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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


(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


(Route B(a)) . . . . . . . . . . . . . . . . . . . . . . . . . 32

5.2.1.2.2. Cyclization of C6-Substituted


(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


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


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


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)


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)


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


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)


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)


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.


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)


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)


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