a) R = H; b) R = OMe c) R = an appropriate substltuent

Fig. 8 Biologically active 1-hydroxyindoles and analogs (2)

(210b, 211b) are more potent than the N(1)-H compounds (210a, 211a). In a test using seeds of rice and cucumber, for example, 211a elongates their roots 1.8 times longer than that of the control. With these and related derivatives in hand, we have begun a challenge this summer to make the Gobi desert greener in Neimenggu, Inner Mongolia, by making the native plants' roots longer and closer to the ground water level.

In conclusion, the initially imaginary world of 1-hydroxytryptamines and -tryptophans has become a real frontier in indole chemistry. Since this undeveloped world is rich in treasures, we hope many investigators come together to hunt down and own some of its valuable jewels. Our discoveries are only a part of the infinite abundance of treasures.

Acknowledgements I am deeply grateful to a number of graduate students and undergraduates for their hard work and dedication. For biological evaluations, I also express cordial gratitude to Dr. Suzuki N (Noto Marine Lab., Kanazawa Univ.), Prof. Hattori A (Tokyo Medical and Dental Univ.), Prof. Shigenobu H, Assoc. Prof. Tanaka Y (Toho Univ.), Dr. Ekimoto H (Nippon Kayaku), and Dr. Kamuro Y (Nissan Chemical Ind. Ltd.).


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Top Heterocycl Chem (2006) 6: 113-156 DOI 10.1007/7081_022 © Springer-Verlag Berlin Heidelberg 2006 Published online: 7 April 2006

Quinazoline Alkaloids and Related Chemistry

Shoji Eguchi

Department of Molecular Design and Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, 468-0863 Nagoya, Japan [email protected]

1 Introduction 115

1.1 Quinazoline Pharmaceuticals 115

1.2 Natural Quinazoline Compounds 116

2 Progress in Synthetic Methodology of Quinazolines 119

2.1 Aza-Wittig Methodology in Quinazoline Synthesis

(Iminophosphorane Mediated Synthesis) 119

2.1.1 The Aza-Wittig Reaction 120

2.1.2 Synthesis of Quinazoline Skeleton by the Aza-Wittig Reaction Followed by Various Cyclizations 120

2.1.3 The Intramolecular Aza-Wittig Reaction 122

2.1.4 Quinazolinone Annelation 122

2.2 Microwave-Assisted Synthesis of Quinazoline Compounds 124

2.2.1 Microwave-Assisted Niementowski Quinazoline Synthesis 125

2.2.2 Microwave-Assisted Multi-Component One-Pot Synthesis of Quinazolines . 125

2.3 Solid-Phase Synthesis of Quinazoline Compounds 125

2.3.1 Polymer-Supported Aza-Wittig Reaction 126

2.3.2 Solid-Phase Synthesis of Quinazoline Derivatives 126

2.4 Other New Synthesis of Quinazoline Derivatives 127

2.4.1 Quinazoline Synthesis by Use of Organometallic Reagents 127

2.4.2 Metal Catalyzed Synthesis of Quinazoline Derivatives 128

2.4.3 Quinazoline Synthesis by Intramolecular Nucleophilic Heterocyclization Reactions 128

2.4.4 Quinazoline Synthesis by Pericyclic Reactions 129

2.4.5 Other Notable Examples of Quinazoline Synthesis 130

3 Synthesis of Quinazoline Alkaloids 130

3.1 Pyrroloquinazolinone Alkaloids 130

3.1.1 Vasicinone and Related Alkaloids 130

3.1.2 Chemoselectivity of Intramolecular Aza-Wittig Cyclizations 132

3.2 Indolopyridoquinazoline- and Indoloquinazoline Alkaloids 133

3.2.1 Rutaecarpine 133

3.2.2 Tryptanthrin 133

3.3 Quinazolinobenzodiazepine Alkaloids 134

3.3.2 Asperlicins, Circumdatin F, and Sclerotigenin 136

3.4 Pyrazinoquinazoline Alkaloids 137

3.4.1 Fumiquinazolines, Glyantrypine, and Fiscaline B 138

3.4.2 Verrucines A, B, and Anacine 139

3.4.3 Ardeemin and N-Acetylardeemin 140

3.4.4 Alantrypinone, etc 141

3.5 Pyrroloquinazolinoquinoline Alkaloids 142

3.6 Antimalarial Quinazoline Alkaloids Having a Piperidine Ring 146

3.6.1 Febrifugine and Isofebrifugine 146

4 Concluding Remarks 149

References 149

Abstract Recent progress in quinazoline alkaloids and related chemistry was reviewed focusing on developments of the synthetic methodologies and their synthetic applications. A brief historical background, aza-Wittig methodology, microwave-assisted synthesis, solid-phase synthesis, and a variety of new syntheses of quinazoline compounds by organometallic reagents, metal-catalyzed reactions, heterocyclizations, pericyclic reactions, etc. are briefly reviewed. Selected topics of total synthesis of various types of quinazoline alkaloids including substituted type like febrifugine and heterocycle-fused type such as pyrroloquinazolines, indolopyridoquinazolines, pyrazinoquinazolines, and pyrroloquinazolinoquinolines, etc. by these methodologies are discussed.

Keywords Aza-Wittig reaction • Quinazolinone annelation • Quinazoline alkaloids • Microwave-assisted synthesis • Solid-phase synthesis




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