Amino Acids, Peptides and Proteins in Organic Chemistry 1: Origins and Synthesis of Amino Acids (Amino Acids, Peptides and Proteins in Organic Chemistry (VCH)) | Andrew B. Hughes | download
Principal Amino Acids, Peptides and Proteins in Organic Chemistry 1: Origins and Synthesis of Amino Acids (Amino..
Amino Acids, Peptides and Proteins in Organic Chemistry 1: Origins and Synthesis of Amino Acids (Amino Acids, Peptides and Proteins in Organic Chemistry (VCH))
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amino3312
amino acids2021
acid1919
synthesis1643
amino acid803
co2h602
chemistry578
chemical541
organic534
tetrahedron492
nh2425
chiral391
yield375
ester359
methyl354
boc340
derivatives302
hcl292
hydroxy289
organic chemistry274
chemical society256
h2n255
co2me245
asymmetric241
esters240
reduction231
tetrahedron letters227
hydrolysis220
thf217
biosynthesis210
journal of organic198
compounds198
substituted185
mmol180
analogs179
meoh178
synthetic176
alkyl169
phenylalanine168
alanine164
ome163
h2o154
enantioselective152
peptides151
american chemical150
catalyzed149
cyclic149
hydrogenation147
nhboc144
diamino141
alkylation140
co2et140
ethyl138
american chemical society132
asymmetry131
tert131
stereoselective130
Engineering the Genetic Code
Expanding the Amino Acid Repertoire
for the Design of Novel Proteins
ISBN: 978-3-527-31243-6
Demchenko, A. V. (ed.)
Handbook of Chemical
Advances in Stereoselectivity and
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Lindhorst, T. K.
Essentials of Carbohydrate
Aehle, W. (ed.)
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Ullmanns Biotechnology and
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Volume 1 - Origins and Synthesis of Amino Acids
Dr. Andrew B. Hughes
# 2009 WIL; EY-VCH Verlag GmbH & Co. KGaA,
Part One Origins of Amino Acids
Extraterrestrial Amino Acids 3
Formation of Amino Acids in the ISM via Solid-Phase Reactions 6
Formation of Amino Acids in the ISM via Gas-Phase Reactions 8
Comets 9
Meteorites 11
Sources of Meteoritic Amino Acids (Extraterrestrial versus
Terrestrial Contamination) 17
Detection of Amino Acids that are Unusual in the Terrestrial
Determination of the Amino Acid Content of the Meteorite Fall
Determination of Enantiomeric Ratios 18
Determination of Compound-Speciﬁc Stable Isotope Ratios
of Hydrogen, Carbon, and Nitrogen 18
Synthesis of Meteoritic Amino Acids 19
Micrometeorites and IDPs 23
Delivery of Extraterrestrial Amino Acid to the Earth and its
Importance to the Origin of Life 24
‘‘Terrestrial’’ Amino Acids and their Evolution
Amino Acids, Peptides and Proteins in Organic Chemistry. Vol.1 – Origins and Synthesis of Amino Acids.
What are the 20 ‘‘Terrestrial’’ Amino Acids? 44
The 21st and 22nd Genetically Encoded Amino Acids 45
Do other Genetically Encoded Amino Acids Await Discovery? 46
Genetic Engineering can Enlarge the Amino Acid Alphabet 47
Signiﬁcance of Understanding the Origins of the
Standard Alphabet 48
What do We Know about the Evolution of the Standard Amino
Acid Alphabet? 49
Nonbiological, Natural Synthesis of Amino Acids 50
Biosynthetic Theories for the Evolutionary Expansion of the
Standard Amino Acid Alphabet 53
Evidence for a Smaller Initial Amino Acid Alphabet 55
Proteins as Emergent Products of an RNA World 56
Stereochemical Rationale for Amino Acid Selection 57
Amino Acids that Life Passed Over: A Role for
Natural Selection? 58
Were the Standard Amino Acids Chosen for High
Biochemical Diversity? 60
Were the Standard Amino Acids Chosen for ‘‘Cheap’’
Biosynthesis? 62
Were the Standard Amino Acids Chosen to Speed Up Evolution? 62
Why Does Life Genetically Encode L-Amino Acids? 64
Summary, Synthesis, and Conclusions 64
Part Two Production/Synthesis of Amino Acids
Use of Enzymes in the Synthesis of Amino Acids 79
Chemo-Enzymatic Processes to Enantiomerically Pure
Acylase Process 81
Amidase Process 83
Amidase Process for a,a-Disubstituted a-Amino Acids 86
Hydantoinase Process 88
Ammonia Lyase Processes 90
Aspartase-Catalyzed Production of L-Aspartic Acid 91
Production of L-Alanine from Fumaric Acid by
an Aspartase–Decarboxylase Cascade 92
Phenylalanine Ammonia Lyase-Catalyzed Production of
L-Phenylalanine and Derivatives 93
Aminotransferase Process 94
Aminotransferase-Catalyzed Production of D-a-H-a-Amino Acids
AADH Process 99
b-Amino Acid Biosynthesis 119
Importance of b-Amino Acids and their Biosynthesis 119
Scope of this Chapter 119
Biosynthesis of b-Amino Acids 120
Biosynthesis of b-Alanine and b-Aminoisobutyric Acid 120
b-Alanine 120
b-Aminoisobutyric Acid 122
Biosynthesis of b-Amino Acids by 2,3-Aminomutases from
a-Amino Acids 122
b-Lysine, b-Arginine, and Related b-Amino Acids 124
b-Phenylalanine, b-Tyrosine, and Related b-Amino Acids 127
b-Glutamate and b-Glutamine 132
b-Leucine 132
b-Alanine 132
Biosynthesis of a,b-Diamino Acids from a-Amino Acids 132
General Biosynthesis of a,b-Diamino Acids 132
Structures and Occurrence of a,b-Diamino Acids in Nature 132
Biosynthesis of Selected a,b-Diamino Acids 135
Biosynthesis of b-ODAP 135
Biosynthesis of the a,b-Diaminopropanoic Acid Moiety in the
Bleomycins 136
Biosynthesis of the Penicillins 137
Biosynthesis of the Capreomycidine Moiety in Viomycine 137
Biosynthesis of the Streptolidine Moiety in Streptothricin F 137
Biosynthesis of a-Keto-b-Amino Acids from a-Amino Acids 139
De Novo Biosynthesis of b-Amino Acids by PKSs 139
General Biosynthesis of Polyketide-Type b-Amino Acids 141
Structures and Occurrence of Polyketide-Type b-Amino Acids
in Nature 142
Biosynthesis of Selected Polyketide-Type b-Amino Acids 149
Long-Chain b-Amino Acids Occurring as Constituents of
the Iturins 149
Biosynthesis of the Ahda Moiety in Microginin 151
Biosynthesis of the Ahpa Residue in Bestatin 151
Biosynthesis of the Adda Residue in the Microcystins 152
b-Amino Acids Whose Biosynthesis is Still Unknown 152
Conclusions and Future Prospects 154
4.2.3.3.3
4.2.3.3.4
4.2.3.3.5
4.2.5.4.3
4.2.5.4.4
Methods for the Chemical Synthesis of Noncoded a-Amino
Acids found in Natural Product Peptides 163
Stephen A. Habay, Steve S. Park, Steven M. Kennedy,
and A. Richard Chamberlin
Noncoded CAAs 164
Noncoded Amino Acids by Chemical Modiﬁcation of Coded
Noncoded Amino Acids with Elaborate Side-Chains 205
Conclusions 226
Synthesis of N-Alkyl Amino Acids 245
N-Methylation via Alkylation 246
SN2 Substitution of a-Bromo Acids 246
N-Methylation of Sulfonamides, Carbamates, and Amides 249
Base-Mediated Alkylation of N-Tosyl Sulfonamides 249
Base Mediated Alkylation of N-Nitrobenzenesulfonamides 250
N-Methylation via Silver Oxide/Methyl Iodide 252
N-Methylation via Sodium Hydride/Methyl Iodide 253
N-Methylation of Triﬂuoroacetamides 257
N-Methylation via the Mitsunobu Reaction 257
N-Methylation via Schiff s Base Reduction 259
Reduction of Schiff s Bases via Transition
Metal-Mediated Reactions 259
Reduction of Schiff s Bases via Formic Acid: The Leuckart
Reaction 260
Quaternization of Imino Species 261
Reduction of Schiff s Bases via Borohydrides 263
Borane Reduction of Amides 264
N-Methylation by Novel Methods 265
1,3-Oxazolidin-5-ones 265
Asymmetric Syntheses 272
Racemic Syntheses 277
N-Alkylation of Amino Acids 280
Borohydride Reduction of Schiff s Bases 280
Sodium Borohydride Reductions 281
Sodium Cyanoborohydride Reductions 281
Sodium Triacetoxyborohydride Reductions 282
N-Alkylation of Sulfonamides 282
Base-Mediated Alkylation of Benzene Sulfonamides 282
Reduction of N-Acyl Amino Acids 283
Reduction of Acetamides 284
Novel Methods for N-Alkylating a-Amino Acids 284
Asymmetric Synthesis of N-Alkyl a-Amino Acids 284
N-Alkylation of 1,3-Oxazolidin-5-ones 284
Recent Developments in the Synthesis of b-Amino Acids 291
Synthesis of b-Amino Acids by Homologation of a-Amino Acids 291
Chiral Pool: Enantioselective Synthesis of b-Amino Acids from
Aspartic Acid, Asparagine, and Derivatives 298
Synthesis of b-Amino Acids by Conjugate Addition of Nitrogen
Nucleophiles to Enones 300
Achiral b-Amino Acids 300
Enantioselective Approaches 304
Addition of ‘‘Chiral Ammonia’’ Equivalents to Conjugated
Prochiral Acceptors 304
Addition of a Nitrogen Nucleophile to a Chiral Acceptor 306
Asymmetric Catalysis 308
Synthesis of b-Amino Acids via 1,3-Dipolar Cycloaddition 312
Synthesis of b-Amino Acids by Nucleophilic Additions 316
Aldol- and Mannich-Type Reactions 316
Morita–Baylis–Hillman-Type Reactions 321
Mannich-Type Reactions 324
Synthesis of b-Amino Acids by Diverse Addition or
Substitution Reactions 328
Synthesis of b-Amino Acids by Stereoselective Hydrogenation
of Prochiral 3-Aminoacrylates and Derivatives 330
Reductions Involving Phosphorus-Metal Complexes 331
Reductions Involving Catalytic Hydrogenations 333
Synthesis of b-Amino Acids by use of Chiral Auxiliaries:
Stereoselective Alkylation 334
Synthesis of b-Amino Acids via Radical Reactions 338
Miscellaneous Methods for the Synthesis of b-Amino Acids 340
Experimental Procedures 348
Representative Experimental Procedure: Synthesis of (S)3-(tert-Butyloxycarbonylamino)-4-phenylbutanoic Acid 348
Representative Experimental Procedure: Synthesis of
(S)-2-(Aminomethyl)-4-phenylbutanoic Acid, (S)-19 350
Representative Experimental Procedure: Synthesis of b3-Amino Acids
by Conjugate Addition of Homochiral Lithium N-Benzyl-N(a-methylbenzyl)amide 352
Representative Experimental Procedure: Synthesis of Cyclic and
Acyclic b-Amino Acid Derivatives by 1,3-Dipolar Cycloaddition 353
Representative Experimental Procedure: Synthesis of (R)-3-tertButoxycarbonylamino-3-phenylpropionic Acid Isopropyl Ester using
a Mannich-Type Reaction 354
Representative Experimental Procedure: General Procedure for the
Hydrogenation of (Z)- and (E)-b-(Acylamino) acrylates by Chiral
Monodentate Phosphoramidite Ligands 354
Representative Experimental Procedure: Synthesis of Chiral
a-Substituted b-Alanine 355
Representative Experimental Procedure: Synthesis of Chiral b-Amino
Acids by Diastereoselective Radical Addition to Oxime Esters 357
Synthesis of Carbocyclic b-Amino Acids 367
Synthesis of Carbocyclic b-Amino Acids 368
Synthesis of Carbocyclic b-Amino Acids via Lithium Amide-Promoted
Conjugate Addition 369
Synthesis of Carbocyclic b-Amino Acids by Ring-Closing
Metathesis 371
Syntheses from Cyclic b-Keto Esters 372
Cycloaddition Reactions: Application in the Synthesis of Carbocyclic
b-Amino Acids 375
Synthesis of Carbocyclic b-Amino Acids from Chiral Monoterpene
b-Lactams 377
Synthesis of Carbocyclic b-Amino Acids by Enantioselective
Desymmetrization of meso Anhydrides 378
Miscellaneous 379
Synthesis of Small-Ring Carbocyclic b-Amino Acid
Derivatives 383
Synthesis of Functionalized Carbocyclic b-Amino Acid
Derivatives 385
Enzymatic Routes to Carbocyclic b-Amino Acids 393
Enantioselective N-Acylations of b-Amino Esters 394
Enantioselective O-Acylations of N-Hydroxymethylated b-Lactams 394
Enantioselective Ring Cleavage of b-Lactams 395
Biotransformation of Carbocyclic Nitriles 396
Enantioselective Hydrolysis of b-Amino Esters 396
Analytical Methods for the Enantiomeric Separation of Carbocyclic
b-Amino Acids 397
Conclusions and Outlook 398
Experimental Procedures 399
Synthesis of Hydroxy Amino Ester Ethyl (1R,2S,4S)2-(Benzyloxycarbonylamino)-4-hydroxycyclohexanecarboxylate (205a)
by Oxirane Ring Opening of with Sodium Borohydride 399
Synthesis of Bicyclic b-Lactam (1R,5S)-6-azabicyclo[3.2.0]hept-3en-7-one (223) by the Addition of Chlorosulfonyl Isocyanate
to Cyclopentadiene 399
Synthesis of b-Amino Ester Ethyl cis-2-aminocyclopent3-enecarboxylate Hydrochloride (223a) by Lactam Ring-Opening
Reaction of Azetidinone 223 400
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
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
Isomerization of Azido Amino Ester to Ethyl (1S,2R,3R,4R)4-Azido-2-(tert-butoxycarbonylamino)-3-hydroxycyclopentanecarboxylate
(230) 401
Lipase-Catalyzed Enantioselective Ring Cleavage of 4,5-Benzo-7azabicyclo[4.2.0]octan-8-one (271), Synthesis of (1R,2R)- and
(1S,2S)-1-Amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic Acid
Hydrochlorides (307 and 308) 402
Lipase-Catalyzed Enantioselective Hydrolysis of Ethyl trans-2aminocyclohexane-1-carboxylate (298), Synthesis of (1R,2R)- and
(1S,2S)-2-Aminocyclohexane-1-carboxylic Acid Hydrochlorides
(309 and 310) 404
Synthetic Approaches to a,b-Diamino Acids 411
Construction of the Carbon Backbone 411
Methods for the Formation of the Cb–Cc Bond 411
Reaction of Glycinates and Related Nucleophiles with Electrophiles 411
Dimerization of Glycinates 416
Through Cyclic Intermediates 417
Methods in Which the Ca–Cb Bond is Formed 420
Nucleophilic Synthetic Equivalents of CO2R 420
Electrophilic Synthetic Equivalents of CO2R and Other Approaches 423
Methods in Which the CbCb0 or CcCc0 Bonds are Formed 424
Introduction of the Nitrogen Atoms in the Carbon Backbone 425
From Readily Available a-Amino Acids 425
From Allylic Alcohols and Amines 427
From Halo Alkanoates 428
From Alkenoates 429
Electrophilic Amination of Enolates and Related Processes 431
From b-Keto Esters and Related Compounds 433
Experimental Procedures 434
(SS,2R,3S)-(þ)-Ethyl-2-N-(diphenylmethyleneamino)-3-N-(p-toluenesulﬁnyl)-amino-3-phenylpropanoate (14b) 434
Synthesis of Ethyl (2R,3R)-3-amino-2-(4-methoxyphenyl)
aminopentanoate 32a via Asymmetric aza-Henry Reaction 434
Synthesis of Halogenated a-Amino Acids 441
Halogenated Amino Acids with a Hydrocarbon Side-Chain 442
Halogenated Alanines and Prolines 442
Halogenated a-Amino Acids with Branched Hydrocarbon
Side-Chains 445
Halogenated Valines and Isoleucines 445
Halogenated Leucines 451
Halogenated Amino Acids with an Aromatic Side-Chain 457
Halogenated Phenylalanines and Tyrosines 457
Halogenated Histidines 460
Halogenated Tryptophans 462
Halogenated Amino Acids with Heteroatoms in the Aliphatic
Side-Chain 463
Halogenated Aspartic and Glutamic Acids 463
Halogenated Threonine and Lysine 465
Synthesis of Isotopically Labeled a-Amino Acids 473
Enzyme-Catalyzed Methods 473
Chiral Pool Approach 477
Chemical Asymmetric Methods 483
Conclusions 488
Experimental Procedures 489
Biocatalysis: Synthesis of [15N]L-amino Acids from a-Keto Esters
using a One-Pot Lipase-Catalyzed Hydrolysis and Amino Acid
Dehydrogenase-Catalyzed Reductive Amination 489
Chiral Pool: Preparation of Aspartic Acid Semi-Aldehydes as Key
Synthetic Intermediates; Synthesis of Methyl (2S)-N,N-di-tertbutoxycarbonyl-2-amino-4-oxobutanoate from L-aspartic Acid 489
Asymmetric Methods: Asymmetric Alkylation Using the Williams
Oxazine and Subsequent Hydrogenation to Give the
a-Amino Acid 490
Synthesis of Unnatural/Nonproteinogenic a-Amino Acids 495
Chemical Methods 497
Resolution Approaches 497
Side-Chain Methods 497
12.2.2.1 Introduction of the Side-Chain 497
12.2.2.2 Modiﬁcations of the Side-Chain 500
Introduction of Functionality 502
12.2.3.1 Nitrogen Introduction 502
12.2.3.2 Carboxylic Acid Introduction 503
12.2.3.2.1 Strecker Reaction 503
Hydrogenation 504
Other Chemical Methods 508
Enzymatic Methods 508
Acylases 509
Hydantoinases 510
Ammonia Lyases 510
Transaminases 511
Dehydrogenases 513
Amino Acid Oxidases 514
Decarboxylases 515
Experimental Procedures 516
Side-Chain Introduction with a Phase-Transfer Catalyst 516
Introduction of Nitrogen Through an Oxazolidinone Enolate
with a Nitrogen Electrophile 517
Asymmetric Hydrogenation with Knowles Catalyst 518
Asymmetric Hydrogenation with Rh(DuPhos) Followed by EnzymeCatalyzed Inversion of the a-Center 519
Synthesis of g- and d-Amino Acids 527
g-Amino Acids 528
GABA Analogs 528
a- and b-Hydroxy-g-Amino Acids 534
Alkene-Derived g-Amino Acids 539
SAAs 541
Miscellaneous Approaches 542
d-Amino Acids 547
SAAs 547
Furanoid d-SAA 547
Pyranoid d-SAA 552
d-Amino Acids as Reverse Turn Mimetics 554
d-Amino Acids for PNA Design 562
Miscellaneous Examples 564
Conclusions 566
Synthesis of g-Aminobutyric Acid Analogs 573
a-Substituted g-Amino Acids 575
b-Substituted g-Amino Acids 579
Pregabalin 581
Baclofen and Analogs 584
g-Substituted g-Amino Acids 592
Vigabatrin 597
Halogenated g-Amino Acids 599
Disubstituted g-Amino Acids 600
a,b-Disubstituted g-Amino Acids 600
a,g-Disubstituted g-Amino Acids 601
b,b-Disubstituted g-Amino Acids 604
b,g-Disubstituted g-Amino Acids 604
Trisubstituted g-Amino Acids 604
Hydroxy-g-Amino Acids 605
a-Hydroxy-g-Amino Acids 605
b-Hydroxy-g-Amino Acids 606
a-Hydroxy-g-Substituted g-Amino Acids 619
b-Hydroxy-g-Substituted g-Amino Acids 619
b-Hydroxy-Disubstituted g-Amino Acids 638
Unsaturated g-Amino Acids 640
Unsaturated Substituted g-Amino Acids 641
Cyclic g-Amino Acids 644
Cyclopropyl g-Amino Acids 644
Cyclobutyl g-Amino Acids 648
Cyclopentyl g-Amino Acids 653
Cyclohexyl g-Amino Acids 663
Conclusions 666
Experimental Procedures 666
(R)-2-Ethyl-4-nitrobutan-1-ol (36c) 666
N-tert-Butyl-N-(p-chlorophenylethyl) a-Diazoacetamide 669
(R )-5-[(1-Oxo-2-(tert-butoxycarbonylamino)-3-phenyl)-propyl]-2,2dimethyl-1,3-dioxane-4,6-dione 670
(R )- and (S)-[2-(Benzyloxy) ethyl]oxirane 671
14.12.5
14.12.6
14.12.8
Dimethyl (S,S)-(–)-3-N,N-bis(a-Methylbenzyl)-amino-2oxopropylphosphonate 672
Boc-L-leucinal 673
Cross-Coupling of N-tert-Butylsulﬁnyl Imine and tert-Butyl
3-oxopropanoate 674
(10 S,4S)-4-Bromomethyl-1-(1-phenyleth-1-yl)-pyrrolidin-2-one
(þ)-(R,S)-4-Amino-2-cyclopentene-1-carboxylic Acid 676
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Origins of Amino Acids
The space between the stars, the interstellar medium (ISM), is composed of gasphase species (mainly hydrogen and helium atoms) and submicron dust grains
(silicates, carbon-rich particles, and ices). The ISM has many different environments
based on its different temperatures (Tk), hydrogen density (nH), and ionization state
of hydrogen (for reviews, see [1–3]); it includes the diffuse ISM (Tk  100 K,
nH  10–300 cm3), molecular clouds (Tk  10–100 K, nH  103–104 cm3; e.g., [4])
[molecular clouds are not uniform but instead have substructures [5] – they contain
high-density clumps (also called dense cores; nH  103–105 cm3), which have
higher densities than the surrounding molecular cloud; even higher densities are
found in small regions, commonly known as hot molecular cores, which will
be the future birth place of stars], and hot molecular clouds (Tk  100–300 K,
nH  106–108 cm3; e.g., [6]). Observations at radio, millimeter, submillimeter, and
infrared frequencies have led to the discovery of numerous molecules (currently
more 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 collapse
of a dense cloud of interstellar gas and dust leads to the formation of a so-called solar
nebula. Atoms and molecules formed in the ISM, together with dust grains are
incorporated in this solar nebula, serving as building blocks from which future
planets, comets, asteroids, and other celestial bodies may originate. Solar system
bodies, 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 extraterrestrial
molecules, which might have a heritage from interstellar, nebular, and/or parent
body processing. Delivery of these molecules to the early Earth and Mars during the
late heavy bombardment (4.5–3.8 billion years ago) may have been important for the
origin of life [13, 14]. Among the molecules delivered to the early Earth, amino acids
may 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 describe
different extraterrestrial environments where amino acids may be present and
H3þ
H2Oþ
HCOþ
HN2þ
HOCþ
H2Sþ
CO2þ
HCSþ
OHþ
CNþ
COþ
N2þ
CFþ
H3Oþ
HCNHþ
HNCO
HOCOþ
NH4þ
H3COþ
c-C3H2
C4H
HNCCC
NH2CHO
H2CCCC
HCCCCH
H2C3Nþ
c-H2C3O
HC2CHO
c-C2H4O
C6H
HCCCCCCH
Table 1.1 Summary of molecules identified in the interstellar and circumstellar mediuma.
C8H
j 1 Extraterrestrial Amino Acids
c-SiC2
Observations suggest the presence of polycyclic aromatic hydrocarbons in the interstellar gas (e.g., [244]).
SOþ
Figure 1.1 Molecular structures of conformers I and II of glycine
in the gas phase (adapted from [21, 29]).
detected, their proposed formation mechanisms, and possible contribution to the
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 [15–28].
While in theory glycine may have several conformers in the gas phase [29], astronomical 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, larger
dipole moment, and therefore stronger spectral lines [30]. Only upper limits of both
conformers were found in the ISM until Kuan et al. [25] reported the detection
of 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 spectral
lines necessary for the identiﬁcation of interstellar glycine have not yet been found.
In addition, they argued that some of the spectral lines identiﬁed as glycine by
Kuan et al. [25] could be assigned to other molecular species. Further negative results
include the astronomical searches of Cunningham et al. and Jones et al. [27, 28], who
claim that their observations rule out the detection of both conformers I and II of
glycine in the hot molecular core Sgr B2(N-LMH). They conclude that it is unlikely
that Kuan et al. [25] detected glycine in either Sgr B2(N-LMH) or Orion-KL. No other
amino acid has been detected in the ISM. Despite these results, amino acids were
proposed 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 (solidphase reactions), or synthesized in the gas phase via ion–molecule reactions (gasphase reactions). These two processes will now be described in more detail (for a
review, see, e.g., [31]).
Formation 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,
1.2 ISM
Table 1.2 Abundances of interstellar ices (normalized to H2O) in the
high-mass protostellar objects W33A and NGC758:IRS9, in the lowmass protostellar object Elias 29, and the field star Elias 16.
Ice specie
NGC758:IRS9
OCN–
1.7–7
0.4–2
Adapted from [31, 32, 52].
which may occur in cold molecular clouds (e.g., [32] and references therein). In these
regions of the ISM, in which temperatures are very low (<50 K), atoms and molecules
in the gas phase will be accreted onto the surface of dust grains leading to the
formation of ice mantles [33, 34]. Diffusion of accreted atoms leads to surface
reactions, forming additional species in the ice mantles. These interstellar ices are
mainly composed of H2O, CO, CO2, CH4, CH3OH, and NH3, with traces of other
species (Table 1.2; [32, 34–38]). Once these ice grains are formed, energetic processes
[e.g., cosmic rays and ultraviolet (UV) irradiation] may change the ice mantle
A range of interstellar ice analogs have been irradiated at low temperatures (10 K)
to produce a variety of amino acids. Holtom et al. [39] used galactic cosmic ray
particles to irradiate an ice mixture containing carbon dioxide (CO2) and methylamine (CH3NH2), which produced hydroxycarbonyl (HOCO) and aminomethyl
(CH2NH2) radicals. The recombination of these radicals would then form glycine
and its isomer (CH3NHCOOH). Briggs et al. [40] UV-irradiated a mixture of CO :
H2O : NH3 (5 : 5 : 1) at 12 K for 24 h. This resulted in the formation of an organic
residue, which included among other organic compounds, 0.27% of glycine. Ice
mixtures containing H2O : CH3OH : NH3 : CO : CO2 (2 : 1 : 1 : 1 : 1 molar composition; [41]), and H2O with NH3, CH3OH, and HCN (0.5–5% NH3, 5–10% CH3OH,
and 0.5–5% HCN, relative to H2O [42]) were UV-irradiated in high vacuum at below
15 K. While Bernstein et al. [42] obtained glycine and racemic mixtures (D/L  1) of
alanine and serine, a large variety of amino acids were found by Munõz Caro et al. [41].
These results were conﬁrmed by Nuevo et al. [43, 44].
The exact formation pathway of amino acids in interstellar ices is unknown, but the
Strecker synthesis ([42]; for more details, see Section 1.4), reactions on the surface of
polycyclic aromatic hydrocarbon ﬂakes [45], and radical–radical reactions [46, 47]
have been proposed. As radical–radical reactions can occur with almost no activation
energy [47], theoretical modeling suggests that glycine may be formed in interstellar
ice mantles via the following radical–radical reaction sequence:
CO þ OH ! COOH
CH3 þ COOH ! CH3 COOH
NH2 þ CH3 COOH ! NH2 CH2 COOH þ H
Quantum chemical calculations indicate that amino acids may also be formed by
recombination of the radicals COOH and CH2NH2, which are produced by dehydrogenation of H2O and CH3OH, and hydrogenation of HCN, respectively [47].
However, all radical–radical reactions described above require the radicals to diffuse
into and/or onto the ice mantle which, as noted by Woon [47], may only occur at
temperatures of 100 K or higher, much higher than the temperature in molecular
clouds. Furthermore, Elsila et al. [48] used isotopic labeling techniques to test whether
Strecker synthesis or radical–radical reactions were responsible for amino acid
formation in interstellar ice analogs. Their results show that amino acid formation
occurs via multiple routes, not matching the previously proposed Strecker synthesis
or radical–radical mechanisms. Ultimately, the need for high UV ﬂux to produce
amino acids in ice mantles contrasts with the low expected efﬁciency of UV photolysis
in dark molecular clouds [4]. This, together with the fact that amino acids have low
resistance to UV photolysis [49], raises concerns about the amino acid formation in
interstellar ices by UV photolysis.
Formation of Amino Acids in the ISM via Gas-Phase Reactions
Potential mechanisms alternative to solid-phase reactions include gas-phase
formation of interstellar amino acids via ion–molecule reactions. Amino acids,
once formed, could potentially survive in the gas phase in hot molecular cores,
because the UV ﬂux is sufﬁciently low (i.e., 300 mag of visual extinction) [31].
Alcohols, aminoalcohols, and formic acid evaporated from interstellar ice grains
(Table 1.2; [50–53]) may produce amino acids in hot molecular cores through
exothermic alkyl and aminoalkyl cation transfer reactions [52]. Aminoalkyl cation
transfer from aminomethanol and aminoethanol to HCOOH can produce protonated glycine and b-alanine, respectively via the following reactions [52]:
NH2 CH2 OH2þ þ HCOOH ! NH2 CH2 COOH2þ þ H2 O
NH2 ðCH2 Þ2 OH2þ þ HCOOH ! NH2 ðCH2 Þ2 COOH2þ þ H2 O
An electron recombination will then produce the neutral amino acids. Further
alkylation may produce a large variety of amino acids through elimination of a water
molecule [31, 52].
1.3 Comets
Alternatively, Blagojevic et al. [54] have experimentally proven the gas-phase
formation of protonated glycine and b-alanine, by reacting protonated hydroxylamine
with acetic and propanoic acid, respectively:
NH2 OH þ þ CH3 COOH ! NH2 CH2 COOH þ þ H2 O
NH2 OH þ þ CH3 CH2 COOH ! NH2 ðCH2 Þ2 COOH þ þ H2 O
Neutral amino acids could then be produced by dissociative recombination
reactions [54].
Independently of the mechanism of synthesis (solid-phase or gas-phase reactions),
once formed, amino acids would need to be resistant and survive exposure to cosmic
rays and UV radiation in the ISM. The stability of amino acids in interstellar gas and
on 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 frozen
argon, nitrogen, or water matrices to test their stability against space radiation. It was
shown that these amino acids have very low stability against UV photolysis.
Therefore, amino acids will not survive in environments subject to high UV ﬂux,
such as the diffuse ISM. This does not eliminate formation of amino acids in the ISM,
but instead requires that amino acids are incorporated into UV-shielded environments such as hot molecular cores, in the interior of comets, asteroids, meteorites,
Comets are agglomerates of ice, organic compounds, and silicate dust, and are
some of the most primitive bodies in the solar system (for reviews about comets, see,
e.g., [55–57]). Comets were ﬁrst proposed to have delivered prebiotic molecules to the
early Earth by Chamberlin and Chamberlin [58]. Since then, space telescopes (such
as the Hubble Space Telescope, Infrared Space Observatory, and Spitzer Space
Telescope; e.g., [59–66]), ground-based observations (e.g., [67–69]), cometary ﬂy-bys
(Deep Space 1 mission, and Vega1, Vega2, Suisei, Sakigake, ICE, and Giotto
spacecraft missions; e.g., [70–76]), impacts (Deep Impact mission, which impacted
into the 9P/Tempel comets nucleus; e.g., [77–79]), collection of dust from the coma
of a comet (Stardust mission to comet Wild-2; e.g., [80–84]), and rendezvous missions
(such as the Rosetta mission, which will encounter the comet 67P/Churyumov–
Gerasimenko 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 on
comet Halley [71], but their presence could not be conﬁrmed due to the limited
resolution of the mass spectrometers on board the Giotto and Vega spacecrafts. In
addition, only an upper limit of less than 0.15 of glycine relative to water has been
determined in the coma of Hale–Bopp using radio telescopes (Table 1.3; [69]).
Although several amino acid precursors (see Section 1.4), including ammonia,
Table 1.3 Molecular abundances of ices for comets Halley, Hyakutake, and Hale–Bopp.
CH3C2H
0.3
0.4
6–30a
0.2–1a
0.2
0.2–0.8a
Abundances are normalized to H2O and were measured at around 1 AU from the Sun. Adapted
from [8, 32, 69, 86, 245].
Extended sources (the abundance is model dependent).
Measured at 2.9 AU from the Sun.
Abundance deduced from CS.
1.4 Meteorites
HCN, formaldehyde, and cyanoacetylene, have been observed in the Hyakutake and
Hale–Bopp comets [7], only a very limited number of carbonyl compounds necessary
for the synthesis of amino acids were detected in comets [7, 32, 86]. The ultimate
proof for the presence of amino acids in comets is a sample return mission such as
Stardust, which collected dust from the coma of the Wild-2 comet using a lightweight
material called aerogel [80]. Analyses of comet-exposed aerogel samples show
a relative molar abundance of glycine that slightly exceeds that found in control
samples, suggesting a cometary origin for this amino acid [83]. Compound-speciﬁc
isotopic analyses of glycine present in comet-exposed aerogel samples have not yet
been performed and therefore it has not been possible to ultimately constrain
its origin. Other amino acids present in the comet-exposed aerogel samples included
e-amino-n-caproic acid, b-alanine, and g-amino-n-butyric acid (g-ABA). The similarity in the distribution of these amino acids in the comet-exposed sample, the witness
tile (which witnessed all the terrestrial and space environments as the comet-exposed
samples, but did not see comet Wild-2), and the Stardust impact location soil
indicates a terrestrial origin (contamination) for these amino acids [83].
Meteorites are extraterrestrial objects that survived the passage through the Earths
atmosphere and the impact with the Earths surface. Excepting the lunar and Martian
meteorites [87–91], all meteorites are thought to have originated from extraterrestrial
bodies located in the asteroid belt (e.g., [92–98]). Although unproven, it was also
suggested that they could have originated from comets ([99–102] and references
therein). 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., [103–105]). A very primitive class
of stony meteorites, named carbonaceous chondrites, has not been melted since
their 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 are
the CI-, CM-, CK-, CO-, CR-, CV-, CH-, and CB-type chondrites. Chondrites are also
classiﬁed and grouped into petrographic types. This refers to the intensity of thermal
metamorphism or aqueous alteration that has occurred on the meteorite parent
body, ranging from types 1 to 6. A petrologic type from 3 to 1 indicates increasing
aqueous alteration. A petrologic type from 3 to 6 indicates increasing thermal
Carbonaceous chondrites have a relatively high carbon content and can contain up
to 3 wt% of organic carbon. More than 70% of it is composed of a solvent-insoluble
macromolecular material, while less than 30% is a mixture of solvent-soluble organic
compounds. Carbonaceous chondrites, as revealed by extensive analyses of the
Murchison meteorite, have a rich organic inventory that includes organic compounds important in terrestrial biochemistry (Table 1.4). These include amino
acids (e.g., [106–108]), carboxylic acids (e.g., [109, 110]), purines and pyrimidines
Table 1.4 Abundances (in ppm) of the soluble organic matter found in the Murchison meteorite.
Carboxylic acids (monocarboxylic)
Hydrocarbons (aromatic)
Hydrocarbons (aliphatic)
Basic N-heterocycles
Adapted from [9, 10, 161, 246].
(e.g., [111–113]), polyols [114], diamino acids [115], dicarboxylic acids (e.g., [116–
119]), 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 ﬁrst evidence of extraterrestrial amino acids in a meteorite was obtained
by Kvenvolden et al. [121], after analyzing a sample of the Murchison meteorite
which had recently fallen in Australia in 1969. These authors detected several amino
acids in this meteorite, including the nonprotein amino acids a-AIB and isovaline,
which suggested an abiotic and extraterrestrial origin for these compounds. Since
then, Murchison has been the most analyzed carbonaceous chondrite for amino
acids, with more than 80 different amino acids identiﬁed, the majority of which are
rare (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 complete
structural diversity (i.e., all isomers of a certain amino acid are present). They can be
divided into two structural types, monoamino alkanoic acids and monoamino
dialkanoic acids, which can occur as N-alkyl derivatives or cyclic amino acids, with
structural preference in abundance order a > g > b. Branched-chain amino acid
isomers predominate over straight ones and there is an exponential decline in
concentration 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 abundances 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
D,L-b-AIB
D-b-ABA
L-b-ABA
a-AIB
D-a-ABA
L-a-ABA
L-Isovaline
51  31
65  16
135  50
261  15
92  32a
2110  144
1063  268
717  192
147  88
617  79
647  58
424  18a
1968  350
463  68a
100  15
342  103
537  117
801  200
436  227a
2919  433
1269  202
1331  472
343  102
720  95
956  171
708  171a
2901  328
295  111
347  98
350  183
458  209
2834  780a
1753e,f
Y-74 662
1306  83a
343  171
352  161
155  16
172  40
2706  377
431  159a
127  24
151  73
317  55
316  55
1448  682
442  238
164  21d
LEW 90 500
<1753
Y-791 198
208  26
495  6
1396  157
6425  645
128  13
113  10
389  180a
72  33
134  12
49  21
130  83
<62a
<72a
458  346
<151a
163  135
418  106
211  74
1003  110
327  84a
1118  729
796  97
1548  187
125  92
332  120
283  144a
740  219
100  70
101  78
136  49
159  136
105  62
145  22
111  48
279  24
68  23a
788  66
897  72
1136  351
240  18
347  57
487  50a
ALHA 77 306
110  44
134  19
33  8
33  12
250  40
19  5a
29  4
43  6
21  7
23  6
300  75
338  31
308  68d
ALH 83 100
Table 1.5 Summary of the average blank corrected amino acid concentration (in ppb) in the 6 M HCl acid-hydrolyzed hot-water extracts of carbonaceous chondrites.
B-7904
Y-79 331
Table NaN
575  159
169  39
259  61
630  135
1028  239
881  280
369  117
197  21
168  35
389  87
605  149
380  97
55  17
16  6
95  10
201  14
228  45
28  10
29  13
24  3
64  10
101  13a
106  27
201  61
54  14
274  74
147  52a
68  18
99  39
33  9
174  50
<174a
LAP 0227
MET 01 070
ALH 88 045
617  83
1401  146
600
84  12
82  22
157  14
438  142a
46  33
12  7a
<163a
39  37
13  11a
<194a
30  2
146  8
81
372  11
217  12a
707  80
2052  311
628  294
148  70
69  9
332  99a
28  16
54  18
15  6
61  31
51  26a
457  121
317  28
307  129
127  92
100  42
329  41
241  149a
<56  a
84  40a
83  8
16  2
306  48
147  17
77  10
75  18
GRA 95 229
551  75
576  51
3489  389
4209  415
1807  84a
40 496  1028
3143  495
1914  398
2091  405
52 465  6860
51 141  6272
3903  377
4239  494
30 257  1226
2956  125
2955  120
29 245  2229a
EET 92 042
409  41
465  24
3090  422
4468  503
742  42a
24 975  608
3046  50
1512  66
1429  333
21 664  1009
22 297  1583
1327  33
1458  99
50 210  870
1123  54
1244  28
22 806  459a
349  33a
57  5
189  23
124  7
489  34
32  11
140  34
417  55
62  10
49  23
274  14
330  59
34  5
Shişr 033
<89a
875  188
223  55
1092  243
534  24a
49  12
173  80
856  188
195  112a
48  3
<131a
136  14
122  6
54  6
74  22
96  20
49  5a
13  2
19  4
40  3
50  11a
GRO 95 577
The associated errors are based on the standard deviation of the average value. Adapted from [126–128, 130–133, 136–138, 140–142].
Enantiomers could not be detected individually, so the total (D þ L) abundance of the amino acids is reported in the row for the D-enantiomer.
Tentative identiﬁcation.
Optically pure standard not available for enantiomeric identiﬁcation.
g-ABA and D,L-b-AIB could not be separated under the chromatographic conditions used, so the total abundance is reported in the cell corresponding to g-ABA.
g-ABA and D,L-b-ABA could not be separated under the chromatographic conditions used, so the total abundance is reported in the cell corresponding to g-ABA.
The value corresponds mostly to g-ABA.
Detected but too small to estimate.
ND ¼ not determined.
abundance similar to the CM2 Murchison. While the CM2 Y-791 198 has an
extremely high total amino acid concentration (71 ppm [131, 132]), which is about
5 times as high as Murchison (15 ppb), the CM2s Essebi, Nogoya, Mighei [133], Allan
Hills (ALHA) 77 306 [134–136], ALH 83 100 [130], Y-79 331, and Belgica (B-)
7904 [137] have much lower amino acid abundances, some being depleted in amino
acids (Table 1.5). For Essebi, Botta et al. [133] consider that the high abundances
(relative to glycine) of g-ABA and b-alanine are derived from terrestrial contamination
at the fall site.
CM1s chondrites were analyzed for the ﬁrst time for amino acids by Botta
et al. [138]. ALH 88 045, MET (Meteorite Hills) 01 070, and LAP (La Paz) 0227 have
total amino acid concentration much lower than the average of the CM2s. According
to Botta et al. [138], these results and the similar relative amino acid abundances
between the CM1 class meteorites and the CM2 Murchison are explained by
decomposition of a CM2-like amino acid distribution during extensive aqueous
alteration in the CM1s meteorite parent body.
The CI1 chondrites Orgueil and Ivuna have total amino acid abundances of about
4.2 ppm, with b-alanine, glycine, and g-ABA as the most abundant amino acids, while
glycine and a-AIB are the most abundant amino acids in the CM2 chondrites
Murchison and Murray [136]. The CV3 Allende [133, 139] and the ungrouped C2
Tagish Lake meteorites [133, 140] are essentially free of amino acids (total amino acid
abundances of 2 and 1 ppm, respectively), with most of the amino acids probably
being terrestrial contaminants.
The highest amino acid abundances ever measured in a meteorite were found
on the CR2s EET 92 042 and GRA 95 229, with total amino acid concentrations of
180 and 249 ppm, respectively [141]. The most abundant amino acids present in
these meteorites are the a-amino acids glycine, isovaline, a-AIB and alanine.
The high d 13 C results together with the racemic enantiomeric ratios determined [141] for most amino acids indicate an extraterrestrial origin for these
compounds (see Section 1.4.1). In addition, these authors analyzed the CR1 GRO
95 577, which was found to be depleted in amino acids (1 ppb). Other CRs analyzed
include the CR2 chondrites Renazzo [133] and Shişr 033 [142]. Renazzo has a total
amino acid abundance of only 4.8 ppm, which is similar to the CI chondrites
Orgueil and Ivuna. This meteorite has a distinct amino acid distribution, with gABA, glycine, and L-glutamic acid as the most abundant amino acids. Only upper
limits for alanine and a-AIB were reported for Renazzo, while isovaline was
tentatively identiﬁed [133]. The most abundant amino acids in the Shişr 033
meteorite are glycine, L-glutamic acid, L-alanine, and L-aspartic acid. In addition
to this, Shişr 033 D/L protein amino acid ratios are smaller than 0.4 and in
agreement with the D/L amino acid ratios of Shişr 033 fall-site soil. These results
suggest extensive amino acid contamination of the meteorite (see Section 1.4.1).
However, Shişr 033 contains a small fraction of extraterrestrial amino acids, as
indicated by the presence of a-AIB [142].
Apart from carbonaceous chondrites, amino acid analyses have also been carried
out on Martian meteorites. As our present knowledge of amino acids potentially
present in Mars may be accessed from these meteorites (see also Section 1.6), amino
acid analyses have been performed in the Martian meteorites EET 79 001 [143],
ALH 84 001 [144], and Miller Range (MIL) 03 346 [145]. In all three samples, the
meteoritic amino acid distribution was similar to the one in the Allan Hills ice, which
suggested that the ice meltwater was the source of the amino acids in these
meteorites. In addition, analysis of the Nakhla meteorite, which fell in Egypt, shows
that the amino acid distribution (including the D/L ratios) is similar to the one in the
sea-ﬂoor sediment from the Nile Delta [146].
Sources of Meteoritic Amino Acids (Extraterrestrial versus Terrestrial Contamination)
In order to determine if the amino acids present in carbonaceous chondrites are
indigenous to the meteorites, four approaches are generally applied: (i) detection
of amino acids that are unusual in the terrestrial environment, (ii) comparison of
the absolute abundances of amino acids in the meteorites to the levels found in the
fall-site environment (soil or ice), (iii) determination of enantiomeric ratios (D/L
ratios), and (iv) determination of compound speciﬁc stable isotope ratios of hydrogen,
carbon, and nitrogen.
1.4.1.1 Detection of Amino Acids that are Unusual in the Terrestrial Environment
The majority of the more than 80 different amino acids identiﬁed in carbonaceous
meteorites are nonexistent (or rare) in terrestrial proteins (for a review, see,
e.g., [108]). Extraterrestrial meteoritic nonprotein amino acids such as a-AIB,
isovaline, b-ABA, and b-AIB have concentrations usually in the order of a few
hundred parts per billion maximum (Table 1.5). However, Murchison [126] has a
higher abundance of a-AIB (2901 ppb), while Murray and LEW90 500 [126, 129, 130]
contain higher abundances of both a-AIB (1968 and 2706 ppb, respectively) and
isovaline (2834 and 1306 ppb, respectively). The highest abundances of a-AIB,
isovaline, b-ABA, and b-AIB were detected in the CR2 chondrites EET92 042
and GRA95 229 [141]. The CM2 Y791 198 ([131, 132]) contained similar abundances
of a-AIB, b-ABA, and b-AIB as EET92 042 and GRA95 229, but lower abundance of
isovaline (Table 1.5).
1.4.1.2 Determination of the Amino Acid Content of the Meteorite Fall Environment
Samples collected from meteorite fall sites have been analyzed for amino acids and
their distribution compared to the one from the carbonaceous chondrites. Ice from
the Antarctic regions of Allan Hills [143, 144] and La Paz [130, 147] contained only
trace levels of aspartic acid, serine, glycine, alanine, and g-ABA (less than 1 ppb of
total amino acid concentration). No isovaline or b-ABA was detected above detection
limits. Only an upper limit of a-AIB (<2 ppt) was detected in the Allan Hills ice [144],
while a relatively high abundance (ranging between 25 and 46 ppt) of a-AIB was
detected in the La Paz Antarctic ice [130, 147].
Soil samples from the Shişr 033 fall site show that the most abundant amino
acids are L-glutamic acid, L-aspartic acid, glycine, and L-alanine, with nonprotein
amino acids absent from the soil [142]. In addition, comparison of the protein
amino acid enantiomeric ratios of Shişr 033 to those of the soil (D/L < 0.4) shows
agreement, indicating that most of the amino acids in this meteorite are terrestrial
in origin. On the other hand, a soil sample collected close to the fall site of the
Murchison meteorite showed much smaller amino acid relative concentrations
(glycine ¼ 1) when compared to the Murchison meteorite, indicating that the
majority of the amino acids present in this meteorite are extraterrestrial in
origin [133].
1.4.1.3 Determination of Enantiomeric Ratios
Chirality is a useful tool for determining the origin (biotic versus abiotic) of amino
acids in meteorites. On Earth most proteins and enzymes are made of only the
L-enantiomer of chiral amino acids; however, abiotic synthesis of amino acids
yields racemic mixtures (D/L  1). If we assume that meteoritic protein amino acids
were racemic (D/L  1) prior to the meteorite fall to Earth, then their D/L ratios can be
used as a diagnostic signature to determine the degree of terrestrial L-amino acid
contamination they have experienced. In fact, racemic amino acid ratios for protein
(and nonprotein) amino acids in carbonaceous chondrites indicate an abiotic
synthetic origin. Although racemic mixtures have been observed for most nonprotein
chiral amino acids (Table 1.5), small L-enantiomeric excess for some nonprotein
amino acids has been reported in the Murchison and Murray meteorites [148–150].
Six a-methyl-a-amino acids unknown or rare in the terrestrial biosphere (both
diastereomers of a-amino-a,b-dimethyl-pentanoic acid, isovaline, a-methylnorvaline, a-methylnorleucine, and a-methylvaline) had L-enantiomeric excesses ranging
from 2.8 to 9.2% in Murchison and from 1.0 to 6.0% in Murray [148, 149]. More
speciﬁcally, Murchison has shown to have an L-enantiomeric excess of isovaline
ranging from 0 to 15.2% with signiﬁcant variation both between meteorite stones
and even within the same meteorite stone [150]. The meteoritic enantiomeric excess
of a-methyl-a-amino acids and the absence for the a-H-a-amino acids may be
explained by the resistance to racemization of a-methyl-a-amino acids during
aqueous alteration in the meteorite parent body, due to their lack of an a-hydrogen [149, 151, 152]. Another explanation could be a different amino acid formation
process, namely pre-solar formation for the a-methyl-a-amino acids and subsequent
incorporation into the parent body, followed by parent body formation of the a-H-aamino acids [149, 152].
1.4.1.4 Determination of Compound-Specific Stable Isotope Ratios of Hydrogen,
Carbon, and Nitrogen
For meteoritic nonchiral amino acids, such as glycine, a-AIB, b-ABA, and b-alanine,
compound-speciﬁc stable isotope measurements are the only means to establish
their origin. The abundances of stable isotopes are expressed in d values. These
indicate the difference in per mil (½) between the ratio in the sample and the same
ratio in the standard, as shown by:
dð½Þ ¼
ðRsample Rstandard Þ
where R represents D=1 H for hydrogen, 13 C=12 C for carbon, and 15 N=14 N for
nitrogen. The standards usually used are standard mean ocean water for hydrogen,
Pee Dee Belemnite for carbon, and air for nitrogen.
Stable isotope analyses of the total amino acid fractions of the Murchison meteorite
showed dD ¼ þ 1370½, d15 N ¼ þ 90½, and d 13 C ¼ þ 23:1½ [153], which were
later conﬁrmed by Pizzarello et al. [154, 155], who obtained dD ¼ þ 1751½,
d 15 N ¼ þ 94½, and d 13 C ¼ þ 26½. Stable isotope analyses were obtained for
individual amino acids in different meteorites (Table 1.6; [126, 141, 150, 156–159]).
These values (with a few exceptions, in which there is terrestrial contribution) are
clearly outside the amino acid terrestrial range (from 70.5 to þ 11.25½; [160]) and
fall within the range of those measured for other indigenous polar organic
compounds present in meteorites [161]. The highly enriched dD, d 15 N, and d13 C
values determined for the meteoritic amino acids indicate primitive extraterrestrial
The deuterium enrichment of amino acids is thought to be the result of interstellar
chemical reactions (e.g., gas-phase ion–molecule reaction and reactions on interstellar grain surfaces) which formed the amino acid precursors. These reactions occur in
the low temperatures of dense clouds (T < 50 K) in which deuterium fractionation is
efﬁcient (e.g., [162–164]). Meteoritic amino acids would have then been formed from
their deuterium-enriched interstellar precursors and deuterium-depleted water
([165] and references therein) by synthesis (aqueous alteration) in the meteorite
parent body (see Section 1.4.2). However, a-amino acids are more deuterium (and
C)-enriched than a-hydroxy acids [117], which is inconsistent with a Streckercyanohydrin-type synthesis from a common precursor [116, 166]. Differences may be
explained by different reaction paths leading to different isotopic distributions [164].
The 15 N enrichment of amino acids is also thought to be due to chemical fractionation in interstellar ion–molecule exchange reactions [167, 168].
The hydrogen isotope composition of meteoritic amino acids follows a relatively
simple pattern, in which dD varies more with the structure of their carbon chains (dD
is higher for amino acids having a branched alkyl chain) than with the chain
length [159]. On the other hand, d 13 C of a-amino acids (a-methyl-a- and a-H-aamino acids) decreases with increasing carbon chain length (with the a-methyl-aamino acids more 13 C-enriched than the corresponding a-H-a-amino acids), while
d 13 C for non-a-amino acids remains unchanged or increases with increasing carbon
chain length [158]. This suggests diverse synthetic processes for meteoritic amino
acids, in particular that the amino acid carbon chain elongation followed at least two
synthetic pathways [158, 159].
Synthesis of Meteoritic Amino Acids
Meteoritic amino acids are thought to be formed by a variety of synthetic pathways.
Namely, it is suggested that a-amino acids form by a two-step process, in which the aamino acid precursors (carbonyl compounds, ammonia, and HCN) were present (or
formed) in a proto-solar nebula and were later incorporated into an asteroidal parent
D,L-Aspartic
D,L-b-ABA
D,L-Isovaline
D,L-a-Methylnorvaline
þ2686
þ461
þ599
þ967
þ429
þ360
þ20.7
þ3058
þ1338
þ1225
þ3419
þ473
þ292
þ60
þ3181
þ66
þ3021
þ3283
þ1505
þ2432
þ2266
þ3097
þ1633
þ184
þ5; þ43
þ29
þ28
þ16; þ22
þ11 to þ20
þ17 to þ22
þ15
þ614
þ510
þ399
þ1063
þ763
þ57
þ58
þ37
þ61
d15 N
þ22; þ52
þ27; þ39
þ22; þ41
þ19
d13 C
þ20
Table 1.6 Compound-specific stable isotope composition (in ½) of individual amino acids in carbonaceous chondrites.
þ51
þ32
þ41
þ35
þ33
þ47
þ34
þ45
þ50
þ23
þ46
L-a-Amino-a,b-dimethylbutyric acid
D,L-g-Aminovaleric acid
d-Aminovaleric acid
b-Amino-a,a-dimethylpropionic acid
b-Amino-b-methylbutyric acid
D,L-g-Amino-a-methylbutyric acid þ D,L-g-aminob-methylbutyric acida
D,L-a-Aminoadipic acid
L-a-Aminoadipic acid
D,L-b-Aminoadipic acid
D,L-a-Methylglutamic acid
D,L-threo-b-Methylglutamic acid
D- or L-threo-b-Methylglutamic acid
D,L-threo-g-Methylglutamic acid
D,L-N-Methylalanine
N-Methyl-a-AIB
þ425
þ962
þ1352
þ2049
þ181
þ1164
þ367
þ362
þ3318
þ36
þ53
þ129
þ478
þ850
þ1337
þ1267
þ3446
þ1255
þ1408
þ1563
þ619
þ2251
þ2465
þ1819
þ965
þ552
þ2590
þ1141
þ3604
Adapted from [126, 141, 142, 150, 157–159].
Isotopic value corresponds to the combined enantiomeric peaks.
The chromatographic order of elution for the two enantiomers could not be established for lack of standards.
D,L-a-Amino-a,b-dimethylbutyric
+ NH2 R3
α-amino or imino acids
Figure 1.2 The Strecker-cyanohydrin synthetic pathway for the
formation of a-amino a-hydroxy and imino acids (adapted
from [116, 133, 171, 247]). R1 and R2 correspond to H or
CnH2n þ 1. If R3 corresponds to H then a-amino acids are
produced; if R3 is an amino acid then imino acids are produced.
body [169]. During aqueous alteration on the asteroidal parent body, Streckercyanohydrin synthesis would have taken place to form a-amino acids (Figure 1.2; [108,
116, 163, 166]). Since the carbonyl precursors (aldehydes and ketones) are thought to
be synthesized by the addition of a single-carbon donor to the growing alkane chain, a
decrease of the a-amino acid abundances with increasing chain length is expected.
Also, synthesis of branched carbon chain analogs is expected to be favored over
straight-carbon chain analogs (e.g., [108]), and this trend is observed in the EET
92 042 and GRA 95 229 meteorites [141]. Additional support for this hypothesis is
the ﬁnding of a-amino acid, a-hydroxy acids [116, 117, 166], and imino acids [170]
in carbonaceous meteorites. However, non-a-amino acids cannot be produced by
the Strecker-cyanohydrin synthesis. Alternatively, meteoritic b-amino acids are
thought to be synthesized by Michael addition of ammonia to a,b-unsaturated
nitriles, followed by reduction/hydrolysis (Figure 1.3; e.g., [108] and references
therein). These precursor molecules have been detected in the ISM (Table 1.1 and
reference therein) and also in comets (Table 1.3 and references therein). A chemical
reaction such as a Michael addition could occur on the parent body of meteorites.
For example, the extensively aqueous altered CI chondrites Orgueil and Ivuna are
rich in b-alanine, but depleted in a-amino acids. As suggested [138], this might
indicate that the CI parent body was depleted in carbonyl compounds (aldehydes
and ketones) necessary for the Strecker-cyanohydrin synthesis to occur. Additional
synthetic pathways in the meteorite parent body have been proposed for non-aamino acids (for a review, see, e.g., [108]). For example, hydrolysis of lactams
and carboxy lactams, which have been detected in carbonaceous meteorites [125],
gives the corresponding b-, g-, and d-amino acids, and dicarboxylic amino acids,
Reduction and hydrolysis
Figure 1.3 Michael-addition of ammonia to a a,b-unsaturated
nitrile to form a b-amino alkylnitrile that is then hydrolyzed to form
a b-amino acid (b-alanine) (adapted from [133]).
Micrometeorites and IDPs
Micrometeorites (MMs) and IDPs are thought to be the remains of comets and
asteroids (for reviews, see, e.g., [171–176]). MMs are small extraterrestrial dust
particles, typically in the range 50 mm to 2 mm [177], that have survived atmospheric
entry. They are collected in deep-sea sediments [171, 178], Antarctic ice [179–181],
and Greenland lake deposits [182–184]. On the other hand, IDPs are extraterrestrial
particles (usually measuring less than 30 mm in size), which are collected from the
Earths stratosphere (at an altitude of 20 km) by NASA aircraft (e.g., [171, 185, 186]).
Several organic molecules have been found in IDPs and MMs, such as ketone
and aliphatic hydrocarbons [12, 187–189], and polycyclic aromatic hydrocarbons [11,
190]. Antarctic micrometeorites (AMMs) have also been analyzed for amino
acids [191–193]. Most AMMs analyzed by Brinton et al. [191] had very low abundances
of amino acids and high L-enantiomeric excess, with a distribution similar to that
found in the Antarctic ice. One set of samples containing around 30 MMs was found
to contain a-AIB at high levels (280 ppm). However, the identiﬁcation of a-AIB was
tentative and needs further conﬁrmation [191]. In addition, Glavin et al. [192] studied
455 AMMs and none of them contained a-AIB. A third study by Matrajt et al. [193]
analyzed 300 AMMs and found a-AIB in around 100 MMs. These authors calculated
that only around 14% of AMMs analyzed so far contained a-AIB.
The possibility of Mars harboring alien life (presently and/or in the past) is the focus
of future space missions planned to the Red Planet. Their target compounds
indicative of life include, among others, amino acids [194–196]. These are key
biomolecules on Earth, but are also produced by abiotic reactions such as those
occurring in the parent body of meteorites (see Section 1.4.2). Amino acids synthesized elsewhere in the solar system may therefore be delivered intact into the surface
of Mars. In fact, large amounts of carbonaceous material are thought to be delivered
to the surface of Mars by IDPs and meteorites every year [14, 197, 198]. However, in
1976 the Viking landers found no organic molecules above the parts per billion to
parts per million levels on the surface of Mars (e.g., [199, 200]), even though they
should have been able to detect amino acids on the order of tens of parts per
million [201, 202]. This might be explained by chemical reactions occurring in the
surface of Mars, leading to the destruction of organic molecules. For example, oxidant
molecules may react with any potential organic compound present in the surface of
the Martian soil, leading to their destruction. These oxidizing molecules may be
formed by UV photolysis of the Martian atmosphere [203–207], interaction of
Martian minerals with atmospheric H2O2 [208] or UV radiation [209], or by chemical
weathering of silicates by low-temperature frost and adsorbed water in the Martian
soil [210, 211]. In addition, amino acids directly exposed to Mars-like UV radiation are
rapidly degraded [212–214]. For example, thin ﬁlms of glycine and D-alanine have
half-lives in the order of 104–105 s when irradiated under simulated noon-time Mars
equatorial surface conditions [213].
If present, amino acids should therefore be in the subsurface of the Red Planet,
shielded from exterior radiation. As shown by Kminek and Bada [215], amino acids
can survive up to 3 billion years at a depth of more than 2 m. In particular, Aubrey
et al. [216] found that the amino acids glycine and alanine have a half-life of up to 1.1
billion years, if buried under simulated Martian conditions. Similar results had
previously been obtained by Kanavarioti and Mancinelli [217], based on amino acid
decomposition rates in aqueous solutions. They found that a fraction of the amino
acids phenylalanine, alanine, and pyroglutamic acid would have been preserved
buried beneath the surface of Mars up to 3.5 billion years.
The mineralogical composition of Martian soils may also have an inﬂuence on the
amino acid stability [216, 218, 219]. Peeters et al. [218, 219] have shown that different
mineralogical compositions of Mars soil analogs lead to differences in amino acid
stability (for a review about Mars soil analogs, see [220]); in particular, clay mineral
matrices seem to have a shielding effect, protecting amino acids against destruction.
In addition, Aubrey et al. [216] determined that amino acids can be preserved for
geologically long periods (billions of years) in sulfate mineral matrices. These results
suggest that locations on Mars containing clay and/or sulfate minerals (for a review,
see, e.g., [221]) should be the prime targets for future missions with the goal to search
for life, in particular for its amino acid constituents.
Delivery of Extraterrestrial Amino Acid to the Earth and its Importance to the Origin
Independently of the environment where extraterrestrial amino acids were formed,
these molecules were exogenously delivered to the early Earth during the period of
1.7 Delivery of Extraterrestrial Amino Acid to the Earth and its Importance to the Origin of Life
late heavy bombardment 4.5–3.8 billion years ago. In fact, comets, meteorites, MMs,
and IDPs are thought to have delivered tons of organic carbon per year to our planet
during this period of time [13, 14, 222], just before life emerged (e.g., [223–225]).
Although we do not know what the production rates of different organic
compounds were on the early Earth (i.e., impact-shock synthesis, endogenous
production by UV light or electrical discharge, and synthesis in submarine hydrothermal vents), the higher the content of key molecules in primitive extraterrestrial
materials, the more likely it is that exogenous material played a role in the origin of
life. As noted by Chyba and Sagan [14], the heavy bombardment may have delivered
or produced organic molecules in the early Earth in quantities comparable to other
sources, possibly playing an important role for the origin of life.
The survival rate of amino acids in extraterrestrial bodies under simulated Earth
atmospheric entry has been studied by several authors. Amino acids present in the
interior of meteorites bigger than 1 mm survive atmospheric deceleration ([226]; see
also Section 1.4), as the meteorite only experiences pyrolytic temperatures (>600  C)
and melting on the surface (<1 mm depth [227]). This does not happen with
smaller particles such as MMs and IDPs, which are uniformly heated. In fact, it is
estimated that most MMs and IDPs are heated for a few seconds to peak temperatures
of up to 1700  C during atmospheric entry [228–230]. However, a small percentage of
dust (MMs and IDPs) enters the atmosphere at temperatures below 700  C [173, 228,
231–233]. Glavin and Bada [234] investigated the sublimation of amino acids from
sub-100 mm Murchison meteorite grains to test the survival of amino acids in MMs
during atmospheric entry. They found that under vacuum (800 mT) and at 550  C,
only glycine survived. All other amino acids (including a-AIB and isovaline) were
completely destroyed, which is not surprising if we consider that, with a few
exceptions, pure amino acids suffer thermal decomposition in the range of
200–600  C [235]. Glavin and Bada [234] also found that methylamine and ethylamine,
which are the a-decarboxylation products of glycine and alanine, respectively, were
not detected. This indicates that a-decarboxylation did not occur or that these amines
were also decomposed during the experiments. Although amino acids are expected
to have a higher atmospheric entry survival in smaller cosmic dust particles
(<50 mm) [228, 231], Matrajt et al. [236] found similar results to Glavin and Bada [234]
using activated alumina with grain sizes ranging from 5 to 9 mm, which suggests that
the amino acid survival is not greatly dependent on the grain size. On the other hand,
Matrajt et al. [236] demonstrated that the combination of porosity and heatshield effect
(i.e., ablative cooling) of extraterrestrial dust particles during atmospheric heating
results in poor heat transfer to the particles interior, providing thermal protection and
allowing organic compounds to survive. This reinforces the idea that IDPs, which are
around 10% organic carbon by mass, can decelerate in the atmosphere and deliver
organic compounds intact [222], and might have been the major source of exogenous
organics in the early Earth as suggested by Chyba and Sagan [14].
Nonprotein amino acids, a-AIB and racemic isovaline, have been detected within
around 1 m above and below the sediments of the iridium-rich Cretaceous/Tertiary
boundary at Stevns Klint, Denmark by Zhao and Bada [237]. These authors suggested
that the sediments represented components of a large bolide (i.e., a comet), which
collided with the Earth 65 million years ago. These results are not in agreement
with xenon measurements at the Cretaceous/Tertiary boundary [238, 239] or with
two-dimensional smoothed particle hydrodynamics simulations of cometary organic
pyrolysis by impacts [13]. However, Chyba et al. [13] noted the lack of relevant kinetic
data for high-temperature pyrolysis of organic molecules. Further work on amino acid
survival in simulated large asteroidal and cometary shock impacts has been performed
[240–243]. Peterson et al. [240] conducted a series of shock impact experiments over a
pressure range of 3.5–32 GPa using powdered Murchison and Allende meteorite
samples. These were previously extracted to eliminate their original amino acid
content and subsequently doped with known amino acids. The results show that
amino acids diminished substantially with increasing high pressures and new
daughter amino acids were formed, in particular b-alanine, glycine, alanine, gABA, and b-AIB. At 30 GPa, the abundances of the daughter compounds exceeded
those of the remaining initial amino acids. However, as noted by Blank et al. [242],
these authors did not refer to the porosity of the starting material or the temperature
conditions of the experiments. Further shock experiments in the range 5–21 GPa and
139–597  C and using aqueous amino acid solutions were performed by Blank
et al. [242]. In all the experiments a large fraction of amino acids survived, supporting
the hypothesis that organic compounds could survive impact processes. In addition,
high-resolution hydrocode simulations of comet impacts, over different projectile
radii, impact velocities, and angles, show that signiﬁcant amounts of amino acids can
be delivered intact to the Earth via kilometer-sized comet impacts [241, 243].
To date, extraterrestrial amino acids have only been unequivocally identiﬁed in
meteorites and a few AMMs. However, the potential precursors of these prebiotic
molecules are abundant in a variety of extraterrestrial environments, including
the ISM and comets. This suggests that meteoritic amino acids may have a
contribution from interstellar, nebular and/or parent body processing. The delivery
of these prebiotic molecules to the early Earth during the period of heavy bombardment (4.5–3.8 billion years ago) may have provided the necessary feedstock for the
evolution of emergent life systems.
Laboratory analyses of meteoritic material together with future missions (including sample return missions) to solar system planets (e.g., Mars Science Laboratory,
ExoMars), satellites, asteroids, and comets may expand our inventory of amino acids
in extraterrestrial environments.
Z.M. and M.A.S. acknowledge ﬁnancial support from the Science and Technology
Facilities Council.
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Amino Acids, Peptides and Proteins in Organic Chemistry 1: Origins and Synthesis of Amino Acids (Amino Acids, Peptides and Proteins in Organic Chemistry (VCH)) | Andrew B. Hughes | download
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yield375
ester359
methyl354
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reduction231
tetrahedron letters227
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journal of organic198
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meoh178
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alkyl169
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Engineering the Genetic Code
Expanding the Amino Acid Repertoire
for the Design of Novel Proteins
ISBN: 978-3-527-31243-6
Demchenko, A. V. (ed.)
Handbook of Chemical
Advances in Stereoselectivity and
ISBN: 978-3-527-31780-6
Lindhorst, T. K.
Essentials of Carbohydrate
Aehle, W. (ed.)
ISBN: 978-3-527-31689-2
Ullmanns Biotechnology and
ISBN: 978-3-527-31603-8
ISBN: 978-3-527-31528-4
Volume 1 - Origins and Synthesis of Amino Acids
Dr. Andrew B. Hughes
# 2009 WIL; EY-VCH Verlag GmbH & Co. KGaA,
Part One Origins of Amino Acids
Extraterrestrial Amino Acids 3
Formation of Amino Acids in the ISM via Solid-Phase Reactions 6
Formation of Amino Acids in the ISM via Gas-Phase Reactions 8
Comets 9
Meteorites 11
Sources of Meteoritic Amino Acids (Extraterrestrial versus
Terrestrial Contamination) 17
Detection of Amino Acids that are Unusual in the Terrestrial
Determination of the Amino Acid Content of the Meteorite Fall
Determination of Enantiomeric Ratios 18
Determination of Compound-Speciﬁc Stable Isotope Ratios
of Hydrogen, Carbon, and Nitrogen 18
Synthesis of Meteoritic Amino Acids 19
Micrometeorites and IDPs 23
Delivery of Extraterrestrial Amino Acid to the Earth and its
Importance to the Origin of Life 24
‘‘Terrestrial’’ Amino Acids and their Evolution
Amino Acids, Peptides and Proteins in Organic Chemistry. Vol.1 – Origins and Synthesis of Amino Acids.
What are the 20 ‘‘Terrestrial’’ Amino Acids? 44
The 21st and 22nd Genetically Encoded Amino Acids 45
Do other Genetically Encoded Amino Acids Await Discovery? 46
Genetic Engineering can Enlarge the Amino Acid Alphabet 47
Signiﬁcance of Understanding the Origins of the
Standard Alphabet 48
What do We Know about the Evolution of the Standard Amino
Acid Alphabet? 49
Nonbiological, Natural Synthesis of Amino Acids 50
Biosynthetic Theories for the Evolutionary Expansion of the
Standard Amino Acid Alphabet 53
Evidence for a Smaller Initial Amino Acid Alphabet 55
Proteins as Emergent Products of an RNA World 56
Stereochemical Rationale for Amino Acid Selection 57
Amino Acids that Life Passed Over: A Role for
Natural Selection? 58
Were the Standard Amino Acids Chosen for High
Biochemical Diversity? 60
Were the Standard Amino Acids Chosen for ‘‘Cheap’’
Biosynthesis? 62
Were the Standard Amino Acids Chosen to Speed Up Evolution? 62
Why Does Life Genetically Encode L-Amino Acids? 64
Summary, Synthesis, and Conclusions 64
Part Two Production/Synthesis of Amino Acids
Use of Enzymes in the Synthesis of Amino Acids 79
Chemo-Enzymatic Processes to Enantiomerically Pure
Acylase Process 81
Amidase Process 83
Amidase Process for a,a-Disubstituted a-Amino Acids 86
Hydantoinase Process 88
Ammonia Lyase Processes 90
Aspartase-Catalyzed Production of L-Aspartic Acid 91
Production of L-Alanine from Fumaric Acid by
an Aspartase–Decarboxylase Cascade 92
Phenylalanine Ammonia Lyase-Catalyzed Production of
L-Phenylalanine and Derivatives 93
Aminotransferase Process 94
Aminotransferase-Catalyzed Production of D-a-H-a-Amino Acids
AADH Process 99
b-Amino Acid Biosynthesis 119
Importance of b-Amino Acids and their Biosynthesis 119
Scope of this Chapter 119
Biosynthesis of b-Amino Acids 120
Biosynthesis of b-Alanine and b-Aminoisobutyric Acid 120
b-Alanine 120
b-Aminoisobutyric Acid 122
Biosynthesis of b-Amino Acids by 2,3-Aminomutases from
a-Amino Acids 122
b-Lysine, b-Arginine, and Related b-Amino Acids 124
b-Phenylalanine, b-Tyrosine, and Related b-Amino Acids 127
b-Glutamate and b-Glutamine 132
b-Leucine 132
b-Alanine 132
Biosynthesis of a,b-Diamino Acids from a-Amino Acids 132
General Biosynthesis of a,b-Diamino Acids 132
Structures and Occurrence of a,b-Diamino Acids in Nature 132
Biosynthesis of Selected a,b-Diamino Acids 135
Biosynthesis of b-ODAP 135
Biosynthesis of the a,b-Diaminopropanoic Acid Moiety in the
Bleomycins 136
Biosynthesis of the Penicillins 137
Biosynthesis of the Capreomycidine Moiety in Viomycine 137
Biosynthesis of the Streptolidine Moiety in Streptothricin F 137
Biosynthesis of a-Keto-b-Amino Acids from a-Amino Acids 139
De Novo Biosynthesis of b-Amino Acids by PKSs 139
General Biosynthesis of Polyketide-Type b-Amino Acids 141
Structures and Occurrence of Polyketide-Type b-Amino Acids
in Nature 142
Biosynthesis of Selected Polyketide-Type b-Amino Acids 149
Long-Chain b-Amino Acids Occurring as Constituents of
the Iturins 149
Biosynthesis of the Ahda Moiety in Microginin 151
Biosynthesis of the Ahpa Residue in Bestatin 151
Biosynthesis of the Adda Residue in the Microcystins 152
b-Amino Acids Whose Biosynthesis is Still Unknown 152
Conclusions and Future Prospects 154
4.2.3.3.3
4.2.3.3.4
4.2.3.3.5
4.2.5.4.3
4.2.5.4.4
Methods for the Chemical Synthesis of Noncoded a-Amino
Acids found in Natural Product Peptides 163
Stephen A. Habay, Steve S. Park, Steven M. Kennedy,
and A. Richard Chamberlin
Noncoded CAAs 164
Noncoded Amino Acids by Chemical Modiﬁcation of Coded
Noncoded Amino Acids with Elaborate Side-Chains 205
Conclusions 226
Synthesis of N-Alkyl Amino Acids 245
N-Methylation via Alkylation 246
SN2 Substitution of a-Bromo Acids 246
N-Methylation of Sulfonamides, Carbamates, and Amides 249
Base-Mediated Alkylation of N-Tosyl Sulfonamides 249
Base Mediated Alkylation of N-Nitrobenzenesulfonamides 250
N-Methylation via Silver Oxide/Methyl Iodide 252
N-Methylation via Sodium Hydride/Methyl Iodide 253
N-Methylation of Triﬂuoroacetamides 257
N-Methylation via the Mitsunobu Reaction 257
N-Methylation via Schiff s Base Reduction 259
Reduction of Schiff s Bases via Transition
Metal-Mediated Reactions 259
Reduction of Schiff s Bases via Formic Acid: The Leuckart
Reaction 260
Quaternization of Imino Species 261
Reduction of Schiff s Bases via Borohydrides 263
Borane Reduction of Amides 264
N-Methylation by Novel Methods 265
1,3-Oxazolidin-5-ones 265
Asymmetric Syntheses 272
Racemic Syntheses 277
N-Alkylation of Amino Acids 280
Borohydride Reduction of Schiff s Bases 280
Sodium Borohydride Reductions 281
Sodium Cyanoborohydride Reductions 281
Sodium Triacetoxyborohydride Reductions 282
N-Alkylation of Sulfonamides 282
Base-Mediated Alkylation of Benzene Sulfonamides 282
Reduction of N-Acyl Amino Acids 283
Reduction of Acetamides 284
Novel Methods for N-Alkylating a-Amino Acids 284
Asymmetric Synthesis of N-Alkyl a-Amino Acids 284
N-Alkylation of 1,3-Oxazolidin-5-ones 284
Recent Developments in the Synthesis of b-Amino Acids 291
Synthesis of b-Amino Acids by Homologation of a-Amino Acids 291
Chiral Pool: Enantioselective Synthesis of b-Amino Acids from
Aspartic Acid, Asparagine, and Derivatives 298
Synthesis of b-Amino Acids by Conjugate Addition of Nitrogen
Nucleophiles to Enones 300
Achiral b-Amino Acids 300
Enantioselective Approaches 304
Addition of ‘‘Chiral Ammonia’’ Equivalents to Conjugated
Prochiral Acceptors 304
Addition of a Nitrogen Nucleophile to a Chiral Acceptor 306
Asymmetric Catalysis 308
Synthesis of b-Amino Acids via 1,3-Dipolar Cycloaddition 312
Synthesis of b-Amino Acids by Nucleophilic Additions 316
Aldol- and Mannich-Type Reactions 316
Morita–Baylis–Hillman-Type Reactions 321
Mannich-Type Reactions 324
Synthesis of b-Amino Acids by Diverse Addition or
Substitution Reactions 328
Synthesis of b-Amino Acids by Stereoselective Hydrogenation
of Prochiral 3-Aminoacrylates and Derivatives 330
Reductions Involving Phosphorus-Metal Complexes 331
Reductions Involving Catalytic Hydrogenations 333
Synthesis of b-Amino Acids by use of Chiral Auxiliaries:
Stereoselective Alkylation 334
Synthesis of b-Amino Acids via Radical Reactions 338
Miscellaneous Methods for the Synthesis of b-Amino Acids 340
Experimental Procedures 348
Representative Experimental Procedure: Synthesis of (S)3-(tert-Butyloxycarbonylamino)-4-phenylbutanoic Acid 348
Representative Experimental Procedure: Synthesis of
(S)-2-(Aminomethyl)-4-phenylbutanoic Acid, (S)-19 350
Representative Experimental Procedure: Synthesis of b3-Amino Acids
by Conjugate Addition of Homochiral Lithium N-Benzyl-N(a-methylbenzyl)amide 352
Representative Experimental Procedure: Synthesis of Cyclic and
Acyclic b-Amino Acid Derivatives by 1,3-Dipolar Cycloaddition 353
Representative Experimental Procedure: Synthesis of (R)-3-tertButoxycarbonylamino-3-phenylpropionic Acid Isopropyl Ester using
a Mannich-Type Reaction 354
Representative Experimental Procedure: General Procedure for the
Hydrogenation of (Z)- and (E)-b-(Acylamino) acrylates by Chiral
Monodentate Phosphoramidite Ligands 354
Representative Experimental Procedure: Synthesis of Chiral
a-Substituted b-Alanine 355
Representative Experimental Procedure: Synthesis of Chiral b-Amino
Acids by Diastereoselective Radical Addition to Oxime Esters 357
Synthesis of Carbocyclic b-Amino Acids 367
Synthesis of Carbocyclic b-Amino Acids 368
Synthesis of Carbocyclic b-Amino Acids via Lithium Amide-Promoted
Conjugate Addition 369
Synthesis of Carbocyclic b-Amino Acids by Ring-Closing
Metathesis 371
Syntheses from Cyclic b-Keto Esters 372
Cycloaddition Reactions: Application in the Synthesis of Carbocyclic
b-Amino Acids 375
Synthesis of Carbocyclic b-Amino Acids from Chiral Monoterpene
b-Lactams 377
Synthesis of Carbocyclic b-Amino Acids by Enantioselective
Desymmetrization of meso Anhydrides 378
Miscellaneous 379
Synthesis of Small-Ring Carbocyclic b-Amino Acid
Derivatives 383
Synthesis of Functionalized Carbocyclic b-Amino Acid
Derivatives 385
Enzymatic Routes to Carbocyclic b-Amino Acids 393
Enantioselective N-Acylations of b-Amino Esters 394
Enantioselective O-Acylations of N-Hydroxymethylated b-Lactams 394
Enantioselective Ring Cleavage of b-Lactams 395
Biotransformation of Carbocyclic Nitriles 396
Enantioselective Hydrolysis of b-Amino Esters 396
Analytical Methods for the Enantiomeric Separation of Carbocyclic
b-Amino Acids 397
Conclusions and Outlook 398
Experimental Procedures 399
Synthesis of Hydroxy Amino Ester Ethyl (1R,2S,4S)2-(Benzyloxycarbonylamino)-4-hydroxycyclohexanecarboxylate (205a)
by Oxirane Ring Opening of with Sodium Borohydride 399
Synthesis of Bicyclic b-Lactam (1R,5S)-6-azabicyclo[3.2.0]hept-3en-7-one (223) by the Addition of Chlorosulfonyl Isocyanate
to Cyclopentadiene 399
Synthesis of b-Amino Ester Ethyl cis-2-aminocyclopent3-enecarboxylate Hydrochloride (223a) by Lactam Ring-Opening
Reaction of Azetidinone 223 400
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
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
Isomerization of Azido Amino Ester to Ethyl (1S,2R,3R,4R)4-Azido-2-(tert-butoxycarbonylamino)-3-hydroxycyclopentanecarboxylate
(230) 401
Lipase-Catalyzed Enantioselective Ring Cleavage of 4,5-Benzo-7azabicyclo[4.2.0]octan-8-one (271), Synthesis of (1R,2R)- and
(1S,2S)-1-Amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic Acid
Hydrochlorides (307 and 308) 402
Lipase-Catalyzed Enantioselective Hydrolysis of Ethyl trans-2aminocyclohexane-1-carboxylate (298), Synthesis of (1R,2R)- and
(1S,2S)-2-Aminocyclohexane-1-carboxylic Acid Hydrochlorides
(309 and 310) 404
Synthetic Approaches to a,b-Diamino Acids 411
Construction of the Carbon Backbone 411
Methods for the Formation of the Cb–Cc Bond 411
Reaction of Glycinates and Related Nucleophiles with Electrophiles 411
Dimerization of Glycinates 416
Through Cyclic Intermediates 417
Methods in Which the Ca–Cb Bond is Formed 420
Nucleophilic Synthetic Equivalents of CO2R 420
Electrophilic Synthetic Equivalents of CO2R and Other Approaches 423
Methods in Which the CbCb0 or CcCc0 Bonds are Formed 424
Introduction of the Nitrogen Atoms in the Carbon Backbone 425
From Readily Available a-Amino Acids 425
From Allylic Alcohols and Amines 427
From Halo Alkanoates 428
From Alkenoates 429
Electrophilic Amination of Enolates and Related Processes 431
From b-Keto Esters and Related Compounds 433
Experimental Procedures 434
(SS,2R,3S)-(þ)-Ethyl-2-N-(diphenylmethyleneamino)-3-N-(p-toluenesulﬁnyl)-amino-3-phenylpropanoate (14b) 434
Synthesis of Ethyl (2R,3R)-3-amino-2-(4-methoxyphenyl)
aminopentanoate 32a via Asymmetric aza-Henry Reaction 434
Synthesis of Halogenated a-Amino Acids 441
Halogenated Amino Acids with a Hydrocarbon Side-Chain 442
Halogenated Alanines and Prolines 442
Halogenated a-Amino Acids with Branched Hydrocarbon
Side-Chains 445
Halogenated Valines and Isoleucines 445
Halogenated Leucines 451
Halogenated Amino Acids with an Aromatic Side-Chain 457
Halogenated Phenylalanines and Tyrosines 457
Halogenated Histidines 460
Halogenated Tryptophans 462
Halogenated Amino Acids with Heteroatoms in the Aliphatic
Side-Chain 463
Halogenated Aspartic and Glutamic Acids 463
Halogenated Threonine and Lysine 465
Synthesis of Isotopically Labeled a-Amino Acids 473
Enzyme-Catalyzed Methods 473
Chiral Pool Approach 477
Chemical Asymmetric Methods 483
Conclusions 488
Experimental Procedures 489
Biocatalysis: Synthesis of [15N]L-amino Acids from a-Keto Esters
using a One-Pot Lipase-Catalyzed Hydrolysis and Amino Acid
Dehydrogenase-Catalyzed Reductive Amination 489
Chiral Pool: Preparation of Aspartic Acid Semi-Aldehydes as Key
Synthetic Intermediates; Synthesis of Methyl (2S)-N,N-di-tertbutoxycarbonyl-2-amino-4-oxobutanoate from L-aspartic Acid 489
Asymmetric Methods: Asymmetric Alkylation Using the Williams
Oxazine and Subsequent Hydrogenation to Give the
a-Amino Acid 490
Synthesis of Unnatural/Nonproteinogenic a-Amino Acids 495
Chemical Methods 497
Resolution Approaches 497
Side-Chain Methods 497
12.2.2.1 Introduction of the Side-Chain 497
12.2.2.2 Modiﬁcations of the Side-Chain 500
Introduction of Functionality 502
12.2.3.1 Nitrogen Introduction 502
12.2.3.2 Carboxylic Acid Introduction 503
12.2.3.2.1 Strecker Reaction 503
Hydrogenation 504
Other Chemical Methods 508
Enzymatic Methods 508
Acylases 509
Hydantoinases 510
Ammonia Lyases 510
Transaminases 511
Dehydrogenases 513
Amino Acid Oxidases 514
Decarboxylases 515
Experimental Procedures 516
Side-Chain Introduction with a Phase-Transfer Catalyst 516
Introduction of Nitrogen Through an Oxazolidinone Enolate
with a Nitrogen Electrophile 517
Asymmetric Hydrogenation with Knowles Catalyst 518
Asymmetric Hydrogenation with Rh(DuPhos) Followed by EnzymeCatalyzed Inversion of the a-Center 519
Synthesis of g- and d-Amino Acids 527
g-Amino Acids 528
GABA Analogs 528
a- and b-Hydroxy-g-Amino Acids 534
Alkene-Derived g-Amino Acids 539
SAAs 541
Miscellaneous Approaches 542
d-Amino Acids 547
SAAs 547
Furanoid d-SAA 547
Pyranoid d-SAA 552
d-Amino Acids as Reverse Turn Mimetics 554
d-Amino Acids for PNA Design 562
Miscellaneous Examples 564
Conclusions 566
Synthesis of g-Aminobutyric Acid Analogs 573
a-Substituted g-Amino Acids 575
b-Substituted g-Amino Acids 579
Pregabalin 581
Baclofen and Analogs 584
g-Substituted g-Amino Acids 592
Vigabatrin 597
Halogenated g-Amino Acids 599
Disubstituted g-Amino Acids 600
a,b-Disubstituted g-Amino Acids 600
a,g-Disubstituted g-Amino Acids 601
b,b-Disubstituted g-Amino Acids 604
b,g-Disubstituted g-Amino Acids 604
Trisubstituted g-Amino Acids 604
Hydroxy-g-Amino Acids 605
a-Hydroxy-g-Amino Acids 605
b-Hydroxy-g-Amino Acids 606
a-Hydroxy-g-Substituted g-Amino Acids 619
b-Hydroxy-g-Substituted g-Amino Acids 619
b-Hydroxy-Disubstituted g-Amino Acids 638
Unsaturated g-Amino Acids 640
Unsaturated Substituted g-Amino Acids 641
Cyclic g-Amino Acids 644
Cyclopropyl g-Amino Acids 644
Cyclobutyl g-Amino Acids 648
Cyclopentyl g-Amino Acids 653
Cyclohexyl g-Amino Acids 663
Conclusions 666
Experimental Procedures 666
(R)-2-Ethyl-4-nitrobutan-1-ol (36c) 666
N-tert-Butyl-N-(p-chlorophenylethyl) a-Diazoacetamide 669
(R )-5-[(1-Oxo-2-(tert-butoxycarbonylamino)-3-phenyl)-propyl]-2,2dimethyl-1,3-dioxane-4,6-dione 670
(R )- and (S)-[2-(Benzyloxy) ethyl]oxirane 671
14.12.5
14.12.6
14.12.8
Dimethyl (S,S)-(–)-3-N,N-bis(a-Methylbenzyl)-amino-2oxopropylphosphonate 672
Boc-L-leucinal 673
Cross-Coupling of N-tert-Butylsulﬁnyl Imine and tert-Butyl
3-oxopropanoate 674
(10 S,4S)-4-Bromomethyl-1-(1-phenyleth-1-yl)-pyrrolidin-2-one
(þ)-(R,S)-4-Amino-2-cyclopentene-1-carboxylic Acid 676
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Origins of Amino Acids
The space between the stars, the interstellar medium (ISM), is composed of gasphase species (mainly hydrogen and helium atoms) and submicron dust grains
(silicates, carbon-rich particles, and ices). The ISM has many different environments
based on its different temperatures (Tk), hydrogen density (nH), and ionization state
of hydrogen (for reviews, see [1–3]); it includes the diffuse ISM (Tk  100 K,
nH  10–300 cm3), molecular clouds (Tk  10–100 K, nH  103–104 cm3; e.g., [4])
[molecular clouds are not uniform but instead have substructures [5] – they contain
high-density clumps (also called dense cores; nH  103–105 cm3), which have
higher densities than the surrounding molecular cloud; even higher densities are
found in small regions, commonly known as hot molecular cores, which will
be the future birth place of stars], and hot molecular clouds (Tk  100–300 K,
nH  106–108 cm3; e.g., [6]). Observations at radio, millimeter, submillimeter, and
infrared frequencies have led to the discovery of numerous molecules (currently
more 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 collapse
of a dense cloud of interstellar gas and dust leads to the formation of a so-called solar
nebula. Atoms and molecules formed in the ISM, together with dust grains are
incorporated in this solar nebula, serving as building blocks from which future
planets, comets, asteroids, and other celestial bodies may originate. Solar system
bodies, 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 extraterrestrial
molecules, which might have a heritage from interstellar, nebular, and/or parent
body processing. Delivery of these molecules to the early Earth and Mars during the
late heavy bombardment (4.5–3.8 billion years ago) may have been important for the
origin of life [13, 14]. Among the molecules delivered to the early Earth, amino acids
may 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 describe
different extraterrestrial environments where amino acids may be present and
H3þ
H2Oþ
HCOþ
HN2þ
HOCþ
H2Sþ
CO2þ
HCSþ
OHþ
CNþ
COþ
N2þ
CFþ
H3Oþ
HCNHþ
HNCO
HOCOþ
NH4þ
H3COþ
c-C3H2
C4H
HNCCC
NH2CHO
H2CCCC
HCCCCH
H2C3Nþ
c-H2C3O
HC2CHO
c-C2H4O
C6H
HCCCCCCH
Table 1.1 Summary of molecules identified in the interstellar and circumstellar mediuma.
C8H
j 1 Extraterrestrial Amino Acids
c-SiC2
Observations suggest the presence of polycyclic aromatic hydrocarbons in the interstellar gas (e.g., [244]).
SOþ
Figure 1.1 Molecular structures of conformers I and II of glycine
in the gas phase (adapted from [21, 29]).
detected, their proposed formation mechanisms, and possible contribution to the
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 [15–28].
While in theory glycine may have several conformers in the gas phase [29], astronomical 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, larger
dipole moment, and therefore stronger spectral lines [30]. Only upper limits of both
conformers were found in the ISM until Kuan et al. [25] reported the detection
of 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 spectral
lines necessary for the identiﬁcation of interstellar glycine have not yet been found.
In addition, they argued that some of the spectral lines identiﬁed as glycine by
Kuan et al. [25] could be assigned to other molecular species. Further negative results
include the astronomical searches of Cunningham et al. and Jones et al. [27, 28], who
claim that their observations rule out the detection of both conformers I and II of
glycine in the hot molecular core Sgr B2(N-LMH). They conclude that it is unlikely
that Kuan et al. [25] detected glycine in either Sgr B2(N-LMH) or Orion-KL. No other
amino acid has been detected in the ISM. Despite these results, amino acids were
proposed 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 (solidphase reactions), or synthesized in the gas phase via ion–molecule reactions (gasphase reactions). These two processes will now be described in more detail (for a
review, see, e.g., [31]).
Formation 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,
1.2 ISM
Table 1.2 Abundances of interstellar ices (normalized to H2O) in the
high-mass protostellar objects W33A and NGC758:IRS9, in the lowmass protostellar object Elias 29, and the field star Elias 16.
Ice specie
NGC758:IRS9
OCN–
1.7–7
0.4–2
Adapted from [31, 32, 52].
which may occur in cold molecular clouds (e.g., [32] and references therein). In these
regions of the ISM, in which temperatures are very low (<50 K), atoms and molecules
in the gas phase will be accreted onto the surface of dust grains leading to the
formation of ice mantles [33, 34]. Diffusion of accreted atoms leads to surface
reactions, forming additional species in the ice mantles. These interstellar ices are
mainly composed of H2O, CO, CO2, CH4, CH3OH, and NH3, with traces of other
species (Table 1.2; [32, 34–38]). Once these ice grains are formed, energetic processes
[e.g., cosmic rays and ultraviolet (UV) irradiation] may change the ice mantle
A range of interstellar ice analogs have been irradiated at low temperatures (10 K)
to produce a variety of amino acids. Holtom et al. [39] used galactic cosmic ray
particles to irradiate an ice mixture containing carbon dioxide (CO2) and methylamine (CH3NH2), which produced hydroxycarbonyl (HOCO) and aminomethyl
(CH2NH2) radicals. The recombination of these radicals would then form glycine
and its isomer (CH3NHCOOH). Briggs et al. [40] UV-irradiated a mixture of CO :
H2O : NH3 (5 : 5 : 1) at 12 K for 24 h. This resulted in the formation of an organic
residue, which included among other organic compounds, 0.27% of glycine. Ice
mixtures containing H2O : CH3OH : NH3 : CO : CO2 (2 : 1 : 1 : 1 : 1 molar composition; [41]), and H2O with NH3, CH3OH, and HCN (0.5–5% NH3, 5–10% CH3OH,
and 0.5–5% HCN, relative to H2O [42]) were UV-irradiated in high vacuum at below
15 K. While Bernstein et al. [42] obtained glycine and racemic mixtures (D/L  1) of
alanine and serine, a large variety of amino acids were found by Munõz Caro et al. [41].
These results were conﬁrmed by Nuevo et al. [43, 44].
The exact formation pathway of amino acids in interstellar ices is unknown, but the
Strecker synthesis ([42]; for more details, see Section 1.4), reactions on the surface of
polycyclic aromatic hydrocarbon ﬂakes [45], and radical–radical reactions [46, 47]
have been proposed. As radical–radical reactions can occur with almost no activation
energy [47], theoretical modeling suggests that glycine may be formed in interstellar
ice mantles via the following radical–radical reaction sequence:
CO þ OH ! COOH
CH3 þ COOH ! CH3 COOH
NH2 þ CH3 COOH ! NH2 CH2 COOH þ H
Quantum chemical calculations indicate that amino acids may also be formed by
recombination of the radicals COOH and CH2NH2, which are produced by dehydrogenation of H2O and CH3OH, and hydrogenation of HCN, respectively [47].
However, all radical–radical reactions described above require the radicals to diffuse
into and/or onto the ice mantle which, as noted by Woon [47], may only occur at
temperatures of 100 K or higher, much higher than the temperature in molecular
clouds. Furthermore, Elsila et al. [48] used isotopic labeling techniques to test whether
Strecker synthesis or radical–radical reactions were responsible for amino acid
formation in interstellar ice analogs. Their results show that amino acid formation
occurs via multiple routes, not matching the previously proposed Strecker synthesis
or radical–radical mechanisms. Ultimately, the need for high UV ﬂux to produce
amino acids in ice mantles contrasts with the low expected efﬁciency of UV photolysis
in dark molecular clouds [4]. This, together with the fact that amino acids have low
resistance to UV photolysis [49], raises concerns about the amino acid formation in
interstellar ices by UV photolysis.
Formation of Amino Acids in the ISM via Gas-Phase Reactions
Potential mechanisms alternative to solid-phase reactions include gas-phase
formation of interstellar amino acids via ion–molecule reactions. Amino acids,
once formed, could potentially survive in the gas phase in hot molecular cores,
because the UV ﬂux is sufﬁciently low (i.e., 300 mag of visual extinction) [31].
Alcohols, aminoalcohols, and formic acid evaporated from interstellar ice grains
(Table 1.2; [50–53]) may produce amino acids in hot molecular cores through
exothermic alkyl and aminoalkyl cation transfer reactions [52]. Aminoalkyl cation
transfer from aminomethanol and aminoethanol to HCOOH can produce protonated glycine and b-alanine, respectively via the following reactions [52]:
NH2 CH2 OH2þ þ HCOOH ! NH2 CH2 COOH2þ þ H2 O
NH2 ðCH2 Þ2 OH2þ þ HCOOH ! NH2 ðCH2 Þ2 COOH2þ þ H2 O
An electron recombination will then produce the neutral amino acids. Further
alkylation may produce a large variety of amino acids through elimination of a water
molecule [31, 52].
1.3 Comets
Alternatively, Blagojevic et al. [54] have experimentally proven the gas-phase
formation of protonated glycine and b-alanine, by reacting protonated hydroxylamine
with acetic and propanoic acid, respectively:
NH2 OH þ þ CH3 COOH ! NH2 CH2 COOH þ þ H2 O
NH2 OH þ þ CH3 CH2 COOH ! NH2 ðCH2 Þ2 COOH þ þ H2 O
Neutral amino acids could then be produced by dissociative recombination
reactions [54].
Independently of the mechanism of synthesis (solid-phase or gas-phase reactions),
once formed, amino acids would need to be resistant and survive exposure to cosmic
rays and UV radiation in the ISM. The stability of amino acids in interstellar gas and
on 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 frozen
argon, nitrogen, or water matrices to test their stability against space radiation. It was
shown that these amino acids have very low stability against UV photolysis.
Therefore, amino acids will not survive in environments subject to high UV ﬂux,
such as the diffuse ISM. This does not eliminate formation of amino acids in the ISM,
but instead requires that amino acids are incorporated into UV-shielded environments such as hot molecular cores, in the interior of comets, asteroids, meteorites,
Comets are agglomerates of ice, organic compounds, and silicate dust, and are
some of the most primitive bodies in the solar system (for reviews about comets, see,
e.g., [55–57]). Comets were ﬁrst proposed to have delivered prebiotic molecules to the
early Earth by Chamberlin and Chamberlin [58]. Since then, space telescopes (such
as the Hubble Space Telescope, Infrared Space Observatory, and Spitzer Space
Telescope; e.g., [59–66]), ground-based observations (e.g., [67–69]), cometary ﬂy-bys
(Deep Space 1 mission, and Vega1, Vega2, Suisei, Sakigake, ICE, and Giotto
spacecraft missions; e.g., [70–76]), impacts (Deep Impact mission, which impacted
into the 9P/Tempel comets nucleus; e.g., [77–79]), collection of dust from the coma
of a comet (Stardust mission to comet Wild-2; e.g., [80–84]), and rendezvous missions
(such as the Rosetta mission, which will encounter the comet 67P/Churyumov–
Gerasimenko 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 on
comet Halley [71], but their presence could not be conﬁrmed due to the limited
resolution of the mass spectrometers on board the Giotto and Vega spacecrafts. In
addition, only an upper limit of less than 0.15 of glycine relative to water has been
determined in the coma of Hale–Bopp using radio telescopes (Table 1.3; [69]).
Although several amino acid precursors (see Section 1.4), including ammonia,
Table 1.3 Molecular abundances of ices for comets Halley, Hyakutake, and Hale–Bopp.
CH3C2H
0.3
0.4
6–30a
0.2–1a
0.2
0.2–0.8a
Abundances are normalized to H2O and were measured at around 1 AU from the Sun. Adapted
from [8, 32, 69, 86, 245].
Extended sources (the abundance is model dependent).
Measured at 2.9 AU from the Sun.
Abundance deduced from CS.
1.4 Meteorites
HCN, formaldehyde, and cyanoacetylene, have been observed in the Hyakutake and
Hale–Bopp comets [7], only a very limited number of carbonyl compounds necessary
for the synthesis of amino acids were detected in comets [7, 32, 86]. The ultimate
proof for the presence of amino acids in comets is a sample return mission such as
Stardust, which collected dust from the coma of the Wild-2 comet using a lightweight
material called aerogel [80]. Analyses of comet-exposed aerogel samples show
a relative molar abundance of glycine that slightly exceeds that found in control
samples, suggesting a cometary origin for this amino acid [83]. Compound-speciﬁc
isotopic analyses of glycine present in comet-exposed aerogel samples have not yet
been performed and therefore it has not been possible to ultimately constrain
its origin. Other amino acids present in the comet-exposed aerogel samples included
e-amino-n-caproic acid, b-alanine, and g-amino-n-butyric acid (g-ABA). The similarity in the distribution of these amino acids in the comet-exposed sample, the witness
tile (which witnessed all the terrestrial and space environments as the comet-exposed
samples, but did not see comet Wild-2), and the Stardust impact location soil
indicates a terrestrial origin (contamination) for these amino acids [83].
Meteorites are extraterrestrial objects that survived the passage through the Earths
atmosphere and the impact with the Earths surface. Excepting the lunar and Martian
meteorites [87–91], all meteorites are thought to have originated from extraterrestrial
bodies located in the asteroid belt (e.g., [92–98]). Although unproven, it was also
suggested that they could have originated from comets ([99–102] and references
therein). 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., [103–105]). A very primitive class
of stony meteorites, named carbonaceous chondrites, has not been melted since
their 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 are
the CI-, CM-, CK-, CO-, CR-, CV-, CH-, and CB-type chondrites. Chondrites are also
classiﬁed and grouped into petrographic types. This refers to the intensity of thermal
metamorphism or aqueous alteration that has occurred on the meteorite parent
body, ranging from types 1 to 6. A petrologic type from 3 to 1 indicates increasing
aqueous alteration. A petrologic type from 3 to 6 indicates increasing thermal
Carbonaceous chondrites have a relatively high carbon content and can contain up
to 3 wt% of organic carbon. More than 70% of it is composed of a solvent-insoluble
macromolecular material, while less than 30% is a mixture of solvent-soluble organic
compounds. Carbonaceous chondrites, as revealed by extensive analyses of the
Murchison meteorite, have a rich organic inventory that includes organic compounds important in terrestrial biochemistry (Table 1.4). These include amino
acids (e.g., [106–108]), carboxylic acids (e.g., [109, 110]), purines and pyrimidines
Table 1.4 Abundances (in ppm) of the soluble organic matter found in the Murchison meteorite.
Carboxylic acids (monocarboxylic)
Hydrocarbons (aromatic)
Hydrocarbons (aliphatic)
Basic N-heterocycles
Adapted from [9, 10, 161, 246].
(e.g., [111–113]), polyols [114], diamino acids [115], dicarboxylic acids (e.g., [116–
119]), 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 ﬁrst evidence of extraterrestrial amino acids in a meteorite was obtained
by Kvenvolden et al. [121], after analyzing a sample of the Murchison meteorite
which had recently fallen in Australia in 1969. These authors detected several amino
acids in this meteorite, including the nonprotein amino acids a-AIB and isovaline,
which suggested an abiotic and extraterrestrial origin for these compounds. Since
then, Murchison has been the most analyzed carbonaceous chondrite for amino
acids, with more than 80 different amino acids identiﬁed, the majority of which are
rare (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 complete
structural diversity (i.e., all isomers of a certain amino acid are present). They can be
divided into two structural types, monoamino alkanoic acids and monoamino
dialkanoic acids, which can occur as N-alkyl derivatives or cyclic amino acids, with
structural preference in abundance order a > g > b. Branched-chain amino acid
isomers predominate over straight ones and there is an exponential decline in
concentration 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 abundances 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
D,L-b-AIB
D-b-ABA
L-b-ABA
a-AIB
D-a-ABA
L-a-ABA
L-Isovaline
51  31
65  16
135  50
261  15
92  32a
2110  144
1063  268
717  192
147  88
617  79
647  58
424  18a
1968  350
463  68a
100  15
342  103
537  117
801  200
436  227a
2919  433
1269  202
1331  472
343  102
720  95
956  171
708  171a
2901  328
295  111
347  98
350  183
458  209
2834  780a
1753e,f
Y-74 662
1306  83a
343  171
352  161
155  16
172  40
2706  377
431  159a
127  24
151  73
317  55
316  55
1448  682
442  238
164  21d
LEW 90 500
<1753
Y-791 198
208  26
495  6
1396  157
6425  645
128  13
113  10
389  180a
72  33
134  12
49  21
130  83
<62a
<72a
458  346
<151a
163  135
418  106
211  74
1003  110
327  84a
1118  729
796  97
1548  187
125  92
332  120
283  144a
740  219
100  70
101  78
136  49
159  136
105  62
145  22
111  48
279  24
68  23a
788  66
897  72
1136  351
240  18
347  57
487  50a
ALHA 77 306
110  44
134  19
33  8
33  12
250  40
19  5a
29  4
43  6
21  7
23  6
300  75
338  31
308  68d
ALH 83 100
Table 1.5 Summary of the average blank corrected amino acid concentration (in ppb) in the 6 M HCl acid-hydrolyzed hot-water extracts of carbonaceous chondrites.
B-7904
Y-79 331
Table NaN
575  159
169  39
259  61
630  135
1028  239
881  280
369  117
197  21
168  35
389  87
605  149
380  97
55  17
16  6
95  10
201  14
228  45
28  10
29  13
24  3
64  10
101  13a
106  27
201  61
54  14
274  74
147  52a
68  18
99  39
33  9
174  50
<174a
LAP 0227
MET 01 070
ALH 88 045
617  83
1401  146
600
84  12
82  22
157  14
438  142a
46  33
12  7a
<163a
39  37
13  11a
<194a
30  2
146  8
81
372  11
217  12a
707  80
2052  311
628  294
148  70
69  9
332  99a
28  16
54  18
15  6
61  31
51  26a
457  121
317  28
307  129
127  92
100  42
329  41
241  149a
<56  a
84  40a
83  8
16  2
306  48
147  17
77  10
75  18
GRA 95 229
551  75
576  51
3489  389
4209  415
1807  84a
40 496  1028
3143  495
1914  398
2091  405
52 465  6860
51 141  6272
3903  377
4239  494
30 257  1226
2956  125
2955  120
29 245  2229a
EET 92 042
409  41
465  24
3090  422
4468  503
742  42a
24 975  608
3046  50
1512  66
1429  333
21 664  1009
22 297  1583
1327  33
1458  99
50 210  870
1123  54
1244  28
22 806  459a
349  33a
57  5
189  23
124  7
489  34
32  11
140  34
417  55
62  10
49  23
274  14
330  59
34  5
Shişr 033
<89a
875  188
223  55
1092  243
534  24a
49  12
173  80
856  188
195  112a
48  3
<131a
136  14
122  6
54  6
74  22
96  20
49  5a
13  2
19  4
40  3
50  11a
GRO 95 577
The associated errors are based on the standard deviation of the average value. Adapted from [126–128, 130–133, 136–138, 140–142].
Enantiomers could not be detected individually, so the total (D þ L) abundance of the amino acids is reported in the row for the D-enantiomer.
Tentative identiﬁcation.
Optically pure standard not available for enantiomeric identiﬁcation.
g-ABA and D,L-b-AIB could not be separated under the chromatographic conditions used, so the total abundance is reported in the cell corresponding to g-ABA.
g-ABA and D,L-b-ABA could not be separated under the chromatographic conditions used, so the total abundance is reported in the cell corresponding to g-ABA.
The value corresponds mostly to g-ABA.
Detected but too small to estimate.
ND ¼ not determined.
abundance similar to the CM2 Murchison. While the CM2 Y-791 198 has an
extremely high total amino acid concentration (71 ppm [131, 132]), which is about
5 times as high as Murchison (15 ppb), the CM2s Essebi, Nogoya, Mighei [133], Allan
Hills (ALHA) 77 306 [134–136], ALH 83 100 [130], Y-79 331, and Belgica (B-)
7904 [137] have much lower amino acid abundances, some being depleted in amino
acids (Table 1.5). For Essebi, Botta et al. [133] consider that the high abundances
(relative to glycine) of g-ABA and b-alanine are derived from terrestrial contamination
at the fall site.
CM1s chondrites were analyzed for the ﬁrst time for amino acids by Botta
et al. [138]. ALH 88 045, MET (Meteorite Hills) 01 070, and LAP (La Paz) 0227 have
total amino acid concentration much lower than the average of the CM2s. According
to Botta et al. [138], these results and the similar relative amino acid abundances
between the CM1 class meteorites and the CM2 Murchison are explained by
decomposition of a CM2-like amino acid distribution during extensive aqueous
alteration in the CM1s meteorite parent body.
The CI1 chondrites Orgueil and Ivuna have total amino acid abundances of about
4.2 ppm, with b-alanine, glycine, and g-ABA as the most abundant amino acids, while
glycine and a-AIB are the most abundant amino acids in the CM2 chondrites
Murchison and Murray [136]. The CV3 Allende [133, 139] and the ungrouped C2
Tagish Lake meteorites [133, 140] are essentially free of amino acids (total amino acid
abundances of 2 and 1 ppm, respectively), with most of the amino acids probably
being terrestrial contaminants.
The highest amino acid abundances ever measured in a meteorite were found
on the CR2s EET 92 042 and GRA 95 229, with total amino acid concentrations of
180 and 249 ppm, respectively [141]. The most abundant amino acids present in
these meteorites are the a-amino acids glycine, isovaline, a-AIB and alanine.
The high d 13 C results together with the racemic enantiomeric ratios determined [141] for most amino acids indicate an extraterrestrial origin for these
compounds (see Section 1.4.1). In addition, these authors analyzed the CR1 GRO
95 577, which was found to be depleted in amino acids (1 ppb). Other CRs analyzed
include the CR2 chondrites Renazzo [133] and Shişr 033 [142]. Renazzo has a total
amino acid abundance of only 4.8 ppm, which is similar to the CI chondrites
Orgueil and Ivuna. This meteorite has a distinct amino acid distribution, with gABA, glycine, and L-glutamic acid as the most abundant amino acids. Only upper
limits for alanine and a-AIB were reported for Renazzo, while isovaline was
tentatively identiﬁed [133]. The most abundant amino acids in the Shişr 033
meteorite are glycine, L-glutamic acid, L-alanine, and L-aspartic acid. In addition
to this, Shişr 033 D/L protein amino acid ratios are smaller than 0.4 and in
agreement with the D/L amino acid ratios of Shişr 033 fall-site soil. These results
suggest extensive amino acid contamination of the meteorite (see Section 1.4.1).
However, Shişr 033 contains a small fraction of extraterrestrial amino acids, as
indicated by the presence of a-AIB [142].
Apart from carbonaceous chondrites, amino acid analyses have also been carried
out on Martian meteorites. As our present knowledge of amino acids potentially
present in Mars may be accessed from these meteorites (see also Section 1.6), amino
acid analyses have been performed in the Martian meteorites EET 79 001 [143],
ALH 84 001 [144], and Miller Range (MIL) 03 346 [145]. In all three samples, the
meteoritic amino acid distribution was similar to the one in the Allan Hills ice, which
suggested that the ice meltwater was the source of the amino acids in these
meteorites. In addition, analysis of the Nakhla meteorite, which fell in Egypt, shows
that the amino acid distribution (including the D/L ratios) is similar to the one in the
sea-ﬂoor sediment from the Nile Delta [146].
Sources of Meteoritic Amino Acids (Extraterrestrial versus Terrestrial Contamination)
In order to determine if the amino acids present in carbonaceous chondrites are
indigenous to the meteorites, four approaches are generally applied: (i) detection
of amino acids that are unusual in the terrestrial environment, (ii) comparison of
the absolute abundances of amino acids in the meteorites to the levels found in the
fall-site environment (soil or ice), (iii) determination of enantiomeric ratios (D/L
ratios), and (iv) d
etermination of compound speciﬁc stable isotope ratios of hydrogen,
carbon, and nitrogen.
1.4.1.1 Detection of Amino Acids that are Unusual in the Terrestrial Environment
The majority of the more than 80 different amino acids identiﬁed in carbonaceous
meteorites are nonexistent (or rare) in terrestrial proteins (for a review, see,
e.g., [108]). Extraterrestrial meteoritic nonprotein amino acids such as a-AIB,
isovaline, b-ABA, and b-AIB have concentrations usually in the order of a few
hundred parts per billion maximum (Table 1.5). However, Murchison [126] has a
higher abundance of a-AIB (2901 ppb), while Murray and LEW90 500 [126, 129, 130]
contain higher abundances of both a-AIB (1968 and 2706 ppb, respectively) and
isovaline (2834 and 1306 ppb, respectively). The highest abundances of a-AIB,
isovaline, b-ABA, and b-AIB were detected in the CR2 chondrites EET92 042
and GRA95 229 [141]. The CM2 Y791 198 ([131, 132]) contained similar abundances
of a-AIB, b-ABA, and b-AIB as EET92 042 and GRA95 229, but lower abundance of
isovaline (Table 1.5).
1.4.1.2 Determination of the Amino Acid Content of the Meteorite Fall Environment
Samples collected from meteorite fall sites have been analyzed for amino acids and
their distribution compared to the one from the carbonaceous chondrites. Ice from
the Antarctic regions of Allan Hills [143, 144] and La Paz [130, 147] contained only
trace levels of aspartic acid, serine, glycine, alanine, and g-ABA (less than 1 ppb of
total amino acid concentration). No isovaline or b-ABA was detected above detection
limits. Only an upper limit of a-AIB (<2 ppt) was detected in the Allan Hills ice [144],
while a relatively high abundance (ranging between 25 and 46 ppt) of a-AIB was
detected in the La Paz Antarctic ice [130, 147].
Soil samples from the Shişr 033 fall site show that the most abundant amino
acids are L-glutamic acid, L-aspartic acid, glycine, and L-alanine, with nonprotein
amino acids absent from the soil [142]. In addition, comparison of the protein
amino acid enantiomeric ratios of Shişr 033 to those of the soil (D/L < 0.4) shows
agreement, indicating that most of the amino acids in this meteorite are terrestrial
in origin. On the other hand, a soil sample collected close to the fall site of the
Murchison meteorite showed much smaller amino acid relative concentrations
(glycine ¼ 1) when compared to the Murchison meteorite, indicating that the
majority of the amino acids present in this meteorite are extraterrestrial in
origin [133].
1.4.1.3 Determination of Enantiomeric Ratios
Chirality is a useful tool for determining the origin (biotic versus abiotic) of amino
acids in meteorites. On Earth most proteins and enzymes are made of only the
L-enantiomer of chiral amino acids; however, abiotic synthesis of amino acids
yields racemic mixtures (D/L  1). If we assume that meteoritic protein amino acids
were racemic (D/L  1) prior to the meteorite fall to Earth, then their D/L ratios can be
used as a diagnostic signature to determine the degree of terrestrial L-amino acid
contamination they have experienced. In fact, racemic amino acid ratios for protein
(and nonprotein) amino acids in carbonaceous chondrites indicate an abiotic
synthetic origin. Although racemic mixtures have been observed for most nonprotein
chiral amino acids (Table 1.5), small L-enantiomeric excess for some nonprotein
amino acids has been reported in the Murchison and Murray meteorites [148–150].
Six a-methyl-a-amino acids unknown or rare in the terrestrial biosphere (both
diastereomers of a-amino-a,b-dimethyl-pentanoic acid, isovaline, a-methylnorvaline, a-methylnorleucine, and a-methylvaline) had L-enantiomeric excesses ranging
from 2.8 to 9.2% in Murchison and from 1.0 to 6.0% in Murray [148, 149]. More
speciﬁcally, Murchison has shown to have an L-enantiomeric excess of isovaline
ranging from 0 to 15.2% with signiﬁcant variation both between meteorite stones
and even within the same meteorite stone [150]. The meteoritic enantiomeric excess
of a-methyl-a-amino acids and the absence for the a-H-a-amino acids may be
explained by the resistance to racemization of a-methyl-a-amino acids during
aqueous alteration in the meteorite parent body, due to their lack of an a-hydrogen [149, 151, 152]. Another explanation could be a different amino acid formation
process, namely pre-solar formation for the a-methyl-a-amino acids and subsequent
incorporation into the parent body, followed by parent body formation of the a-H-aamino acids [149, 152].
1.4.1.4 Determination of Compound-Specific Stable Isotope Ratios of Hydrogen,
Carbon, and Nitrogen
For meteoritic nonchiral amino acids, such as glycine, a-AIB, b-ABA, and b-alanine,
compound-speciﬁc stable isotope measurements are the only means to establish
their origin. The abundances of stable isotopes are expressed in d values. These
indicate the difference in per mil (½) between the ratio in the sample and the same
ratio in the standard, as shown by:
dð½Þ ¼
ðRsample Rstandard Þ
where R represents D=1 H for hydrogen, 13 C=12 C for carbon, and 15 N=14 N for
nitrogen. The standards usually used are standard mean ocean water for hydrogen,
Pee Dee Belemnite for carbon, and air for nitrogen.
Stable isotope analyses of the total amino acid fractions of the Murchison meteorite
showed dD ¼ þ 1370½, d15 N ¼ þ 90½, and d 13 C ¼ þ 23:1½ [153], which were
later conﬁrmed by Pizzarello et al. [154, 155], who obtained dD ¼ þ 1751½,
d 15 N ¼ þ 94½, and d 13 C ¼ þ 26½. Stable isotope analyses were obtained for
individual amino acids in different meteorites (Table 1.6; [126, 141, 150, 156–159]).
These values (with a few exceptions, in which there is terrestrial contribution) are
clearly outside the amino acid terrestrial range (from 70.5 to þ 11.25½; [160]) and
fall within the range of those measured for other indigenous polar organic
compounds present in meteorites [161]. The highly enriched dD, d 15 N, and d13 C
values determined for the meteoritic amino acids indicate primitive extraterrestrial
The deuterium enrichment of amino acids is thought to be the result of interstellar
chemical reactions (e.g., gas-phase ion–molecule reaction and reactions on interstellar grain surfaces) which formed the amino acid precursors. These reactions occur in
the low temperatures of dense clouds (T < 50 K) in which deuterium fractionation is
efﬁcient (e.g., [162–164]). Meteoritic amino acids would have then been formed from
their deuterium-enriched interstellar precursors and deuterium-depleted water
([165] and references therein) by synthesis (aqueous alteration) in the meteorite
parent body (see Section 1.4.2). However, a-amino acids are more deuterium (and
C)-enriched than a-hydroxy acids [117], which is inconsistent with a Streckercyanohydrin-type synthesis from a common precursor [116, 166]. Differences may be
explained by different reaction paths leading to different isotopic distributions [164].
The 15 N enrichment of amino acids is also thought to be due to chemical fractionation in interstellar ion–molecule exchange reactions [167, 168].
The hydrogen isotope composition of meteoritic amino acids follows a relatively
simple pattern, in which dD varies more with the structure of their carbon chains (dD
is higher for amino acids having a branched alkyl chain) than with the chain
length [159]. On the other hand, d 13 C of a-amino acids (a-methyl-a- and a-H-aamino acids) decreases with increasing carbon chain length (with the a-methyl-aamino acids more 13 C-enriched than the corresponding a-H-a-amino acids), while
d 13 C for non-a-amino acids remains unchanged or increases with increasing carbon
chain length [158]. This suggests diverse synthetic processes for meteoritic amino
acids, in particular that the amino acid carbon chain elongation followed at least two
synthetic pathways [158, 159].
Synthesis of Meteoritic Amino Acids
Meteoritic amino acids are thought to be formed by a variety of synthetic pathways.
Namely, it is suggested that a-amino acids form by a two-step process, in which the aamino acid precursors (carbonyl compounds, ammonia, and HCN) were present (or
formed) in a proto-solar nebula and were later incorporated into an asteroidal parent
D,L-Aspartic
D,L-b-ABA
D,L-Isovaline
D,L-a-Methylnorvaline
þ2686
þ461
þ599
þ967
þ429
þ360
þ20.7
þ3058
þ1338
þ1225
þ3419
þ473
þ292
þ60
þ3181
þ66
þ3021
þ3283
þ1505
þ2432
þ2266
þ3097
þ1633
þ184
þ5; þ43
þ29
þ28
þ16; þ22
þ11 to þ20
þ17 to þ22
þ15
þ614
þ510
þ399
þ1063
þ763
þ57
þ58
þ37
þ61
d15 N
þ22; þ52
þ27; þ39
þ22; þ41
þ19
d13 C
þ20
Table 1.6 Compound-specific stable isotope composition (in ½) of individual amino acids in carbonaceous chondrites.
þ51
þ32
þ41
þ35
þ33
þ47
þ34
þ45
þ50
þ23
þ46
L-a-Amino-a,b-dimethylbutyric acid
D,L-g-Aminovaleric acid
d-Aminovaleric acid
b-Amino-a,a-dimethylpropionic acid
b-Amino-b-methylbutyric acid
D,L-g-Amino-a-methylbutyric acid þ D,L-g-aminob-methylbutyric acida
D,L-a-Aminoadipic acid
L-a-Aminoadipic acid
D,L-b-Aminoadipic acid
D,L-a-Methylglutamic acid
D,L-threo-b-Methylglutamic acid
D- or L-threo-b-Methylglutamic acid
D,L-threo-g-Methylglutamic acid
D,L-N-Methylalanine
N-Methyl-a-AIB
þ425
þ962
þ1352
þ2049
þ181
þ1164
þ367
þ362
þ3318
þ36
þ53
þ129
þ478
þ850
þ1337
þ1267
þ3446
þ1255
þ1408
þ1563
þ619
þ2251
þ2465
þ1819
þ965
þ552
þ2590
þ1141
þ3604
Adapted from [126, 141, 142, 150, 157–159].
Isotopic value corresponds to the combined enantiomeric peaks.
The chromatographic order of elution for the two enantiomers could not be established for lack of standards.
D,L-a-Amino-a,b-dimethylbutyric
+ NH2 R3
α-amino or imino acids
Figure 1.2 The Strecker-cyanohydrin synthetic pathway for the
formation of a-amino a-hydroxy and imino acids (adapted
from [116, 133, 171, 247]). R1 and R2 correspond to H or
CnH2n þ 1. If R3 corresponds to H then a-amino acids are
produced; if R3 is an amino acid then imino acids are produced.
body [169]. During aqueous alteration on the asteroidal parent body, Streckercyanohydrin synthesis would have taken place to form a-amino acids (Figure 1.2; [108,
116, 163, 166]). Since the carbonyl precursors (aldehydes and ketones) are thought to
be synthesized by the addition of a single-carbon donor to the growing alkane chain, a
decrease of the a-amino acid abundances with increasing chain length is expected.
Also, synthesis of branched carbon chain analogs is expected to be favored over
straight-carbon chain analogs (e.g., [108]), and this trend is observed in the EET
92 042 and GRA 95 229 meteorites [141]. Additional support for this hypothesis is
the ﬁnding of a-amino acid, a-hydroxy acids [116, 117, 166], and imino acids [170]
in carbonaceous meteorites. However, non-a-amino acids cannot be produced by
the Strecker-cyanohydrin synthesis. Alternatively, meteoritic b-amino acids are
thought to be synthesized by Michael addition of ammonia to a,b-unsaturated
nitriles, followed by reduction/hydrolysis (Figure 1.3; e.g., [108] and references
therein). These precursor molecules have been detected in the ISM (Table 1.1 and
reference therein) and also in comets (Table 1.3 and references therein). A chemical
reaction such as a Michael addition could occur on the parent body of meteorites.
For example, the extensively aqueous altered CI chondrites Orgueil and Ivuna are
rich in b-alanine, but depleted in a-amino acids. As suggested [138], this might
indicate that the CI parent body was depleted in carbonyl compounds (aldehydes
and ketones) necessary for the Strecker-cyanohydrin synthesis to occur. Additional
synthetic pathways in the meteorite parent body have been proposed for non-aamino acids (for a review, see, e.g., [108]). For example, hydrolysis of lactams
and carboxy lactams, which have been detected in carbonaceous meteorites [125],
gives the corresponding b-, g-, and d-amino acids, and dicarboxylic amino acids,
Reduction and hydrolysis
Figure 1.3 Michael-addition of ammonia to a a,b-unsaturated
nitrile to form a b-amino alkylnitrile that is then hydrolyzed to form
a b-amino acid (b-alanine) (adapted from [133]).
Micrometeorites and IDPs
Micrometeorites (MMs) and IDPs are thought to be the remains of comets and
asteroids (for reviews, see, e.g., [171–176]). MMs are small extraterrestrial dust
particles, typically in the range 50 mm to 2 mm [177], that have survived atmospheric
entry. They are collected in deep-sea sediments [171, 178], Antarctic ice [179–181],
and Greenland lake deposits [182–184]. On the other hand, IDPs are extraterrestrial
particles (usually measuring less than 30 mm in size), which are collected from the
Earths stratosphere (at an altitude of 20 km) by NASA aircraft (e.g., [171, 185, 186]).
Several organic molecules have been found in IDPs and MMs, such as ketone
and aliphatic hydrocarbons [12, 187–189], and polycyclic aromatic hydrocarbons [11,
190]. Antarctic micrometeorites (AMMs) have also been analyzed for amino
acids [191–193]. Most AMMs analyzed by Brinton et al. [191] had very low abundances
of amino acids and high L-enantiomeric excess, with a distribution similar to that
found in the Antarctic ice. One set of samples containing around 30 MMs was found
to contain a-AIB at high levels (280 ppm). However, the identiﬁcation of a-AIB was
tentative and needs further conﬁrmation [191]. In addition, Glavin et al. [192] studied
455 AMMs and none of them contained a-AIB. A third study by Matrajt et al. [193]
analyzed 300 AMMs and found a-AIB in around 100 MMs. These authors calculated
that only around 14% of AMMs analyzed so far contained a-AIB.
The possibility of Mars harboring alien life (presently and/or in the past) is the focus
of future space missions planned to the Red Planet. Their target compounds
indicative of life include, among others, amino acids [194–196]. These are key
biomolecules on Earth, but are also produced by abiotic reactions such as those
occurring in the parent body of meteorites (see Section 1.4.2). Amino acids synthesized elsewhere in the solar system may therefore be delivered intact into the surface
of Mars. In fact, large amounts of carbonaceous material are thought to be delivered
to the surface of Mars by IDPs and meteorites every year [14, 197, 198]. However, in
1976 the Viking landers found no organic molecules above the parts per billion to
parts per million levels on the surface of Mars (e.g., [199, 200]), even though they
should have been able to detect amino acids on the order of tens of parts per
million [201, 202]. This might be explained by chemical reactions occurring in the
surface of Mars, leading to the destruction of organic molecules. For example, oxidant
molecules may react with any potential organic compound present in the surface of
the Martian soil, leading to their destruction. These oxidizing molecules may be
formed by UV photolysis of the Martian atmosphere [203–207], interaction of
Martian minerals with atmospheric H2O2 [208] or UV radiation [209], or by chemical
weathering of silicates by low-temperature frost and adsorbed water in the Martian
soil [210, 211]. In addition, amino acids directly exposed to Mars-like UV radiation are
rapidly degraded [212–214]. For example, thin ﬁlms of glycine and D-alanine have
half-lives in the order of 104–105 s when irradiated under simulated noon-time Mars
equatorial surface conditions [213].
If present, amino acids should therefore be in the subsurface of the Red Planet,
shielded from exterior radiation. As shown by Kminek and Bada [215], amino acids
can survive up to 3 billion years at a depth of more than 2 m. In particular, Aubrey
et al. [216] found that the amino acids glycine and alanine have a half-life of up to 1.1
billion years, if buried under simulated Martian conditions. Similar results had
previously been obtained by Kanavarioti and Mancinelli [217], based on amino acid
decomposition rates in aqueous solutions. They found that a fraction of the amino
acids phenylalanine, alanine, and pyroglutamic acid would have been preserved
buried beneath the surface of Mars up to 3.5 billion years.
The mineralogical composition of Martian soils may also have an inﬂuence on the
amino acid stability [216, 218, 219]. Peeters et al. [218, 219] have shown that different
mineralogical compositions of Mars soil analogs lead to differences in amino acid
stability (for a review about Mars soil analogs, see [220]); in particular, clay mineral
matrices seem to have a shielding effect, protecting amino acids against destruction.
In addition, Aubrey et al. [216] determined that amino acids can be preserved for
geologically long periods (billions of years) in sulfate mineral matrices. These results
suggest that locations on Mars containing clay and/or sulfate minerals (for a review,
see, e.g., [221]) should be the prime targets for future missions with the goal to search
for life, in particular for its amino acid constituents.
Delivery of Extraterrestrial Amino Acid to the Earth and its Importance to the Origin
Independently of the environment where extraterrestrial amino acids were formed,
these molecules were exogenously delivered to the early Earth during the period of
1.7 Delivery of Extraterrestrial Amino Acid to the Earth and its Importance to the Origin of Life
late heavy bombardment 4.5–3.8 billion years ago. In fact, comets, meteorites, MMs,
and IDPs are thought to have delivered tons of organic carbon per year to our planet
during this period of time [13, 14, 222], just before life emerged (e.g., [223–225]).
Although we do not know what the production rates of different organic
compounds were on the early Earth (i.e., impact-shock synthesis, endogenous
production by UV light or electrical discharge, and synthesis in submarine hydrothermal vents), the higher the content of key molecules in primitive extraterrestrial
materials, the more likely it is that exogenous material played a role in the origin of
life. As noted by Chyba and Sagan [14], the heavy bombardment may have delivered
or produced organic molecules in the early Earth in quantities comparable to other
sources, possibly playing an important role for the origin of life.
The survival rate of amino acids in extraterrestrial bodies under simulated Earth
atmospheric entry has been studied by several authors. Amino acids present in the
interior of meteorites bigger than 1 mm survive atmospheric deceleration ([226]; see
also Section 1.4), as the meteorite only experiences pyrolytic temperatures (>600  C)
and melting on the surface (<1 mm depth [227]). This does not happen with
smaller particles such as MMs and IDPs, which are uniformly heated. In fact, it is
estimated that most MMs and IDPs are heated for a few seconds to peak temperatures
of up to 1700  C during atmospheric entry [228–230]. However, a small percentage of
dust (MMs and IDPs) enters the atmosphere at temperatures below 700  C [173, 228,
231–233]. Glavin and Bada [234] investigated the sublimation of amino acids from
sub-100 mm Murchison meteorite grains to test the survival of amino acids in MMs
during atmospheric entry. They found that under vacuum (800 mT) and at 550  C,
only glycine survived. All other amino acids (including a-AIB and isovaline) were
completely destroyed, which is not surprising if we consider that, with a few
exceptions, pure amino acids suffer thermal decomposition in the range of
200–600  C [235]. Glavin and Bada [234] also found that methylamine and ethylamine,
which are the a-decarboxylation products of glycine and alanine, respectively, were
not detected. This indicates that a-decarboxylation did not occur or that these amines
were also decomposed during the experiments. Although amino acids are expected
to have a higher atmospheric entry survival in smaller cosmic dust particles
(<50 mm) [228, 231], Matrajt et al. [236] found similar results to Glavin and Bada [234]
using activated alumina with grain sizes ranging from 5 to 9 mm, which suggests that
the amino acid survival is not greatly dependent on the grain size. On the other hand,
Matrajt et al. [236] demonstrated that the combination of porosity and heatshield effect
(i.e., ablative cooling) of extraterrestrial dust particles during atmospheric heating
results in poor heat transfer to the particles interior, providing thermal protection and
allowing organic compounds to survive. This reinforces the idea that IDPs, which are
around 10% organic carbon by mass, can decelerate in the atmosphere and deliver
organic compounds intact [222], and might have been the major source of exogenous
organics in the early Earth as suggested by Chyba and Sagan [14].
Nonprotein amino acids, a-AIB and racemic isovaline, have been detected within
around 1 m above and below the sediments of the iridium-rich Cretaceous/Tertiary
boundary at Stevns Klint, Denmark by Zhao and Bada [237]. These authors suggested
that the sediments represented components of a large bolide (i.e., a comet), which
collided with the Earth 65 million years ago. These results are not in agreement
with xenon measurements at the Cretaceous/Tertiary boundary [238, 239] or with
two-dimensional smoothed particle hydrodynamics simulations of cometary organic
pyrolysis by impacts [13]. However, Chyba et al. [13] noted the lack of relevant kinetic
data for high-temperature pyrolysis of organic molecules. Further work on amino acid
survival in simulated large asteroidal and cometary shock impacts has been performed
[240–243]. Peterson et al. [240] conducted a series of shock impact experiments over a
pressure range of 3.5–32 GPa using powdered Murchison and Allende meteorite
samples. These were previously extracted to eliminate their original amino acid
content and subsequently doped with known amino acids. The results show that
amino acids diminished substantially with increasing high pressures and new
daughter amino acids were formed, in particular b-alanine, glycine, alanine, gABA, and b-AIB. At 30 GPa, the abundances of the daughter compounds exceeded
those of the remaining initial amino acids. However, as noted by Blank et al. [242],
these authors did not refer to the porosity of the starting material or the temperature
conditions of the experiments. Further shock experiments in the range 5–21 GPa and
139–597  C and using aqueous amino acid solutions were performed by Blank
et al. [242]. In all the experiments a large fraction of amino acids survived, supporting
the hypothesis that organic compounds could survive impact processes. In addition,
high-resolution hydrocode simulations of comet impacts, over different projectile
radii, impact velocities, and angles, show that signiﬁcant amounts of amino acids can
be delivered intact to the Earth via kilometer-sized comet impacts [241, 243].
To date, extraterrestrial amino acids have only been unequivocally identiﬁed in
meteorites and a few AMMs. However, the potential precursors of these prebiotic
molecules are abundant in a variety of extraterrestrial environments, including
the ISM and comets. This suggests that meteoritic amino acids may have a
contribution from interstellar, nebular and/or parent body processing. The delivery
of these prebiotic molecules to the early Earth during the period of heavy bombardment (4.5–3.8 billion years ago) may have provided the necessary feedstock for the
evolution of emergent life systems.
Laboratory analyses of meteoritic material together with future missions (including sample return missions) to solar system planets (e.g., Mars Science Laboratory,
ExoMars), satellites, asteroids, and comets may expand our inventory of amino acids
in extraterrestrial environments.
Z.M. and M.A.S. acknowledge ﬁnancial support from the Science and Technology
Facilities Council.
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