Academic Press is an imprint of Elsevier 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, USA 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 125 London Wall, London EC2Y 5AS, UK The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK First edition 2016 Copyright © 2016 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein ISBN: 978-0-12-804682-1 ISSN: 1099-4831 For information on all Academic Press publications visit our website at http://store.elsevier.com/ Dedicated to the memory of Ekkehard Winterfeldt (1932–2014) v j CONTRIBUTORS Gregory L Adams Merck Research Laboratories, West Point, PA, USA James M Cook University of Wisconsin-Milwaukee, Chemistry Department, Milwaukee, WI, USA Petra Kercmar Sandoz Biopharmaceuticals, Menges, Slovenia Mariko Kitajima Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan Ojas A Namjoshi RTI International, Center for Drug Discovery, Research Triangle Park, NC, USA Amos B Smith, III Department of Chemistry, Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, PA, USA; Monell Chemical Senses Center, Philadelphia, PA, USA Joachim St€ ockigt Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, Dali University, Dali, Yunnan, P.R China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R China Hiromitsu Takayama Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan Fangrui Wu Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, Dali University, Dali, Yunnan, P.R China; Department of Pharmacology, Baylor College of Medicine, Houston, TX, USA Chenggui Zhang Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, Dali University, Dali, Yunnan, P.R China ix j PREFACE In thematic volumes of The Alkaloids seminal developments in areas of exceptional interest are summarized and highlighted The previous thematic volume of this series, Volume 71, focused on halogenated alkaloids In Volume 76, all four chapters are devoted to indole alkaloids, one of the supreme fields in alkaloid chemistry In the first chapter, Fangrui Wu, Petra Kercmar, Chenggui Zhang, and Joachim St€ ockigt describe the enzyme-catalyzed biosynthetic pathway to sarpagan–ajmalan-type monoterpenoid indole alkaloids The biosynthesis of alkaloids in Rauvolfia serpentina was covered previously in this series by Joachim St€ ockigt in Chapter of Volume 47 (published in 1995) Toni M Kutchan briefly discussed the biosynthesis of the ajmalan- and sarpagan-type alkaloids in his treatise on the “Molecular Genetics of Plant Alkaloid Biosynthesis” (Chapter 7, Volume 50, 1998) Short compilations of the biosynthesis of the sarpagine and ajmaline groups of indole alkaloids were subsequently provided by Mauri Lounasmaa et al in Chapter of Volume 52 (1999) and Chapter of Volume 55 (2001) In the present chapter, St€ ockigt et al present the current knowledge of the biosynthetic routes to sarpagan–ajmalan-type indoles Application to synthesis leads to biomimetic and chemoenzymatic approaches which open up the way to generate compound libraries with novel alkaloid structures Ojas A Namjoshi and James M Cook summarize in Chapter the progress on “Sarpagine and Related Alkaloids.” Sarpagine alkaloids were covered in this series many years ago by J Edwin Saxton in his review “The Indole Alkaloids” (Chapter 10, Volume 7, 1960) and by W I Taylor in his two articles on “The Ajmaline–Sarpagine Alkaloids” (Chapter 22, Volume 8, 1965 and Chapter 2, Volume 11, 1968) The most recent coverage was provided by Mauri Lounasmaa and coworkers in their review “The Sarpagine Group of Indole Alkaloids” (Chapter 2, Volume 52, 1999) Thus, an update summarizing the recent developments in the chemistry of this important family of alkaloids was more than overdue In Chapter 3, Gregory L Adams and Amos B Smith III give an overview on the recent progress in “The Chemistry of the Akuammiline Alkaloids.” Akuammiline alkaloids have been discussed previously in “The Alkaloids” by J Edwin Saxton (Chapter 10, Volume 7, 1960; Chapter 7, Volume 8, 1965; Chapter 11, Volume 10, 1968; Chapter 4, Volume 14, 1973) and xi j xii Preface more recently by Toh-Seok Kam and Kuan-Hon Lim (Chapter 1, Volume 66, 2008) In the present chapter, Adams and Smith describe recent isolations of akuammiline alkaloids, their biological activity, and novel achievements in total synthesis In Chapter 4, Mariko Kitajima and Hiromitsu Takayama present “Monoterpenoid Bisindole Alkaloids.” Previous full coverages of the bisindole alkaloids from terrestrial plants have been published in this series by Geoffrey A Cordell and J Edwin Saxton in Chapter of Volume 20 (1981) and by Toh-Seok Kam and Yeun-Mun Choo in Chapter of Volume 63 (2006) In the present article, the authors reviewed the research on monoterpenoid bisindole alkaloids published from the middle of 2006 till the middle of 2015, a time span with a highly dynamic development in this area Hans-Joachim Kn€ olker Technische Universit€at Dresden, Dresden, Germany CHAPTER ONE Sarpagan-Ajmalan-Type Indoles: Biosynthesis, Structural Biology, and Chemo-Enzymatic Significance Fangrui Wu*, x, 1, Petra Kercmar{, Chenggui Zhang* € ckigt*, jj, and Joachim Sto *Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, Dali University, Dali, Yunnan, P.R China x Department of Pharmacology, Baylor College of Medicine, Houston, TX, USA { Sandoz Biopharmaceuticals, Menges, Slovenia jj College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R China Corresponding authors: E-mail: fangrui.wu@bcm.edu; joesto2000@yahoo.com Contents Introduction Rauvolfia AlkaloidsdSources, Therapeutic Value, and Enzyme Detection 2.1 Choosing an Efficient Biological System 2.2 The Alkaloid Pattern of Rauvolfia Cell Cultures 2.3 Chemical Syntheses of Biosynthetic Intermediates 2.4 Detection of Enzyme Activities and Enzyme Purification Enzymes of the Ajmaline Pathway (AP) 3.1 Strictosidine Synthase (STR) 3.2 Strictosidine Glucosidase (SG) 3.3 Sarpagan Bridge Enzyme/Geissoschizine Dehydrogenase (GDH) 3.4 Polyneuridine Aldehyde Esterase (PNAE) 3.5 Vinorine Synthase (VS) 3.6 Vinorine Hydroxylase (VH) Forming Vomilenine 3.7 Vomilenine Reductases (VR, DHVR) 3.8 Acetylajmaline Esterase (AAE) 3.9 Norajmaline Na-methyltransferase (NAMT) Side Routes of the Ajmaline Pathway 4.1 Vellosimine Side Routes 4.1.1 Vellosimine Reductase (VER) 4.1.2 Deoxysarpagine Hydroxylase (DH) 31 33 4.2 Vinorine Side Route The Alkaloids, Volume 76 ISSN 1099-4831 http://dx.doi.org/10.1016/bs.alkal.2015.10.001 4 10 10 18 20 21 24 26 27 29 30 31 31 33 © 2016 Elsevier Inc All rights reserved j Fangrui Wu et al 4.3 Vomilenine Side Routes 4.3.1 Vomilenine Glucosyltransferse (VGT) 4.3.2 Raucaffricine Glucosidase (RG) 4.3.3 Perakine Reductase (PR) 34 34 35 39 4.4 Side Routes Beyond Perakine and Raucaffrinoline 4.5 The Route Beyond Ajmaline 42 43 4.5.1 Side Route: From Ajmaline to Raumaclines 4.5.2 Biosynthesis of Raumaclines 4.5.3 Dialdehyde Reductase 43 43 44 Monitoring Bioconversions by In vivo NMR Chemo-Enzymatic Approaches 6.1 From Single to BunchdFrom Strictosidine Synthase (STR) to Novel Alkaloids 6.2 Chemo-Enzymatic Application of Raucaffricine Glucosidase (RG) Summary Acknowledgments References 45 49 49 52 54 55 55 INTRODUCTION Despite its therapeutic uses as an antiarrhythmic drug to balance arrhythmic heart failures,1 its well-known properties to reduce high blood pressure, and the very long history of the ancient plant Rauvolfia in South and South-East Asian traditional medicine,2 very little was known about the biosynthesis of the monoterpenoid indole alkaloid ajmaline (1) Our limited knowledge of this alkaloid’s biosynthesis was based on a very few in vivo feeding experiments that have used labeled, putative biosynthetic precursors such as tryptophan for the indole part of the alkaloid.3 Most interesting was the unusual complex chemical structure of harboring a hexacyclic carbon skeleton that contains the chiral Nb atom and nine other asymmetric carbon centers (Figure 1).4 The complexity of the ajmaline structure makes it difficult to identifying its biosynthetic pathway The solution to this problem is an in-depth elucidation of each reaction step and each enzyme involved in the catalysis.4e9 This article reviews the relevant research on the ajmaline’s main biosynthetic pathway and its side routes, the route beyond ajmaline, the application of in vivo NMR, the chemo-enzymatic significance of the involved enzymes and, their reaction mechanisms and the enzyme X-ray crystal structures Sarpagan-Ajmalan-Type Indoles Figure Chemical structure of ajmaline (1), the typical ajmalan-type alkaloid of Rauvolfia (The chiral centers are marked with atom numbers) RAUVOLFIA ALKALOIDSdSOURCES, THERAPEUTIC VALUE, AND ENZYME DETECTION The previous pioneering work by Court and coworkers resulted in the most comprehensive phytochemical analysis of Rauvolfia species For instance, during their work on 10 mainland African species, 133 individual indole alkaloids were identified.10e18 Moreover, recently eight new indole alkaloids have been isolated from Rauvolfia species of mainland China and the structures of them were identified by Liu and colleagues.19,20 Seven novel indole alkaloids from the leaves and twigs of Rauvolfia verticillata were also identified.13 During the recent decades, attempts were made to detect novel biological and pharmacological activities of alkaloids from the genus Rauvolfia.21 The results demonstrated that ajmaline and derivatives interact with ion channels.22e24 Moreover, Rauvolfia alkaloids from a molecular library were computationally screened by molecular docking studies to search for inhibitors of the site of human aldose reductase (AR) Potent inhibition of AR may lead to effective therapies against diabetes.25 Two peraksine-type alkaloids were screened out and identified as leads of AR inhibitor from the library.26 Recently a small collection of alkaloids isolated from the Marquesan plant Rauvolfia nukuhivensis (Fosberg & Sachet) Lorence & Butaud was arranged in a postulated biosynthetic scheme highlighting the role of 16-epi-vellosimine in the biosynthetic formation of ajmalan- and sarpagantype alkaloids of this particular Rauvolfia species (see also Sections 3.4 and 4.1) Moreover, docking experiments were performed in this study to underline the biological activity observed on human ion channel structure (hERG).27 These findings documented a growing phytochemical and pharmacological interest in Rauvolfia alkaloids research Fangrui Wu et al 2.1 Choosing an Efficient Biological System The biological material can be the key to successfully investigate a biosynthetic pathway at the molecular level This is especially true for pathways operating in higher plants due to their slow growth characteristics Compared to microbial systems as for instance bacteria, yeasts and fungi, plant cells have a much bigger size and exhibits a much lower duplication rate, exhibiting a much slower metabolism of natural secondary products Impressive examples are plant species of the genus Rauvolfia such as Rauvolfia serpentina Benth ex Kurz, the major example for the delineation of the ajmaline pathway (see Figure 6) R serpentina is a traditional medicinal plant which has been used in India for w3000 years, since the “pre-Vedic” and “Ayurvedic” periods.28 At that time it was known as the Rauvolfia root (Radix rauwolfiae) However, Rauvolfia has also an important, long-standing place in the Traditional Chinese Medicine (TCM) where it is one of the 50 fundamental herbs.29 Differentiated plant material of Rauvolfia is not very useful for enzymatic biosynthetic research because of in general low physiological activity of plants They need several years (6e8) to accumulate the alkaloids, which are then isolated for medicinal purposes by the pharmaceutical industry (such as reserpine, ajmaline, raubasine, etc.) Moreover, cultivating the plants in green-houses or in laboratories (phytotrones) is difficult and time consuming The insufficient amount of physiologically active cell material was probably the major reason that hampered the research progress on Rauvolfia alkaloid biosynthesis in the past A breakthrough occurred, however, in the research on plant natural product biosynthesis when tissue and cell suspension cultures were developed by M.H Zenk.30,31 Such cultures easily provided continuously fresh Rauvolfia cell material at kg level in a few weeks in cell culture laboratories where Erlenmeyer flasks were used for cell growth (Figure 2) 2.2 The Alkaloid Pattern of Rauvolfia Cell Cultures Alkaloid analysis of cell suspensions showed the great advantage of such plant cell systems in providing a diverse collection of indole alkaloids (see Figure 3).8,30,32 In addition, as a second plant source, intergeneric hybrid cell culture between R serpentina and Rhazya stricta was established by somatic Sarpagan-Ajmalan-Type Indoles Figure Mass production of Rauvolfia fresh plant material (cell suspension) Enzyme production in Escherichia coli is conducted in the similar manner hybridization/protoplast fusion Their content of monoterpenoid indole alkaloids was in general low, but could be enhanced by induction with methyljasmonate.33 The detected alkaloids are displayed in Figure Moreover, a third Rauvolfia source for alkaloids was identified, the so called “hairy root” cultures These were genetically engineered roots, which showed faster growth compared to non-engineered roots The phytochemical investigation of “hairy roots”34e37 revealed a bunch of structures including novel alkaloids as illustrated in Figure 5.37 Conclusively, these three plant systems of Rauvolfia including cell suspension cultures, hybrid cell suspension cultures, and hairy root cultures became available for the first analysis of their alkaloid pattern, including isolation and identification of the single alkaloid metabolites in concentrations of about 100 mg to w1.6 per liter nutrition medium.38 The alkaloid libraries derived from this phytochemical system were rare, valuable, and unavailable from commercial sources They provided for the first time putative enzyme substrates and products typical of Rauvolfia, which were later employed for establishing numerous enzyme assays These enzyme activity assays are the ultimate prerequisite for enzyme detection, enrichment, purification, sequencing, heterologous expression and crystallization, followed by X-ray structure analysis These alkaloids were also, together with alkaloid samples provided over the years by colleagues worldwide especially from the UK, France, Japan, the USA, and Germany, the prerequisite for establishing an excellent “alkaloid tool” in elucidating the ajmaline pathway (AP) by detecting most of the enzymes 326 Aspidospermatan–aspidospermatan-type alkaloids, 297–298 Asymmetric Diels–Alder reaction, 196–197 Asymmetric Pictet–Spengler Reaction, 137 reagents and conditions, 138f tetracyclic core formation, 138–139 tetracyclic ketone, 137–138 Azabicyclic ketone, 250–251, 250f 2-azabicyclo[3.3.1]nonan-8-one system, 210, 210f Azanacycline, 52 Azastrictosidine, 52 Azastrictosidine lactam, 52 Azatetrahydroalstonine, 52 Azidocarbazole, 237–239, 239f 1,10 -azobis(cyclohexanecarbonitrile) (ACHN), 240–241 B BAHD See Benzylalcohol acetyl-, anthocyanin-O-hydroxycinnamoyl-, anthranilate-Nhydroxy-cinnamoyl/benzoyl-and deacetylvindoline acetyltransferase (BAHD) 9-BBN See 9-borabicyclo[3.3.1]nonane (9-BBN) Benzamide, 210, 210f Benzylalcohol acetyl-, anthocyaninO-hydroxy-cinnamoyl-, anthranilate-N-hydroxycinnamoyl/benzoyl-and deacetylvindoline acetyltransferase (BAHD), 24–25 Benzylamine, 216, 217f b-keto-a-diazoester, 191, 192f b-ketoester, 191, 192f BHT See 3,5-di-tert-butyl-4hydroxytoluene (BHT) Bicyclic lactone, 228–231, 230f Bicyclic pyrrole, 218, 219f, 220 Bicyclic scaffold, 218–220, 219f Biosynthetic intermediates, chemical syntheses of, 7–9 Bipleiophylline, 298–299, 303–305 Bis-nitrile, 156–157 Index Biscarpamontamine A, 271–272, 282 Biscarpamontamine B, 271–272 Bischler–Napieralski cyclization, 157–158 Bisindole alkaloids, 86t–88t Bisleucocurine A, 290–292 Bisleuconothine A, 284–285 Bisnicalaterine A, 268–269 Bisnicalaterines B, 290 Bisnicalaterines C, 290 Bisnordihydrotoxiferine, 292–296 Bistabercarpamines, 267–268 N-Boc derivative, 157–158 Boc-protected 5-methoxytryptamine, 204–206, 205f Boc-protected amine, 189–191, 190f Nb-Boc-protected L-tryptophan methyl ester, 157–158 Boc-protected tryptamine, 194–196, 196f 9-borabicyclo[3.3.1]nonane (9-BBN), 189–191 Bosch and Bennasar, synthetic efforts of, 212–217 Bousigonia mekongensis (B mekongensis), 286–287 Bredereck’s reagent, 218–220 Bridged lactone, 240, 241f (Z)-1-bromo-2-iodo-2-butene, 140 2-bromofuran, 199f, 200 BtCN See 1-cyanobenzotriazole (BtCN) BTPP See tert-butylimino-tri(pyrrolidino) phosphorane (BTPP) C 13 C NMR spectroscopy, 121–135 C-19 Methyl-Substituted Sarpagine Alkaloids synthesis, 150–152 C-Quaternary Alkaloid (+)-Dehydrovoachalotine synthesis, 149 C-toxiferine I, 10–13 Camptotheca acuminata (C acuminata), 67–69 CAN See Ceric ammonium nitrate (CAN) 4-carbethoxycyclohexanone, 211, 211f Carboxylate, 233, 234f Carboxylic acid, 192–193, 194f, 226–227, 226f 327 Index Cathafoline, 173–175, 174f, 176t–184t, 185 Catharanthine, 284 Catharanthus roseus (C roseus), 67–69, 282–284 Ceric ammonium nitrate (CAN), 237–239 Chemo-enzymatic approaches RG, 52–54 STR to novel alkaloids, 49, 50f 3D X-ray structures of STR1, 49–51 N-analogous heteroyohimbines, 52 STR from C roseus mutant genes, 51 tryptamine analogues, 49, 51t tryptoline, 49 Chloroacetamide, 211, 212f Nb-chloromethosungucine, 294–295 Cinchona derived catalyst, 226–227, 226f cis-1, 3-disubstituted tetrahydrob-carboline, 156–157 cis-hydroxycarboxylic acid, 236f, 237 Comins’ reagent, 189–191, 190f Condylocarpine, 297–298 2b(R)configuration, 27–28 Conjugated iminium species, 214, 215f Conodiparine A, 262–263 Cononitarine B, 264 Conophyllidine, 274, 277, 278f Conophylline, 264, 277, 278f Cook diazonium cyclization approach, 224 Copper(I) thiophene-2-carboxylate (CuTC), 200 Corymine, 173–175, 174f, 176t–184t, 185 Corynanthe–aspidosperma-type alkaloids, 284–285, 299–300 See also Eburnan–aspidosperma-type alkaloids goniomedines, 300–301 goniomedinone, 301 Corynanthe–aspidospermatan-type alkaloids, 298 Corynanthe–corynanthe-type alkaloids, 298–299 Corynanthe–strychnos-type alkaloids, 295–297 Cox and Robinson study, 187 CuTC See Copper(I) thiophene2-carboxylate (CuTC) 1-cyanobenzotriazole (BtCN), 231 Cyclic 1-aza-1,3-diene, 218, 219f Cyclobutanone, 224, 225f, 234–235, 235f Matsuo acid promoted cycloaddition of, 233–235 Cyclobutyltryptamine, 234–235, 235f Cyclohexane-1,3-dione, 247, 248f Cyclohexanone, 187, 187f–188f, 206–208, 208f, 210, 210f Cyclohexene, 197–198, 198f, 210, 210f, 237, 238f Cyclohexenol, 237, 238f Cyclohexenone, 199f, 200, 220–222, 221f Cyclooctene, 235–236, 236f Cyclopentene derivative, 277–280 Cyclovinblastines A, 283–284 Cyclovinblastines B, 283–284 D DAPase See Dipeptidyl peptidase (DAPase) DBN See 1,5-diazabicyclo[4.3.0]-non5-ene (DBN) DBU See 1,8-diazabicyclo[5.4.0]undec7-ene (DBU) DCC See N,N-dicyclohexylcarbodiimide (DCC) DCE See Dichloroethane (DCE) 17-deacetoxycyclovinblastine, 282–283 17-deacetoxyvinamidine, 282–283 Deacetylvinorine, 66–67 160 -decarbomethoxyvoacamine, 262–266 160 -decarbomethoxyvoacaminepseudoindoxyl, 263 Dehydro-16-Epi-Affinisine synthesis, 148–149 Dehydro-16-Epi-Normacusine B synthesis, 148–149 4,21-dehydro-isomer, 20 Dehydrogeissoschizine, 52, 69–70 Demethoxyguiaflavine, 297 11-demethoxyquaternine, 175–184 10-demethoxyvincorine, 175–184 N(1)-Demethylalstonal, 110 N(1)-Demethylalstonerinal, 101 N(1)-Demethylalstonerine, 101, 110 N(1)-Demethylalstophyllal, 96 328 N(1)-Demethylalstophylline, 96 Deoxoapodine, 272–273 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), 67–69 200 -deoxyleurosidine, 283–284 Deoxysarpagine hydroxylase (DH), 33, 70 10-deoxysarpagine, 20–23, 70 Deoxyvobtusine, 272 lactone, 272 17-desacetoxyvinblastine, 283–284 Desmethyl vincorine, 201–204, 203f DH See Deoxysarpagine hydroxylase (DH) DHVR See 1,2-dihydrovomilenine reductase (DHVR) 3,5-di-tert-butyl-4-hydroxytoluene (BHT), 245–247 Dialdehyde reductase, 44–45 Dianion, 237 Diaryl prolinol, 197, 197f 1,5-diazabicyclo[4.3.0]-non-5-ene (DBN), 157–158 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 244 Diazo compound, 224, 225f DIBAL–H See Diisobutylaluminum hydride (DIBAL–H) DIC See N,N0 -diisopropylcarbodiimide (DIC) Dichloroethane (DCE), 227–228 N,N-dicyclohexylcarbodiimide (DCC), 193 140 ,150 -Didehydrocyclovinblastine, 282–283 Diene, 235–236, 236f Dienophile, 240, 241f Dienyl triflate, 189–191, 190f 20,21-Dihydroalstonerine, 100–101 Dihydroanhydrovobtusine, 272–273 Dihydrocarbazole, 189–193, 190f, 197–198, 198f, 216, 217f Dihydrocarboline, 141–142 19,20-dihydroervahanine A, 266–267 19(S),20(R)-dihydroperaksine, 71, 150–152 19(S),20(R)-dihydroperaksine-17-al, 71–79, 150–152 Index (dihydropyridinylmethyl)indole, 214, 215f Dihydroraucaffricine, 29, 35–36, 38 19,20-dihydrotabernamine, 266–267 19,20-dihydrovalparicine, 292 1,2-dihydrovomilenine reductase (DHVR), 27, 70 1,2-dihydrovomilenine, 27–29 Diisobutylaluminum hydride (DIBAL–H), 192–193, 201 N,N0 -diisopropylcarbodiimide (DIC), 224 Diketone, 218, 219f 1,2-dimethoxyethane (DME), 204–206 2,5-dimethoxytetrahydrofuran, 228, 229f Dimethyl fumarate, 187–189, 188f Dimethyl maleate, 187–189, 188f 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU), 222 4-dimethylaminopyridine (DMAP), 244 Dimethylformamide (DMF), 191 Diol, 223, 223f, 232–233, 232f Dipeptidyl peptidase (DAPase), 18 2,20 -dipyridyldisulfide (PySeSPy), 226–227 (P)-(+)Dispegatrine, nature-inspired stereospecific synthesis of, 146–148 (+)-dispegatrine, 270–271, 271f Dithioacetal, 214–215, 216f Dithiolane, 152–154 Divarine, 292, 295–296 DMAP See 4-dimethylaminopyridine (DMAP) DME See 1,2-dimethoxyethane (DME) DMF See Dimethylformamide (DMF) DMPU See 1,3-dimethyl-3,4,5,6tetrahydro-2(1H)-pyrimidinone (DMPU) Dolby, synthetic efforts of, 209–212 Doubly vinylogous urethane, 214, 215f DXR See 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) E Eburnan–aspidosperma-type alkaloids, 284–285 See also Corynanthe– aspidosperma-type alkaloids Angustifonines A and B, 287–288 329 Index leucophyllidine, 289 Mekongenines, 286–287 Melodinine J, 285–287 Melodinines H and I, 288 Eburnan–corynanthe-type alkaloids, 290 Eburnan–vobasine-type alkaloids, 289–290 ECD See Electronic circular dichroism (ECD) Echitamine, 173, 173f, 186f Electronic circular dichroism (ECD), 269–270 Enal, 250–251, 250f Enamine, 189–191, 190f, 218, 218f–219f, 240, 241f Enaminone, 224, 225f Enecarbamate, 237–239, 238f Enylhydrazine product, 204, 204f Enzyme activities detection, 9–10 Enzyme purification, 9–10 16-epi-affinine, 150 (E)-16-epi-Affinisine synthesis, 148–149 epi-condyfoline, 297–298 16-epi-Na-methylgardneral, 158–159 (E)-16-epi-Normacusine B synthesis, 148–149 19-Epi-talcarpine, 96 16-epi-vellosimine, 9, 21, 31, 34f, 66–67, 69–70 19Z-16-epi-Voacarpine, 90 16-epi-Vobasinediol, 150 Epoxide, 277–280 Erinine, 173–175, 174f Ervachinines, 262–263 Ervachinines A, 262–264 Ervachinines B, 262–264 Ervachinines C, 262–264, 268 Ervachinines D, 262–263 Ervahainanmine, 90 Ervatensines, 263 Ervatensines A, 263 Ervatensines B, 263 Expressed sequence tag (EST), 67 F Fast performance protein liquid chromatography (FPLC), 9–10 Fischer indole synthesis, 277–280 Fritz and Fisher study, 186–187 Fukuyama indole synthesis, 277 Furoindole, 223f, 224, 244–247, 245f, 248f G Gardneria ovate (G ovate), 292 Gardnerine synthesis, 148–149 Gardovatine, 292 Garg total synthesis of (Ỉ)-Aspidophylline A, 220–224 of (Ỉ)-Picrinine, 249–251 GDH See Geissoschizine Dehydrogenase (GDH) Geissoschizine, 8, 20, 173, 173f Geissoschizine Dehydrogenase (GDH), 20–21 Geissoschizoline, 292 Geleganamide, 269–270 Geleganimines A, 269–270 Geleganimines B, 269–270 Gelsemium elegans (G elegans), 269–270 Gelsempervine-A, 89 Gelsempervine-B, 89 Gelsempervine-C, 89–90 Gelsempervine-D, 90 Gelseziridine, 269–270 GH See Glycosyl hydrolases (GH 1) Globospiramine, 272 Glu207, 18–19 Glu207Asp, 18–19 Glu207Gln, 18–19 Glu309, 14, 16–17 Glu416, 18–19 Glu416Asp, 18–19 Glu416Gln, 18–19 Glucoalkaloid, 10–13, 35–36 21-O-b-D-glucopyranoside, 34–35 Glycosyl hydrolases (GH 1), 35–36 Gonioma malagasy (G malagasy), 300–301 Goniomedine A-methylene chloride, 301 Goniomedine A-N-oxide, 301 Goniomedines A, 300–301 Goniomedines B, 300–301 Goniomedinone, 301 330 H H NMR spectroscopy, 71–121 “Hairy root” cultures, 5, 8f Haplophytine, 277, 279f, 280–282, 281f (–)-haplophytine, 282 HbHNL See Hydroxynitrile lyase from Hevea brasiliensisM€ ull Arg (HbHNL) HCT/HQT See HydroxycinnamoylCoA shikimate/quinate hydroxycinnamoyl-transferase (HCT/HQT) Hemiaminal, 226–227, 226f, 277–282 hERG See human ion channel structure (hERG) Heteronuclear single quantum multiple bond correlation (HSQMBC), 269–270 Hexahydro-1H-1,5-methanoazocino [3,4-b]indole scaffold, 213–214 2,3,4,5,6,11-hexahydro-1H-1,5methanoazocino[3,4-b]indole, 186, 186f Hexamethylphosphoramide (HMPA), 244–245 Higuchi oxidative cyclization, 235–237 His160, 24–25, 26f His161, 18–19 His6-PNAE, 21–23, 23f HMPA See Hexamethylphosphoramide (HMPA) Horner–Wadsworth–Emmons reaction, 156–157 HPLC-based enzyme assays, HSQMBC See Heteronuclear single quantum multiple bond correlation (HSQMBC) human ion channel structure (hERG), Huncaniterine A, 299–300 Hunteria zeylanica (H zeylanica), 268–269, 290, 299–300 Hydrazine, 230f, 231 Hydrazone, 187, 188f 10-Hydroxy-19(S),20(R)dihydroperaksine, 79–84 19-hydroxy-Nb-methylraumacline, 44 Hydroxycarboxylic acid, 236f, 237 Index Hydroxycinnamoyl-CoA shikimate/ quinate hydroxycinnamoyltransferase (HCT/HQT), 25–26 3-Hydroxylongicaudatine Y, 295–296 Hydroxymethyltetrahydrocarbazole, 211, 211f Hydroxynitrile lyase from Hevea brasiliensisM€ ull Arg (HbHNL), 21–23 7a-hydroxypyrrolizidine derivative, 220 21-hydroxyraumacline, 44–45 6-hydroxyraumacline, 43 3-Hydroxysarpagine, 84 30 (R/S)-hydroxytabernaelegantine A, 260 30 (S)-hydroxytabernaelegantine, 260 (30 R)-hydroxytabernaelegantines A, 260–262 (30 R)-hydroxytabernaelegantines C, 260–262 (30 R)-hydroxytabernaelegantines D, 260–262 3-hydroxyvobtusine, 271–272 Hystrixnine, 89 I Iboga–vobasine-type alkaloids, 260 acetylcholinesterase inhibitory activity, 266–267 bioassay-guided fractionation of extract, 260–262 bistabercarpamines, 267–268 ervachinines, 262–263 ervatensines, 263 T divaricata, 267 tabercarpamines, 268 tabercorines, 264–266 tabernaelegantines C and B, 267 tabernaricatines, 264 voacalgine F, 263–264 IBX See 2-iodoxybenzoic acid (IBX) IEA See 1H-indole-1-ethanamine (IEA) Imidazolidinone catalyst, 196–197, 196f Imidazolinone catalyst, 204–206, 205f Iminium intermediate, 260–262 Iminium ion, 198, 199f, 204–206, 205f, 213, 213f Iminium species, 213, 214f 331 Index 1,3-(iminoethano)carbazole, 209–210, 210f, 212, 212f, 218, 218f In vivo NMR, monitoring bioconversions by, 45, 49 delineation of biosynthesis, 45 HSQC spectra of feeding experiment, 47f metabolism of vanillin, 46 at natural abundance of 13C, 48f sugar concentrations, 46 time course of ajmaline metabolism, 47f time course of vinorine feeding experiment, 46f 2D HSQC NMR, 45 Indole, 194–196, 196f, 201–204, 202f–203f, 228, 232f, 233 alkaloids, 64 1H-indole-1-ethanamine (IEA), 14–16, 49, 51f Indolenine, 187, 187f–188f, 200–201, 200f, 206–209, 208f, 210f, 223f, 224, 225f, 232f, 233, 237, 238f, 240–243, 242f, 251, 252f, 292 Indoline, 191, 192f, 193, 195f, 199f, 200–204, 203f, 206–209, 208f–209f, 212, 212f, 242–243, 242f, 247, 248f Indoylmethylcarboxylate, 214, 215f Iodide, 191, 193f Iodo olefin, 140 Nb-(Z)-20 -iodo-20 -butenyl-substituted tetracyclic ketone, 140 2-iodoxybenzoic acid (IBX), 201 Isoalstonisine, 108 Isoalstonoxine B, 109 Isoleurosine, 283–284 Isonorsandwicine, 106 Isoretuline, 292–294 J Joule, synthetic efforts of, 217–220 K Ketone, 137–138, 211, 211f, 218, 219f, 221f, 222, 240, 241f, 250–251, 250f Kopsia arborea (K arborea), 298 Kopsiyunnanine A, 298 (–)-koumidine, 139 L Lactam, 192–193, 194f, 216–217, 217f, 220–222, 221f, 239–240, 239f, 241f Lactol, 251, 252f Lactone, 208–209, 209f, 223f, 224, 231–232, 232f, 236f, 237, 240, 241f Lanciferine, 173–175, 174f Leucofoline, 297–298 Leuconoline, 116, 135–136, 289–290, 297–298 Leuconotis griffithii (L griffithii), 284–285, 289–292 Leucophyllidine, 289 Leucoridine A N-oxide, 292 Leucoridines A, 291–292, 293f Leucoridines B, 291–292 Leucoridines C, 291–292 Leucoridines D, 291–292 Leurosine, 282–284 Levy Diels–Alder reaction of vinyl tryptamines, 187–189 Liang vinyl halide Fischer indole protocol, 204 Lithium hexamethyldisilazide (LiHMDS), 244 Lochnerine, 136–137 (+)-lochnerine, 146–148, 270–271 Longicaudatine, 295–296 Longicaudatines F, 295–296 Longicaudatines Y, 295–296 Lumusidine A, 112, 303 Lumusidine B, 112, 303 Lumusidine C, 112–113, 303 Lumusidine D, 113 Lumutinine A, 116, 301–303 Lumutinine B, 116–117, 301–303 Lumutinine C, 117, 303 Lumutinine D, 117, 301–303 Lumutinine E, 117–118, 301–306 M Ma synthesis of (–)-Vincorine, 201–204 Ma total synthesis of (Ỉ)-Aspidophylline A, 244–247 332 MacMillan synthesis of (–)-Vincorine, 204–206 MacMillan total synthesis of (+)-Minfiensine, 193–197 Macralstonine, 302–303 Macrocarpine A, 97 Macrocarpine B, 97 Macrocarpine C, 97 Macrocarpine D, 97–98 Macrocarpine E, 98 Macrocarpine F, 98 Macrocarpine G, 98 Macrocarpine H, 98–99 Macrodasine A, 93 Macrodasine B, 93, 135–136 Macrodasine C, 93–94, 135–136 Macrodasine D, 94 Macrodasine E, 94, 135–136 Macrodasine F, 94–95 Macrodasine G, 95 Macrodasine H, 95, 135–136 Macrogentine, 108 Macrogentine A, 110 Macroline alkaloids, 65f, 66–67 and sarpagine biosynthetic relationship, 66f Macroline indole alkaloids synthesis See also Sarpagine/macrolinerelated indole alkaloids synthesis 11-Methoxymacroline synthesis, 155–156 6-Oxoalstophylline synthesis, 158–159 Suaveoline synthesis, 156–157 talcarpine synthesis, 154–155 Macroline-type indole alkaloids, 80t–82t Macroline/sarpagine-related oxindole alkaloids, 85t Macroline–corynanthe-type alkaloids, 305–307 Macroline–macroline-type alkaloids, 301–303 Macroline–vobasine-type alkaloids, 303–305 (+)-majvinine, 145–146 Matsuo acid promoted cycloaddition of cyclobutanones, 233–235 Index MC See Monte Carlo (MC) mCPBA See meta-chloroperoxybenzoic acid (mCPBA) MECS See 2-C-methyl-d-erythritol 2,4-cyclodiphosphate synthase (MECS) Mekongenines A, 286–287 Mekongenines B, 286–287 Mekongenines C, 287 Mekongenines E, 287 Mekongenines F, 287 Melodinine H, 274, 285–286, 288 Melodinine J, 274–275, 285–288 Melodinine K, 274, 285–286 Melodinus suaveolens (M suaveolens), 275–276 Melodinus tenuicaudatus (M tenuicaudatus), 274, 285–286, 288 Melosuavines A, 274–275 Melosuavines B, 274–275 Melosuavines C, 274–275 Melosuavines D, 274–275 Melosuavines E, 274–275 Melosuavines F, 274–275 Melosuavines G, 274–276 Melosuavines H, 274–276 Meloyunine C, 287–288 11-membered cyclic amide, 277–280 MEP See 2-C-methyl-d-erythritol 4-phosphate (MEP) meso-anhydride, 226–227, 226f meso-diol, 228–231, 230f meta-chloroperoxybenzoic acid (mCPBA), 201 10-Methoxy-16-de(methoxycarbonyl) pagicerine, 90–91 (–)-11-Methoxy-17-Epi-Vincamajine, stereocontrolled total synthesis of, 163 11-methoxy-6-oxomacroline derivative, 158–159 5-methoxy-D-tryptophan ethylester, 146–148, 270–271 (+)-10-methoxyaffinisine, 145–146 10-methoxyaffinisine, 136–137 11-methoxyaffinisine, 155–156 10-Methoxyalstonerine, 102 333 Index 4-methoxybenzyl chloride (PMB–Cl), 194–196 2(S)-10-methoxycathafoline, 175–184 11-methoxygelsemamide, 269–270 11-Methoxymacroline synthesis, 155–156 Methoxymethyltriphenylphosphonium chloride, 250–251, 250f 10-Methoxypanarine, 92 10-Methoxyraucaffrinoline, 107 6-methoxyraumacline, 43 5-methoxytryptamine, 201, 202f (+)-10-methoxyvellosimine, 146–148 11-methoxyvincorine, 175–184 N-Methyl aspidodasycarpine, 175–184 Methyl coumalate, 240, 241f 5-methyl ester, 228, 229f (+)-Na-Methyl-16-Epi-Pericyclivine synthesis, 142–143 N(4)-Methyl-19-epi-talpinine, 91 Na-methyl-5-methoxy-D-tryptophan ethyl ester, 146 Na-methyl-6-methoxy-D-tryptophan ethyl ester, 155–156 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (MECS), 67–69 2-C-methyl-D-erythritol 4-phosphate (MEP), 67–69 Nb-methyl-longicaudatine, 297 Nb-Methylajmaline, 103 N-methylindole, 212, 212f Nb-Methylisoajmaline, 103 Nb-Methylisosandwicine, 106–107 N-methylmorpholine N-oxide (NMO), 226–227 Nb-methylraumacline, 43–44 (+)-Na-methylsarpagine, 145 N(4)-methyltalpinine, 91, 135–136 1-methyltryptamine (NMTR), 14–16 (+)-Na-Methylvellosimine, biomimetic total synthesis of, 141–142 Minfiensine, 189, 190f, 191 MacMillan total synthesis of, 193–197 Overman synthesis of, 189–191 Padwa synthesis of, 198–200 Qiu synthesis of, 200–201 Miranda’s studies toward alstoscholarine scaffold, 228 Mitsunobu reaction, 277 “Molecular replacement” method, 21–23 Monoacetate, 228–231, 230f Monoterpenoid bisindole alkaloids, 259–260 See also Akuammiline alkaloids; Sarpagine and related alkaloids aspidosperma–aspidosperma-type alkaloids, 271–282 aspidosperma–iboga-type alkaloids, 282–284 aspidospermatan–aspidospermatan-type alkaloids, 297–298 corynanthe–aspidosperma-type alkaloids, 299–301 corynanthe–aspidospermatan-type alkaloids, 298 corynanthe–corynanthe-type alkaloids, 298–299 corynanthe–strychnos-type alkaloids, 295–297 eburnan–aspidosperma-type alkaloids, 284–289 eburnan–corynanthe-type alkaloids, 290 eburnan–vobasine-type alkaloids, 289–290 iboga–vobasine-type alkaloids, 260–268 macroline–corynanthe-type alkaloids, 305–307 macroline–macroline-type alkaloids, 301–303 macroline–vobasine-type alkaloids, 303–305 strychnos–strychnos-type alkaloids, 290–295 vobasine–vobasine-type alkaloids, 268–271 Monoterpenoid indole alkaloids, 67–69 Monte Carlo (MC), 276 Mukaiyama reagent, 192–193, 194f Muntafara sessilifolia (M sessilifolia), 260 N NaHMDS See Sodium hexamethyldisilazide (NaHMDS) Nareline, 173–175, 174f 334 Neuville/Zhu total synthesis of alstoscholarines, 226–228 Ni-nitrilo-triacetic acid (Ni-NTA), 21–23 Nitric oxide (NO), 136–137 Nitrile, 211, 211f, 228–231, 230f NMO See N- methylmorpholine N-oxide (NMO) NMTR See 1-methyltryptamine (NMTR) NO See Nitric oxide (NO) Norajmaline Na-methyltransferase (NAMT), 30–31, 30f Normacusine B, 139, 143–144 synthesis, 143 Norsandwicine, 106 Nortetraphyllicine, 33–34 Nortueiaoine, 102 Nosylate, 251, 252f O (Z)-olefin unit, 140 u-methyltryptamine (uMTR), 14–16 Ophiorrhiza pumila (O pumila), 67–69 Overman synthesis of (+)-Minfiensine, 189–191 Oxazole, 157–158 Oxindole alkaloids synthesis, 159–162 See also Macroline indole alkaloids synthesis alstonisine synthesis, 159–160 sterospecific synthesis of sarpaginerelated (–)-affinisine oxindole, 161–162 Oxirane, 230f, 231, 250–251, 250f 6-Oxoalstophylline synthesis, 158–159 (E)-4-oxopent-2-enoic acid, 206–208, 208f 30 -Oxotabernaelegantine A, 260 30 -Oxotabernaelegantine B, 260 3-Oxovoafrine B, 272–273 Oxyallyl dipole, 208–209, 209f 3-Oxygenated Sarpagine Alkaloids synthesis, 150 P p-ABSA See p-acetamidobenzenesulfonyl azide (p-ABSA) Index p-acetamidobenzenesulfonyl azide (p-ABSA), 191 Padwa synthesis of (+)-Minfiensine, 198–200 (–)-Panarine synthesis, 143 Pentacyclic furoindole, 248–249, 249f Pentacyclic ketone, 146–148 Perakine, 39–40, 42–45, 70 Perakine reductase (PR), 39–40, 42–43, 70 AKR13 enzyme family, 41, 41f close-up view of four single crystals of, 40f crystallization, 40 displayed sequence of steps, 39f methylated reductase, 40, 42f 2D structures, 41f unusual structural features, 41 Peraksine, 150–152 Perhentidine A, 113–114, 302–305 Perhentidine B, 114, 302–303 Perhentidine C, 114, 303–305 Perhentinine, 111–112, 135–136, 302–303 Perhentisine A, 114–115, 303–306 Perhentisine B, 115, 303–306 Perhentisine C, 115, 303–306 Pfaltz ligand, 189–191, 190f Phe226, 16 1,10-phenanthroline, 204, 204f 2-phenyl-4H-benzoxazin-4-one, 218–220, 219f Phenylhydrazine, 187, 188f 2-(phenylthio)acetyl chloride, 216, 217f N-phenyltrifluoromethanesulfonimide (PhNTf2), 247 PhNTf See N-phenyltrifluoromethanesulfonimide (PhNTf2) Phosphonate, 156–157 Picraline, 173–175, 174f, 176t–184t, 185, 186f, 249 Garg total synthesis of, 249–251 Pictet-Spenglerase, 13 Piperazino[1, 2-a]indolylstrictosidine (PIS), 49 Piperidine, 213, 213f PIS, [1,2-a]indolylstrictosidine (PIS) See Piperazino Index PMB–Cl See 4-methoxybenzyl chloride (PMB–Cl) PNAE See Polyneuridine aldehyde esterase (PNAE) Polyneuridine aldehyde, 9, 21, 69–70 Polyneuridine aldehyde esterase (PNAE), 21, 69–70 catalytic amino acids, 23–24 catalytic function, 21f comprehensive purification of, 21–23 His6-PNAE, 21–23, 23f Polyneuridine aldehydoacid, 21 PPTS See Pyridinium p-toluenesulfonate (PPTS) PR See Perakine reductase (PR) Propynal, 196–197, 196f Pseudoakuammigine, 173–175, 174f Pummerer rearrangement cyclization, 216–217 Pyridine, 213, 213f Pyridinium bromide, 214, 215f Pyridinium p-toluenesulfonate (PPTS), 240–241 Pyridinium salt, 213, 213f Pyridinone, 220–222, 221f (pyridinylmethyl)indole, 218, 218f Pyrrole, 218–220, 219f, 228, 229f Pyrrolidinone, 187, 188f Pyrrolizine, 218–220, 219f Pyrroloindole, 187–191, 187f–188f, 190f, 192f, 196–198, 196f, 199f, 200, 204, 204f PySeSPy See 2,20 -dipyridyldisulfide (PySeSPy) Q Qin total synthesis of (Ỉ)-Vincorine, 191–193 Qiu synthesis of (+)-Minfiensine, 200–201 Quaternoline, 173–175, 174f Quinine, 10–13 R Racemic homoallyl bromide, 235–236, 236f Raubasine See Ajmalicine Raucaffricine, 35–36, 70 335 Raucaffricine glucosidase (RG), 18–20, 35 See also Strictosidine glucosidase (SG) catalyzed reaction, 35, 36f cDNA, 36–38 chemo-enzymatic application of, 52–54 glucoalkaloid, 35–36 kinetic data and activity, 38–39 and SG complexes, 37f surface of cavity, 38f tryptophan residues, 38 Raucaffricine-O-b-glucosidase (RG), 70 Raucaffrinoline, 42–43, 70 Raumacline, 43–44 biosynthesis of, 43–44 Rauverine A, 103 Rauverine B, 92 Rauverine C, 92–93 Rauvolfia alkaloids, AR, biological system, chemical syntheses of biosynthetic intermediates, 7–9 docking experiments, enzyme activities detection, 9–10 enzyme purification, 9–10 pattern of rauvolfia cell cultures, 4–7, 6f, 8f Rauvolfia plant, mass production of, 5f R nukuhivensis, R serpentina, 4, 8f typical ajmalan-type alkaloid of, 3f Rauvotetraphylline A, 102 Rauvotetraphylline D, 107 Rauvoyunine A, 96 Receptor-operated Ca2+ channels (ROC), 136–137 Reisman [3 + 2] cycloaddition of 2-Amidoacrylates, 198 Representative akuammiline scaffolds, 173–175, 174f Reserpine, 10–13 Retuline, 292–294 Reverse genetic approach, 13, 24–25 RG See Raucaffricine glucosidase (RG); Raucaffricine-O-b-glucosidase (RG) 336 Rhazimine, 173–175, 174f Ring A-alkoxy-substituted indole alkaloids, 144–146 ROC See Receptor-operated Ca2+ channels (ROC) Rough enzyme characterization, S Salicylic acid binding protein (SABP 2), 21–23 Sarpagan bridge enzyme (SBE), 20–21, 20f, 69–70 Sarpagan-ajmalan-type indoles antiarrhythmic drug, AP enzymes, 10–31 chemo-enzymatic approaches, 49–54 rauvolfia alkaloids, 3–10 route beyond ajmaline, 43–45 in vivo NMR, monitoring bioconversions by, 45–49 Sarpagine, 9, 34f, 146–148 Sarpagine and related alkaloids, 64, 65f See also Akuammiline alkaloids; Monoterpenoid bisindole alkaloids and ajmaline biosynthetic relationship, 67f ajmaline-type indole alkaloids, 83t–84t biosynthesis, 67 monoterpenoid indole alkaloids, 67–69 STR, 69–70 VeR, 70 Vinorine, 70 bisindole alkaloids, 86t–88t classification, 65–67 isolated, 71, 72t–77t and macroline biosynthetic relationship, 66f macroline-type indole alkaloids, 80t–82t macroline/sarpagine-related oxindole alkaloids, 85t occurrence, 70–71 pharmacology, 135–137 sarpagine-type indole alkaloids, 78t–79t, 135f spectroscopy 13 C NMR spectroscopy, 121–135 H NMR spectroscopy, 71–121 synthesis, 137 Index asymmetric Pictet–Spengler reaction, 137–139 macroline indole alkaloids synthesis, 154–159 oxindole alkaloids synthesis, 159–162 sarpagine-related ajmaline alkaloids, 162–163 sarpagine/macroline-related indole alkaloids, 139–154 Sarpagine-related (–)-affinisine oxindole, sterospecific synthesis of, 161–162 Sarpagine-related ajmaline alkaloids, 162–163 stereocontrolled total synthesis of (–)-11-Methoxy-17-EpiVincamajine, 163 stereocontrolled total synthesis of (–)-Vincamajinine, 162–163 Sarpagine-type indole alkaloids, 78t–79t, 135f Sarpagine/macroline-related indole alkaloids synthesis, 139, 139f (–)-Alkaloid Q3 synthesis, 143 biomimetic total synthesis of (+)-Na-Methylvellosimine, 141–142 C-19 Methyl-Substituted Sarpagine Alkaloids synthesis, 150–152 C-Quaternary Alkaloid (+)-Dehydrovoachalotine synthesis, 149 dehydro-16-Epi-Affinisine synthesis, 148–149 dehydro-16-Epi-Normacusine B synthesis, 148–149 enantioselective, protecting-group-free total synthesis, 152–154 enantiospecific total synthesis of (+)-Vellosimine, 139–140 (E)-16-Epi-Affinisine synthesis, 148–149 (E)-16-Epi-Normacusine B synthesis, 148–149 gardnerine synthesis, 148–149 (+)-Na-Methyl-16-Epi-Pericyclivine synthesis, 142–143 nature-inspired stereospecific synthesis of (P)-(+) Dispegatrine, 146–148 (+)-Normacusine B synthesis, 143 Index 3-Oxygenated Sarpagine Alkaloids synthesis, 150 (–)-Panarine synthesis, 143 reagents and conditions, 140f ring A-alkoxy-substituted indole alkaloids, 144–146 trinervine synthesis, 143–144 SBE See Sarpagan bridge enzyme (SBE) Scholarisin I, 175–184 Scholarisin II, 176t–184t, 184–185 Scholarisin III, 176t–184t, 184–185 Scholarisin VI, 175–185, 176t–184t Scholarisine A, 173–175, 174f, 186f Adams/Smith total synthesis of, 228–233 Snyder total synthesis of, 240–243 Scholarisine F, 176t–184t, 184–185 Scholarisine H, 176t–184t, 184–185 Scholarisine I, 176t–184t, 184–185 Scholarisine J, 176t–184t, 184–185 Scholarisine K, 176t–184t, 184–185 Scholarisine L, 176t–184t, 184–185 Scholarisine M, 176t–184t, 184–185 SDS-PAGE See Sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) Secologanin, 13–18, 14f, 67–70 Selenide, 201, 202f SG See Strictosidine glucosidase (SG) SGD See Sarpagine and related alkaloids Shi synthesis of Aspidophylline A core, 237–240 Siloxyaniline, 189–191, 190f Silyl-protected 3-hydroxypropionaldehyde, 156–157 Snyder total synthesis of (+)-Scholarisine A, 240–243 Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), 27–28 Sodium hexamethyldisilazide (NaHMDS), 189–191 (+)-spegatrine, 146–148 Spiro[pyrrolidine-3,30 -oxindole], 159–160 Stemmadenine, 295 STR synthase See Strictosidine synthase (STR synthase) Strictamine, 173–175, 174f, 249 337 Zhu oxidative coupling efforts toward, 243–244 Strictosidine, 10–13, 12f, 14f, 19–20, 35–36, 69–70 Strictosidine aglycone, 20 Strictosidine glucosidase (SG), 18, 36–38, 69–70 See also Raucaffricine glucosidase (RG) amino acids, 18–19 His161, 19 and raucaffricine glucosidase, 18 relative enzyme activity of, 19t Trp388, 19–20 2D structural representation of SG Glu207Gln mutant, 19f Strictosidine synthase (STR synthase), 10–13, 69–70 See also Vinorine synthase (VS) biosynthetic pathway, 11f Glu309, 14, 16–17 IEA, 14–16 indole part of ligands, 16 mechanistic considerations of STR1, 15f to novel alkaloids, 49, 50f N-analogous heteroyohimbines, 52 STR from C roseus mutant genes, 51 3D X-ray structures of STR1, 49–51 tryptamine analogues, 49, 51t tryptoline, 49 reverse genetic approach, 13 simplified binding pocket of STR1, 15f STR1-NMTR and STR1-uMTR structures, 17–18 structural comparison of catalytic pockets, 17f, 18 substrate specificities, 13 X-ray structure of STR1, 13–16 Strychnine, 10–13 Strychnobaillonine, 292–294 Strychnochrysine, 297 Strychnoflavine, 297 Strychnogucine C, 294–295 Strychnos icaja (S icaja), 292–294 Strychnos–strychnos-type alkaloids, 290–291 angustiphylline, 295 gardovatine, 292 geissoschizoline, 292 338 Strychnos–strychnos-type alkaloids (Continued ) leucoridine A N-oxide, 292 leucoridines, 291–292 strychnobaillonine, 292–294 sungucine, 294–295 Suaveoline synthesis, 156–157 via Intramolecular Diels–Alder Reaction, 157–158 Subsessiline, 272–273 Sulfonamide, 220–222, 221f, 250–251, 250f Sulfoxide, 214–216, 216f–217f Sungucine, 292–295 T t-BuOCH(NCH3)2, 218–220 t-butyl ester, 141–142 Tabercarpamines, 268 Tabercarpamines A, 268 Tabercarpamines B, 268 Tabercorines, 264–266 Tabercorines A, 264–266 Tabercorines B, 264–266 Tabercorines C, 264–266 Tabernaecorymbosines A, 264 Tabernaecorymbosines B, 264–266 (30 R)-tabernaelegantinals A, 260–262 (30 R)-tabernaelegantinals B, 260–262 (30 R)-tabernaelegantinals E, 260–262 Tabernaelegantines A, 260 Tabernaelegantines B, 260, 267 Tabernaelegantines C, 260–262, 267 Tabernaelegantines D, 260 Tabernaemontana corymbosa (T corymbosa), 263–268 Tabernaemontana divaricata (T divaricata), 264, 267 Tabernaemontana elegans (T elegans), 267, 276 Tabernaemontana sphaerocarpa (T sphaerocarpa), 271–272 Tabernaricatines, 264 Tabernaricatines A, 264–266 Tabernaricatines B, 264–266 Tabernaricatines C, 264 Tabernaricatines D, 264–266 Tabernaricatines E, 264 Index Talcarpine, 159–160 synthesis, 154–155 Talpinine, 135–136 7(S)-Talpinine oxindole, 111 TBAF See Tetrabutylammonium fluoride (TBAF) TBDPSCl See tert-butyldiphenylsilyl chloride (TBDPSCl) TCM See Traditional Chinese Medicine (TCM) TDC See Tryptophan decarboxylase (TDC) TEMPO See 2,2,6,6tetramethylpiperidine 1-oxyl (TEMPO) Tenuicausine, 274–275, 286–287 tert-butyl vinylcarbamate, 189–191, 190f tert-butyldiphenylsilyl chloride (TBDPSCl), 231 tert-butylimino-tri(pyrrolidino) phosphorane (BTPP), 233 Tertiary amine, 193, 195f Tetrabutylammonium fluoride (TBAF), 234–235 Tetracyclic dinitrile, 156–157 Tetracyclic ketone, 137–140, 146 Tetracyclic pyrroloindole, 206–208, 208f Tetracyclic scaffold, 251, 252f Tetracyclic tetrahydrocarbazole, 187–189, 188f Tetracyclic vincorine core, 204–206, 205f 1,2,3,4-tetrahydro-9a,4a-(iminoethano)9H-carbazole, 185, 186f Tetrahydro-b-carboline, 157–158, 191, 192f, 224, 225f, 277–282 Tetrahydro(iminoethano)carbazole, 197, 197f, 204–206, 205f Tetrahydrocarbazole, 198, 199f–200f, 200–201, 204–206, 205f, 213, 213f, 226–227, 227f, 234–235, 235f Tetrahydrofuran (THF), 187 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), 240 Tetraphyllicine, 33–34 TFA See Trifluoroacetic acid (TFA) THF See Tetrahydrofuran (THF) Thioaminal, 214–215, 216f Index Thioester, 277–280 Thioimidate, 242–243, 242f TIM barrel See Triosephosphate isomerase barrel (TIM barrel) N-tosylindole, 244, 245f Tosylindoline, 237, 238f N-tosyllactam, 206–208, 208f Tosyltetrahydro-b-carboline, 243–244, 243f Traditional Chinese Medicine (TCM), Trans-diester, 137–138 Trans-formylacrylate, 197, 197f Trichloroacetamide, 239–240, 239f Tricyclic amine, 230f, 231 Tricyclic ketone, 230f, 231, 250–251, 250f, 277–280 Tricyclic lactone, 223, 223f, 240, 241f Trifluoroacetic acid (TFA), 137–138, 189–191 Trimethylsilyl-protected diphenylprolinol catalyst, 201, 202f Trinervine synthesis, 143–144 Triosephosphate isomerase barrel (TIM barrel), 36–38, 40 Trp388, 19–20, 38 Trp392, 38 Tryptamine, 13–16, 14f, 67–70, 191, 192f, 206–209, 208f–209f, 234–235, 235f, 243–244 Tryptoline, 49 Tryptophan, 67–69, 224, 225f Tryptophan decarboxylase (TDC), 67–69 D-tryptophan methyl ester, 137–138, 140, 143–144, 159–160 Tubifoline, 291–292 Tueiaoine, 102 Tyr151, 16 U Uridine diphosphate glucose (UDPG), 35, 35f V Val167, 14 Val208, 14 Val208Ala, STR1 mutant, 14 Vallesiachotamine, 298 339 (E)-vallesiachotamine, 298 VDC See Voltage-dependent Ca2+ channels (VDC) Vellosimine, 70, 139, 143 enantiospecific total synthesis of, 139–140 Vellosimine reductase (VeR), 31–33, 70 Vellosimine side routes, 31–33 DH, 33 VER, 31–33 VeR See Vellosimine reductase (VeR) VGT See Vomilenine Glucosyltransferse (VGT) VH See Vinorine hydroxylase (VH) Villalstonidine A, 118, 303–306 Villalstonidine B, 118–119, 303–306 Villalstonidine C, 119, 303–306 Villalstonidine D, 119–120, 303–307 Villalstonidine E, 120, 135–136, 303–307 Villalstonidine F, 120–121, 307 Villalstonine, 135–136 Villastonidine N(4)-oxide, 306–307 Villastonine, 305–306 Vilsmeier-Haack-type reaction, 280–282 Vinblastine, 10–13, 283–284 Vincamajine 17-O-30 ,40 ,50 trimethoxybenzoate, 136–137 Vincamajine 17-O-veratrate, 136–137 Vincamajine 17-O-veratrate N(4)-oxide, 106 Vincamajine N(4)-oxide, 106 (–)-Vincamajinine, stereocontrolled total synthesis of, 162–163 Vincamedine, 136–137 Vincorine, 173–175, 174f, 186f, 191–192 Qin total synthesis of, 191–193 (–)-Vincorine Ma synthesis of, 201–204 MacMillan synthesis of, 204–206 Vincristine, 10–13, 284 Vindoline, 284 Vinorine, 29, 33–34, 66–67, 70 side route, 33–34 Vinorine hydroxylase (VH), 26–27, 27f, 70 Vinorine synthase (VS), 24, 26f, 70 See also Strictosidine synthase (STR synthase) BAHD superfamily, 25–26 340 Vinorine synthase (VS) (Continued ) enzymatic synthesis, 24f reverse-genetics approach, 24–25 Vinyl bromide, 204, 204f Vinyl ether, 154–155, 159–160 Vinyl iodide, 270–271 Vinyl ketene acetal, 141–142 Vinyl triflate, 247, 248f Vinyl tryptamines, Levy Diels–Alder reaction of, 187–189 Vinylcarbamate, 247, 248f Vinylindole, 194–197, 196f–197f, 204–206, 205f, 218, 218f Vinylogous ester, 224, 225f Vinyltryptamine, 187–189, 188f Voacalgine B, 99 Voacalgine C, 99 Voacalgine D, 99–100 Voacalgine E, 100 Voacalgine F, 263–264 Voacamine, 262–263, 272–273 Voacandimines A, 272–273 Voacandimines B, 272–273 Voacandimines C, 272–273 Voacanga globosa (V globosa), 272 Voacanga grandifolia (V grandifolia), 263–264 Vobasinediol, 150 Vobasine–vobasine-type alkaloids, 268–269 See also Aspidosperma– aspidosperma-type alkaloids dimeric indole alkaloid synthesis, 270–271 geleganimines A and B, 269–270 Vobtusine, 271–273, 276 lactone, 271–272, 276 Voltage-dependent Ca2+ channels (VDC), 136–137 Vomilenine, 26–27, 29, 34–35, 39–40, 70 Vomilenine Glucosyltransferse (VGT), 34–35 Index Vomilenine reductase (VR), 27–28, 28f, 70 Vomilenine side routes, 34–41 PR, 39–40 AKR13 enzyme family, 41, 41f close-up view of four single crystals of, 40f crystallization, 40 displayed sequence of steps, 39f methylated reductase, 40, 42f 2D structures, 41f unusual structural features, 41 RG, 35 catalyzed reaction, 35, 36f cDNA, 36–38 glucoalkaloid, 35–36 kinetic data and activity, 38–39 and SG complexes, 37f surface of cavity, 38f tryptophan residues, 38 VGT, 34–35 VR See Vomilenine reductase (VR) VS See Vinorine synthase (VS) W Wang Gold–catalyzed formation of indulines, 197–198 Wittig cyclization, 218–220 Wu [3 + 2] cycloaddition, 208–209 Z Zhang and Yang work, 206–208 Zhao Enantioselective Diels–Alder reaction, 197 Zhu oxidative coupling efforts toward strictamine, 243–244 Zhu total synthesis of (Ỉ)-Aspidophylline A, 247–249 Zwitterionic intermediate, 234–235, 235f ... that the localization of the three new ligands closely corresponds to that of 43 All of them are arranged around the axis of the propeller, located at the bottom of the STR1 activity center The. .. in the catalysis.4e9 This article reviews the relevant research on the ajmaline’s main biosynthetic pathway and its side routes, the route beyond ajmaline, the application of in vivo NMR, the. .. (continued) of the pathway together with side routes branching from the AP as outlined in this chapter 2.3 Chemical Syntheses of Biosynthetic Intermediates Works concerning the chemical synthesis of