Uv7p7.Amino.acids.peptides.and.Proteins.in.Organic.chemistry.volume.1

Amino Acids, Peptides and Proteins

in Organic Chemistry

Edited by

Andrew B. Hughes

Further Reading

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Lutz, S., Bornscheuer, U. T. (eds.)

Protein EngineeringHandbook2 Volume Set

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Essentials of CarbohydrateChemistry and Biochemistry2007

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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.

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# 2009 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim

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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

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

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

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

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

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

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

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

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

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

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

List of Contributors

XVII


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

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

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


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


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]).


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].


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].


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.


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.


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.


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.


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.


(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


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.


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.


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.


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-


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.


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.


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.


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.


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.


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

.


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.


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.


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

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Uv7p7.Amino.acids.peptides.and.Proteins.in.Organic.chemistry.volume.1