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TRANSCRIPT
W0
88
Fortschritte der Chemieorganischer Naturstoffe
Progress in theChemistry of Organic
Natural Products
Founded byL. Zechmeister
Edited byW. Herz, H. Falk,and G. W. Kirby
Authors:J. F. Grove, E. Reimann, S. Roy
SpringerWienNewYork
Prof. W. Herz, Department of Chemistry,
The Florida State University, Tallahassee, Florida, U.S.A.
Prof. H. Falk, Institut fur Chemie,
Johannes-Kepler-Universitat, Linz, Austria
Prof. G. W. Kirby, Chemistry Department,
The University of Glasgow, Glasgow, Scotland
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Contents
List of Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX
Synthesis Pathways to Erythrina Alkaloids and Erythrina Type CompoundsE. Reimann . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Structural Classification of Erythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . 4
3. New Erythrina Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4. Biosynthesis of Erythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4.1. Erythrinane Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4.2. Homoerythrinane Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5. Syntheses of Erythrina Alkaloids and Erythrina Type Compounds . . . . . . . . . 21
5.1. Methodical Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
5.2. Erythrinanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
5.2.1. Final Formation of One Ring . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
5.2.1.1. Ring C (Route C) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
5.2.1.1.1. Cyclization of N-Phenethylhydroindole
Derivatives (Route C(a)) . . . . . . . . . . . . . . . . 23
5.2.1.1.2. Cyclization of Angulary Arylated Hydroindole
Derivatives (Route C(b)) . . . . . . . . . . . . . . . . 29
5.2.1.2. Formation of Ring B (Route B) . . . . . . . . . . . . . . . . . . . 32
5.2.1.2.1. Cyclization of N-substituted
C5-Spiroisoquinoline Derivatives
(Route B(a)) . . . . . . . . . . . . . . . . . . . . . . . . 32
5.2.1.2.2. Cyclization of C6-Substituted
C5-Spiroisoquinoline Derivatives
(Route B(b)) . . . . . . . . . . . . . . . . . . . . . . . . 35
5.2.1.3. Formation of Ring A (Route A) . . . . . . . . . . . . . . . . . . . 35
5.2.1.3.1. Cycloaddition to Pyrroloisoquinolines
(Route A(a)) . . . . . . . . . . . . . . . . . . . . . . . . 35
5.2.1.3.2. Intramolecular Aldol Condensation
of Angularly Substituted Pyrroloisoquinoline
(Route A(b)) . . . . . . . . . . . . . . . . . . . . . . . . 37
5.2.2. Simultaneous Formation of More Than One Ring. . . . . . . . . . . . . 38
5.2.2.1. Simultaneous Formation of Rings B
and C (Route B/C) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
5.2.2.1.1. Cyclization of Secondary Diphenethyl-
or (Cycloalkyl)ethyl-phenethylamine Derivatives
(Route B/C(a)) . . . . . . . . . . . . . . . . . . . . . . . . . 39
5.2.2.1.2. Cyclization of Tertiary Cyclohexyl-ethyl-
phenethyl-amide Derivatives
(Route B/C(b)) . . . . . . . . . . . . . . . . . . . . . . . . 42
5.2.2.2. Cyclization of N-Substituted 1-Acyldihydroisoquinolinium
Derivatives (Route A/B) . . . . . . . . . . . . . . . . . . . . . . . . 44
5.2.2.3. Cyclization of a Highly Functionalized
Homoveratrylimide (Route A/B/C) . . . . . . . . . . . . . . . . . 45
5.3. Homoerythrinanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
5.3.1. Biomimetic Routes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
5.3.2. Final C Ring Formation Starting from N-Substituted
Phenylhydroindoles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
5.3.3. A Ring Formation by [2þ 2] Photocycloaddition
to Pyrrolobenzazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
5.3.4. Simultaneous B Ring Formation/C Ring Expansion
Starting from Spiro-2-tetralones . . . . . . . . . . . . . . . . . . . . . . . . . 52
6. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
7. Concluding Remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
The Trichothecenes and Their BiosynthesisJ. F. Grove (y) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
2. The Trichothecenes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
2.1. Macrocyclic and Non-Macrocyclic Compounds . . . . . . . . . . . . . . . . . . . 64
2.2. Trichothecene Relatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
2.3. Sources. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
2.4. Oxygenation Pattern. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
3. Biosynthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983.1. Simple Trichothecenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
3.1.1. Mevalonic Acid to Trichodiene . . . . . . . . . . . . . . . . . . . . . . . . . 98
3.1.2. Trichodiene to 12,13-Epoxytrichothecene and Isotrichodermol . . . . 101
3.1.3. Further Oxygenation and Esterification of the Trichothecene
Nucleus: Biosynthesis of Specific Metabolites . . . . . . . . . . . . . . . 104
3.1.3.1. Trichothecolone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
3.1.3.2. Vomitoxin and Derivatives . . . . . . . . . . . . . . . . . . . . . . . 104
3.1.3.3. T-2 Toxin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
3.1.3.4. Nivalenol and Derivatives . . . . . . . . . . . . . . . . . . . . . . . 108
3.1.4. Trichothecene Biosynthetic Gene Clusters . . . . . . . . . . . . . . . . . . 108
3.2. Trichoverroids and Macrocyclic Trichothecenes. . . . . . . . . . . . . . . . . . . 109
3.3. Trichothecene Relatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
VI Contents
Melanin, Melanogenesis, and VitiligoS. Roy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
1. Melanin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
1.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
2. Chemistry of Melanin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
2.1. Isolation and Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
2.2. Solubilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
2.3. Protein Content . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
2.4. Carboxylic and Phenolic Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
2.5. Chemical Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
2.5.1. Reductive Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
2.5.2. Oxidative Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
2.5.3. Pyrolytic Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
2.6. Spectroscopic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
2.6.1. UV and IR Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
2.6.2. NMR Spectroscopy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
2.6.3. X-Ray Defraction Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
2.6.4. ESR Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
2.7. Structure of Melanin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
2.7.1. Melanin as Homopolymer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
2.7.2. Melanin as Poikilopolymer . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
2.7.3. Melanin as Bipolymer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
2.7.4. Biophysical Model of Melanin Structure . . . . . . . . . . . . . . . . . . . 141
2.7.5. Structure of Phaeomelanin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
2.8. Synthesis of Melanin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
2.8.1. Electrochemical Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
2.8.2. Photochemical Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
3. Characteristic Biophysicochemical Properties of Melanin . . . . . . . . . . . . . . . 145
3.1. Interaction of Melanin with Light . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
3.1.1. Melanin in UV and Visible Light . . . . . . . . . . . . . . . . . . . . . . . . 146
3.1.2. Melanin in the Photoprotection of Skin . . . . . . . . . . . . . . . . . . . . 146
3.1.3. Melanin as Light Screen in Eyes . . . . . . . . . . . . . . . . . . . . . . . . 147
3.2. Melanin and Its Redox Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
3.3. Binding Complexation and Medicinal Aspects of Melanin . . . . . . . . . . . 149
3.4. Use of Melanin for Defence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
4. Melanogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
4.1. Melanogenesis in vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
4.1.1. Melanocytes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
4.1.2. The Characteristics of the Enzyme . . . . . . . . . . . . . . . . . . . . . . . 152
4.1.3. Regulation of Melanogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
4.1.3.1. Physiological Factors. . . . . . . . . . . . . . . . . . . . . . . . . . . 154
4.1.3.2. Organic Sulfur Compounds . . . . . . . . . . . . . . . . . . . . . . 154
4.1.3.3. Metal Ions and Other Chemicals. . . . . . . . . . . . . . . . . . . 154
4.1.3.4. Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
4.1.3.5. Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
4.1.3.6. Neural Influence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
4.1.3.7. Malpighian Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
4.1.3.8. UV Light . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Contents VII
4.2. Melanogenesis in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
4.2.1. Enzymatic Melanin Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . 157
4.2.1.1. Rearrangement of Dopachrome. . . . . . . . . . . . . . . . . . . . 158
4.2.1.2. Polymerization of DHI . . . . . . . . . . . . . . . . . . . . . . . . . 159
4.2.2. Non-Enzymatic Melanin Synthesis: Model Reaction . . . . . . . . . . . 161
4.2.2.1. Udenfriend System: A Model for Mixed Function
Oxidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
4.2.2.2. Melanin Formation Under Udenfriend Conditions . . . . . . . 162
5. Vitiligo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
5.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
5.2. Melanocytotoxicity: Antimelanocyte-Antibodies Formation. . . . . . . . . . . 164
5.2.1. The Immune Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
5.2.2. The Neural Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
5.2.3. The Self-Destruction Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . 165
5.2.4. The Composite Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
5.3. Chemotherapy of Vitiligo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
5.3.1. Psoralens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
5.3.2. Psoralen Action and UV Light . . . . . . . . . . . . . . . . . . . . . . . . . . 166
5.3.3. Psoralen Action on Melanogenesis . . . . . . . . . . . . . . . . . . . . . . . 167
5.4. Abnormal Biochemical Parameters in Vitiligo . . . . . . . . . . . . . . . . . . . . 168
5.5. Status of Tryptophan in the Melanogenic System . . . . . . . . . . . . . . . . . 169
5.6. A Composite Hypothesis on Vitiligo . . . . . . . . . . . . . . . . . . . . . . . . . . 171
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
VIII Contents
List of Contributors
Grove, Dr. J. F., 3 Homestead Court, Welwyn Garden City, Herts AL7 4LY, England
(deceased)
Reimann, Prof. Dr. E., Department of Pharmacy, Ludwig-Maximilians-Universitat,
Butenandtstrasse 5–13, 81377 Munchen, Germany,
e-mail: [email protected]
Roy, Dr. S., Institute of Natural Products, 8 J. N. Roy Lane, Kolkata 700006, India,
e-mail: [email protected]
Synthesis Pathways to Erythrina Alkaloidsand Erythrina Type Compounds
Eberhard Reimann
Department of Pharmacy,
Ludwig-Maximilians-Universitat Munchen, Germany
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Structural Classification of Erythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . 4
3. New Erythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4. Biosynthesis of Erythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4.1. Erythrinane Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4.2. Homoerythrinane Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5. Syntheses of Erythrina Alkaloids and Erythrina Type Compounds . . . . . . . . . 21
5.1. Methodical Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
5.2. Erythrinanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
5.2.1. Final Formation of One Ring . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
5.2.1.1. Ring C (Route C) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
5.2.1.1.1. Cyclization of N-Phenethylhydroindole
Derivatives (Route C(a)) . . . . . . . . . . . . . . . . . 23
5.2.1.1.2. Cyclization of Angulary Arylated Hydroindole
Derivatives (Route C(b)) . . . . . . . . . . . . . . . . 29
5.2.1.2. Formation of Ring B (Route B) . . . . . . . . . . . . . . . . . . . 32
5.2.1.2.1. Cyclization of N-substituted
C5-Spiroisoquinoline Derivatives
(Route B(a)) . . . . . . . . . . . . . . . . . . . . . . . . . 32
5.2.1.2.2. Cyclization of C6-Substituted
C5-Spiroisoquinoline Derivatives
(Route B(b)) . . . . . . . . . . . . . . . . . . . . . . . . . 35
5.2.1.3. Formation of Ring A (Route A) . . . . . . . . . . . . . . . . . . . 35
5.2.1.3.1. Cycloaddition to Pyrroloisoquinolines
(Route A(a)) . . . . . . . . . . . . . . . . . . . . . . . . . 35
5.2.1.3.2. Intramolecular Aldol Condensation
of Angularly Substituted Pyrroloisoquinoline
(Route A(b)) . . . . . . . . . . . . . . . . . . . . . . . . . 37
5.2.2. Simultaneous Formation of More Than One Ring . . . . . . . . . . . . . 38
5.2.2.1. Simultaneous Formation of Rings B
and C (Route B/C) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
5.2.2.1.1. Cyclization of Secondary Diphenethyl-
or (Cycloalkyl)ethyl-phenethylamine Derivatives
(Route B/C(a)) . . . . . . . . . . . . . . . . . . . . . . . . 39
5.2.2.1.2. Cyclization of Tertiary Cyclohexyl-ethyl-
phenethyl-amide Derivatives
(Route B/C(b)) . . . . . . . . . . . . . . . . . . . . . . . 42
5.2.2.2. Cyclization of N-Substituted 1-Acyldihydroisoquinolinium
Derivatives (Route A/B) . . . . . . . . . . . . . . . . . . . . . . . . 44
5.2.2.3. Cyclization of a Highly Functionalized
Homoveratrylimide (Route A/B/C) . . . . . . . . . . . . . . . . . 45
5.3. Homoerythrinanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
5.3.1. Biomimetic Routes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
5.3.2. Final C Ring Formation Starting from N-Substituted
Phenylhydroindoles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
5.3.3. A Ring Formation by [2þ 2] Photocycloaddition
to Pyrrolobenzazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
5.3.4. Simultaneous B Ring Formation/C Ring Expansion
Starting from Spiro-2-tetralones . . . . . . . . . . . . . . . . . . . . . . . . . 52
6. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
7. Concluding Remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
1. Introduction
The history of erythrina research begins at the end of the 19th
century. During the last two decades of that time extracts from speciesof Erythrina have been found to exhibit curare-like neuromuscularblocking activities which are caused by alkaloids occurring therein(1–4).
It was Altamirano (2), who obtained a silky shining, crystallinic acetateas well as Greshoff (3) who already isolated several basic unspecifiedcompounds. Because of their remarkable biological activity he suggesteda systematic phytochemical examination of the genusErythrina. But it stillhas taken at least half a century before this has been realized for the firsttime by Folkers. He has shown that more than fifty Erythrina species –as an example, E. crista-galli is shown in Plate 1 – are containing thetypical alkaloids exhibiting the same curare-like activity reported earlier(5, 6). Moreover, his group succeeded in isolating the first crystallizederythrinane alkaloid named erythroidine (14; Fig. 2) (7). Soon after nu-merous alkaloids have been isolated, e.g. erythramine (8) (8), erythraline(3) (9), erythratine (9) (10), erysodine (6), erysopine (4), and erysovine(5) (11). Another decade later the fundamental investigations of Prelog
References, pp. 56–62
2 E. Reimann
Plate 1. Erythrina crista-galli L (Coral Tree)
(12, 13) and Boekelheide (14) have finally led to the correct structuralframework of the erythrinane alkaloids (parent compound 1, Fig. 1).
In the late 1960s ring C-homologues of erythrinane alkaloids havebeen anticipated from the biosynthetic pathway of certain alkaloids, whichare known to be generated from 1-phenethyl-isoquinoline derivatives asprecursors (15, 16). Only a short time later such compounds namedhomoerythrinanes, homoerythrina alkaloids, or schelhammeranes indeedhave been found in the plant kingdom (17) (parent compound 2, Fig. 1).
Due to the increasing attraction and rapid extension in this field theErythrina alkaloids have been regularly reviewed concerning occur-rence, structure, analytic and spectral properties, biosynthesis, total syn-thesis, and biological activities covering the literature up to 1997. Themost important reviews are cited in Refs. 18–24.
The present contribution will give a brief classification of theErythrina alkaloids, a compilation of new alkaloids isolated from 1997to 2004 covering source, structure, analytical/spectral data, a new path-way of their biosynthesis, an overview of all the synthesis strategieshitherto known for the erythrinane alkaloids including several ap-proaches to the homoerythrinane group, and finally a short review oftheir biological activities.
2. Structural Classification of Erythrina Alkaloids
The erythrina-type alkaloids are characterized by their unique tet-racyclic spiroamine framework. They are generally classified into twomain groups: Alkaloids predominantly possessing a 6-5-6-6-memberedindoloisoquinoline core are called erythrinanes and those exhibiting a6-5-7-6-membered indolobenzazepine skeleton are generally called schel-hammeranes or homoerythrinane alkaloids (see Fig. 1).
Depending on the nature of the D ring both groups in turn may besubdivided into aromatic and non-aromatic alkaloids, the latter of which
Fig. 1. Stereostructure and atom labeling of the Erythrina alkaloid frameworks
References, pp. 56–62
4 E. Reimann
including ring D oxa-compounds, are usually also called the lactonicalkaloids. In addition, in both series there have been isolated alkaloidscontaining a pyridyl instead of a phenyl unit, which are known aserymelanthine (11) and holidine (12) (16-azaerythrinane and 17-aza-homoerythrinane derivatives) belonging to two further different subtypes ofthese alkaloids (25, 26) (see below andFig. 2). SeveralD-seco-derivatives inthe homoerythrinane group should also be mentioned (see e.g. 32, Table 2).
Finally, the typical position and the number of olefinic bonds in the Aand B ring have led to a further subdivision into dienoids and alkenoidsin both alkaloid series. The former are characterized by a conjugateddiene unit covering C atoms 1, 2, 6, and 7, while the latter possess onlyone double bond in the 1,6-position (see Fig. 2).
The aromatic erythrinanes and homoerythrinanes as the most impor-tant members of the Erythrina alkaloids show substitution patterns of
Fig. 2. General classification of Erythrina alkaloids: Dienoid and alkenoid type alkaloids
and D ring modifications
Erythrina Alkaloids and Erythrina Type Compounds 5
Table
1.New
ErythrinaneAlkaloids
Nr.
Trivialnam
e(s)/
M.p./� C
IR:� ��/cm
�1
1H
NMR:�/ppm
Natural
Ref.
Form
ula/Structure
�[�] D/�
cm2g�1
UV:l m
ax/nm
(log"/mol�
1dm
3cm
�1)
13CNMR:�/ppm
source
MS:m/z
16
Erythrosotidienone
C17H15NO3
(281.31)
250
2930,2860,1740,1610,1460,
1440,1380,1280–1260,1160,
1130,1075,1040,975,960,
860–840,730,720,675,645,
610,580
6.02(d,J¼10Hz,
1-H
),5.94
(s,OCH2O),5.72,6.02(d,J¼10Hz,
1-H
),5.94(s,OCH2O),5.72
(m,2-H
),3.63(t,J¼1.5
and4.5Hz,
2H,10-H
),3.27–1.87(m
,6H)
E.variegata
Flowers
(33)
–– 281(5.0),280(22.5),279(100),
267(7.5),265(7.5),253(17.5),
227(2.5),226,199(15.4),
174(15.0),167(10.0),133(5.0),
81(31.6),20(8.0),77(5.0),
76(80.0),56(27.3),55(42.5)
184.0
(CO),152.0
(C-16),152.4
(C-15),132.0
(C-2),131.0
(C-1),
129.6
(C-7),128.3
(C-12),128.1
(C-13),114.0
(C-17),110.1
(C-14),
104.0
(C-6),102.8
(OCH2O),68.1
(C-5),40.3
(C-10),32.0
(C-3),30.4
(C-4),23.2
(C-11)
17
Erythromotidienone
C18H19NO3
(297.35)
172
2920,2880,1760,1600,1450,
1380,1280–1260,1250,1170,
1110,1075,1055,1025,975,
960,925,885,835,800,765,
730,700
7.32(dd,J¼2.5/9.0Hz,
16-or
15-H
),7.21(d,J¼2.7Hz,
14-H
),
7.13(d,J¼2.3Hz,
17-H
),6.62
(s,7-H
),6.34(d,J¼9.6Hz,
1-H
),
6.02(dd,J¼2.5/7.5Hz,
2-H
),
3.86and3.36(2s,2OCH3),
3.76–1.92(m
,7H)
E.variegata
Flowers
(33)
–297(5),296(8),295(11),269
(19),255(30),239(8),235(10),
213(16),185(16)83,81(43)
13Cnotreported
References, pp. 56–62
6 E. Reimann
18
(þ)-10,11-
Dioxoerysotrine
C19H19NO5
(341.36)
174–176
1710,1680,1650,1610
351(3.54),292(sh,3.62),247
(4.17),206(4.38)
7.48(s,17-H
),7.17(s,14-H
),6.74
(dd,J¼11.5/2.4Hz,
1-H
),6.00
(d,J¼11.5Hz,
2-H
),5.88(brs,7-H
),
4.64(brs,8-H
),3.95(16-O
CH3),
3.91(s,15-O
CH3),3.64(t,J¼7.9Hz,
3-H
),3.23(s,3-O
CH3),2.30
(d,J¼7.9Hz,
4-H
)
E.latissima
(34)
þ167.5
341(M
þ ,100),310(30),282
(25),257(20)
181.8
(C-11),159.7
(C-10),153.5
(C-15),149.5
(C-16),141.7
(C-13),
138.0
(C-6),132.6
(C-2),124.9
(C-1),
124.2
(C-12),121.2
(C-7),111.1
(C-17),106.4
(C-14),76.1
(C-3),70.8
(C-5),56.9
(3-O
CH3),56.7
(15-
and16-O
CH3),54.7
(C-8),49.9
(C-4)
19
11-A
cetylerysotrine
C21H25NO4
(355.43)
yellow
oil
1760(COCH3),1600(C¼C
)
283.1
(3.7),230.5
(4.2)
355(M
þ )
6.95(s,17-H
),6.82(s,14-H
),6.65
(d,J¼10.0Hz,
2-H
),6.05(d,
J¼10.0Hz,
1-H
),4.74(t,J¼3.4Hz,
11-H
),4.05(m
,3-H
ax),3.94
(s,16-O
CH3),3.85(s,15-O
CH3),
3.68(dd,J¼13.5/3.5Hz,
10-H
ax),
3.32(s,3-O
CH3),3.14(dd,
J¼13.5/6.6Hz,
10-H
eq),2.42
(dd,J¼11.5/3.5Hz,
4-H
eq),2.13
(s,COCH3),1.87(t,J¼11.5Hz,
4-H
ax)
E.stricta
(35)
–13C
notreported
Erythrina Alkaloids and Erythrina Type Compounds 7
Table
1(continued)
Nr.
Trivialnam
e(s)/
M.p./� C
IR:� ��/cm
�11H
NMR:�/ppm
Natural
Ref.
Form
ula/Structure
�[�] D/�
cm2g�1
UV:l m
ax/nm
(log"/mol�
1dm
3cm
�1)
13C
NMR:�/ppm
source
MS:m/z
20
10,11-
Dioxoerythraline
C18H15NO5
(325.32)
amorph.
solid
1710,1680,1650,1610
351(3.53),292(sh,3.62),247
(4.17),204(4.32)
7.41(s,17-H
),7.12(s,14-H
),6.68
(dd,J¼10.3/2.2Hz,
1-H
),6.10
(d,J¼1.5Hz,
1H,OCH2O),6.07
(d,J¼1.5Hz,
1H,OCH2O),5.97
(d,J¼10.3Hz,
2-H
),5.84(brs,
7-H
),4.61(brs,2H,8-H
),3.63
(m,3-H
),3.24(s,OCH3),
2.25–2.31(m
,2H,4-H
)
E.bidwillii
(36)
þ254
325(M
þ ,100),310(12),294
(46),292(34),282(37),266
(83),264(63),254(11),252
(15),240(27),226(26),213
(18),209(21),165(13),152(22)
181.5
(C-11),159.3
(C-10),152.0
(C-16orC-15),148.0
(C-15
orC-16),143.5
(C-13),137.5
(C-6),132.2
(C-2),125.8
(C-12),
124.2
(C-1),120.6
(C-7),108.6
(C-17),104.1
(C-14),102.4
(OCH2O),75.5
(C-3),70.5
(C-5),
56.5
(OCH3),54.2
(C-8),49.6
(C-4)
21
8-O
xoerythraline-
epoxide
C18H17NO5
(327.34)
colourl.
oil þ94
1680
289(3.78),205(4.59)
327(M
þ ,53),311(14),298
(30),296(22),278(14),266
(14),241(100),212(43)
6.72(s,17-H
),6.55(s,14-H
),
6.49(s,7-H
),5.98(d,J¼1.5Hz,
1H,OCH2O),5.94(d,J¼1.5Hz,
1H,OCH2O),4.24(d,J¼4.0Hz,
1-H
),3.83(ddd,J¼12.5/9.5/7.3Hz,
10-H
ax),3.83(d,J¼4.0Hz,
2-H
),
3.64(m
,3-H
),3.57(ddd,
J¼12.5/7.3/3.7Hz,
10-H
eq),
E.bidwillii
(36)
References, pp. 56–62
8 E. Reimann
3.41(s,OCH3),3.09(ddd,
J¼16.1/9.5/7.3Hz,
11-H
ax),2.93
(ddd,J¼16.1/7.3/3.7Hz,
11-H
eq),
2.36(dd,J¼11.7/5.1Hz,
4-H
eq),
1.59(t-like,
J¼11.7Hz,
4-H
ax)
CD:�"/mol�
1dm
3cm
�1
(l/nm)¼þ3
.51(292),
�17.31(228),þ2
0.76(202)
170.2
(C-8),155.0
(C-6),147.2
(C-15orC-16),146.0
(C-16or
C-15),130.0
(C-13),129.7
(C-7),
128.0
(C-12),109.8
(C-17),105.7
(C-14),101.3
(OCH2O),74.6
(C-3),67.4
(C-5),56.6
(CH3),
52.9
(C-2),48.7
(C-1),37.4
(C-10),32.9
(C-4),27.5
(C-11)
22
(þ)-Erythbidin
B
C18H17NO5
(327.34)
amorph.
solid
þ148
3450,1670,1650
205(4.52),243(4.04),
291(3.54)
327(M
þ ,100),312(23),296
(74),294(34),284(6),278(13),
270(7),268(12),266(14),250
(5),240(7),238(7),227(6.5),
181(6.7),165(8),149(10)
7.22(s,17-H
),6.88(s,14-H
),
6.63(dd,J¼10.3/2.2Hz,
1-H
),
5.99(d,J¼10.3Hz,
2-H
),5.98
(d,J¼1.5Hz,
1H,OCH2O),5.94
(d,J¼1.5Hz,
1H,OCH2O),5.76
(brs,7-H
),5.26(s,10-H
),4.43
(d,J¼17.6Hz,
1H,8-H
),4.37
(dd,J¼17.6/2.2Hz,
1H,8-H
),
4.05(brs,OH),3.72(m
,3-H
),
3.30(s,OCH3),2.60(dd,
J¼11.0/5.1Hz,
4-H
eq),1.95
(t,J¼11.0Hz,
4-H
ax)
E.bidwillii
(37)
Erythrina Alkaloids and Erythrina Type Compounds 9
Table
1(continued)
Nr.
Trivialnam
e(s)/
M.p./� C
IR:� ��/cm
�1
1H
NMR:�/ppm
Natural
Ref.
Form
ula/Structure
�[�] D/�
cm2g�1
UV:l m
ax/nm
(log"/mol�
1dm
3cm
�1)
13CNMR:�/ppm
source
MS:m/z
CD:�"/mol�
1dm
3cm
�1
(l/nm)¼
þ226(286),þ4
.40
(252),�9
.16(218)(M
eOH,
c3.06�10�5)
172.8
(C-11),147.4
(C-15),146.7
(C-16),138.6
(C-6),131.6
(C-2),
131.2
(C-13),129.6
(C-12),124.1
(C-1),119.9
(C-7),106.1
(C-17),
103.9
(C-14),101.4
(OCH2O),
76.1
(C-3),71.7
(C-5),67.7
(C-10),
56.4
(OCH3),54.1
(C-8),39.5
(C-4)
23
(þ)-Epierythrinine
C18H19NO4
(313.35)
amorph.a
–
spectranot
reported
1H:differentiated
signalsforthe
epi-isomer:7.04(s,17-H
),6.84
(s,14-H
),6.54(dd,1-H
),6.03
(dm,2-H
),5.94(d,J¼1.4Hz,
OCH2O),5.91(d,J¼1.4Hz,
OCH2O),5.72(m
,7-H
),4.93
(dd,11-H
),4.18(m
,3-H
),3.71
(dd,8-H
),3.64(dm,8-H
),3.47
(dd,10-H
),3.37(3-O
CH3),3.16
(dd,10-H
),2.68(dddd,4-H
),1.86
(dd,4-H
);positionofcoupling
H-atomsHa,
Hb/J
[Hz]:1,2/10.1;
1,3/2.2;4ax,3/10.6;4eq,2/1.1;
4eq,3/5.5;4eq,7/1.1;4gem/11.6;
8gem/14.2;8a,7/3.0;10ax,11/10.0;
10eq,11/6.7;10gem/14.4
E.caffra
(38)
13Cnotreported
References, pp. 56–62
10 E. Reimann
24
(þ)-15�-D
-
Glucoerysopine
C23H29NO8
(447.49)
150–152
(dark
brown
solid)
3415,2920,1507
279(3.74),222(4.40),
206(4.38)
447(M
þ ,80),299(80),268
(100),251(70)
6.99(s,17-H
),6.75(s,14-H
),6.60
(dd,J¼10.1/2.1Hz,
1-H
),6.02
(d,J¼10.1Hz,
2-H
),5.79(brs,
7-H
),4.74(d,J¼7.2Hz,
10 -H
),
4.00(m
,3-H
),3.95(dd,
J¼11.0/3.9Hz,
60 -H
ax),3.74
(m,60 -H
eq)3.61(m
,8-H
ax),3.48
(m,40 -H
),3.48(m
,20 -H
),3.45
(m,8-H
eq),3.40(m
,50 -H
),3.40
(m,10-H
ax),3.34(s,OCH3),3.30
(m,30 -H
),2.91(m
,11-H
ax),2.91
(m,10-H
eq),2.67(m
,11-H
eq),
2.52(dd,J¼10.6/5.7Hz,
4-H
ax),
1.78(dd,J¼10.9/10.9Hz,
4-H
eq)
E.latissima
(39)
þ67.5
147.6
(C-15),145.8
(C-16),143.3
(C-6),
133.9
(C-13),132.2
(C-2),125.4
(C-12),
124.7
(C-1),122.6
(C-7),118.1
(C-17),
114.6
(C-14),103.8
(C-1
0 ),77.7
(C-3
0 ),77.1
(C-3),77.0
(C-5
0 ),74.3
(C-2
0 ),70.8
(C-4
0 ),67.5
(C-5),61.9
(C-6
0 ),57.1
(C-8),55.9
(OCH3),44.4
(C-10),
41.3
(C-4),24.3
(C-11)
25
(þ)-16�-D
-
Glucoerysopine
158–160
3415,2920,1507
7.03(s,17-H
),6.79(s,14-H
),6.61
(dd,J¼10.1/2.1Hz,
1-H
),6.04
E.latissima
(39)
Erythrina Alkaloids and Erythrina Type Compounds 11
Table
1(continued)
Nr.
Trivialnam
e(s)/
M.p./� C
IR:� ��/cm
�11H
NMR:�/ppm
Natural
Ref.
Form
ula/Structure
�[�] D/�
cm2g�1
UV:l m
ax/nm
(log"/mol�
1dm
3cm
�1)
13CNMR:�/ppm
source
MS:m/z
C23H29NO8
(447.49)
(dark
brown
solid)
279(3.74),222(4.40),
206(4.38)
447(M
þ ,80),299(80),268
(100),251(70)
(d,J¼10.1Hz,
2-H
),5.79(brs,
7-H
),4.78(d,J¼7.2Hz,
10 -H
),4.00
(m,3-H
),3.95(dd,J¼11.0/3.9Hz,
60 -H
ax),3.74(m
,60 -H
eq)3.61
(m,8-H
ax),3.48(m
,40 -H
),3.48
(m,20 -H
),3.45(m
,8-H
eq),3.40
(m,50 -H
),3.40(m
,10-H
ax),3.34
(s,OCH3),3.30(m
,30 -H
),2.91
(m,11-H
ax),2.91(m
,10-H
eq),2.67
(m,11-H
eq),2.52(dd,J¼10.6/5.7Hz,
4-H
ax),1.79(dd,J¼10.9/10.9Hz,
4-H
eq)
þ76.5
145.8
(C-15),145.1
(C-16),143.8
(C-6),
134.1
(C-13),132.1
(C-2),126.1
(C-12),
125.4
(C-1),122.8
(C-7),118.2
(C-17),
113.9
(C-14),103.6
(C-1
0 ),77.7
(C-3
0 ),77.0
(C-3),77.4
(C-5
0 ),74.2
(C-2
0 ),70.7
(C-4
0 ),67.5
(C-5),61.8
(C-6
0 ),57.1
(C-8),55.9
(OCH3),44.3
(C-10),
41.2
(C-4),24.2
(C-11)
26
Coculidine
N-oxide
150–152
–spectranotreported
Cocculus
laurifolius
(40)
C18H23NO3
(301.39)
(HCl:
236–238)
287(3.40),225(3.95),
205(4.37)
References, pp. 56–62
12 E. Reimann
–301(M
þ ,3.4),285,284,283
27
(þ)-8-O
xo-�-
erythroidine
epoxide
C16H17NO5
(303.31)
colourl.
oil þ211
1715,1680
250(sh,3.69),216(4.23)
303(M
þ ,100),287(31),274
(31),272(22),271(43),255
(24),244(29),242(32),231
(51),217(46)
CD
(MeO
H,c3.30�10�5):�"
þ6.63(263),�2
.61(228),
þ7.87(208)
¼6.51(s,7-H
),6.09(s,14-H
),
4.51(dd,J¼11.7/5.1Hz,
17-H
eq),4.36(m
,10-H
eq),4.17
(dd,J¼11.7/4.4Hz,
17-H
ax),
4.05(d,J¼3.7Hz,
1-H
),3.64
(d,J¼3.7Hz,
2-H
),3.55(dd,
J¼11.0/5.1Hz,
3-H
),3.49(s,OCH3),
3.08(ddd,J¼13.2/13.2/3.7Hz,
10-H
ax),2.76(dd,J¼13.2/5.1Hz,
4-H
eq),2.74(m
,12-H
),1.94
(m,11-H
eq),1.73(dddd,
J¼13.2/12.5/6.6/5.1Hz,
11-H
ax),
1.55(dd,J¼13.2/11.0Hz,
4-H
ax)
E.poeppigiana
(41)
aInseparable
79:21mixture
withtheisomeric
knownalcohol(þ
)-erythrinine.
Erythrina Alkaloids and Erythrina Type Compounds 13
Table
2.New
HomoerythrinaneAlkaloids
Nr.
Trivialnam
e(s)/
Form
ula/Structure
M.p./� C
�[�] D/�
cm2g�1
IR:� ��/cm
�1
UV:l m
ax/nm
(log"/mol�
1dm
3cm
�1)
MS:m/z
1H
NMR:�/ppm
13CNMR:�/ppm
Natural
source
Ref.
28
1,6�-
Epoxyrobustivine
C20H27NO5
(361.44)
nodata
reported
3575,3400,2910,2830,
1590,1394,1305
283(3.11),207(4.55)
6.55(15-H
),3.89,3.83and3.79
(3OCH3),3.79(1-H
),3.46(3-H
),3.46
(12-H
),3.46(10-H
),3.32(10-H
),3.02
(8-H
),2.83(8-H
),2.57(12-H
),2.50
(4-H
eq),2.40(2-H
),2.28(7-H
),2.03
(2-H
),1.86(4-H
ax),1.80(7-H
),1.76
(11-H
),1.58(11-H
)
Phelline
comosa
Labill.var.
robusta
(Baill.)
Loesner
(42)
þ99
361(M
þ ),344,181,180,
167,166(100)
151.81,149.90,141.42,137.24,
129.44,108.75(C-15),70.57(C-5),
67.15(C-6),64.44(C-3),61.34
(OCH3),60.87(O
CH3),57.43(C-1),
56.24(O
CH3),49.78(C-10),
45.82(C-8),36.05(C-4),33.36(C-2),
27.95(C-7),25.72(C-12),22.70(C-11)
29
18-D
e-O-
methylholidine
C19H25NO4
(331.41)
140
(colourl.
crystals)
3425,3100(s),1595,1480,
1440,1360,1325
276(3.09),208(4.47);
inalcalinesolution:293(4.18)
6.39(s,15-H
),5.50(m
,1-H
),3.87
(s,OCH3),3.51(2m,12-H
a,10-H
a),3.30
(m,3-H
),3.25(s
andm,3-O
CH3and
10-H
b),2.78(ddandm,4-H
eqand8-H
a,b),
2.58(m
,12-H
band2-H
a),2.45(m
,7-H
a),
2.30(m
,7-H
b),2.02(m
,2-H
b),1.76
(m,11-H
a),1.56(ddandm,2H,4-H
ax)
Phelline
comosa
Labill.
var.robusta
(Baill.)
Loesner
(42)
References, pp. 56–62
14 E. Reimann
þ111
331(M
þ ),300,273,272,
180(100)
147.0,145.3,141.7,117.0,110.8
(CH),74.2
(C-3),70.0
(C-5),60.6
(OCH3),55.8
(3-O
CH3),50.5
(C-10),
46.8
(C-8),37.7
(C-4),32.0
(C-2),
27.5
(C-7),25.3
(C-12),23.1
(C-11)
30
Fortunine
C19H21NO4
(327.38)
120–121.5
2980,2930,2890,2820,1610,
1500,1480,1350,1325,1298,
1229,1090,1030,915
–
6.94(s,15-H
),6.57(s,18-H
),6.01
(brd,J¼10.2Hz,
1-H
),5.85(d,
J¼1.40Hz,
OCH2O),5.75(dd,
J¼10.2/2.0Hz,
2-H
),3.52(ddd,
3-H
),3.29(s,OCH3),3.22/2.62
(m,11-H
a,b),3.20(m
,7-H
),2.85
(dd,J¼12.7/4.2Hz,
8-H
a,b),2.63
(m,10-H
a,b),1.80(m
,11-H
a,b),
1.68–1.65(brd,J¼10.6Hz,
4-H
a,b)
Cephalotaxus
fortunei
(43)
–327(M
þ ,75),312(100),296,
284,267,254,240,228,160,
152,128,115,77
146.1
(C-17),145.1
(C-16),134.4
(C-13),133.3
(C-2),132.8
(C-14),
127.2
(C-1),111.9
(C-18),109.5
(C-15),100.1
(OCH2O),76.3
(C-3),
69.3
(C-5),68.9
(C-6),60.1
(C-7),
56.2
(3-O
CH3),55.5
(C-8),49.7
(C-10),35.4
(C-12),31.7
(C-4),29.1
(C-11)
31
CephalezomineM
colourl.
solid
3360,2930,1670,1510,1200
6.75(s,15-H
),6.71(s,18-H
),6.05
(s,1-H
),3.77(m
,10-H
b),3.51(d,
J¼14.2Hz,
10-H
a),3.35(s,8-H
b),
Cephalotaxus
harringtonia
var.nana
(44)
Erythrina Alkaloids and Erythrina Type Compounds 15