharmaceutical ProductsInnovative Synthesis & CatalysisPO Box 186160 MD GeleenThe Netherlands
Theo SonkeDSM Pharmaceutical ProductsInnovative Synthesis & CatalysisPO Box 186160 MD GeleenThe Netherlands
Peter SpitellerTechnische Universitt MnchenInstitut fr Organische Chemie undBiochemie IILichtenbergstrae 485747 Garching bei MnchenGermany
Madeleine StricklandUniversity of BristolSchool of ChemistryCantock's CloseBristol BS8 1TSUK
Andrew SutherlandUniversity of Glasgow, WestChemDepartment of ChemistryThe Joseph Black BuildingUniversity AvenueGlasgow G12 8QQUK
Andrea TrabocchiUniversit degli Studi di FirenzePolo Scientico e TecnologicoDipartimento di Chimica OrganicaUgo Schiff Via della Lastruccia 1350019 Sesto FiorentinoFirenzeItaly
Alma VisoCSICInstituto de Qumica OrgnicaJuan de la Cierva 328006 MadridSpain
Christine L. WillisUniversity of BristolSchool of ChemistryCantocks CloseBristol BS8 1TSUK
List of Contributors XIX
-
Part OneOrigins of Amino Acids
Amino Acids, Peptides and Proteins in Organic Chemistry. Vol.1 Origins and Synthesis of Amino Acids.Edited by Andrew B. HughesCopyright 2009 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 978-3-527-32096-7
-
1Extraterrestrial Amino AcidsZ. Martins and M.A. Sephton
1.1Introduction
The space between the stars, the interstellar medium (ISM), is composed of gas-phase species (mainly hydrogen and helium atoms) and submicron dust grains(silicates, carbon-rich particles, and ices). The ISMhasmany different environmentsbased on its different temperatures (Tk), hydrogen density (nH), and ionization stateof hydrogen (for reviews, see [13]); it includes the diffuse ISM (Tk 100K,nH 10300 cm3), molecular clouds (Tk 10100K, nH 103104 cm3; e.g., [4])[molecular clouds are not uniform but instead have substructures [5] they containhigh-density clumps (also called dense cores; nH 103105 cm3), which havehigher densities than the surrounding molecular cloud; even higher densities arefound in small regions, commonly known as hot molecular cores, which willbe the future birth place of stars], and hot molecular clouds (Tk 100300K,nH 106108 cm3; e.g., [6]). Observations at radio, millimeter, submillimeter, andinfrared frequencies have led to the discovery of numerous molecules (currentlymore than 151) in the interstellar space, some of which are organic in nature(Table 1.1; an up-to-date list can be found at www.astrochemistry.net). The collapseof a dense cloud of interstellar gas and dust leads to the formation of a so-called solarnebula. Atoms and molecules formed in the ISM, together with dust grains areincorporated in this solar nebula, serving as building blocks from which futureplanets, comets, asteroids, and other celestial bodies may originate. Solar systembodies, such as comets (e.g., [7] and references therein; [8]), meteorites (e.g., [9, 10]),and interplanetary dust particles (IDPs [11, 12]) are known to contain extraterrestrialmolecules, which might have a heritage from interstellar, nebular, and/or parentbody processing. Delivery of thesemolecules to the early Earth andMars during thelate heavy bombardment (4.53.8 billion years ago)may have been important for theorigin of life [13, 14]. Among themolecules delivered to the early Earth, amino acidsmay have had a crucial role as they are the building blocks of proteins and enzymes,therefore having implications for the origin of life. In this chapter we describedifferent extraterrestrial environments where amino acids may be present and
j3
Amino Acids, Peptides and Proteins in Organic Chemistry. Vol.1 Origins and Synthesis of Amino Acids.Edited by Andrew B. HughesCopyright 2009 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 978-3-527-32096-7
-
Table1.1Su
mmaryof
molecules
iden
tifiedin
theinterstellaran
dcircum
stellarmed
ium
a .
Num
berof
atom
s
23
45
67
89
1011
1213
H2
H3
CH
3CH
4C2H
4CH
3NH
2CH
3CH
3C2H
5OH
CH
3CH
2CHO
CH
3C6H
C6H
6HC11N
CH
CH
2NH
3NH
4
CH
3OH
CH
3CCH
C3H
4O
CH
3OCH
3CH
3COCH
3HC9N
CH
NH
2H
3O
CH
2NH
CH
3CN
c-C2H
4O
CH
2OHCHO
CH
3CH
2CN
HOCH
2CH
2OH
NH
H2O
C2H
2H
3CO
CH
3NC
CH
3CHO
CH
3COOH
CH
3CONH
2NH
2CH
2COOH
OH
H2O
H2C
NSiH
4NH
2CHO
CH
2CHCN
HCOOCH
3CH
3C4H
OH
C2H
HCNH
c-C3H
2CH
3SH
C6H
CH
2CCHCN
C8H
HF
HCN
H2C
OH
2CCC
H2C
CCC
C6H
CH
3C3N
C8H
C2
HNC
c-C3H
CH
2CN
HCCCCH
HC5N
C6H
2HC7N
CN
HCO
l-C3H
H2CCO
H2C
3N
HCCCCCCH
CN
HCO
HCCN
NH
2CN
c-H
2C3O
C7H
CO
HN2
HNCO
HCOOH
HC2CHO
CO
HOC
HNCO
C4H
C5H
N2
HNO
HOCO
C4H
HC4N
SiH
H2S
H2C
SHC3N
C5N
NO
H2S
C3N
HCCNC
SiC4
CF
C3
C3O
HNCCC
HS
C2O
HNCS
C5
HS
CO2
SiC3
HCl
CO2
C3S
SiC
N2O
SiN
HCS
CP
NaC
NCS
MgC
N
4j 1 Extraterrestrial Amino Acids
-
SiO
MgN
CPN
c-SiC2
AlF
AlNC
NS
SiCN
SOSiNC
SO
C2S
NaC
lOCS
SiS
SO2
AlCl
S 2 FeO
KCl
aObservation
ssuggestthepresen
ceof
polycyclicarom
atichydrocarbon
sin
theinterstellargas(e.g.,[244]).
1.1 Introduction j5
-
detected, their proposed formation mechanisms, and possible contribution to theorigin of life on Earth.
1.2ISM
The search for amino acids, in particular for the simplest amino acid glycine(NH2CH2COOH), in the ISM has been carried on for almost 30 years [1528].While in theory glycine may have several conformers in the gas phase [29], astro-nomical searches have only focused on two (Figure 1.1, adapted from [21, 29]).Conformer I is the lowest energy form,while conformer II has a higher energy, largerdipole moment, and therefore stronger spectral lines [30]. Only upper limits of bothconformers were found in the ISM until Kuan et al. [25] reported the detectionof glycine in the hot molecular cores Sgr B2(N-LMH), Orion-KL, and W51 e1/e2.This detection has been disputed by Snyder et al. [26], who concluded that the spectrallines necessary for the identication of interstellar glycine have not yet been found.In addition, they argued that some of the spectral lines identied as glycine byKuan et al. [25] could be assigned to other molecular species. Further negative resultsinclude the astronomical searches of Cunningham et al. and Jones et al. [27, 28], whoclaim that their observations rule out the detection of both conformers I and II ofglycine in the hot molecular core Sgr B2(N-LMH). They conclude that it is unlikelythat Kuan et al. [25] detected glycine in either Sgr B2(N-LMH) or Orion-KL. No otheramino acid has been detected in the ISM. Despite these results, amino acids wereproposed to be formed in the ISM by energetic processing on dust grain surfaces,which will then be evaporated, releasing the amino acids into the gas phase (solid-phase reactions), or synthesized in the gas phase via ionmolecule reactions (gas-phase reactions). These two processes will now be described in more detail (for areview, see, e.g., [31]).
1.2.1Formation of Amino Acids in the ISM via Solid-Phase Reactions
Several mechanisms have been proposed for amino acid formation in the ISM.These include solid-phase reactions on interstellar ice grains by energetic processing,
N
O
OH
H
H H
H
I
N
O
OH
H
H
HH
II
Figure 1.1 Molecular structures of conformers I and II of glycinein the gas phase (adapted from [21, 29]).
6j 1 Extraterrestrial Amino Acids
- whichmay occur in coldmolecular clouds (e.g., [32] and references therein). In theseregions of the ISM, inwhich temperatures are very low (
-
polycyclic aromatic hydrocarbon akes [45], and radicalradical reactions [46, 47]have been proposed. As radicalradical reactions can occur with almost no activationenergy [47], theoretical modeling suggests that glycine may be formed in interstellarice mantles via the following radicalradical reaction sequence:
COOH!COOH 1:1
CH3COOH!CH3COOH 1:2
NH2CH3COOH!NH2CH2COOHH 1:3Quantum chemical calculations indicate that amino acids may also be formed byrecombination of the radicals COOH and CH2NH2, which are produced by dehy-drogenation of H2O and CH3OH, and hydrogenation of HCN, respectively [47].However, all radicalradical reactions described above require the radicals to diffuseinto and/or onto the ice mantle which, as noted by Woon [47], may only occur attemperatures of 100K or higher, much higher than the temperature in molecularclouds. Furthermore, Elsila et al. [48] used isotopic labeling techniques to testwhetherStrecker synthesis or radicalradical reactions were responsible for amino acidformation in interstellar ice analogs. Their results show that amino acid formationoccurs via multiple routes, not matching the previously proposed Strecker synthesisor radicalradical mechanisms. Ultimately, the need for high UV ux to produceamino acids in icemantles contrastswith the low expected efciency ofUVphotolysisin dark molecular clouds [4]. This, together with the fact that amino acids have lowresistance to UV photolysis [49], raises concerns about the amino acid formation ininterstellar ices by UV photolysis.
1.2.2Formation of Amino Acids in the ISM via Gas-Phase Reactions
Potential mechanisms alternative to solid-phase reactions include gas-phaseformation of interstellar amino acids via ionmolecule reactions. Amino acids,once formed, could potentially survive in the gas phase in hot molecular cores,because the UV ux is sufciently low (i.e., 300 mag of visual extinction) [31].Alcohols, aminoalcohols, and formic acid evaporated from interstellar ice grains(Table 1.2; [5053]) may produce amino acids in hot molecular cores throughexothermic alkyl and aminoalkyl cation transfer reactions [52]. Aminoalkyl cationtransfer from aminomethanol and aminoethanol to HCOOH can produce protonat-ed glycine and b-alanine, respectively via the following reactions [52]:
NH2CH2OH2 HCOOH!NH2CH2COOH2 H2O 1:4
NH2CH22OH2 HCOOH!NH2CH22COOH2 H2O 1:5An electron recombination will then produce the neutral amino acids. Furtheralkylation may produce a large variety of amino acids through elimination of a watermolecule [31, 52].
8j 1 Extraterrestrial Amino Acids
-
Alternatively, Blagojevic et al. [54] have experimentally proven the gas-phaseformation of protonated glycine andb-alanine, by reacting protonatedhydroxylaminewith acetic and propanoic acid, respectively:
NH2OH CH3COOH!NH2CH2COOH H2O 1:6
NH2OH CH3CH2COOH!NH2CH22COOH H2O 1:7
Neutral amino acids could then be produced by dissociative recombinationreactions [54].Independently of themechanismof synthesis (solid-phase or gas-phase reactions),
once formed, amino acids would need to be resistant and survive exposure to cosmicrays and UV radiation in the ISM. The stability of amino acids in interstellar gas andon interstellar grains has been simulated [49]. Different amino acids [i.e., glycine,L-alanine, a-aminoisobutyric acid (a-AIB), and b-alanine] were irradiated in frozenargon, nitrogen, or watermatrices to test their stability against space radiation. It wasshown that these amino acids have very low stability against UV photolysis.Therefore, amino acids will not survive in environments subject to high UV ux,such as the diffuse ISM.This doesnot eliminate formation of amino acids in the ISM,but instead requires that amino acids are incorporated into UV-shielded environ-ments such as hot molecular cores, in the interior of comets, asteroids, meteorites,and IDPs.
1.3Comets
Comets are agglomerates of ice, organic compounds, and silicate dust, and aresome of themost primitive bodies in the solar system (for reviews about comets, see,e.g., [5557]). Cometswererst proposed to have delivered prebioticmolecules to theearly Earth by Chamberlin and Chamberlin [58]. Since then, space telescopes (suchas the Hubble Space Telescope, Infrared Space Observatory, and Spitzer SpaceTelescope; e.g., [5966]), ground-based observations (e.g., [6769]), cometary y-bys(Deep Space 1 mission, and Vega1, Vega2, Suisei, Sakigake, ICE, and Giottospacecraft missions; e.g., [7076]), impacts (Deep Impact mission, which impactedinto the 9P/Tempel comets nucleus; e.g., [7779]), collection of dust from the comaof a comet (Stardustmission to cometWild-2; e.g., [8084]), and rendezvousmissions(such as the Rosetta mission, which will encounter the comet 67P/ChuryumovGerasimenko in 2014) advanced our knowledge about these dirty snowballs.Several organic compounds have been detected in comets (Table 1.3; for reviews,
see, e.g., [7, 8, 85]). Fly-by missions have suggested the presence of amino acids oncomet Halley [71], but their presence could not be conrmed due to the limitedresolution of the mass spectrometers on board the Giotto and Vega spacecrafts. Inaddition, only an upper limit of less than 0.15 of glycine relative to water has beendetermined in the coma of HaleBopp using radio telescopes (Table 1.3; [69]).Although several amino acid precursors (see Section 1.4), including ammonia,
1.3 Comets j9
-
Table 1.3 Molecular abundances of ices for comets Halley, Hyakutake, and HaleBopp.
Molecule Halley Hyakutake HaleBopp
H2O 100 100 100H2O2
-
HCN, formaldehyde, and cyanoacetylene, have been observed in the Hyakutake andHaleBopp comets [7], only a very limited number of carbonyl compounds necessaryfor the synthesis of amino acids were detected in comets [7, 32, 86]. The ultimateproof for the presence of amino acids in comets is a sample return mission such asStardust, which collected dust from the coma of theWild-2 comet using a lightweightmaterial called aerogel [80]. Analyses of comet-exposed aerogel samples showa relative molar abundance of glycine that slightly exceeds that found in controlsamples, suggesting a cometary origin for this amino acid [83]. Compound-specicisotopic analyses of glycine present in comet-exposed aerogel samples have not yetbeen performed and therefore it has not been possible to ultimately constrainits origin. Other amino acids present in the comet-exposed aerogel samples includede-amino-n-caproic acid, b-alanine, and g -amino-n-butyric acid (g-ABA). The similari-ty in the distribution of these amino acids in the comet-exposed sample, the witnesstile (whichwitnessed all the terrestrial and space environments as the comet-exposedsamples, but did not see comet Wild-2), and the Stardust impact location soilindicates a terrestrial origin (contamination) for these amino acids [83].
1.4Meteorites
Meteorites are extraterrestrial objects that survived the passage through the Earthsatmosphere and the impact with the Earths surface. Excepting the lunar andMartianmeteorites [8791], all meteorites are thought to have originated from extraterrestrialbodies located in the asteroid belt (e.g., [9298]). Although unproven, it was alsosuggested that they could have originated from comets ([99102] and referencestherein). Meteorites can be divided into iron, stony-iron, and stony meteorites.They can be further divided into classes according to their chemical, mineralogical,and isotopic composition (for reviews, see, e.g., [103105]). A very primitive classof stony meteorites, named carbonaceous chondrites, has not been melted sincetheir formation early in the history of the solar system, around 4.6 billion years ago(for reviews, see, e.g., [9, 10]). Within the class of carbonaceous chondrites, there arethe CI-, CM-, CK-, CO-, CR-, CV-, CH-, and CB-type chondrites. Chondrites are alsoclassied and grouped into petrographic types. This refers to the intensity of thermalmetamorphism or aqueous alteration that has occurred on the meteorite parentbody, ranging from types 1 to 6. A petrologic type from 3 to 1 indicates increasingaqueous alteration. A petrologic type from 3 to 6 indicates increasing thermalmetamorphism.Carbonaceous chondrites have a relatively high carbon content and can contain up
to 3wt% of organic carbon. More than 70% of it is composed of a solvent-insolublemacromolecularmaterial, while less than 30% is amixture of solvent-soluble organiccompounds. Carbonaceous chondrites, as revealed by extensive analyses of theMurchison meteorite, have a rich organic inventory that includes organic com-pounds important in terrestrial biochemistry (Table 1.4). These include aminoacids (e.g., [106108]), carboxylic acids (e.g., [109, 110]), purines and pyrimidines
1.4 Meteorites j11
-
(e.g., [111113]), polyols [114], diamino acids [115], dicarboxylic acids (e.g., [116119]), sulfonic acids [120], hydrocarbons (e.g., [121, 122]), alcohols (e.g., [123]),amines and amides (e.g., [124, 125]), and aldehydes and ketones [123].The rst evidence of extraterrestrial amino acids in a meteorite was obtained
by Kvenvolden et al. [121], after analyzing a sample of the Murchison meteoritewhich had recently fallen in Australia in 1969. These authors detected several aminoacids in this meteorite, including the nonprotein amino acids a-AIB and isovaline,which suggested an abiotic and extraterrestrial origin for these compounds. Sincethen, Murchison has been the most analyzed carbonaceous chondrite for aminoacids, with more than 80 different amino acids identied, the majority of which arerare (or nonexistent) in the terrestrial biosphere (for reviews, see, e.g., [107, 108]).These amino acids have carbon numbers from C2 through C8, and show completestructural diversity (i.e., all isomers of a certain amino acid are present). They can bedivided into two structural types, monoamino alkanoic acids and monoaminodialkanoic acids, which can occur as N-alkyl derivatives or cyclic amino acids, withstructural preference in abundance order a> g >b. Branched-chain amino acidisomers predominate over straight ones and there is an exponential decline inconcentration with increasing carbon number within homologous series.Amino acids have also been reported in several other carbonaceous chondrites
besides Murchison (Table 1.5). Within the CM2 group the total amino acid abun-dances and distributions are highly variable; Murray [126], Yamato (Y-) 74 662 [127,128], and Lewis Cliff (LEW) 90 500 [129, 130] show an amino acid distribution and
Table 1.4 Abundances (in ppm) of the soluble organic matter found in the Murchison meteorite.
Compounds Concentration
Carboxylic acids (monocarboxylic) 332Sulfonic acids 67Amino acids 60Dicarboximides >50Dicarboxylic acids >30Polyols 24Ketones 17Hydrocarbons (aromatic) 1528Hydroxycarboxylic acids 15Hydrocarbons (aliphatic) 1235Alcohols 11Aldehydes 11Amines 8Pyridine carboxylic acid >7Phosphonic acid 1.5Purines 1.2Diamino acids 0.4Benzothiophenes 0.3Pyrimidines 0.06Basic N-heterocycles 0.050.5
Adapted from [9, 10, 161, 246].
12j 1 Extraterrestrial Amino Acids
-
Table1.5Su
mmaryof
theaverag
eblan
kco
rrectedam
inoacid
conc
entration(inpp
b)in
the6M
HClacid-hydrolyzed
hot-water
extracts
ofcarbon
aceo
usch
ondrite
s.
CM2
Aminoacid
Murchison
Murray
Y-74
662
LEW
90500
Y-791198
Essebi
Nog
oya
Mighei
ALH
A77
306
ALH
83100
D-Asparticacid
10015
5131
160a
12724
226
7233
163135
10562
186a
294
L-Asparticacid
342103
6516
a15173
280
13412
418106
14522
a436
D-Glutamicacid
537117
13550
532a
31755
530
4921
21174
11148
177a
217
L-Glutamicacid
801200
26115
a31655
588
13083
1003110
27924
a236
D-Serine
436227a
9232
a21
a95
% d
e
1. H
Cl,
MeO
H, -
20 o
C
1. P
d(db
a)2,
Dpp
b
mer
capt
oben
zoic
aci
d, T
HF,
r.t.
2. A
mbe
rlys
t 15,
MeO
H, 6
5 o C
2. 1
M H
Cl
3. K
OH
, MeO
H, H
2O, r
.t.
83 %
(2
step
s)
62 %
(3
step
s)>
97 %
ee
afte
r pu
rifi
catio
n
1
2
3
Sche
me5.1
Larche
vequ
esynthe
sisof
enan
tiopu
re(2S,3S
)-3-OH
Pro.
166j 5 Methods for the Chemical Synthesis of Noncoded a-Amino Acids found in Natural Product Peptides
-
OO
OH
HO
OH
OH
HO
OMe
O
NHPf
O
O
OH
IOMe
O
NHPf
O
OOMe
O
NHPf
TBSO
N
OTBS
CO2Me
Pf
N H
OH CO2H1.
NaI
O4,
NaB
H4
E
tOH
, r.t.
2. M
sCl,
Et 3
N, T
HF,
0 o
C
3. L
iI, D
MF,
80
o C
1. T
sOH
H2O
(
MeO
) 2C
HM
e/A
ceto
ne/M
eOH
2. T
f 2O
, py,
CH
2Cl 2
, -10
oC
3. B
u 4N
N3,
MeC
N
4. P
hFlB
r, E
t 3N
,
Pb(
NO
3)2,
CH
2Cl 2
5. D
owex
50W
x8, M
eOH
70 %
(5
step
s)
91%
(3
step
s)
1.n-
BuL
i, T
HF,
-40
o C
2. T
BSC
l, im
id, D
MF,
r.t.
83 %
(2
step
s)
1. B
H3
SMe 2
, TH
F, 0
oC
2. M
sCl,
Et 3
N, T
HF,
0 o
C
60 %
(2
step
s)
1. H
2, P
d/C
, MeO
H, 6
0 o C
2. D
owex
50W
x8,
T
FH/H
2O (
2:1)
, ref
lux
76 %
(2
step
s)80
% e
e
D-g
luco
no-
-lac
tone
(4)
(2S,
3S)-
3-O
H P
ro (9
)
5
67
8
Sche
me5.2
Park
synthe
sisof
the(2S,3S
)-3-OH
Pro.
5.2 Noncoded CAAs j167
-
Theunprotected secondary alcoholwas transformed into a viable leaving groupusingtriic anhydride and the resulting intermediate underwent an SN2 reaction withtetrabutylammonium azide to yield the manno-azide compound. The azide func-tionality was reduced and protected as the 9-phenyluoren-9-yl (PhFl)-protectedamine followed by selective cleavage of the terminal isopropylidene to afford 5 [41].The terminal diol 5 underwent oxidative cleavage to the aldehyde, followed byNaBH4 reduction, mesylation of the primary alcohol, and a substitution reactionwith lithium iodide to give 2,3-isopropylidene iodide 6. Removal of the isopropy-lidene group and dealkyloxyhalogenation occurred simultaneously under basicconditions. The free alcohol was protected with a TBS group to afford the pentenoicacid derivative 7. The terminal alkene of the pentenoic acid derivative 7 wasoxidized via hydroboration to a primary alcohol intermediate, followed by mesyla-tion to induce an intramolecular amination to produce the N-protected prolineester 8. Finally, all protecting groups were removed and the methyl ester washydrolyzed to the carboxylic acid yielding (2S,3S)-3-OH Pro 9 in good yield withacceptable enantiomeric excess.To complete the synthesis of the (2R,3S)-3-OH Pro isomer 11, the same synthetic
strategy was used (starting from L-gluconic acid g -lactone 10) (Scheme 5.3) [35, 42].Jurczak et al. have synthesized the (2R,3S)-3-OH Pro isomer in a very efcient
manner starting from L-serinal (Scheme 5.4) [30]. The L-serinals were prepared froman L-serine 2,2,6,6-tetramethylpiperidinooxy (TEMPO) oxidation protocol which isknown for minimal epimerizatin of the a-stereocenter. Various L-serinal derivativesand Lewis acids were screened to nd a diastereoselective 1,2-addition reaction withallyltrimethylsilane. The optimum result was obtained with N-Cbz-O-TBS-L-serinal12 and 1 equiv. of SnCl4, giving the syn product 13 as the major diastereomer (98 :2 syn : anti). Silyl protection of the resulting syn adduct, followed by oxidation of theterminal alkene produced an aldehyde species 14 that spontaneously cyclized to thehemi-aminal 15. Upon treatment withNaBH3CN the hemi-aminal 15was reduced toa N-protected pyrrolidine derivative. Selective desilylation revealed primary alcohol16 which was oxidized to the carboxylic acid with a catalytic amount of ruthenium
OMe
O
NHPf
OH
NH
OH
CO2H
92 % ee
O
O
OH
OHOHHO
steps
steps
L-gulonic acid -lactone (10)
29 % overall yield
(2R,3S)-3-OH Pro (11)
Scheme 5.3 Park synthesis of the (2R,3S)-3-OH Pro.
168j 5 Methods for the Chemical Synthesis of Noncoded a-Amino Acids found in Natural Product Peptides
-
trichloride in the presence ofNaIO4. The remaining protecting groupswere removedunder standard conditions to afford the (2R,3S)-3-OH Pro isomer 17 in enantio-merically pure form.Discovery of natural products that can induce apoptosis of cancer cells has been a
major research area in development of novel anticancer agents [43]. In 1998,Umezawa et al. isolated hexadepsipeptides polyoxytoxins A and B from Streptomycesculture broth. These compounds are believed to be potent inducers of apoptosis inhumanpancreatic carcinoma adenocarcinomaAsPC-1 cells [4447]. Apart from theirinteresting biological activity, polyoxytoxins A and B contain the unusual CAA(2S,3R)-3-hydroxy-3-methylprolines (3-OH MePro) 20 (Scheme 5.5). Recently, en-antioselective preparation of 3-OH MePro has been the focus of many researchgroups in response to the need for methodology to produce 3-OH MePro in largequantities for the total synthesis of the polyoxytoxins [4857].Hamada et al. have reported three synthetic methods to prepare 3-OH MePro to
date, with the latest two versions deserving attention due to the efciency of thesynthesis [49, 56, 57]. In their 2002 report, 3-OHMeProwas synthesized by a tandemMichael-aldol reaction using N-1-naphthylsulfonylglycine (R)-binaphthyl ester 18and methyl vinyl ketone as the starting materials (Scheme 5.5) [56]. Addition of 1equiv. of lithium chloride was necessary as an additive to control the diastereoselec-tivity of the reaction. Although the origin of this selectivity is ambiguous at present,the reaction afforded 77%yield of product 19with an impressive 91 : 8 diastereomericratio favoring the desired (2R,3S)-syn adduct. The nal product 20 was obtained as ap-toluenesulfonic acid salt in a total of ve steps, starting from the chiral glycine
TBSO ONHCbz
TMS
NHCbz
OH
TBSO
ONHCbz
OTIPS
TBSO
N OH
TBSO
TIPSO
N
TBSO
Cbz
HO
Cbz
NH
HO
HO2C
+SnCl4, CH2Cl2, -78
oCNHCbz
OH
TBSO+
88 %syn anti
98 : 2
1. TIPSOTf, 2,6-lutidine CH2Cl2, 0
oC to r.t.2. OsO4, NMO, acetone
3. NaIO4, silica gel CH2Cl2/H2O
NHCbz
OH
TBSO
81 % (3steps)
1. NaBH3CN, AcOH, MeOH
2. AcOH, MeOH, reflux
1. NaIO4, RuCl3 H2O CCl4/MeCN/H2O
2. H2SiF6, CH2Cl2, 50 oC
3. H2, Pd/C, MeOH
91 % (2 steps) 80 % (3 steps)(2R,3S)-3-OH Pro (17)
12 13
1413 15
16
Scheme 5.4 Jurczaks synthesis of (2R,3S)-3-OH Pro from L-serinals.
5.2 Noncoded CAAs j169
-
derivative 18, in 39% overall yield and in essentially enantiomerically pure form(>99%e.e. after recrystallization).In the most recent publication by Hamada et al., an intramolecular aldol reaction
was featured as the key step [57]. The substrate for the intramolecular aldol reactionwas prepared in three steps: tosylallylamide conjugate addition to methyl vinylketone, dihydroxylation of the terminal alkene, and oxidative cleavage to afford thealdehyde species 21 with a 77% overall yield. In the key step, 3-OH MePro wasused in catalytic amount to produce 22 in good yield with high enantioselectivity(Scheme 5.6). The reason for the high selectivity of the intramolecular aldol reactionis not clear at this moment. However, Hamada et al. proposed that the reaction goesthrough a closed transition state 23where the 3-hydroxyl group on the catalyst assistsin ordering the transition state. Intermediate 22 was then transformed into thedesired product 24, with standard functional group manipulations in good yield andwith excellent enantioselectivity.Yao et al. prepared 3-OHMePro from the inexpensive startingmaterial, 3-butyn-1-
ol 25, utilizing a Sharpless dihydroxylation reaction as the key step [50]. The alkynestarting material was converted into a (2Z)-a,b-unsaturated ester in three stepsfollowed by the Sharpless dihydroxylation of the trisubstituted olen, using AD-mix-a, to afford the dihydroxylated compound in 90%yieldwith 91%enantiomeric excess(Scheme 5.7). The dihydroxylated compound was transformed into cyclic sulfate 26that was then selectively opened with sodium azide. After a series of reduction,protection and deprotection, diol 27 was obtained in good yield. Subsequenttreatment of the diol species with methane sulfonyl chloride and triethylaminefollowed by ester hydrolysis and Boc deprotection gave 3-OH MePro 28 as the nalproduct in 40% overall yield.
HN
O
OH
SO OHN
O
O
SO O
HO
N
HO
S OO
O
OHO
NH
CO2H
HO
TsOH
2 Steps
74 %
MVK (1.5 equiv.)DBU (0.2 equiv.)LiCl (1.0 equiv.)
THF, -15 oC, 24 h77 % (91:8 dr)
2 Steps
68 %
3-OH Me Pro (20)> 99% ee
18
19
Scheme 5.5 Hamadas synthesis of 3-OH MePro from naphthylsulfonylglycine.
170j 5 Methods for the Chemical Synthesis of Noncoded a-Amino Acids found in Natural Product Peptides
-
OTs
H N+
O
N Ts
H
ON
Ts
OH
OH
O
N
Ts
O
ON H
OH
OH
O
3 St
eps
77 %
1. 3
-OH
MeP
ro (
5 m
ol %
)
H2O
(5
equi
v.),
TH
F
0 o
C to
r.t.
, 7.5
h
2. N
aClO
2, N
aH2P
O4
2
-met
hyl-
2-bu
tene
t B
uOH
, H2O
0
oC
to r
.t. 3
h
WSC
l, D
MA
P
CH
2Cl 2
, 0 o
C to
r.t.
13.5
h66
%, 8
8 %
ee
(3 s
teps
)98
% e
e af
ter
recr
ysta
lliza
tion
3-O
H M
ePro
(24)
N
N
Ts
HO
O
O OH
H
95:5
syn
/ant
i21
2223
via
22
Sche
me5.6
Ham
adasintram
olecular
aldo
lsynthesisof
3-OH
MeP
ro.
5.2 Noncoded CAAs j171
-
HO
OMe
O
OBn
SO
OBnO
OMeO
OO
O
OMe
HO
NHBoc
OH
N HCO2H
OH
1. A
D-m
ix-
, CH
3SO
2NH
2,
t BuO
H/H
2O, 0
oC
2. E
t 3N
, SO
Cl 2
, CH
2 C
l 2,
0
oC
to r
.t.
3. N
aIO
4, c
at. R
uCl 3
C
Cl 4
/CH
3CN
/H2O
0
oC
to r
.t.
1. N
aN3,
DM
F, 8
0 o C
2. c
at. P
d/C
, Boc
2O, E
tOA
c
3. c
at. P
d(O
H) 2
/C, M
eOH
1. M
sCl,
Et 3
N, C
H2C
l 22.
aq.
LiO
H, T
HF/
MeO
H/H
2O
3. T
FA, C
H2C
l 2
then
Dow
ex x
2
93 %
(3
step
s)
81 %
(3
step
s)
62 %
( 3
ste
ps)
3-O
H M
ePro
(28
)94
% e
e
25
26
27
Sche
me5.7
Yaossynthe
sisof
3-OH
MeP
ro.
172j 5 Methods for the Chemical Synthesis of Noncoded a-Amino Acids found in Natural Product Peptides
-
(2S,3S,4S)-3-Hydroxy-4-methylproline (Hmp) 32 (Scheme 5.8) is another prolinederivative found in many biologically important natural products such as echino-candins [58, 59], mulundocanins [60], aculeacin A [61, 62], and nostopeptins [63].Among thesenatural products, the echinocandins are potent antifungal agentswherethe analogs, LY303366-anidulafungin (Eraxis) and FK463/micafungin (Mycamine),are currently being used in the clinic. Also, nostopeptins are known to beelastase inhibitors [63]. Elastases are involved in many inammatory diseases suchas pulmonary emphysema, rheumatoid arthritis, and adult respiratory distresssyndrome [64]. Due to the important bioactivity of natural products containing theHmp moiety, many research groups have disclosed reports involving preparationof free Hmp and its protected derivatives [31, 6573].The rst stereocontrolled synthesis of Hmp was completed by Ohfune et al. en
route to a total synthesis of echinocandin D [65, 68]. The critical intermediate,O-benzyl-epoxy alcohol 29, was prepared by knownmethods developed by Kishi et al.to establish the stereocenter at C-3 (Scheme 5.8) [74]. The epoxy alcohol 29 wasoxidized to carboxylic acid 30 and the epoxide was opened selectively with aqueousammonia. The free amine was Boc-protected, followed by esterication of thecarboxylic acid with diazomethane. The benzyl group was then removed, followedby tosylation of the primary alcohol to provide the O-tosylated methyl ester 31. Theresulting O-tosylated methyl ester compound was treated with 1 equiv. of sodiumhydride to close the ring into an Hmp precursor. After removal of all protectinggroups, enantiopure Hmp 32 was obtained in 18% overall yield.One year after Ohfunes synthesis of Hmp, Evans et al. reported a different
approach to Hmp utilizing an oxazolidinone chiral auxiliary and hydroborationcycloalkylation strategy [66]. To install the C-2 and C-3 stereocenters, an aldolreaction was carried out with bromoacetyl oxazolidinone 33a and methacroleinmediated by dibutylboron triate to afford the syn adduct 33b diastereoselectively(Scheme 5.9). The bromide was displaced with inversion of stereochemistry bytreatment with sodium azide. The chiral auxiliary was removed in the presence ofbromomagnesium methoxide to give methyl ester 34 directly. Addition of dicy-clohexylborane to methyl ester 34 followed by treatment with 1N HCl inducedcyclization into the pyrrolidine through a migratory insertion pathway and hydro-lysis of the aminoborane, to establish the stereochemistry at C-4 while cleaving theNB bond in one pot, yielding Hmp methyl ester 35 in 72% yield. The stereo-chemical outcome of the reaction was rationalized by a closed transition state in itslowest energy conformation where the migrating alkyl and departing diazoniumare orbitally aligned in an anti orientation.Huang et al. prepared Hmp by asymmetric induction from the innate chirality of
the starting material [72]. Their synthesis began by stepwise treatment of chiralmethylmalic acid 36 with acetyl chloride and p-methoxy benzyl amine, giving theprotected malimide 37 as an inseparable mixture of diastereomers, favoring the cisproduct by a 9 : 1 ratio (Scheme 5.10). The secondary alcohol was protected withbenzyl bromide, affording the fully protectedmalimide derivative 38. To the resultingmalimide, 2-lithiofuran, generated in situ from furan and nBuLi at 78 C, wasadded, forming a racemic mixture of the adduct. This racemic mixture was treated
5.2 Noncoded CAAs j173
-
HO
OtBu
Me
BnO
Me O
HBnO
Me
OH
BnO
Me
OH
O
BnO
Me
CO2H
O
TsO
Me
CO2Me
OHNHBoc
N HCO2H
OH
Me
1. B
nBr,
NaH
, DM
F2.
TFA
3. S
wer
n O
xida
tion
90%
(3
step
s)
1. (
i PrO
) 2P(
O)C
H2C
O2E
t
KO
t Bu,
TH
F, -
78 o
C
84
% (
59:1
E/Z
)
2. D
IBA
L-H
1
00 %
L-(+
)-di
ethy
l tar
trat
et B
uOO
H, T
i(O
i Pr)
4
CH
2Cl 2
, -23
oC
88 %
(95
:5 d
r)
PDC
, DM
F, r
.t., 4
5 h
79 %
1. 2
8 %
aq.
NH
3, r
.t., 5
d2.
Boc
-ON
, Et 3
N, d
ioxa
ne/H
2O, r
.t.3.
CH
2N2
4. H
2, P
d/C
, MeO
H5.
TsC
l, py
62-6
5% (
5 st
eps)
1. N
aH (
1 eq
uiv.
), T
HF,
0 o C
2. 0
.5N
NaO
H, C
H2C
l 2, 0
oC
3. T
FA, C
H2C
l 2, r
.t.4.
Dow
ex 5
0Wx4
53 %
(3
step
s)(2
S,3S
,4S)
-3-O
H-4
Me
Pro
3029 31
(32)
Sche
me5.8
Ohfun
essynthe
sisof
enan
tiopu
reHmp.
174j 5 Methods for the Chemical Synthesis of Noncoded a-Amino Acids found in Natural Product Peptides
-
ONH
O
Bn
Br
O
Br
+O
N
O
BnO
Br
ON
O
BnO
Me
BrOH
NO
O
BnO
Me
OH
N3
MeO
O
Me
OH
N3
NCO2Me
OH
Me
Boc
NB
Me
H
MeO
2CN2
R
R
HO
H
n-B
uLi,
TH
F, -
78 o C
87 %
Bu 2
BO
Tf,
Et 2
O,
-78
o C to
r.t.
then
met
hacr
olei
n (n
eat)
-78
o C to
0 o
C
50 %
, 97
% d
r
NaN
3, D
MSO
, r.t.
82 %
(c-C
6H11
) 2B
H, C
H2C
l 2, 0
oC
then
1N
HC
l
MeO
MgB
rM
eOH
/CH
2Cl 2
, 0 o
C
87 %
72 %
(2S,
3S,4
S)-3
-OH
-4M
e Pr
ode
riva
tive
(35)
> 9
7 %
pur
ity b
y N
MR
33a
34
33b
Sche
me5.9
Evanssynthesisof
(2S,3S
,4S)-3-O
H-4-M
ePro
derivative.
5.2 Noncoded CAAs j175
-
with boron triuoride diethyl etherate and triethylsilane to give a separablemixture ofthe coupled products 39 and 40 in a ratio of 3 : 1. The reaction is believed to go throughan N-acyliminium intermediate and the stereoselection comes from the addition ofhydride from silane at the more hindered face. The 2-furyl group was transformedinto a carboxylic acid chemoselectively under oxidative conditions using rutheniumtrichloride and then it was esteried with diazomethane to afford the methyl esterg-lactam 41. Finally the lactam carbonyl was selectively reduced with boranedimethylsulde, the benzyl and p-methoxy benzyl groups were removed simulta-neously by treatment with Pearlmans catalyst, and the pyrrolidine nitrogen wasprotected with Boc2O to afford the N-Boc-methyl ester Hmp derivative 42.Pipecolic acid, a noncoded CAA, is a six-membered ring derivative of proline. It is
isolated as a secondarymetabolite fromsomeplants and fungi [75]. Also, it is found tobe incorporated in pharmaceutically important natural products such as immuno-suppressors FK506 [76] and rapamycin [77], oxytocin antagonist L-356209 [78],antiprotozal agent ampicidin [79], antifungal agent petriellin A [80], and antitumorantibiotic sandramycin [81]. Although pipecolic acid is available commercially, theenantiomerically pure form of it is quite expensive, which can be a problem whenlarge quantities are needed. These reasons fostered interest in its large-scaleenantioselective preparation. Currently, many synthetic methods (for preparingpipecolic acid) have been reported in the literature and have been compiled inreview articles [82, 83]. In addition,microwave-assisted hydrogenation reactions havebeen used in preparation of pipecolic acid recently [84, 85]. In this section, a few
HO2C CO2H
MeHO
N
HO Me
OO
PMBN
BnO Me
OO
PMB
N
BnO Me
O
PMB
N
BnO Me
O
PMB
N
BnO Me
O
PMB
O O
MeO2CN
HO Me
MeO2C
Boc
1. AcCl2. PMBNH2, CH2Cl2
3. AcCl4. AcCl, EtOH
58% (4 steps)9:1 dr
BnBr, Ag2O, Et2O
82 %
1. furan, n-BuLi THF, -78 oC
2. Et3SiH, BF3 OEt2 CH2Cl2, -78
oC
+
91 % :3 1
1. RuCl3 3H2O, NaIO4 H2O/MeCN/CCl 4
2. CH2N2, Et2O
75 % (2 steps)
1. BH3 Me2S, THF r.t. to 60 oC
2. H2, Pd(OH)2/C, EtOH, (Boc)2O, 36 h
(2S,3S,4S)-3-OH-4Me Proderivative (42)55 % (2 steps)
36 3837
4039
41
Scheme 5.10 Huangs synthesis of the (2S,3S,4S)-3-OH-4MePro derivative.
176j 5 Methods for the Chemical Synthesis of Noncoded a-Amino Acids found in Natural Product Peptides
-
interesting examples have been selected for discussion, including the most recentmethodology.Corey et al. elegantly assembled pipecolic acid using chiral phase transfer cataly-
sis [86]. Their synthesis began with an asymmetric alkylation of the protected glycine43 with 1-chloro-4-iodobutane in the presence of cinchonidine catalyst 45, affordingthe alkylated product 44 in high yieldwith excellent enantiopurity (Scheme 5.11). Theexceptionally high enantioselectivity (200 : 1) is believed to come from the selectivefacial screening exerted by the tight ion pair consisting of the cinchonidinium cationand the ester enolate [87]. The diphenyl imine was reduced subsequently withsodium borohydride and the resulting amine 46 cyclized under basic conditions.Finally, (S)-pipecolic acid tert-butyl ester 47 was obtained by removal of the nitrogenprotecting group under typical hydrogenolysis conditions.In Rieras preparation of pipecolic acid, the synthesis was accomplished by
Sharpless asymmetric epoxidation of alcohol 48 to provide the epoxide 49 in highyield and high enantiomeric purity (Scheme 5.12) [88]. The epoxide was openedregioselectively by allylamine and treated subsequently with Boc2O, under basicconditions, to give the N-protected diol 50. The two terminal alkenes of the diolspecies underwent treatment with Grubbs catalyst, followed by reduction of theendocyclic double bond. The nal product,N-Boc-(S)-pipecolic acid 51, was acquiredby oxidative cleavage of the diol. Recrystallization of each intermediate givesessentially enantiopure product.Fadel et al. synthesized (R)-pipecolic acid by an asymmetric Strecker synthesis [89].
The dihydropyran 52 was opened in the presence of a chiral amine and sodiumcyanide, under acidic conditions, to give the secondary amine 54with high yield andexcellent diastereoselectivity (Scheme 5.13). Fadel et al. rationalized the high diaster-eoselection using anAhnEisenteinmodel, depicted in 53, where cyanide ion attacksthe less hindered si face of the iminium species. The amino nitrile was convertedto the amide under acidic conditions. The piperidine ring was closed by treatmentwith I2/PPh3/imidazole. Next, the nitrogen protecting group was removed withPearlmans catalyst, followed by acidic hydrolysis of the amide to give (R)-pipecolicacid 55 with high enantiomeric purity.In 1994, Murakami et al. isolated a new class of serine protease inhibitor called
aeruginosin 298A from the blue-green alga Microcystis aeruginosa [90]. Since thenmany different aeruginosins have been discovered and isolated from naturalsources [91]. Aeruginosins have grasped immediate attention in the scienticcommunity due to possible uses as anticoagulants and anticancer agents [90, 92102]. Aeruginosins are linear peptides containing a novel octahydroindole core,L-2-carboxy-6-hydroxyoctahydroindole (L-Choi), which is a noncoded CAA. The key tothe total synthesis of all aeruginosins lies presumably in the efciency of themethodused to prepare L-Choi enantioselectively.The rst synthesis of the L-Choi motif was completed by Bonjoch et al. in 1996 and
again in 2001 with revised absolute conguration of aeruginosin 298 A/B [103, 104].Bonjochs group started their synthesis of L-Choi by Birch reduction of L-Tyr(OMe)-OH 56 (Scheme 5.14). The resultant enol ether was cleaved by treatment with HClto yield the intermediate cyclohexenone 57, which underwent intramolecular 1,4-
5.2 Noncoded CAAs j177
-
OOt Bu
NPh
Ph
O
Ot Bu
NPh
Ph
(CH2) 4Cl
O
Ot Bu
H NPh
Ph
(CH2) 4Cl
N HCO2
t Bu
NH
HO
N
Br
cat.=
10 m
ol %
cat
., C
sOH
H2O
Cl(
CH
2)4I
, CH
2Cl 2
-78
o C to
-50
oC
88%
, 99
% e
e
NaB
H4,
MeO
H, 0
oC
96 %
1. N
aHC
O3,
NaI
, MeC
N, r
eflu
x
2. H
2, P
d/C
, MeO
H
91 %
(2
step
s)(S
)-Pi
peco
lic a
cid
tert
-But
yl e
ster
(47
)
4344
45
46
Sche
me5.11
Coreyssynthe
sisof
(S)-pipe
colic
acid
tert-butylester.
178j 5 Methods for the Chemical Synthesis of Noncoded a-Amino Acids found in Natural Product Peptides
-
OH
OH
O
OH
OH
NBoc
NBoc
OH
OH
RuPCy 3
PCy 3
Cl
Cl
Ph
NCO2H
Boc
D-(
-)D
ET
, tB
uOO
H,
Ti(
Oi P
r)4
CH
2Cl 2
, 4A
MS,
-20
oC
1. a
llyla
min
e, L
iClO
4, M
eCN
2. B
oc2O
, NaH
CO
3, M
eOH
60 %
(2
step
s)84
%, 9
3 %
ee
CH
2Cl 2
1. H
2, P
d/C
, AcO
Et
2. N
aIO
4, K
MnO
4,
Na 2
CO
3, d
ioxa
ne/H
2O72
%(S
)-N
-Boc
-pip
ecol
ic a
cid
(51)
> 99
% e
e af
ter
recr
ysta
lliza
tion
87 %
(2
step
s)
4948
50
Sche
me5.12
Rierasprep
arationof
(S)-N-Boc-pipecolicacid.
5.2 Noncoded CAAs j179
-
conjugate addition to afford a mixture of the desired endo 59 and exo 58 bicyclicproducts. The exo adduct 58 was converted to the endo 59 (the thermodynamicallyfavored isomer) under acidic conditions. After switching the nitrogen protectinggroup, the bicycle was treated with LS-Selectride to reduce the ketone functionality toan alcohol with 8 : 1 selectivity favoring the desired stereochemistry. By this efcientroute, Bonjochs group was able to prepare the N-Boc-protected methyl esterderivative of L-Choi 60 in six steps with 18% overall yield. Wipf et al. have developeda route with similar efciency to protected L-Choi where the key transformation wasthe oxidative ring-closing reaction of Cbz-L-Tyr-OH with iodobenzene diacetate,giving a high diastereomeric ratio favoring the desired product [105].Analogous to Bonjochs synthesis of L-Choi, Shibasaki et al. used a 1,4-conjugate
addition reaction to prepare a protected L-Choi derivative [106, 107]. In Shibasakiet al.s synthesis, the precursor for the 1,4-conjugate addition reactionwas built usinga chiral phase transfer-catalyzed glycine alkylation affording both high yield andhigh enantiomeric excess from relatively simple starting materials 61 and 62(Scheme 5.15). The resulting intermediate 63 was treated with acid, to unmask theketone, induce alkene migration, and 1,4-conjugate addition. Treatment withBonjochs conditions reported by Bonjoch then led to the desired product 65 inenantiomerically pure form.Currently, the most efcient route to the L-Choi core (Scheme 5.16) is the method
reported by Hanessian et al. [101, 102]. One interesting facet of their approach is thatthey avoid the step involving acid-mediated thermodynamic equilibration of theendo/exo mixture of the fused-ring compound, which can be problematic in somecases. Hanessian et al. began their synthesis by diastereoselective alkylation of theprotected glutamate 66 at the g-carbonusing 3-butenol triate as an electrophile [108].The alkylated compound 67 underwent intramolecular cyclization at elevated tem-perature once the free secondary amine was exposed. Following conversion of theimide carbonyl 68 into acetate 69, the substituted pyrrolidine compoundwas cyclizedthrough a Lewis acid-mediated aza-Prins reaction. The cyclization reaction affordedthe desired bicyclic bromide 71 as single isomerwith good yield.Hanessian et al.haverationalized the outcome of the reaction using their transition state model 70 where
OHNHO
Ph
CNMe H
NHH
OH3
CN
N CONH2
PhNH
CO2H
(R)-methylbenzylamine
NaCN, 1M HCl, r.t.,2 d 86 % > 96 % de
1. H2SO4, CH2Cl22. I2, PPh3, imid
1. H2, Pd(OH)2/C, EtOH/AcOH
2. HCl then propylene oxide
(R)-Pipecolic acid (55)59 % (2 steps) 77 % (2 steps)> 98 % ee
52
5354
Scheme 5.13 Fadels synthesis of (R)-pipecolic acid.
180j 5 Methods for the Chemical Synthesis of Noncoded a-Amino Acids found in Natural Product Peptides
-
MeO
CO2H
NH2
CO2H
ONH2
NO
Bn
H H
CO2Me
NO
Bn
CO2Me
H HN Boc
CO2Me
H HHO
1. L
i, N
H3,
TH
F/t B
uOH
, -78
oC
2. M
eOH
, 7.5
N H
Cl,
35 o C
BnB
r, N
aHC
O3,
EtO
H, 7
0 o C
+
MeO
H, 8
N H
Cl,
65 o C
44 %
(4
step
s)
1. H
2, P
d(O
H) 2
, Boc
2O, E
tOA
c
2. L
S-Se
lect
ride
, TH
F, -
78 o C
42 %
(2
step
s)L-
Cho
i der
ivat
ive
(60)
5657
5859
Sche
me5.14
Bon
jochssynthe
sisof
N-Boc-protected
methyle
ster
derivativeof
L-Cho
i.
5.2 Noncoded CAAs j181
-
NCO2tBu
Ph
Ph
Br
O
OO O
Me
NMe(PMB) 2
NMe(PMB) 2
I I
NCO2tBu
Ph
Ph
O
O
N Boc
CO2H
H HHO L-
Cho
i der
ivat
ive
(65)
+
10 m
ol %
cat
., C
sOH
H2O
,7:
3 Ph
CH
3/C
H2C
l 2ca
t. =
80 %
, 88
% e
e
ste
ps
>99
% e
e af
ter
recr
ysta
lliza
tion
CO2H
ONH2
6162
63
64
H+
Sche
me5.15
Shibasakis
synthe
sisof
L-Cho
iderivative.
182j 5 Methods for the Chemical Synthesis of Noncoded a-Amino Acids found in Natural Product Peptides
-
MeO
2C
CO2Me
NHBoc
MeO
2CCO2Me
NHBoc
NO
Boc
CO2Me
NAcO
Boc
CO2Me
NCO2Me
Br
H HBoc
N H
CO2Me
H HAcO
HN
Boc
MeO
2CH
Br
N
MeO
2CH
Boc
Br
syn-
clin
ical
anti-
peri
plan
ar
LiH
MD
S, T
HF,
-78
o C
then
3-b
uten
ol tr
ifla
te
85 %
1. T
FA, C
H2C
l 22.
tol,
refl
ux
3. B
oc2O
, Et 3
N
DM
AP,
CH
2Cl 2
81 %
(3
step
s)
1. L
iHB
Et 3
, TH
F, -
78 o
C
2. A
c 2O
, Et 3
N
DM
AP,
CH
2Cl 2
91 %
(2
step
s)
SnB
r 4, C
H2C
l 2, -
78 o
C
78 %
2 st
eps
78 %
L-C
hoi d
eriv
ativ
e (7
2)
6667
68
69
70a
71
70b
Sche
me5.16
Han
essiansefficient
synthe
sisof
L-Cho
iderivative72
.
5.2 Noncoded CAAs j183
-
syn-clinal approach of the alkene tether creates an unfavorable steric clash betweenthe axial hydrogen and themethyl ester substituent of the pyrrolidine ring. However,in the case of the anti-periplanar approach of the alkene tether, such an interaction isabsent. The L-Choi derivative 72was obtained in 36%yield, starting from L-N-Boc-Glu(OMe)-OMe, after displacement of bromine by acetate and Boc removal.Hydropyrroloindole (Hpi) is another structural motif found in nonproteinogenic
natural CAAs incorporated into many natural products, such as chloptosin [109],himastatin [110, 111], okaramines [112], phakellistatins [113], gypsetin [114], kapa-kahines [115], omphalotins [116], and sporidesmins [117]. These Hpi-containingnatural products are known to exhibit impressive antibacterial and anticanceractivities; consequently, those compounds and Hpi have become important syn-thetic targets. Shioiri et al. [118], Christophersen et al. [119], and Van Vrankenet al. [120] used a photooxidative method to transform the tryptophan of structure73 into the Hpi of phakellistatin 3 74, although at the expense of low product yield,low diastereoselectivity, and laborious purication of the desired product 74(Scheme 5.17) [118120].On the other hand, Savige has prepared Hpi by epoxidation of tryptophan using
m-chloroperoxybenzoic acid (mCPBA) followed by intramolecular ring closurewhere the nucleophile was the a-amine [121]. However, this approach was not
N
O
N
O
O
HN
O NH
NH
O
O
NHN
O
NH
HO
Ph
HO
H
Phakellistatin 3
HN
O
N
O
O
HN
O NH
NH
O
O
NHN
O
NH
HO
Ph
Phakellistatin 13
isoPhakellistatin 3
1. O2, hv sensitizer
2. Me2S
+
>95 % purity after5 HPLC runs
20 % yield of mixture
N
O
N
O
O
HN
O NH
NH
O
O
NHN
O
NH
HO
Ph
HO
H
73
74
75
Scheme 5.17 Photooxidative conversion of tryptophan to afford Hpi.
184j 5 Methods for the Chemical Synthesis of Noncoded a-Amino Acids found in Natural Product Peptides
-
free from the problems seen in the photooxidation method mentioned above.Danishefsky et al. overcame all the difculties related to the Hpi synthesis by using3,3-dimethyldioxirane (DMDO) as the oxidant. In their synthesis, both syn-cis 77and anti-cis 76were prepared independently as single isomers (Scheme 5.18) [122].It is interesting to note that, for preparation of the anti-cis isomer, intramolecularring closure was mediated by the bromination of the C-2C-3 p-bond of the indolecore 78. The dihydropyrroloindole intermediate 79 was treated with DMDO toafford anti product 80 with stereoselectivity greater than 15 : 1.In contrast, the syn-cis isomer 83was prepared by direct oxidation of theC-2C-3p-
bond on the indole core 82 by DMDO followed by spontaneous intramolecularepoxide ring opening by the a-trityl amine to produce the desired isomer 83stereospecically (Scheme 5.19) [122].Recently, Perrin et al. adapted Danishefskys strategy to prepare the Hpi moiety in
linear peptides [123]. Their strategy minimizes protecting group manipulation andincreases the ease of incorporation of the Hpi moiety into peptide natural products.The tryptophanylated amino acid 84 was treated with DMDO to produce diaster-eomers 85 and 86 (Scheme 5.20). Perrin et al. reported that the mixture of productscan be separated readily, giving access to both diastereomers, syn-cis 85 and anti-cis 86,in pure form.In 2003, Ley et al. reported the most efcient synthesis of the syn-cis isomer of the
Hpi amino acid 91while en route to the total synthesis of ( )-okaramineC [124, 125].Ley et al.s method started by protection of the indole nitrogen with Boc2O andesterication of the carboxylic acid functionality on Cbz-L-Trp 87 (Scheme 5.21).In the key synthetic step, the fully protected tryptophan 88 was treated withN-phenylselenyl phthalimide (N-PSP) to induce intramolecular cyclization, followedby oxidative cleavage of the SeC bond with excess mCPBA. Under optimizedconditions, Ley et al. obtained the diastereomerically pure product 90 in nearquantitative yield. After removal of the Boc and Cbz groups, the syn-cis isomer ofHpi methyl ester 91 was obtained in 74% overall yield, starting from L-N-Cbz-Trp-OH 87, as a single product.
5.3Noncoded Amino Acids by Chemical Modification of Coded Amino Acids
Numerous variants of b-hydroxy-a-amino acids (Figure 5.2) are found in manycomplex natural products, such as azinothricin [126], A83586C [127], papua-mides [128], polyoxypeptines [44, 46], GE3 [129], vancomycin [130], and cyclospor-ins [131]. These natural products are very important in both clinical and therapeuticdevelopment due to the antibiotic, anticancer, and immunosuppressant activitiesthey possess. Vancomycin, in particular, has drawn much attention in the clinicowing to the fact that it is the nal line of defense against methicillin-resistantStaphylococcus aureus infection. In addition, b-hydroxy-a-amino acids are used aschiral building blocks in preparing precursors to important molecules [132137].Currently, various synthetic methods have been developed to prepare b-hydroxy-a-
5.3 Noncoded Amino Acids by Chemical Modification of Coded Amino Acids j185
-
N H
NH2
CO2H
N H
NHSO2Anth
CO2tBu
N H
N
CO2tBu
SO2Anth
N H
N
CO2tBu
SO2Anth
HO
HN H
N
CO2Me
CO2Me
HO
H
1. A
nthS
O2C
l, E
t 3N
, TH
F
2. t B
utyl
isou
rea,
CH
2Cl 2
, r.t.
70 %
(2
step
s)
NB
S, E
t 3N
, CH
2Cl 2
, 0
oC
to r
.t.
1. D
MD
O, C
H2C
l 2, -
78 o
C
2. N
aBH
4, M
eOH
,
0 o
C to
r.t.
>15:
1 sy
n/an
ti75
% (
3 st
eps)
1. T
FA, C
H2C
l 22.
CH
2N2,
Et 2
O
3. A
l(H
g), T
HF,
aq
NH
4OA
c4.
ClC
O2M
e, p
yrid
ine
C
H2C
l 2, -
78 o
C to
r.t.
50 %
(4
step
s)
N H
N
CO2Me
CO2Me
HO
HN H
N
CO2Me
CO2Me
HO
H
anti-
cis
(76)
syn-
cis
(77)
7879
8081
Sche
me5.18
Dan
ishefskyssynthe
sisof
anti-cisHpi.
186j 5 Methods for the Chemical Synthesis of Noncoded a-Amino Acids found in Natural Product Peptides
-
NH
NH2
CO2H
NH
NHTr
CO2tBu
NH
NH
CO2tBuHO
H
1. TrCl, Et3N, THF
2. tButyl isourea, CH2Cl2, r.t.
76 % (2 steps)
2. HOAc, MeOH, CH2Cl2
1. DMDO, CH2Cl2, -78 oC
55 % (2 steps)
82
83
Scheme 5.19 Danishefskys synthesis of syn-cis Hpi.
TrHN
O
NH
O
OMe
NH
R
NH
N
O
NH O
OMeR
Tr
HO
H NH
N
O
NH O
OMeR
Tr
HO
H
+
DMDO/acetone, CH2Cl2, -78 oC
mixture of diastereomers
40 - 99 %
R = naturally occuring amino acids except Cys, Met, Trp
84
85 86
Scheme 5.20 Perrins synthesis of an Hpi dipeptide.
NH
CO2H
NHCbz
N
CO2Me
NHCbz
Boc
N
N
PhSe
H
CO2Me
Boc
Cbz
N
N
HO
H
CO2Me
Boc
CbzNH
NH
HO
H
CO2Me
1. SOCl2, MeOH
2. Boc2O, NaOH CH2Cl2, Bu4NHSO4
93 % (3 steps)
N-PSP, CH2Cl2PPTS, Na2SO4
93 %
wet mCPBA (5 equiv.), K2CO3, CH2Cl2, 0
oC to r.t.
100 %
1. TFA, CH2Cl2
2. H2, Pd/C, MeOH
85 % (2 steps) syn-cis
87 88 89
9091
Scheme 5.21 Leys most efficient synthesis of syn-cis isomer of Hpi.
5.3 Noncoded Amino Acids by Chemical Modification of Coded Amino Acids j187
-
ONH
NHO
O
O
HN
NH
O O NH
OMe
O
NO
OH
MeO
OH
HN O
HNO
NH2
OHN
H2NO
OHHN
ONH
O
HO
OH
Papuamide B
O
NH
O HN
O
OH
NH
O HN
CH3
H3C
CH3
OH2N
O
HNOHN
ONH
HO2C
HO
O O
OO
H3C
OH
OH
H3C
HONH2
OH
Vancomycin
O Cl
Cl
HO OHOH
R2 N
NO Me
R1
O
NNH
O
O
NHN
HN
O
O O
HO
O