Preparation of Compounds Labeled with Tritium and Carbon-14 »

Rolf Voges studied chemistry at the Universities of Marburg and Freiburg, where he received his Ph.D. in organic chemistry on investigations into steric isotope effects, for which he received the Go¨deke Award. After postdoctoral research on stereoselective syntheses he joined the isotope group of Sandoz Pharma AG (now Novartis AG) being involved for thirty years in organic radiochemical synthesis as Head of the Isotope Laboratories and then Head of Isotope Section. He is author or coauthor of about 40 publications, one patent, and coeditor of two previous conference proceeding volumes in the field, co-organizer of two international symposia on the synthesis and application of isotopically labeled compounds, founder and co-organizer of eleven Bad Soden meetings of the Central European Division of the International Isotope Society (CED-IIS), and co-editor of the proceedings. For three years he held a leadership position in the IIS, serving as its 2001 president. In recognition of his scientific achievements and his service to the isotope society he received the IIS-CED Award in 1995 and in 2003 the IISAward. He is now retired and lives in southwestern Germany, near the Swiss and French borders.

Richard Heys received his Ph.D. in organic chemistry from Stanford University in 1976 and conducted postdoctoral research in the chemistry department at Yale; both involved the synthesis of radiolabeled compounds and their use in elucidation of biosynthetic pathways. His subsequent 29-year career in organic radiochemical synthesis both in the laboratory and as a manager took him to the Radiochemistry Department of Midwest Research Institute (now part of Aptuit, Inc.),Smith Kline & French Laboratories/SmithKline Beecham Pharmaceuticals (now GlaxoSmithKline) and AstraZeneca Pharmaceuticals. Author or coauthor of over 85 publications, 8 patents and a previous conference proceedings volume in the field, organizer of an international symposium on the synthesis of isotopically labeled compound and holder of leadership positions (including president and CFO) in the International Isotope Society for 9 years, he is retired and lives in northwestern Connecticut.

Thomas Moenius received his Ph.D. in organic chemistry from the University of Erlangen-Nu¨rnberg in 1986. He is a member of the isotope group of Novartis Pharma AG, working in the field of carbon-14 and tritium labeling. Since 2007 he is also European Editor for Journal for Labelled Compounds and Radiopharmaceuticals.

Compounds labeled with carbon-14 and tritium are indispensable tools for research in biomedical sciences, discovery and development of pharmaceuticals and agrochemicals.

Preparation of Compounds Labeled with Tritium and Carbon-14 is a comprehensive, authoritative and up-to-date discussion of the strategies, synthetic approaches, reactions techniques, and resources for the preparation of compounds labeled with either of these isotopes. A large number of examples are presented for the use of isotopic sources and building blocks in the preparation of labeled target compounds, illustrating the range of possibilities for embedding isotopic labels in selected moieties of complex structures.  Topics include:

•  Formulation of synthetic strategies for preparing labeled compounds
• Isotope exchange methods and synthetic alternatives for preparing tritiated compounds
• In-depth discussion of carbon-14 building blocks and their utility in synthesis
• Preparation of enantiomerically pure isotopically labeled compounds
• Applications of biotransformations

Preparation of Compounds Labeled with Tritium and Carbon-14 is an essential guide to the specialist strategies and tactics used by chemists to prepare compounds tagged with theradioactive atoms carbon-14 and tritium.

Preface xi

Glossary xiii

Author Biographies xvii

1 Introduction 1

1.1 Physical Properties of Tritium and Carbon-14 3

1.2 Purification 5

1.3 Analysis 6

1.3.1 Chemical Identity 6

1.3.2 Chemical (and Enantiomeric) Purity 7

1.3.3 Radiochemical (and Radionuclidic) Purity 8

1.3.4 Specific Activity 9

1.3.5 Position of Label 10

1.4 Stability and Storage of Compounds Labeled with Tritium or Carbon-14 11

1.5 Specialist Techniques and Equipment 15

References 21

2 Strategies for Target Preparation 25

2.1 Formulating Target Specifications 26

2.2 Planning Radiotracer Preparations 31

2.2.1 The Construction Strategy 31

2.2.2 Reconstitution Strategies 32

2.2.3 The Derivatization Strategy 34

2.2.4 Selection of an Appropriate Strategy 34

2.2.5 Case Studies of Strategy Development 36

References 44

3 Preparation of Tritium-Labeled Compounds by Isotope Exchange Reactions 47

3.1 Homogeneous Acid-or Base-Catalyzed Exchange 49

3.1.1 Exchange without Added Acid or Base 49

3.1.2 Exchange under Acidic Conditions 51

3.1.3 Exchange under Basic Conditions 56

3.2 Heterogeneous Catalysis with Tritium in Solvent 60

3.2.1 Metals 61

3.2.2 Other Catalysts 65

3.3 Heterogeneous Catalysis in Solution with Tritium Gas 66

3.3.1 Metal Catalysts with Nonreducible Substrates in Aqueous Solution 67

3.3.2 Metal Catalysts with Nonreducible Substrates in Organic Solvents 68

3.3.3 Other Catalysts 69

3.3.4 Metal Catalysts with Reducible Substrates 70

3.4 Homogeneous Catalysis in Solution with Tritiated Water 71

3.4.1 Exchange Catalyzed by Metal Salts 71

3.4.2 Exchange Catalyzed by Organoruthenium Complexes 73

3.4.3 Exchange Catalyzed by Iridium Dionates74

3.4.4 Exchange Catalyzed by Iridium Cyclopentadienides 76

3.5 Homogeneous Catalysis with Tritium Gas 77

3.5.1 Iridium Phosphines 77

3.5.2 Iridium Dionate Complexes 90

3.5.3 Iridium Cyclopentadienide Complexes 91

3.6 Solvent-Free Catalytic Exchange 93

3.6.1 High-Temperature Solid-State Catalytic Isotope Exchange 93

3.6.2 Thermal Tritium Atom Bombardment 96

3.6.3 Other Radiation-Induced Labeling Methods 97

References 98

4 Preparation of Tritium-Labeled Compounds by Chemical Synthesis 109

4.1 Catalytic Tritiations 110

4.1.1 Tritiation of Carbon-Carbon Multiple Bonds 111

4.1.2 Tritiation of Carbon-Heteroatom Multiple Bonds 125

4.1.3 Homogeneously Catalyzed Reactions 126

4.2 Catalytic Tritiolyses 132

4.2.1 Tritiodehalogenations 133

4.2.2 Tritiolyses of Benzylic N- and O-Functions 144

4.2.3 Tritiodesulfurizations 145

4.3 Tritide Reductions 146

4.3.1 Sodium Borotritide (NaB3H4) 148

4.3.2 Sodium Cyanoborotritide (NaB3H3CN) 157

4.3.3 Sodium/Tetramethylammonium Triacetoxyborotritide [Na/NMe4B3H(OAc)3] 159

4.3.4 Lithium Tritide (Li3H) 160

4.3.5 Lithium Borotritide (LiB3H4) 161

4.3.6 Lithium Triethylborotritide (LiEt3B3H, Li-Super-Tritide) 163

4.3.7 Lithium Tri-sec-Butylborotritide [Li(sec-Bu3)B3H, Li T-Selectride] 165

4.3.8 Lithium [3H2]Boratabicyclo[3.3.1]nonane 166

4.3.9 Tritiated Borane (THF-Complex) (B23H6; B3H3.THF) 167

4.3.10 Tritiated Alkylboranes 169

4.3.11 Lithium Aluminum Tritide (LiAl3H4) 170

4.3.12 Tri-n-Butyltin Tritide (n-Bu3Sn3H) 172

4.3.13 Tritiated Schwartz's Reagent (ZrCp2Cl3H) 176

4.3.14 Tritiated Triethylsilane and Trihexylsilane 177

4.4 Small Tritiated Building Blocks 178

4.4.1 Tritiated Water (3H2O; 3HHO) 179

4.4.2 Tritiated Diimide (3HN = N3H) 182

4.4.3 Tritiated Methyl Iodide (C3H3l; C3HH2I) 183

4.4.4 Tritiated Diiodomethane (C3HHI2) 190

4.4.5 Tritiated Formaldehyde (3HCHO, 3HC3HO) 191

4.4.6 Dimethyl [3H]formamide (3HCONMe2), Acetic [3H]Formic Anhydride (3HCOOCOMe) 192

4.4.7 Tritiated Diazomethane (C3HHN2) 193

4.4.8 N-Tritioacetoxyphthalimide 194

4.4.9 N-Succinimidyl [2,3-3H]Propionate ([3H]NSP) 195

References 195

5 Barium [14C]Carbonate and the Preparation of Carbon-14-Labeled Compounds via One-Carbon Building Blocks of the [14C]Carbon Dioxide Tree 211

5.1 [14C]Carbon Dioxide (14CO2) 212

5.1.1 [14C]Carboxylations of Organometallic Compounds 212

5.1.2 Manipulations of [14C]Carboxylation Products 218

5.1.3 N-[14C]Acyl Building Blocks 219

5.1.4 Preparation of Other Building Blocks from [14C]Carbon Dioxide 221

5.2 [14C]Carbon Monoxide (14CO) 222

5.2.1 [14C]Phosgene 229

5.3 [14C]Formic Acid (H14COOH) 233

5.4 [14C]Formaldehyde (H14CHO) 240

5.4.1 Carbanion-Mediated Hydroxy[14C]methylation and [14C]Methylenenation 242

5.4.2 Acid-Catalyzed Hydroxy[14C]methylations 246

5.4.3 Amino[14C]methylation 248

5.4.4 Reductive Methylations 254

5.4.5 Polycondensations 255

5.4.6 Thio[14C]methylations 256

5.5 [14C]Methyl Iodide (14CH3I) 256

5.5.1 [14C]Methyl Iodide as an Electrophilic One-[14C]Carbon Building Block 257

5.5.2 [14C]Methyl Iodide as a Source of Nucleophilic [14C]Methyl and [14C]Methylene Building Blocks 262

5.5.3 Further Building Blocks Derived from [14C]Methyl Iodide 268

5.6 [14C]Nitromethane (14CH3NO2) 270

References 277

6 Preparation of Carbon-14-Labeled Compounds via Multi-Carbon Building Blocks of the [14C]Carbon Dioxide Tree 287

6.1 [14C]Acetic Acid and Its Derivatives 287

6.1.1 [14C]Acetic Acid 287

6.1.2 [14C]Acetyl Chloride 289

6.1.3 [14C]Acetic Anhydride 298

6.1.4 [14C]Acetic Acid Alkyl/Aryl Esters 301

6.2 Halo[14C]acetates 307

6.2.1 Reaction at the Carboxyl Group 309

6.2.2 Reactions at the Methylene Group 312

6.2.3 Reactions at the Halogen Atom 314

6.3 [14C]Acetone 337

6.3.1 Reaction at the Carbonyl Group 338

6.3.2 Reaction at the Methyl Group 343

6.4 Alkyl [14C]Acetoacetate 346

6.4.1 Alkylation Reactions 348

6.4.2 Acylation Reactions 351

6.4.3 Aldol Reactions 352

6.4.4 Knoevenagel-Michael Reactions 353

6.4.5 Reactions at the Functional Groups 356

6.5 [14C]Malonates 357

6.5.1 Reactions at the Methylene Group 359

6.5.2 Reactions at the Carboxyl Functions 374

References 381

7 Preparation of Carbon-14-Labeled Compounds via the [14C]Cyanide Tree 393

7.1 Metal [14C] Cyanides 393

7.1.1 Preparation 393

7.1.2 Introduction of [14C]Cyanide into Organic Substrates 394

7.1.3 Synthetic Transformations of Organic [14C]Nitriles 399

7.2 Preparation of Other Building Blocks from [14C]Cyanide 411

7.2.1 Trimethylsilyl[14C]Cyanide (TMS14CN) 412

7.2.2 [14C]Cyanogen Bromide (Br14CN) 413

7.2.3 Alkali Metal [14C]Cyanates (M14CNO; M = Na, K) 415

7.2.4 Alkali Metal Thio[14C]cyanate (M14CNS; M = Na, K) 417

7.2.5 Triethy [14C]Orthoformate [H14C(OEt)3] 419

7.2.6 [14C]Cyanoacetic Acid [14CNCH2COOH] 420

7.2.7 [14C]Diazomethane (14CH2N2) 431

References 433

8 Preparation of Carbon-14-Labeled Compounds via the [14C2]Acetylene Tree 441

8.1 [14C2]Acetylene (H14C = 14CH) 441

8.2 [14C2]Acetaldehyde (14CH314CHO) 445

8.3 [1,2-14C2]Acetic Acid (14CH314COOH) 446

8.4 2-[2,3-14C2]Propyne-1-ol ([2,3-14C2]Propargyl Alcohol) and 2-[2,3-14C2]Butyne-1,4-diol 447

8.5 Methyl [2,3-14C2]Propiolate (H14C$$14CCOOMe) and Dimethyl [2,3-14C2]Acetylenedicarboxylate (HOOC14C$$14CCOOH) 447

8.6 1,2-[14C2]Dibromoethane (Br14CH214CH2Br) 448

8.7 [14C2]Ethylene Oxide 448

8.8 [14Cn]Benzene and the Synthesis of Ring-Labeled Aromatic Compounds 448

8.8.1 Nitrobenzene Branch 451

8.8.2 Phenol Branch 454

8.8.3 Bromobenzene Branch 456

8.8.4 Iodobenzene Branch 457

8.8.5 Benzoic Acid Branch 458

8.8.6 Alkyl Phenyl Ketone Branch 459

8.8.7 Sulfonylbenzene Branch 459

References 460

9 Preparation of Carbon-14-Labeled Compounds via the [14C]Cyanamide Tree 465

9.1 [14C]Cyanamide (H2N14C$$N) 465

9.2 [14C]Guanidine (H2N14C(=NH)NH2) 467

9.3 [14C]Urea, H2N14CONH2 468

9.4 [14C]Thiourea, H2N14CSNH2 472

References 477

10 Reconstitution Strategies 479

10.1 Replacement Strategies 479

10.1.1 1H/3H Replacement Strategies 479

10.1.2 12C/14C Replacement Strategies 485

10.2 Disconnection-Reconnection Strategies 488

10.2.1 Dealkylation-Re[3H/14C]alkylation Procedures 488

10.2.2 CO2/14CO2 Replacement Strategies 492

10.2.3 CO/14CO Replacement Strategy 501

10.2.4 Oxidative Cleavage of C=C Bonds in the Reconstitution Approach 502

References 517

11 Preparation of Enantiomerically Pure Compounds Labeled with Isotopes of Hydrogen and Carbon 523

11.1 Resolution of Racemates 524

11.2 Enantioselective Synthetic Methods 529

11.2.1 Hydrogenation/Tritiation of Labeled/Unlabeled Δ2,3-Amino Acid Derivatives 530

11.2.2 Reduction of Labeled Prochiral Carbonyl Compounds and Oximes 535

11.2.3 Enantioselective Oxidation of Olefins and Allylic Alcohols 541

11.3 Diastereoselective Synthetic Procedures 546

11.3.1 α-Alkylation of Chiral Imide Enolates 551

11.3.2 Aldol Reactions of Chiral Imides and Ester Enolates 558

11.3.3 1,4-Additions of Chiral Imide Enolates to Michael Acceptors 564

11.3.4 α-Amination of Chiral Imide Enolates 566

11.3.5 α-Hydroxylation of Chiral Imide Enolates 571

11.3.6 α-Alkylation of Chiral Glycinates 571

11.3.7 Aldol Reactions of Chiral Glycinates 583

11.3.8 Aldol Reactions of Chiral Glycolates 586

11.3.9 Aldol Reactions of Chiral Haloacetates 586

11.3.10 Reactions on Chiral α,β-Unsaturated Imides and Esters 591

References 596

12 Biotransformations in the Preparation of Compounds Labeled with Carbon and Hydrogen Isotopes 607

12.1 Applications of Isolated Enzymes 608

12.1.1 Optical Resoultions via Derivatives 608

12.1.2 Synthesis of Isotropically Labeled, Enantiomerically Pure Compounds 612

12.1.3 Conjugation Reactions 618

12.2 Application of Cell-Containing Systems 618

12.2.1 Transformations of Functional Groups 619

12.2.2 Fermentative Synthesis of Structurally Complex Molecules by Incorporation of Labeled Precursors 621

12.2.3 Specific Requirements for Fermentations Using Isotopically Labeled Compounds 623

12.3 Biocatalyzed Synthesis of Key Intermediates for Reconstitution Approaches 630

12.3.1 Oxidation-Reduction Approach 631

12.3.2 Dealkylation-Realkylation Approach 632

References 634

Index 639