Foreword ...................................................................... vii Preface ........................................................................ ix Contributors ................................................................. xiii Part I A Discussion of Carbohydrate Chemistry Chapter 1 An Historical Overview ................................................ 3 Robert J. Ferrier 1.1 Introduction ................................................................ 3 1.2 The Beginnings .............................................................. 4 1.3 The Era of Emil Fischer ..................................................... 5 1.4 The Post-Fischer Era ........................................................ 8 1.5 New Methods: New Thinking .................................................. 11 1.6 New Horizons: Glycobiology ................................................. 15 1.7 The Beginning of the 21st Century .......................................... 19 1.8 Postscript ................................................................. 20 Acknowledgments ................................................................ 22 References ..................................................................... 22 Chapter 2 Introduction to Carbohydrates ........................................ 25 Janos Kuszmann 2.1 Definitions and Conventions ................................................ 25 2.2 Acyclic Derivatives ........................................................ 26 2.2.1 Rules of the Fischer Projection ..................................... 26 2.2.2 Trivial and Systematic Names ........................................ 28 2.2.3 Absolute and Relative Configuration ................................. 31 2.2.4 Depiction of the Conformation of Open Chain Carbohydrates ........... 31 2.2.5 The Newman Projection ............................................... 33 2.3 Cyclic Derivatives ......................................................... 34 2.3.1 Rules of the Fischer Projection ..................................... 34 2.3.2 Mutarotation ........................................................ 35 2.3.3 The Haworth Projection .............................................. 36 2.3.4 The Mills Projection ................................................ 37 2.3.5 The Reeves Projection ............................................... 37 2.3.6 Conformations of the Six-Membered Rings ............................. 39 2.3.7 Conformations of the Five-Membered Rings ............................ 40 2.3.8 Conformations of the Seven-Membered Rings ........................... 40 2.3.9 Conformations of Fused Rings ........................................ 41 2.3.10 Steric Factors ...................................................... 43 2.3.11 The Anomeric and Exo-Anomeric Effects ............................... 45 2.4 Definition and Nomenclature of Di- and Oligosaccharides .................... 47 2.4.1 Disaccharides ....................................................... 47 2.4.2 Oligosaccharides .................................................... 50 Further Reading ................................................................ 52 Chapter 3 Protective Group Strategies .......................................... 53 Stefan Oscarson 3.1 Introduction ............................................................... 54 3.2 Protecting Groups .......................................................... 54 3.2.1 Hydroxyl Protecting Groups ........................................... 54 3.2.2 Anomeric (Hemiacetal) Protecting Groups .............................. 60 3.2.3 Amino Protecting Groups .............................................. 61 3.2.4 Carboxyl Protecting Groups ........................................... 63 3.3 Selective Protection Methodologies (Regioselective Protection of Hydroxyl Groups)..................................................................... 64 3.3.1 Selective Protection ................................................. 64 3.3.2 Selective Deprotection ............................................... 70 3.4 Selective Protection Strategies ............................................ 72 3.4.1 Monosaccharides ...................................................... 72 3.4.2 Disaccharides ........................................................ 75 3.4.3 Oligosaccharides ..................................................... 80 3.5 Summary and Conclusions .................................................... 84 References ..................................................................... 85 Chapter 4 Glycosylation Methods ................................................ 89 Peter Fugedi 4.1 Introduction ............................................................... 90 4.2 Stereochemical Aspects of Glycoside Bond Formation ......................... 91 4.3 Glycosylations by Nucleophilic Substitutions at the Anomeric Carbon ........ 96 4.3.1 Synthesis of Glycosides from Glycosyl Halides ........................ 96 4.3.2 Synthesis of Glycosides from Anomeric Thio Derivatives .............. 102 4.3.3 Synthesis of Glycosides from Anomeric O-Derivatives ................. 113 4.3.4 Synthesis of Glycosides from Donors with Other Heteroatoms at the Anomeric Center .............................................. 142 4.4 Glycosylations by Nucleophilic Substitution at the Aglycone Carbon ........ 144 4.5 Synthesis of Glycosides by Addition Reactions ............................. 146 4.6 Other Glycosylation Methods ............................................... 149 4.7 Summary and Outlook ....................................................... 150 References .................................................................... 151 Chapter 5 Oligosaccharide Synthesis ........................................... 181 Peter Fugedi 5.1 Introduction .............................................................. 181 5.2 General Concept of Oligosaccharide Synthesis .............................. 182 5.3 Stepwise and Block Syntheses of Oligosaccharides .......................... 183 5.4 Glycosylation Strategies in Block Syntheses ............................... 190 5.4.1 Reactivation by Exchange of the Anomeric Substituent ................ 190 5.4.2 Sequential Glycosylations with Different Types of Glycosyl Donors .............................................................. 190 5.4.3 Two-Stage Activation ................................................ 193 5.4.4 Orthogonal Glycosylations ........................................... 194 5.4.5 Armed-Disarmed Glycosylations ....................................... 196 5.4.6 Active-Latent Glycosylations ........................................ 197 5.5 Methods and Techniques in Oligosaccharide Synthesis ....................... 202 5.5.1 Intramolecular Aglycone Delivery .................................... 202 5.5.2 One-Pot Multistep Glycosylations .................................... 204 5.5.3 Polymer-Supported and Solid-Phase Oligosaccharide Synthesis ......... 208 5.6 Summary and Outlook ....................................................... 214 References .................................................................... 216 Part II From Sugars to Sugar-Like Structures to Non-Sugars Chapter 6 Functionalization of Sugars ......................................... 225 Daniel E. Levy 6.1 Introduction ............................................................. 226 6.1.1 Definition of Concept .............................................. 226 6.1.2 SN2 Reactions ...................................................... 227 6.2 Special Considerations with Sugars ....................................... 227 6.2.1 Axial vs. Equatorial Approach ...................................... 228 6.2.2 Substitution vs. Elimination ....................................... 228 6.2.3 Neighboring Group Participation .................................... 229 6.3 Formation of Leaving Groups .............................................. 231 6.3.1 Halides as Leaving Groups .......................................... 232 6.3.2 Sulfonates as Leaving Groups ....................................... 232 6.3.3 Epoxysugars (Anhydro Sugars) ....................................... 232 6.3.4 Other Leaving Groups (Mitsunobu Reaction, Chlorosulfate Esters, Cyclic Sulfates) ................................................... 233 6.4 Halogenation Reactions ................................................... 235 6.4.1 SN2 Displacements of Sulfonates .................................... 235 6.4.2 SN2 Opening of Epoxides ............................................ 236 6.4.3 Use of Alkylphosphonium Salts ...................................... 237 6.4.4 Use of Chlorosulfate Esters ........................................ 238 6.4.5 Use of Iminoesters and Sulfonylchlorides ........................... 238 6.4.6 Fluorination Reactions ............................................. 239 6.4.7 Halogenation of O-Benzylidene Acetals .............................. 239 6.4.8 Radical Processes .................................................. 241 6.5 Reactions Involving Nitrogen ............................................. 241 6.5.1 SN2 Reactions ...................................................... 241 6.5.2 Formation of Nitrosugars ........................................... 243 6.5.3 The Mitsunobu Reaction ............................................. 243 6.6 Reactions Involving Oxygen and Sulfur .................................... 244 6.6.1 Manipulation of Sugar Hydroxyl Groups .............................. 244 6.6.2 Deoxygenation Reactions ............................................ 245 6.6.3 Sulfuration Reactions .............................................. 249 6.6.4 Desulfuration Reactions ............................................ 250 6.7 Formation of Carbon-Carbon Bonds ......................................... 251 6.7.1 Addition of Nucleophiles ........................................... 251 6.7.2 Condensation Reactions ............................................. 254 6.7.3 Wittig/Horner-Emmons Reactions ..................................... 256 6.7.4 Claisen Rearrangements ............................................. 256 6.8 Reductions and Oxidations ................................................ 257 6.8.1 Reduction Reactions ................................................ 257 6.8.2 Oxidation Reactions ................................................ 260 6.9 Rearrangements and Isomerizations ........................................ 261 6.9.1 Base Catalyzed Isomerizations ...................................... 261 6.9.2 The Amadori Rearrangement .......................................... 261 6.10 Conclusion ............................................................... 263 References .................................................................... 263 Chapter 7 Strategies towards C-Glycosides ..................................... 269 Daniel E. Levy 7.1 Introduction .............................................................. 271 7.1.1 Definition and Nomenclature of C-Glycosides ........................ 271 7.1.2 O-Glycosides vs. C-Glycosides: Comparisons of Physical Properties, Anomeric Effects, H-Bonding Abilities, Stabilities and Conformations .................................................. 271 7.1.3 Natural Occurring C-Glycosides ..................................... 273 7.1.4 C-Glycosides as Stable Pharmacophores .............................. 273 7.2 Synthesis of C-Glycosides via Electrophilic Substitutions ................. 274 7.2.1 Anomeric Activating Groups and Stereoselectivity ................... 275 7.2.2 Cyanation Reactions ................................................ 275 7.2.3 Alkylation, Allenylation, Allylation and Alkynation Reactions ...... 278 7.2.4 Arylation Reactions ................................................ 286 7.2.5 Reactions with Enol Ethers, Silylenol Ethers and Enamines .......... 291 7.2.6 Nitroalkylation Reactions .......................................... 294 7.2.7 Reactions with Allylic Ethers ...................................... 295 7.2.8 Wittig Reactions with Lactols ...................................... 297 7.2.9 Nucleophilic Additions to Sugar Lactones Followed by Lactol Reductions ......................................................... 299 7.2.10 Nucleophilic Additions to Sugars Containing Enones ................. 302 7.2.11 Transition Metal-Mediated Carbon Monoxide Insertions ............... 304 7.2.12 Reactions Involving Anomeric Carbenes .............................. 305 7.2.13 Reactions Involving Exoanomeric Methylenes ......................... 305 7.3 Synthesis of C-Glycosides via Nucleophilic Sugar Substitutions ............ 307 7.3.1 C-1 Lithiated Anomeric Carbanions by Direct Metal Exchange ......... 307 7.3.2 C-1 Lithiated Anomeric Carbanions by Reduction ..................... 310 7.3.3 C-1 Carbanions Stabilized by Sulfones, Sulfoxides, Carboxyl and Nitro Groups .......................................... 311 7.4 Synthesis of C-Glycosides via Transition Metal-Based Methodologies ........ 314 7.4.1 Direct Coupling of Glycals with Aryl Groups ........................ 315 7.4.2 Coupling of Substituted Glycals with Aryl Groups ................... 316 7.4.3 Coupling of π-Allyl Complexes of Glycals ........................... 317 7.5 Synthesis of C-Glycosides via Anomeric Radicals ........................... 319 7.5.1 Sources of Anomeric Radicals and Stereochemical Consequences ....... 319 7.5.2 Anomeric Couplings with Radical Acceptors .......................... 320 7.5.3 Intramolecular Radical Reactions ................................... 322 7.6 Synthesis of C-Glycosides via Rearrangements and Cycloadditions ........... 324 7.6.1 Rearrangements by Substituent Cleavage and Recombination ........... 324 7.6.2 Electrocyclic Rearrangements Involving Glycals ..................... 326 7.6.3 Rearrangements from the 2-Hydroxyl Group ........................... 326 7.7 Synthesis of C-Glycosides via Formation of the Sugar Ring ................. 327 7.7.1 Wittig Reactions of Lactols Followed by Ring Closures .............. 329 7.7.2 Addition of Grignard and Organozinc Reagents to Lactols ............ 331 7.7.3 Cyclization of Suitably Substituted Polyols ........................ 331 7.7.4 Rearrangements ..................................................... 333 7.7.5 Cycloadditions ..................................................... 335 7.7.6 Other Methods for the Formation of Sugar Rings ..................... 336 7.8 Further Reading ........................................................... 336 Acknowledgments ............................................................... 337 References .................................................................... 337 Chapter 8 From sugars to carba-sugars ......................................... 349 Matthieu Sollogoub, Pierre Sinay 8.1 Introduction .............................................................. 349 8.2 Why Synthesize Carba-Sugars? .............................................. 350 8.2.1 Carba-Monosaccharides ............................................... 350 8.2.2 Carba-Oligosaccharides .............................................. 352 8.2.3 Carba-Glycosyl-Phosphates ........................................... 353 8.3 Synthesis of Carba-Sugars from Sugars ..................................... 355 8.3.1 Cyclization of Open-Chain Sugars .................................... 355 8.3.2 Rearrangements of Cyclic Sugars ..................................... 371 8.4 Conclusion ................................................................ 378 References .................................................................... 378 Chapter 9 Sugars with endocyclic heteroatoms other than oxygen ................ 383 Peter Greimel, Josef Spreitz, Frederich K. (Fitz) Sprenger, Arnold E. Stutz, Tanja M. Wrodnigg 9.1 Introduction .............................................................. 384 9.2 Thiosugars with Sulfur in the Ring ........................................ 385 9.2.1 Furanoid Systems .................................................... 386 9.2.2 Pyranoid Systems --- 5-Thioaldohexoses, 6-Thioketohexoses and Derivatives ..................................................... 388 9.2.3 Septanoses and Derivatives .......................................... 390 9.2.4 Examples of Glycomimetics with Sulfur in the Ring ................... 390 9.3 Iminosugars ............................................................... 395 9.3.1 Typical Approaches to Iminosugars and Analogs ....................... 396 9.3.2 Biological Activities and Applications .............................. 401 9.4 Other Heteroatoms in the Ring ............................................. 411 9.5 Further Reading ........................................................... 412 References .................................................................... 412 Part III Sugars as Tools, Chiral Pool Starting Materials and Formidable Synthetic Targets Chapter 10 Sugars as chiral auxiliaries ....................................... 427 Norbert Pleuss, Gernot Zech, Bartlomiej Furman, Horst Kunz 10.1 Introduction ............................................................. 427 10.2 Asymmetric Cycloaddition Reactions ....................................... 428 10.2.1 [2+1] Cycloadditions .............................................. 428 10.2.2 [2+2] Cycloadditions .............................................. 429 10.2.3 [3+2] Cycloadditions .............................................. 435 10.2.4 [4+2] Cycloadditions (Diels--Alder Reactions) ..................... 439 10.2.5 Hetero Diels--Alder Reactions ..................................... 448 10.3 Stereoselective Addition and Substitution Reactions ...................... 454 10.3.1 Additions to Glycosyl Imines and Other Nucleophilic Additions ..... 454 10.3.2 Conjugate Additions ............................................... 460 10.3.3 Reactions Involving Enolates ...................................... 466 10.4 Rearrangement Reactions .................................................. 472 10.5 Radical Reactions ........................................................ 475 10.6 Miscellaneous Applications of Carbohydrate Auxiliaries ................... 478 10.7 Conclusion ............................................................... 480 References .................................................................... 481 Chapter 11 Sugars as Chiral Starting Materials in Enantiospecific Synthesis ... 489 Yves Chapleur and Francoise Chretien 11.1 Introduction ............................................................. 490 11.2 Carbohydrates as Sources of Carbon Atoms in Total Syntheses .............. 491 11.3 Branching a Carbon Chain on the Carbohydrate Ring ........................ 492 11.3.1 Using Epoxides .................................................... 492 11.3.2 Using Unsaturated Carbohydrates ................................... 496 11.3.3 Using Keto-Sugars ................................................. 501 11.3.4 Using Carbohydrates as Nucleophiles ............................... 511 11.3.5 Using Rearrangements .............................................. 516 11.4 Chain Extensions of Sugars ............................................... 520 11.4.1 Chain Extensions at the Primary Carbon Atom ....................... 521 11.4.2 Chain Extensions at the Anomeric Center ........................... 532 11.5 Creation of C-Glycosidic Bonds ........................................... 534 11.5.1 Creation of C-Glycosidic Bonds with Retention of the Anomeric Hydroxyl Group .................................... 535 11.5.2 Creation of C-Glycosidic Bonds with Replacement of the Anomeric Hydroxyl Group .................................... 537 11.6 Formation of Carbocycles ................................................. 545 11.6.1 Carbocyclization of the Sugar Backbone ............................ 546 11.6.2 Annulation Reactions on the Sugar Template ........................ 553 11.7 Conclusions .............................................................. 557 References .................................................................... 558 Chapter 12 Synthesis of Carbohydrate Containing Complex Natural Compounds ..... 575 Kazunobu Toshima 12.1 Introduction ............................................................. 576 12.2 O-Glycoside Antibiotics .................................................. 576 12.2.1 Methymycin ....................................................... 576 12.2.2 Erythromycin A ................................................... 577 12.2.3 Tylosin .......................................................... 577 12.2.4 Mycinamicins IV and VII .......................................... 578 12.2.5 Avermectins ...................................................... 580 12.2.6 Efrotomycin ...................................................... 582 12.2.7 Amphotericin B ................................................... 583 12.2.8 Elaiophylin ...................................................... 583 12.2.9 Cytovaricin ...................................................... 584 12.2.10 Calicheamicin γI1 ................................................ 587 12.2.11 Neocarzinostatin Chromophore ..................................... 596 12.2.12 Eleutherobin ..................................................... 596 12.2.13 Olivomycin A ..................................................... 599 12.2.14 Everninomicin 13,284-1 ........................................... 602 12.2.15 Polycavernoside A ................................................ 604 12.2.16 Vancomycin ....................................................... 606 12.2.17 Apoptolidin ...................................................... 608 12.3 C-Glycoside Antibiotics .................................................. 611 12.3.1 Vineomycinone B2 Methyl Ester .................................... 611 12.3.2 Medermycin ....................................................... 614 12.3.3 Urdamycinone B ................................................... 615 12.3.4 Gilvocarcin M .................................................... 621 12.4 Others ................................................................... 621 12.4.1 Bidesmosidic Triterpene Saponin .................................. 621 12.4.2 Digitoxin ........................................................ 621 12.5 Concluding Remarks ...................................................... 621 References .................................................................... 624 Chapter 13 Total Asymmetric Synthesis of Monosaccharides and Analogs .......... 629 Pierre Vogel 13.1 Introduction ............................................................. 630 13.2 The Formose Reaction ..................................................... 631 13.3 Prebiotic Synthesis of Carbohydrates ..................................... 632 13.4 Aldolase-Catalyzed Asymmetric Aldol Condensations ........................ 634 13.4.1 Resolution of Racemic Aldehydes ................................... 634 13.4.2 One-Pot Total Syntheses of Carbohydrates .......................... 634 13.4.3 Synthesis of 1,5-Dideoxy-1,5-Iminoalditols ........................ 638 13.4.4 Synthesis of 2,5-Dideoxy-2,5-Iminoalditols ........................ 639 13.4.5 Synthesis of Deoxy-Thiohexoses .................................... 641 13.5 Chain Elongation of Aldehydes through Nucleophilic Additions ............. 642 13.5.1 Total Synthesis of D- and L-Glyceraldehyde and Other C-3 Aldose Derivatives ................................................ 642 13.5.2 One-Carbon Homologation of Aldoses: The Thiazole-Based Method ..... 645 13.5.3 Other Methods of One-Carbon Chain Elongation of Aldoses ........... 647 13.5.4 Additions of Enantiomerically Pure One-Carbon Synthons ............ 648 13.5.5 Two-Carbon Chain Elongation of Aldehydes .......................... 648 13.5.6 Three-Carbon Chain Elongations .................................... 665 13.5.7 Four-Carbon Chain Elongations ..................................... 668 13.5.8 Synthesis of Branched-Chain Monosaccharides from C3-Aldoses ....... 672 13.6 Hetero Diels-Alder Additions ............................................. 674 13.6.1 Achiral Aldehydes as Dienophiles .................................. 674 13.6.2 Chiral Aldehydes as Dienophiles: Synthesis of Long-Chain Sugars ... 675 13.6.3 Hetero Diels-Alder Additions of 1-Oxa-1,3-dienes .................. 679 13.6.4 Nitroso Dienophiles: Synthesis of Azasugars ....................... 681 13.6.5 N-Methyltriazoline-3,5-Dione as a Dienophile: Synthesis of 1-Azafagomine ........................................ 682 13.7 Cycloadditions of Furans ................................................. 684 13.7.1 Diels-Alder Additions ............................................. 684 13.7.2 The "Naked Sugars of the First Generation" ........................ 685 13.7.3 Dipolar Cycloadditions of Furans .................................. 694 13.7.4 [4 + 3]-Cycloadditions of Furan ................................... 697 13.8 Carbohydrates and Analogs from Achiral Hydrocarbons ...................... 698 13.8.1 From Cyclopentadiene .............................................. 698 13.8.2 From Benzene and Derivatives ...................................... 701 13.8.3 From Cycloheptatriene ............................................. 701 13.8.4 From Penta-1,4-Diene .............................................. 703 13.9 Enantioselective Epoxidation of Allylic Alcohols ......................... 703 13.9.1 Desymmetrization of meso Dienols .................................. 704 13.9.2 Kinetic Resolution of Racemic Allylic Alcohols .................... 705 13.10 Enantioselective Sharpless Dihydroxylations and Aminohydroxylations ..... 707 13.11 Conclusion .............................................................. 710 References .................................................................... 710 Part IV Additional Topics Chapter 14 Combinatorial Carbohydrate Chemistry ............................... 729 Prabhat Arya and Bugga VNBS Sarma 14.1 Introduction ............................................................. 729 14.2 Solution-Phase Library Synthesis of Carbohydrates ........................ 731 14.2.1 Hindsgaul's Random Glycosylation .................................. 731 14.2.2 Boons's Latent-Active Glycosylation ............................... 731 14.2.3 Ichikawa's Stereoselective (and Nonregioselective) Glycosylation ............................................................ 732 14.2.4 Orthogonal Protection in Library Synthesis ........................ 733 14.3 Solid-Phase Library Synthesis of Carbohydrates ........................... 733 14.3.1 Kahne's Split-Mix Approach to Glycosylation ....................... 734 14.3.2 Boons's Two-Directional Approach .................................. 734 14.3.3 Ito's Capture and Release Strategy ................................ 736 14.3.4 Linkers in Solid-Phase Synthesis .................................. 737 14.4 Dynamic Combinatorial Chemistry .......................................... 738 14.5 Carbohydrate Scaffolds in Combinatorial Chemistry ........................ 739 14.6 Carbohydrate/Glycoconjugate-Like Compounds (Glycomimetics) by Combinatorial Chemistry .................................................. 741 14.6.1 Multiple component condensations (MCC) ............................ 741 14.6.2 Glycohybrids ...................................................... 742 14.7 Glycopeptide-like Derivatives by Combinatorial Chemistry ................. 743 14.7.1 Glycosylated Amino Acids as Building Blocks ....................... 745 14.7.2 Cyclic Artificial Glycopeptides ................................... 747 14.7.3 Automated Synthesis of Artificial Glycopeptides ................... 747 14.8 Summary and Outlook ...................................................... 749 Acknowledgments ............................................................... 749 References .................................................................... 750 Chapter 15 Glycopeptides ...................................................... 755 Michael Mogemark and Jan Kihlberg 15.1 Structures and Biological Functions of Protein-Linked Carbohydrates ...... 755 15.2 General Aspects of Glycopeptide Synthesis ................................ 759 15.2.1 Strategic Considerations .......................................... 759 15.2.2 Selection of Protecting-Groups .................................... 759 15.2.3 Practical Aspects of Solid-Phase Synthesis ........................ 762 15.3 Synthesis of O-Linked Glycopeptides ...................................... 764 15.3.1 1,2-trans-O-Linked Glycopeptides .................................. 764 15.3.2 1,2-cis-O-Linked Glycopeptides .................................... 771 15.4 Synthesis of N-Linked Glycopeptides ...................................... 781 15.5 Chemoenzymatic Synthesis of Glycopeptides ................................ 788 15.6 Synthesis of Glycoproteins ............................................... 792 References .................................................................... 792 Chapter 16 Carbohydrate Mimetics in Drug Discovery ............................ 803 Beat Ernst, Hartmuth C. Kolb and Oliver Schwardt 16.1 Introduction ............................................................. 804 16.2 MAG Antagonists .......................................................... 804 16.2.1 Biological Rationale .............................................. 804 16.2.2 The Siglec Family ................................................. 806 16.2.3 MAG Antagonists ................................................... 807 16.2.4 Summary of the Structure Affinity Relationship .................... 812 16.2.5 Summary and Outlook ............................................... 814 16.3 Glycosidase Inhibitors ................................................... 814 16.3.1 Biological Rationale .............................................. 814 16.3.2 α-Glucosidase Inhibitors .......................................... 815 16.3.3 Neuraminidase Inhibitors .......................................... 821 16.4 Selectin Antagonists ..................................................... 828 16.4.1 Biological Rationale .............................................. 828 16.4.2 Structure Affinity Relationship ................................... 831 16.4.3 Families of Antagonists Identified So Far ......................... 833 16.4.4 Biological Evaluation ............................................. 843 16.4.5 Summary and Outlook ............................................... 844 Acknowledgments ............................................................... 845 References .................................................................... 845 Index ......................................................................... 863